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Journal of Pakistan Association of Dermatologists

Volume 14, Number 4 October-December, 2004

Editor Ijaz Hussain Associate Editors Farhana Muzaffar Zahida Rani Faria Asad Advisory Board Abdul Ghafoor Qamar Ashfaq Ahmed Khan Atif Hasnain Kazmi Badr S. Dhanani Hasina Thawerani Iqbal Choudhary Iqbal Tareen Khadimullah Kakakhel Khurshid Hasan Alvi Muhammad Jahangir Naeem Iqbal Raza Muhammad Khan S. M. Azam Bokhari S.M. Shamim Sabrina Suhail Pal Simeen Ber Rahman Tahir Saeed Haroon Publication Manager Mr. Omar Abdul Aziz JPAD, the official journal of Pakistan Association of Dermatologists is published quarterly, four issues per volume and one volume per year (ISSN 1560-9014). The journal is recognized by Pakistan Medical and Dental Council and is indexed in College of Physicians and Surgeons Pakistan MEDLIP; Ulrich's International Periodical Directory, USA; ExtraMED, London; EMBASE/Excerpta Medica, The Netherlands; and Index Medicus, WHO Alexandria, Egypt. Subscription A complimentary copy of the journal is provided to all PAD members. Subscription rates per volume are Rs. 1000.00 for Pakistan, £80.00 for UK and $120.00 for US and rest of the world. Copyright © 2003 Any material published in JPAD is copyright of Pakistan Association of Dermatologists. Editorial Board Ahsan Hameed Amor Khachemoune Arfan ul Bari Muhammad Arif Maan Ghulam Mujtaba Ian MacColl Jameel A. Shaheen Khalid Hussain Khawar Khurshid Muhammad Khalid Naseema Kapadia

Nasser Rashid Dar Pervaiz Iqbal Shahbaz A. Janjua Shahbaz Aman Tahir Anees Tahir Jamil Ahmad Tariq Rashid Tariq Zaman Yasmeena Khan Zarnaz Wahid Zohra Zaidi

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Dermatology in Pakistan....

T.S. Haroon

Journal of Pakistan Association of Dermatologists

Volume 14, Number 4 October-December, 2004

Contents

Editorial Dermatology in Pakistan: past, present and future Tahir Saeed Haroon Genetic mosaicism Ian McColl PAD Silver jubilee special History of dermatology in Pakistan Ijaz Hussain Military dermatology in Pakistan Arfan ul Bari Original articles Dermatological literacy among medical graduates Muhammad Jahangir, Tariq Zaman, Tariq Rashid Hematological changes in adults with chicken pox Arfan ul Bari, Simeen Ber Rahman 189 193 172 184 165 168

The effect of itraconazole pulse therapy on quality of life in Pakistani patients of disto-lateral subungual onychomycosis 198 Shahbaz Aman, Talat Masood Akbar, Ijaz Hussain, Muhammad Jahangir, Tahir Saeed Haroon Study on the histopathology of chronic arsenicosis S. Sikder, M.H. Rahman, A.Z.M. Maidul, M.S.U. Khan, M.M. Rahman 204

Histopathological spectrum of cutaneous leishmaniasis in North West Frontier Province 209 Asher Ahmed Mashhood, Iqbal Khan, Shagufta Nazir Topical calcipotriol in the treatment of chronic plaque psoriasis in Bangladeshi patients Agha Masood Choudhary, AZM Maidul Islam, SMMMA Ahad Spectrum of cutaneous infections in patients of leukemia Tariq Zaman, Muhammad Jahangir, Abbas Raza, Tahir Saeed Haroon Urticaria: a threat to betel consumers Javed Anwer, Pervaiz Iqbal, Noor Muhammad Ursani 214 218 229

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Review articles Nitric oxide may directly induce the psoriatic disease process via suppression of keratinocyte apoptosis and induction of keratinocyte hyperproliferation M.R. Namazi, R. Salmanpour, F. Handjani, F. Jowkar Herpes zoster: complications and management Jayakar Thomas Papular mucinosis : an overview Arfan ul Bari, Simeen Ber Rahman Case reports Ehlers-Danlos syndrome: not so rare entity Asher Ahmad Mashood Acral persistent papular mucinosis: a rare variant of cutaneous mucinois Arfan ul Bari, Muhammad Rashid, Simeen Ber Rahman Malignant melanoma of index finger Moizuddin, Azmeenah Valimohd, Athar Ansari 249 254 257 233 238 245

Leukemia cutis: an indicator of relapse in a patient with myeloid leukemia ­ a case report 260 Faria Asad, Mansoor Haider, Sabrina Suhail Pal Photodermdiagnosis What caused this plaque? Amor Kachemoune, Shahbaz A. Janjua International Committee of Medical Journal Editors guideline for manuscripts News Subject and author index of volume 14 Information for authors 263 266 276 277 280

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Editorial

Dermatology in Pakistan: past, present and future

Prof. Tahir Saeed Haroon

President Pakistan Association of Dermatologists

The theme of the 19th World Congress held at Sydney, Australia , in 1997, was `Look back, look around and look forward.' On the eve of Sliver Jubilee of Pakistan Association of Dermatologists (PAD), let us look at the past, present and future of dermatology in Pakistan in the context of this theme. The dawn of modern dermatology can be traced back to around 200 years in Europe. The centre of dermatological research shifted to United States by the mid dle of the last century, around the time Pakistan gained freedom from the colonial rule in 1947. Ironically, there was not a single qualified dermatologist in both the eastern and the western wings of the nascent country. Dermatology as a distinct entity was virtually non-existent at the time. The challenge was well taken up by the medical hierarchy of that era, with the Pak military taking the lead. A trainee was sent to St. John's Institute of Dermatology, London in 1948. Later, he was able to set up a department at the military hospital, Rawalpindi, in 1962. In the civil, two class fellows from the King Edward Medical College, Lahore, returned with MRCP (Edinburgh), with dermatology as the special subject, in 1955 and 1957, respectively. One took charge of Skin and Social Hygiene Centre, Karachi, Sindh

(established in 1952) and the other succeeded in setting up the first teaching department of dermatology, in the country, at the King Edward Medical/Mayo Hospital, Lahore, Punjab, in 1960. In the North West Frontier Province, a Canada-trained consultant dermatologist was appointed at the Lady Reading Hospital, Peshawar, in 1966. In Baluchistan, the department of dermatology was set up at the Bolan Medical College, Quetta, in 1978, by a Pakistani-trained dermatologist. In East Pakistan (now Bangladesh), a trainee from St. John' Institute of Dermatology pioneered this specialty in the late 50's. He also established the first dermatological society in the country, the forerunner of the current Bangladesh Dermatological Society. In 1970's the government opened many new medical colleges to overcome the shortage of health personnel. Over the ensuing years dermatology departments were established and manned in all these institutions. Clinical dermatology was firmly rooted by then. Nonetheless, academic spurt came in late 70's when departments of dermatology at the Jin nah Postgraduate Medical Centre, Karachi, Mayo hospital, Lahore and the military hospital, Rawalpindi started to train a sizeable number of members and fellows of the College of Physician and Surgeons Pakistan and MD candidates. These trainees now man important posts round the country.

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From 1976 to 2000 can be considered as the golden era of dermatology when exponential growth occurred in every aspect. Another landmark was achieved in January, 1979, when Pakistan Association of Dermatologists (PAD) was founded at Karachi. Over the quarter of a century it has provided a platform for the local dermatologists to get together and exchange clinical, academic and research information. As a member of the International League of Dermatological Societie s and the South Asian Regional Association of Dermatologists, it is also represented at the international forums. Since 1991, PAD publishes its own quarterly periodical, the Journal of the Pakistan Association of Dermatologists. It is recognized by the Pakistan Medical and Dental Council and is indexed in various medical database resources. JPAD has recently gone on line, a step forward in the right direction. Pakistan Medical and Dental Council recognizes dermatology as an essential specialty and currently the curriculum is being worked out at the undergraduate level. At present, around 420 dermatologists providing skin care in all provinces of country (1:350000 population) , improvement from 1947 when specialized care was available . are the an no

train ing abroad. About 90% of the medical colleges in public sector are staffed by properly qualified teachers, 80% have inpatient wards, and some of them provide specialized facilities e.g. laser, phototherapy, dermatosurgery. At present there are seven chairs in dermatology and the number is likely to increase in future. Many institutions are actively involved in research work and are imparting training at the undergraduate and the postgraduate levels. The indigenous research work is published and cross-referenced in many peer-reviewed journals. Spectrum of dermatological diseases in Pakistan is mainly tropical including infestations, pyodermas, superficial mycoses, mycobacterial infections and sexually transmitted infections (barring AIDS). Due to the Afghan war and influx of refugees new foci of leishmaniasis have been identified. Local research in areas of mycology and leishmaniasis has been acknowledged the world over. The prevalence of other dermatoses e.g. eczemas, psoriasis, pigmentary disorders is similar to elsewhere. Malignant melanoma is a rare entity. The phenomenon of globalization and industrialization is likely to alter the present spectrum of skin disease. Leprosy, due to integrated efforts of the government of Pakistan, WHO and other NGOs, has been brought under control. Dermatology in Pakistan is firmly rooted but faces many challenges. To meet the contemporary needs, undergraduate and postgraduate teaching needs to be customized. Dermatoepidemiology, genetic and molecular dermatology, photobiology, pediatric dermatology, geriatric

More than half of the dermatologists possess a qualification (MCPS and FCPS) of the College of Physicians and Surgeon Pakistan. Some have been accredited by the national universitie s (MD) while the rest have been

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dermatology, evidence-based dermatology etc. are other areas to be explored. Cosmetic dermatology and dermatosurgery are relatively newer rewarding subspecialties which need to be given due importance in the postgraduate training. The use of information technology, computerized retrieval of information should be stressed. Training facilities in higher seats of learning abroad should be provided. There is a dire need to establish an independent Institute of Dermatology with state of the art facilities for advanced clinical care and research activities in the aforementioned fields. Considering the rich legacy, vigour, enthusiasm and ethical standards set by their forebears, the youngsters seem set to steer the ship of dermatology in the rough seas of tomorrow. Let us wish them the best of luck.

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Editorial

Genetic mosaicism

Ian McColl Dermatologist, John Flynn Medical Centre, Tugun, Gold Coast, Australia.

A knowledge of mosaicism and the mechanisms involved is important in understanding the distribution of lesions i n many skin diseases, particularly those with a genetic basis. Mosaicism refers to an organism having cells with a different genetic make-up adjacent to each other giving rise to a variety of patterns in the skin, particularly linear and segmental lesions. These clinical patterns have been described by Happle 1 as follows: · Type 1a are lines of Blaschko with narrow bands. The representative disease is incontinentia pigmenti. · Type 1b are lines of Blaschko with broad bands. The representative disorder is the McCune-Albright syndrome. · Type 2 is the checkerboard pattern. An example would be a large generalized speckled lentiginous nevus or Becker's nevus. · Type 3 is phylloid or leaf like pattern. An example would be phylloid hypomelanosis. · Type 4 is the patchy pattern without any midline separation. An example would be a congenital giant melanocytic nevus.

Address for correspondence Dr. Ian McColl Dermatologist, John Flynn Medical Centre, Inland Drive, Tugun, Gold Coast 4224, Australia Email: [email protected]

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Type 5 is lateralization. An example would be the CHILD syndrome.

The genetic mechanisms underlying mosaicism include those affecting germ cells, somatic cells and sometimes a combination of both. 2 It depends to some extent on when in the development of the embryo the mutation occurs. If it is very early on, before germ cell differentiation has occurred, then both germ cells and somatic cells may be involved, but if after the thousand cell stage, it can be one or the other. Blaschko's lines are probably the commonest examples of mosaicism that we see because they involve cells of the epidermis.3 The cells of the epidermis originate from the neural crest and in the developing fetus they grow out laterally. However, as the fetus bends and unfolds, so these originally straight lines start to assume the shape of a fountain or volcano and hence give the characteristic patterns we are all aware of. The genetic causes of mosaicism are described as follows: 1. Half chromatid mutation 2. Lyonization 3. Post zygotic mutation 4. Chromosomal non-disjunction 5. Chimerism

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To deal with each of these in turn, a half chromatid mutation is a defect in the formation of DNA during the first meiotic division of gametogenesis where one strand of the double strands of DNA carries a mutation. The phenomenon of semi conservative replication within the zygote or fertilised egg gives rise in one of the daughter cells to a complete point mutation, usually a wrong base pair amino acid. If this half chromatid mutation has occurred in the gamete then mosaicism will already be present at the two cell stage, hence epidermal nevi or nevoid like disorders in the epidermis that are bilateral and widely spread may be explained by this mechanism although a very early post-zygotic mutation, after fertilization has taken place in the early four or eight cell stage, can also give rise to this pattern. Lyonization refers to the X chromosomes. In females where there are two X chromosomes, one of them is inactivated at a very early stage and becomes what is known as a Barr body. This occurs in all women. The X chromosome that is inactivated may have come from the child's mother or from the child's father but once this inactivation has occurred it is the same in all daughter cells derived from it. Hence, if there is a disorder carried on an X chromosome from one of the parents, it will only be expressed in some of the cells. Again because of the randomization process, this is likely to be a widespread epidermal nevus type disorder rather than a small localized area. A post-zygotic mutation is a mutation occurring after fertilization and the initial multicell stages of the embryo. If it occurs early in the multicell stage formation then the condition will be widespread. If it

occurs later then it may well be localized, either linear, segmental or one of the other clinical patterns described by Happle.1 Chromosomal non dysjunction is the failure of chromosomes to separate correctly during either meiosis or mitosis giving variations in chromosomal numbers or structures e.g. trisomy or translocations. These may occur early or late. Chimerism is where an organism has two very genetically distinct cell populations either due to fertilization of one egg by two sperms or fusion of two fertilised eggs. Hence, the mosaicism is due to two different genetic organisms with two different cell lines. The patterns of cutaneous mosaicism will also vary according to the cell type involved. Involvement of epidermal cells gives rise to the classic pattern of Blaschko's lines because of the way in which epidermal cells grow out laterally from the neural crest.4 Melanoblasts in comparison grow out in single cell migration and proliferate antenatally in the skin, so they can give a variety of patterns including Blaschko's lines or phylloid and leaf-like or even checkerboard sometimes known as block type. Think of all the hyperpigmented variations that you have seen and you will get the idea. Blood vessels, fibroblasts and other mesodermal cells tend to take more direct routes into structures and hence nevi made up of these will usually be seen in embryonic segments or in actual dermatomes. As a summary, if there are multiple o rgans involved then mosaicism occurred before organogenesis , and if the lesions are bilateral then mosaicism occurred before

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lateralization. Mosaicism in the later stages of pregnancy, after the embryo has unfurled, is less likely to cause linear lesions than if it occurred early on when the embryo was still folded on itself. Mosaicism in the later stages of pregnancy from a somatic mutation is likely to cause oval or round patches while if the mutation is post natal you develop a tumour. It is also useful to look at known inheritance patterns of various diseases and consider what effect mosaicism may have on them. These include some X -linked disorders that are often examples of X chromosome mosaicism and lyonization. There are other disorders that are autosomal lethal mutations, but they survive because of mosaicism. For example males get their X chromosome from their mothers. If the mother is heterozygous for a particular X linked disorder the sons have a 50-50 chance of getting an abnormal X chromosome. If the condition is X-linked dominant the males usually die before birth e.g. incontinentia pigmenti and Goltz syndrome or focal dermal hypoplasia. If by some chance they survive then it is because of mosaicism, either somatic or half chromatid mutations.5 Chromosomal mosaicism occurs in hypomelanosis of Ito. This condition affects both males and females unlike i continentia n pigmenti. The chromosomal mosaicism can take the form of defects in both the chromosomal structure and number including both triploidy and translocations. The proteus syndrome is also interesting as an example of an autosomal lethal mutation that can only survive in a mosaic state. It occurs sporadically and has epidermal nevi

suggesting mosaicism although the exact nature of the mosaic disorder is not known. The last concept to get over is what are known as type 1 mosaic disorders and type 2 mosaic disorders. In type 1 mosaic disorders you can have one segment involved with the rest of the skin being normal. 6 In type 2 disorders the rest of the skin is abnormal but you have one normal segmental section and this is usually due to what is known as revertant mosaicism, where a gene defect that is affecting the rest of the body has reversed in this particular segment. This has been described as natural gene therapy. It is thought to explain some patients with conditions such as xeroderma pigmentosum who may have areas of normal skin in spite of their autosomal recessive trait. Other clinical examples include recessive epidermolysis bullosa simplex with an area of normal skin. Twin spotting refers to the situation where two different mutations occur in the genetic material at the same site in paired chromosomes. When these split and recombine in mitosis two clones of cells may be formed that are now homozygous for each mutation and in close proximity to each other. An example is seen in adjacent segments of excessive or absent lesions in the skin in Darier's disease. Occasionally knowledge of mosaicism is important in the field of genetic counseling. For example, if you have an early postzygotic or post-fertilization mutation that involves both somatic and genetic cells, then the parent who suffered from this may have just a linear or localised variant of the disorder, but because the genetic cells or germ cells are involved, they may then have

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a child with the generalized type of this disorder. An example of this is a localised epidermal nevus showing features of epidermolytic hyperkeratosis in a parent with the child subsequently having the generalized version of epidermolytic hyperkeratosis. This situation also may arise when called upon to give genetic advice on a child who is born with a rare genetic disease when both parents are apparently unaffected. You have to consider whether one of the parents may in fact have mosaicism in their germ cells even though they are not showing anything in the somatic cells because obviously, if they do, the risk of having a subsequent pregnancy affected by the same rare disease would be very much higher and some form of pre natal analysis of the embryo would be necessary. Work in mosaicism is occurring all around the world. The mosaic nature of linear forms of common conditions such as psoriasis and eczema and vitiligo allows geneticists access to skin material which may give a greater insight into the genetic component of these disorders by comparing material from normal and abnormal areas in the same individual. The analysis of the human genome has given us the equivalent of the Rosetta tablet to explore these genetic disorders further and provide a greater understanding of the myriad forms of skin disease that we see. References

1. Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol 1993; 129:1460-70. Paller A, Syder AJ, Chan Y et al. -M Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med 1994; 331:1408-15.

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4.

5.

6.

Moss C. Cytogenetic and molecular evidence for cutaneous mosaicism: the ectodermal origin of Blaschko lines. Am J Med Genet 1999; 85: 330-3. Moss C, Larkins S, Stacey M et al. Epidermal mosaicism and Blaschko's lines. J Med Genet 1993; 30: 752-5. Kenwrick S. Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet 2001; 69: 1210-7. Tinschert S, Naumann I, Stegmann E et al. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet 2000; 8: 455-9.

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History of dermatology in Pakistan

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PAD Silver Jubilee Special

History of dermatology in Pakistan

Ijaz Hussain

Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore

"Those who do not remember their past are condemned to repeat it." Santayana Pakistan emerged as a sovereign country on world map on 14th August, 1947. Like all walks of life, there was acute shortage of medical and health facilities in the new born state. The majority of specialist doctors and teachers were Hindus and had left for India. There were only two medical colleges, King Edward Medical College, Lahore and Dow Medical College, Karachi, with no postgraduate medical institute in the whole country. Although, venereology out-patient clinics were run in the major hospitals, there was not a single qualified dermatologist at that time. Five to six lectures covering the common dermatological diseases were delivered by the internists. It can be said that dermatology, as a specialty, virtually started from scratch. For descriptive purposes, three general periods of dermatology in Pakistan can be distinguished, from 1947 to 1975, from 1976 to 2000 and then from 2001 onwards. From 1947 to 1975: Early progress During the period from 1947 to 1975, a few names, who pioneered dermatology in

Address for correspondence Dr. Ijaz Hussain, Associate Professor, Department of Dermatology, Unit I, King Edward Medical College/Mayo Hospital, Lahore, Pakistan. Email: [email protected]

Abbreviations used in the article CPSP College of Physicians & Surgeons Pakistan FCPS Fellow College of Physicians and Surgeons Pakistan JPAD Journal of Pakistan Association of Dermatologists KEMC King Edward Medical College MCPS Member College of Physicians and Surgeons Pakistan PAD Pakistan Association of Dermatologists PMDC Pakistan Medical and Dental Council

public sector, teaching hospitals and military medical services, stand out prominently. These are Dr. Nusrat Ali Shaikh, Prof. Syed Ghulam Shabbir, Brig. Dr. Syed Muhammad Jaffer, Lt. General Mahboob Ahmad and Dr. Dur-e-Kamil. Considering the scarcity of qualified dermatologists in the country, two class fellows and graduates of 1948 from KEMC, Lahore, opted for dermatology as postgraduate subject. Dr. Nusrat Ali Shaikh and Dr. Syed Ghulam Shabbir did their MRCP (Edinburgh) with dermatology as special subject in 1955 and 1957, respectively. After returning from UK, Dr. Shaikh (Figure 1) joined the Skin and Social Hygiene Centre, Karachi. This was the first institute in public sector established for care of dermatological patients in 1952. He served as director of the center from 1956 to 1978. He, along with Prof. Syed Ghulam

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Shabbir, started MCPS in dermatology. He was the founder President of the Pakistan Association of Dermatologists but unfortunately died a year later in 1980. Another legend of that era was Prof. Syed Ghulam Shabbir (Figure 2). He succeeded in establishing dermatology as an independent specialty in a teaching hospital in 1960 when a 20-bedded in-patient ward was started in Mayo Hospital, Lahore. He was the first Assistant Professor of the subject in the country. Dr. Tahir Saeed Haroon happened to be the first medical officer in the new-born unit. In 1964, the first chair in dermatology was created and Dr. Syed Ghulam Shabbir was elevated as Professor of Dermatology. Due to his tireless efforts the department was relocated to a larger new building and the bed strength was increased to 56 in 1970. A leprosy clinic was added in 1972. He also started the histopathology laboratory on self-help basis. He described a genodermatosis `laryngoonycho-cutaneous syndrome syn. Shabbir syndrome' in Punjabi children, which is characterized by refractory, granulating erosions affecting periorificial areas, laryngeal, ocular and genital mucosa and early decaying teeth. After his retirement in 1987, Prof. Shabbir served as Professor Emeritus till his death in 2002. He trained many MCPS and MD students in the subject. The history of military dermatology is also rich in eminent dermatologists. Major (later Brigadier) Dr. Syed Muhammad Jaffer (Figure 3) was the pioneer. He graduated from the King Edward Medical College, Lahore in 1944 and joined the military services in the same year. He trained in dermatology with Dr. Stephen Gold at the

British Medical Hospital, Banglore, and at St. John's Institute, London from 1948 to 1950 and then set up dermatology services at Military Hospital, Rawalpindi. He was an early Vice President of PAD. He participated actively in postgraduate training and organized MCPS in dermatology. His trainees included Major (later Lt. General) Mahboob Ahmad and Major (later Major General) Ashfaq Ahmad Khan. He headed the department till his retirement in November, 1977, except for a brief period from 1963 to 1964. He was replaced by Major Dr. Ashfaq Ahmad Khan in 1977. Late Lt. General Mahboob Ahmad (Figure 4) did his MRCP (Edinburgh) in 1963. He led the department at military Hospital, Rawalpindi for a brief period from 1963 to 1964. He was then transferred to internal medicine department. Remaining out of the mainstream, he practiced, taught and supported dermatology. He served as Vic e President of PAD, as well. Dr. Dur-e-Kamil (Figure 5) will be remembered as the founder of dermatology in NWFP. He also graduated from the KEMC in 1955 and did his fellowship in dermatology from Canada in 1966. He was posted as Consultant Dermatologist at Lady Reading Hospital, Peshawar. Later, he helped with the establishment of leprosy unit at Mission Hospital, Peshawar. He was actively involved in imparting postgraduate training in dermatology at Lady Reading Hospital, Peshawar and had many publications to his credit. He died in 1990. Dr. Abdul Basit is credited to be the founder dermatologist in the East Pakistan. He founded the first dermatological society

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Figure 1 Dr. Nusrat Ali Shaikh, the founder President of PAD (1979).

Figure 2 Professor Syed Ghulam Shabbir, the founder of the first teaching dermatology department in Pakistan. President PAD (198084).

Figure 3 Brig. Syed Muhammad Jaffer, the pioneer of dermatology in the military. Vice President, PAD.

(which later became the Bangladesh Dermatological Society) at Dhaka, in 1962. From 1976 to 2000 This period marked the dawn of golden era in the history of dermatology when the second generation of dermatologists was ready to take over. Out of a score of dermatologists at that time, two names, Dr. Tahir Saeed Haroon and Dr. Ashfaq Ahmad Khan, stand out. These two contemporaries played a vital role in the recognition and proliferation of the specialty. Structured postgraduate training of FCPS was started

Figure 4 Lt. General Mahboob Ahmad, another eminent figure of military dermatology. Vice President, PAD.

and Pakistan Association of Dermatologists was founded during this period. Prof. Tahir Saeed Haroon (Figure 6) can be called a Champion of dermatology in Pakistan. Prof. Haroon, an alumnus of 1961 from King Edward Medical College, Lahore, did his MRCP from Glasgow in 1973. During his stay in UK, he trained with Dr. Alan Lyell (famous for Lyell's disease) and later served as a consultant

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dermatologist at Bradford, West Yorkshire, only the second Pakistani to do so at the time. After returning to Pakistan in 1976, he established the department of dermatology at Jinnah Postgraduate Medical Centre, Karachi. As a real academician, he started courses for MCPS dermatology and then along with General (R) Dr. Ashfaq Ahmad Khan organized FCPS dermatology. He was the co-founder of PAD along with Dr. Nusrat Ali Shaikh, serving as the first General Secretary. He also organized the first PAD National Conference at Karachi in 1982. In 1989, Prof. Haroon moved to the King Edward Medical College, Lahore to head the department of dermatology at Mayo Hospital, Lahore. With him, the centre of dermatological activities shifted from Karachi to Lahore. The vision, vitality and enthusiasm of Prof. Haroon transformed the Mayo dermatology unit into a state of the art department. The existing facilities were upgraded and new sections pertaining to dermatopathology, mycology, immunofluorescence, laser, patch test, dermatosurgery, audiovisual aids and library were added. He was a true research worker and academician. He authored more than one hundred articles published in peerreviewed national and international journals and various books besides contributing chapters to a number of textbooks. He trained 40 FCPS, 30 MCPS and 1 MD student. Even after his retirement in 2002, he remains the driving force behind the dermatology affairs of the country, PAD and JPAD. He is currently the President of the PAD, having served in the same capacity from 1984 to 1988. Maj. General Dr. Ashfaq Ahmad Khan (Figure 7), also a graduate of KEMC, in

1964, was basically an internist who later on received training in dermatology from UK. He was an excellent clinician and academician. He emphasized the significance of core knowledge of medicine for the externists. He upheld the standards of postgraduate qualification in dermatology. He was co-organizer of FCPS (dermatology) in Pakistan. Under his command, Military Hospital, Rawalpindi became a centre of excellence in Pakistan. He trained many MCPS, FCPS and MD (dermatology) students. General Ashfaq was President, PAD from 1997 to 1998. He was succeeded by Brig. Simeen Ber Rahman in 1999. During 1970's, many new medical colleges and postgraduate institutes were established in the country. This ushered the opening of new avenues for the young dermatologists in the country. New departments were set up and new teaching posts were created. Amongst the contemporaries of that period who merit mention are Prof. Iqbal Chaudhary [Figure 8] (Nishtar Medical College, Multan), Prof. Zafar Ahmad (Dow Medical College/Civil Hospital, Karachi), Dr. Aleem Saeed Qureshi [Figure 9] (The Aga Khan Medical University, Karachi), Dr. Mahmud Hasan Zubairy (Karachi), Prof. Ali Khan Tareen [Figure 10] (Bolan Medical College, Quetta), Dr. Manzoor ul Hasan (KEMC, Lahore), Prof. Abdul Ghafoor Qamar [Figure 11] (Quaid-e-Azam Medical College, Bahawalpur), Prof. Raza Muhammad Khan [Figure 12] (Khyber Medical College, Peshawar), Dr. Khadimullah Kakakhel (Khyber Medical College, Peshawar), Dr. Javed Anwer (Liaquat Medical University, Hyderabad), Dr. Hamid Zaib Khan (CDA Hospital,

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Figure 5 Dr. Dur-e-Kamil, the first Consultant Dermatologist in the North Western Frontier Province. Vice President, PAD.

Figure 6 Professor Tahir Saeed Haroon, a legendary teacher and academician and founding General Secretary of PAD. President, PAD (1985-1988 & 2002-2004).

Figure 7 Major General Dr. Ashfaq Ahmad Khan, a legend in the military dermatology and President, PAD (1997-1998).

Figure 8 Professor Iqbal Choudhary, a respected Senior Dermatologist. President, PAD (19891992)

Islamabad) and many others. All these strived hard for the recognition and upgradation of dermatology in their respective institutions. Dr. Aleem Saeed Qureshi was the first Joint Secretary of PAD, later General Secretary. He along with Prof. TS Haroon drafted its constitution. A graduate from Nishtar Medical College, Multan, in1960, did his MCPS in dermatology in 1977. He then joined the Aga Khan University, Karachi as

a consultant dermatologist. He was very actively involved in the affairs of PAD till his death in 1995. Dr. Khurshid Hassan Alvi (Figure 13) has also been closely associated with PAD since its early days. Later he served as President from 1998 to 2000. In 1996, the first unit of Pediatric dermatology was established at Institute of Child Health, Lahore, by Dr. Farhana Muzaffar.

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Figure 9 Dr. (late) Aleem Saeed Qu reshi, the founding Joint Secretary of PAD. Later General Secretary. A moving force behind PAD.

Figure 10 Professor Ali Khan Tareen, the founder of dermatology in Baluchis tan. President, PAD (1993-1994)

Figure 11 Prof. Abdul President, PAD (2001-2002)

Ghafoor

Qama r. Figure 12 Prof. Raza Muhammad Khan, one of the pioneers in dermatology in NWFP. President, PAD (1995-1996).

From 2001 onwards Since 2001, dermatology has gained sufficient momentum to keep it progressing in the fields of clinical work, research and academics. After the retirement of Prof. Tahir Saeed Haroon in 2002, Dr. Sabrina Suhail succeeded him at the Mayo Hospital. In 2004, an additional chair was created, currently occupied by Prof. Atif Hasnain Kazmi. In 2004, Prof. Atif Hasnain Kazmi inaugurated the first teledermatology unit at Mayo Hospital, Lahore.

Figure 13 Dr. Khurshid Hasan Alvi. President, PAD (1999-2000).

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Other principal figures of the third generation of dermatologists include Dr. Zarnaz Wahid (Dow Medical College/Civil Hospital, Karachi), Prof. Muhammad Jahangir (Allama Iqbal Medical College/Jinnah Hospital, Lahore), Prof. Muhammad Azam Bokhari (Punjab Medical College, Faisalabad), Prof. Iqbal Tareen (Bolan Medical College, Quetta), Prof. Ghulam Mujtaba (Nishtar Medical College, Multan), Dr. Muhammad Khalid (Quaid-eAzam Medical College, Bahawalpur), Dr. Tariq Rashid (Allama Iqbal Medical College/Jinnah Hospita l, Lahore), Dr. Shahid Javaid Akhtar (Punjab Medical College, Faisalabad), Dr. Hamid Zaki, Dr. Naseema Kapadia (Abbasi Shaheed Hospital, Karachi), Dr. Yasmeena Khan (Liaqat National Hospital, Karachi), Dr. Sharaf Ali Shah (Civil Hospital, Karachi), Dr. Badr Dhanani (Institute of Skin Diseases, Karachi), Dr. Naeem Iqbal (KV SITE Hospital, Karachi), Dr. Daulat Ram Pinjani and Dr. Manzoor Memon (Institute of Skin Diseases, Karachi), Prof. S.M. Shamim (Baqai Medical University, Karachi), and many more, all spiritual heirs to Prof. Tahir Saeed Haroon. Other prominent names are Prof. Azer Rashid (Khyber Medical College, Peshawar), Dr. Zubair Khan and Dr. Mairaj Muhammad Khan (Lady Reading Hospital, Peshawar), Dr. Abdul Mannan Bhutto (Chandka Medical College, Larkana), and Dr. Imranullah Khan (Ayub Medical College, Abbotabad). Since 1999, the military dermatology has been led by Brig. Dr. Simeen Ber Rahman. She has been actively engaged in research activities especially leishmaniasis and has

been instrumental in upgradation of her department. Other worth mentioning stalwarts of military dermatology are Col. Ahsan Hameed, Col. Khalid Hussain, Col. Rehanuddin, Col. Syed Dilawar Hussain, Col. Zafar Iqbal Sheikh and Col. Nasser Rashid Dar. In 2004, Dr. Shahbaz A. Janjua, in collaboration with Dr. Ian McColl (Australia) and Dr. Jayakar Thomas (India) launched an on-line dermatology atlas (www.globalatlas.com) depicting the ethnic diversity of dermatoses. Table 1 highlights the milestones in the history of dermatology in Pakistan. Dermatology community today Currently there are around 420 practicing dermatologists in the country (one dermatolo gist per 350000 population), in contrast to none in 1947 and a score in 1970's. The majority is in the private sector and in the larger cities so that the big cities are oversaturated whereas the rural areas and smaller towns (where the 70% of country's population dwells) are underserved. Socioeconomic factors and the government policies are partly responsible for this uneven distribution. Separate dermatology departments are functioning in almost all medical colleges in the public sector whereas only a few in the private sector have the dermatology faculty. These departments are manned by properly qualified teachers. A few departments are equipped with lasers, phototherapy units, dermatosurgery theatres, patch testing facilities and mycology and histopathology

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Table 1 Milestones Year 1947 1950 1952 1955 1960 1962 1964 1966 1970 1972 1973 1975 1976

1977 1978 1979 1982

1983 1984 1986

1989 1990 1991 1994 1995 1996 1998 2000 2002 2004

in the history of dermatology in Pakis tan Event Pakistan came into being Brig. S.M. Jaffer first trainee in dermatology abroad. Skin and Social Hygiene Centre, Karachi established. First dermatology institution in the country. Dr. Nusrat Ali Sheikh became first qualified dermatologist Prof. Syed Ghulam Shabbir did MRCP, the second qualified dermatologist. First teaching dermatological unit established at KEMC/Mayo Hospital, Lahore. · Dr. Abdul Basit established the Dermatology Association in East Pakistan · Dermatology department created at the Military Hospital, Rawalpindi. First chair of dermatology at KEMC/Mayo Hospital, Lahore. Dr. Dur-e-Kamil appointed as first Consultant Dermatologist at Lady Reading Hospital, Peshawar MCPS dermatology started by College of Physicians and Surgeons Pakistan. Dermatology department established at Dow Medical College/Civil Hospital, Karachi. Dermatology department established at Nishtar Medical College/Nishtar Hospital, Multan by Prof. Iqbal Chaudhary. First MCPS dermatology qualified. · Prof. Tahir Saeed Haroon founded department of dermatology at Jinnah Postgraduate Medical Centre, Karachi. · Dermatology department created at Khyber Medical College, Peshawar by Prof. Raza Muhammad Khan. Major Dr. Ashfaq Ahmad Khan joined Military Hospital, Rawalpindi. Dermatology department established at Bolan Medical College, Quetta by Dr. Ali Khan Tareen. Pakistan Association of Dermatologists launched · First National Conference of dermatology under the aegis of PAD · Dermatology departments created at Services Hospital, Lahore and Liaqat National Hospital, Hyderabad Dermatology department started at Punjab Medical College/DHQ hospital, Faisalabad Dermatology department started at Quaid-e-Azam Medical College, Bahawalpur · FCPS dermatology started by College of Physicians and Surgeons Pakistan · Dermatology department created at Fatima Jinnah Medical College/Sir Ganga Ram Hospital, Lahore Prof. Haroon moved to King Edward Medical College/Mayo Hospital, Lahore · First FCPS dermatology qualified · Dermatology department created at Ayub Medical College, Abbottabad First issue of JPAD published Dermatology department at Allama Iqbal Medical/Jinnah Hospital, Lahore First laser in public sector installed at department of dermatology, Mayo Hospital, Lahore First unit of Pediatric dermatology started at the Institute of Child Health, Lahore JPAD recognized by Pakistan Medical and Dental Council Maj. General Dr. Ashfaq Ahmad Khan retired Prof. Tahir Saeed Haroon retired · First teledermatology unit inaugurated at Mayo Hospital, Lahore · First on-line atlas of ethnic dermatoses launched · JPAD made available on-line · Silver Jubilee conference of PAD at Karachi

laboratories. Private sector is sharing the burden of cosmetic dermatology; however, the academic activities are mainly confined

to the teaching hospitals. Different departments round the country are actively involved in imparting postgraduate training

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for MD, FCPS and DCPS in dermatology. At present there are 7 chairs in dermatology in the whole country. Foundation of Pakistan Association of Dermatologists Pakistan Association of Dermatologists (PAD) came into being in January, 1979. The idea to provide a forum for the dermatologists of the country to meet together and their colleagues from allied disciplines was conceived by Dr. Nusrat Ali Shaikh, Dr. Tahir Saeed Haroon, Dr. Aleem Saeed Qureshi and Dr. Zarina Fazal Bhoy. The constitution was drafted by Dr. Tahir Saeed Haroon and Dr. Aleem Saeed Qureshi. Other objectives of this forum were to hold regular meetings to discuss clinical dermatology and present scientific papers on dermatology and relevant subjects, to improve patient care, to encourage research in dermatology, to promote teaching of dermatology to the medical postgraduates and undergraduates and to formulate policies on matters of dermatological interest in Pakistan and bring them to the notice of the Government and other relevant authorities. Karachi was selected as the Headquarter of the Association. The first office bearers of this nascent association were Dr. Nusrat Ali Shaikh (President), Dr. Tahir Saeed Haroon (General Secretary), Dr. Aleem Saeed Qureshi (Joint Secretary), Dr. Dr. Mrs. Malik Tharani (Treasurer), Prof. Syed Ghulam Shabbir (Chairman Editorial Board) and Dr. Zarina Fazal Bhoy, Dr. Jalil Siddiqui, Dr. A. Sajid Khan and Dr. Iqbal A. Chaudhary as Executive members. At the time of inception, PAD comprised of only 33 members. Over the years it grew

and currently in 2004, it has 225 members in its fold. The first national conference of Dermatology was h at Karachi in 1982 eld whereas the first International Conference was organized at Rawalpindi in 1983. Since 1982, these annual conferences have become a regular event. These are attended by a large number of delegates not only from Pakistan but also from other countries. These conferences provide interaction between senior academicians and youngsters and promote continuous medical education programme. New office bearers are selected after every two years in the general body meeting. So far 12 biennial and 10 annual conferences have been organized. In December, 2004, PAD is holding its Silver Jubilee Conference at Karachi, where it originated 25 years ago. Besides annual conferences, PAD has been actively involved in various academic and clinical activities. Monthly clinical meetings are held in different cities in which interesting clinical cases are discussed and lectures are delivered on dermatological and allied subjects by the dermatologists and other eminent personalities. Youngsters are particularly encouraged to participate. Courses and seminars on dermatology are arranged for family physicians. Free consultation camps are held in outreach areas to provide free clinical consultation and drugs. Various recommendations are sent to the government, from time to time. A scheme to provide financial assistance to postgraduate trainees is under consideraation. PAD is also a member of International League of Dermatological Societies (ILDS) and South

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Asian Regional Association of Dermatology (SARAD). Associate d dermatological organizations In 1996, the alumni of Bangkok Institute of Dermatology, Thailand gathered under the forum of Association of Bangkok Alumni of Dermatology (ABAD). ABAD comprises of 51 members and it holds regular annual meetings. Welfare Association for Dermatological Patients (WADeP) was started by Dr. Manzoor Memon, Karachi. In collaboration with local NGOs, it holds fortnightly free skin camps in the out reach rural areas of Sindh Province. So far, around 600 such camps have been arranged in the interior Sindh. Journal of Pakistan Dermatologists Association of

Figure 14 Dr. Sharaf Ali Shah, the first Editor of JPAD (1990-1996)

Journal of Pakistan Association of Dermatologists (JPAD) is the official journal of the association. Published quarterly, it primarily aims at documenting the local research. The first issue of JPAD was made public in 1991 by Dr. Sharaf Ali Shah (Figure 14) who continued to publish it against great odds for the next five years. In 1997, Dr. Yasmeena Khan (Figure 15) took over as the editor of JPAD. Due to her tireless efforts the standard of the journal was improved and it was published regularly. It was recognized by PMDC in 1998. In 1999 it was registered with ISSN and indexed in Embase/ Excerpta Medica, Netherlands, and Index Medicus WHO Alexandria , Egypt. In the year 2000 i was t included in Extramed consortium in UK. In

Figure 15 Dr. Yasmeena Khan, Editor, JPAD from 1997 to 2003.

Figure 16 Dr. Ijaz Hussain, the current editor

the following year it was listed in Ulric h's Periodicals Directory, New Jersey USA and in Indian National Scientific Documentation Centre Delhi, India. In 2003 Dr. Yasmeena Khan was succeeded by the author [IH] (Figure 16). Recently, the on-line version of

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JPAD (www.jpad.org.pk) launched. Undergraduate education

has

been

Dermatology has not been an examination subject; hence, its teaching has not been so regular and uniform. Recently, Pakistan Medical and Dental Council has conferred on dermatology the status of essential specialty for undergraduates, the new curriculum is in the preparatory phase and it is hoped that it would be implemented in true letter and spirit. Postgraduate education At the time of independence, in 1947, there was scarcity of health facilities including an acute shortage of medical teachers and specialists. There was no postgraduate medical institution in the country. Although Punjab University awarded MD and MS degrees, medical graduates had to proceed to UK for higher medical education. Government of Pakistan responded to this challenge by establishing College of Physicians and Surgeons Pakistan (CPSP) on the pattern of Royal Colleges of UK in 1962. The objective was to introduce and promote postgraduate specialization in the country. CPSP started postgraduate qualification at two levels i.e. Membership (MCPS - Member College of Physicians and Surgeons Pakistan) and Fellowship (FCPS Fellow College of Physicians and Surgeons Pakistan). MCPS was aimed at providing district level specialists and FCPS to provide teachers in the medical colleges. MCPS and FCPS in dermatology were started in 1970 and 1986, respectively. Dr.

Ch. Muhammad Rashid, who qualified in 1975, was the first MCPS in dermatology. Similarly, Col. (R) Dr. Ahsan Hameed has the honour to be the first FCPS in dermatology in 1990. Till the year 2004, 160 MCPS and 75 FCPS dermatology were registered with CPSP and these constitute the major bulk of dermatologists in the country. Others hold MRCP (UK), American board/diplomat in dermatology, diploma in dermatology from St. John's Institute of Dermatology, London, diploma in dermatology from Bangkok, Thailand and diploma in dermatology from Singapore, masters in dermatology from UK and diploma/fellowship in dermatology and venereology from Austria. Research and publications Research activities, mainly clinical, have been largely confined to the teaching hospitals. Nonetheless, research in areas of mycology and leishmaniasis has been of a high standard and it has been acknowledged world over. The culture of medical writing has not flourished; nevertheless, there have been individual efforts, mostly from teaching institutions. There has been intermittent flow of research articles published in the peerreviewed journals, many of them have been indexed in MEDLINE. A number of treatises and monographs have been authored (Table 2).

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Table 2 Books and monographs written by Pakistani dermatologis ts Book/monograph Author/editor ABC of Dermatology (nine editions) Prof. Tahir Saeed Haroon Skin and Systemic Disease Prof. Tahir Saeed Haroon Amraz-e-Jild (Urdu) Prof. Tahir Saeed Haroon Common Skin Diseases Prof. Tahir Saeed Haroon Skin Diseases (Specialist Quarterly) Prof. Tahir Saeed Haroon Skin Diseases -2 (Specialist Quarterly) Prof. Tahir Saeed Haroon Skin Cancer (Specialist Quarterly) Prof. Tahir Saeed Haroon Chamri Jon Bimaryun (Sindhi) Prof. Tahir Saeed Haroon and Dr. Sulaiman Shaikh MCQs in Dermatology Prof. Tahir Saeed Haroon and Dr. Manzoor ul Hasan Apras (Urdu) Dr. Sharaf Ali Shah Manual of Dermatology Dr. Zohra Zaidi An Atlas and Textbook of Pediatric Dermatology Dr. Yasmeena Khan Textbook of Dermatology Dr. Khadimullah Kakakhel A Monograph on the Management of Pemphigus Dr. Shahid Javaid Akhtar Management of Acne Dr. Umair Mansoor Bajwa Uses and Misuses of Topical Steroids Dr. Umair Mansoor Bajwa An Approach to Practice of Dermatology Dr. Syed Muhammad Shamim Amraz-e-Jild (Urdu) Dr. Syed Muhammad Shamim

Future Despite difficult ies, dermatology in Pakistan has flourished and evolved into a wellrespected independent specialty. Considering the vigour and potential of youngsters, the future of dermatology in Pakistan seems bright. Acknowledgement The author is highly grateful to Prof. (late) Syed Ghulam Shabbir, Prof. Iqbal Chaudhary, Prof. Tahir Saeed Haroon, General (R) Ashfaq Ahmad Khan, Prof. Ali Khan Tareen, Dr. Khurshid Hasan Alvi, Dr. Manzoor ul Hasan, Dr. Abdul Ghafoor Qamar, Prof. Muhammad Jahangir, Dr. Muhammad Zubair Khan, Dr. Zohra Zaidi, Dr. Yasmeena Khan, Squadron Leader Dr. Arfan ul Bari, Dr. Shahid Jamil and many other dermatology colleagues for providing the historical data.

Bibliography

1. 2. Abstract books of all conferences held under the auspices of PAD. Bari AU. Military dermatology in Pakistan. J Pak Assoc Dermatol 2004; 14: 184-8.

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Military dermatology in Pakistan

Arfan ul Bari

PAD Silver Jubilee Special

Military dermatology in Pakistan

Arfan ul Bari

Consultant Dermatologist, PAF Hospital, Sargodha

The military is one of the oldest and the largest organizations in existence. It serves to defend and protect the nation, and is an instrument of the national policy. Ideally a well-trained, well-equipped, and well-led military serves to deter hostilities, however, when deployed; it has to be ready to carry out its combat mission. From ancient battles to modern conflicts, disease and non battle injury have claimed more soldiers than combat itself.1 A single qualified dermatologist at the start of World War II had to face with a high rate of hospital admissions for dermatologic disease, as high as one man for every ten soldiers in the Middle East and Southwest Pacific theaters of operation.2 Military training traditionally emphasizes combat. More recently, however, operations other than war e.g. as peacekeeping humanitarian assistance and nation building have become major items in the lexicon of military responsibility. In the military system, the physicians have no financial incentive or disincentive for using specific modalities in treating patients. Most military physicians are interested in the best treatment for their patients at a reasonable cost. Dermatologic disease has been a major source of morbidity for military personnel whether at war or in peace.3 Dermatologists have a significant role in maintaining the

Address for correspondence Dr. Arfan ul Bari, Consultant Dermatologist, PAF Hospital, Sargodha. Email: [email protected]

health and readiness of troops. In fact, cutaneous diseases are an important factor in determining whether an individual is considered medically fit to enter or continue in the military. Dermatology practice in armed forces is somewhat different, because the primary purpose of military medicine is to support the active duty soldier, sailor, marine, or airman wherever he or she may be assigned. This occasionally means being deployed to remote parts of the country, sometimes for peaceful missions and sometimes for not so peaceful missions in other third world countries. Military patients may be involved in mountain climbing, exploring the desert, or wandering in the jungles and they can bring remote diseases and unusual injuries into military dermatologist's office. Military dermatology in Pakistan Military dermatology in Pakistan has produced many of the great leaders in our specialty and it has made immense progress during the last two decades. Today, many of our peers continue to be active in research, writing, speaking and teaching and military training programs have a reputation for training excellent dermatologists. Military and cutaneous leishmaniasis Military has traditionally played a prominent role in the study of globally important infectious diseases.4 In our country

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dedicated military dermatologists have made significant contributions towards understanding of the epidemiology, pathogenesis, diagnosis, and treatment of leishmaniasis. Contracting leishmaniasis is an unavoidable risk to military personnel, especially those who are deployed in Baluchistan and interior Sindh and isolated areas of Punjab and NWFP .5,6 The complicated epidemiology of this parasite, deficiencies in rapid, reliable diagnostic tests, and the need for safe, less costly and more effective treatment make Leishmania a unique challenge to medical science. Military dermatologists, working under supervision of an eminent researcher in the field of leishmaniasis "Brigadier Simeen Ber Rahman" and with collaboration of WHO are endeavoring to contribute greatly to the discoveries impacting this ubiquitous infectious disease. Centre of excellence (Military Hospital Rawalpindi) Introduction The department of dermatology in Military Hospital, Rawalpindi was established in 1962 and Major S.M. Jaffer (later retired as Brigadier) was the first dermatologist appointed, followed by Major Mahboob Ahmad (later retired as Lieutenant General). In 1977, Major Ashfaq Ahmad Khan (later retired as Major General) ( Figure 1) took over as head of department and remained in chair for 22 years. Due to his endless efforts and commitment to the profession, dermatology gained recognition in the country and the department was recognized as postgraduate training institute in 1988. He had the honor of training the first fellow in dermatology from Pakistan. He trained a

large number of dermatologists. Few big names include Brigadier Simeen Ber Rahman, Colonel Khalid Hussain , Colonel Zafar Iqbal, Lieutenant Colonel Ahsan Hameed, Lieutenant Colonel Dilawar Abbass, Lieutenant Colonel Nasser Rashid Dar and Lieutenant Colonel Rehan, who had earned very good name in the field of dermatology, not only in the country, but also at the international level. After the retirement of Major General Ashfaq Ahmed Khan, Brigadier Simeen Ber Rahman (Figure 2) became the next head of department in 1999 and she is performing her duties till date. Under her dynamic leadership, the centre has gained a newer, more attractive look; latest equipments and techniques have been acquired for the management of complex dermatological conditions. Now the centre is equipped with PUVA, UVB machines, microdermabrasion, diode laser, eximer laser, mycology lab, leishmania sis research cell, patch testing facilities, various modalities for electrocautery, cryosurgery and dermatosurgery. Dermatopathology services provided in collaboration with Armed Forces Institute of Pathology are considered the best in the country. The centre has a huge bank of clinical as well as histopathological slides. To facilitate learning and research work a library containing all well-reputed international journals has also been maintained. Simultaneously latest computer, printer, scanner and digital camera are notable contributions to enhance the training facilities for both postgraduate and undergraduate level. Complete renovation of the department provides healthy working environment and patients' satisfaction

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(Figures 3 and 4). With modern and sophisticated equipment, highly qualified

Figure 1 Major Ge neral (Rtd) Ashfaq Ahmad Khan: the real builder of dermatology services in Armed Forces.

Figure 3 and 4 Dermatology Department, Military Hospital, Rawalpindi

Satellite dermatology centres About two dozens of peripheral centers, situated in all four provinces, Azad Kashmir and Northern areas of the country, are providing the best dermatological care to the afflicted population. These are reasonably equipped and are being supervised by competent and devoted military dermatologists. Some of the dermatologists have also served in United Nations peacekeeping missions. Achievements Dermatologists Dermatology department of Military Hospital, Rawalpindi has so far

Figure 2 Brigadier Simeen Ber Rahman, the Present Head of Dermatology Department, Military Hospital, Rawalpindi.

staff, the ultimate goal of patient management and training facilities are comparable with any center in the world.

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produced more than 50 dermatologists that make about 1/3rd of total number of dermatologists in the country. About half of them have cleared fellowship examination (FCPS). In addition, two (Major Khalid Mehmood Raja and Major Nadia Iftikhar) have also attained MRCP, two are qualified dermatopathologists (Brigadier Simeen Ber Rahman is the first and leading dermatopathologist of the country). Colo nel Zafar Iqbal acquired special training from UK in prevention and management of sexually transmitted infections and did his Dip GUM (Diploma in Genitourinary medicine) from UK. Publications More than 100 research articles covering various fields of dermatology have so far been published in different well reputed national and international journals by researchers working in this institution. A large number of these articles are indexed in Medline (Appendix "A" ). A significant contribution has been made towards research in cutaneous leishmaniasis. Conferences, workshops, symposia, seminars To promote academic activities various conferences, workshops, symposia and seminars have been organized from time to time. The centre has the pride of organizing two Biennial International Conferences of Dermatology in 1985 and 2000 and three dermatopathology workshops in 1990, 1992 and 2000. Leishmaniasis research cell A research cell has been established in the skin centre (in collaboration with WHO) to carry out further research in management and prevention of cutaneous leishmaniasis that

has become an endemic parasitic disease in various regions of the country. A largescaled vaccination trial was carried out (2500 cases) in 1995-96. Recently another vaccination trial has been started in an attempt to prevent and control the disease. Future plans UVB chamber and photodynamic therapy unit are very soon expected in the department. The centre is also ready to host the 11th National Conference of Dermatology in 2005. References

1. Gorden JE. The strategic and tactical influence of disease in world war II. Am J Med Sci 1948; 215: 311-26. Pilsbury DM, Livingood CS. Experiences in military dermatology. Arch Dermatol Syphilol; 55: 441-62. Allen AM. Skin diseases in Vietnam. In: Ognibene AJ (ed). Internal Medicine in Vietnam, Vol. 1. Washington DC: Medical Department, US Army, 1982. Kenner JR, Aronson NE, Benson PM. The United States military and leishmaniasis. Dermatol Clin 1999; 17: 77-92. Rahman SB, Bari AU. Morphological patterns of cutaneous leishmaniasis seen in Pakistan. J Pak Assoc Dermatol 2002; 12: 122-9. Rahman SB, Bari AU. A new f ocus of cutaneous leishmaniasis in Pakistan. J Pak Assoc Dermatol 2003; 13: 3-6.

2.

3.

4.

5.

6.

Appendix "A" List of the publications indexed in Medline.

1. Bari AU, Rahman SB Multiple Familial trichoepithelioma. A rare cutaneous tumour. J Coll Physicians Surg Pak 2004; 14: 560-1. Bari AU, Iqbal Z, Rahman SB. Tolerance and safety of superficial chemical peeling in various facial dermatoses . Ind J Dermatol

2.

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Venereol Lepr publication). 3.

2004

(Accepted

for

9.

4.

5.

6.

7.

8.

Bari AU. Mahmood T, Hussain S et al. Neurofibromatosis with Caroli's disease. J Coll Physician Surg Pak 2004; 14: 241-3. Zubairi NA, Bari AU. Mahmood T. Klippel Trenaunay syndrome. J Coll Physicians Surg Pak 2004; 14: 423-4. Rahman SB, Bari AU. Laboratory profile in patients of CL from various regions of Pakistan. J Coll Physicians Surg Pak 2003; 13: 313-6. Iftikhar N, Bari AU, Ejaz A. Whitlow and paronychial cutaneous eis hmaniasis. Int J l Dermatol 2003; 42: 807-9. Bari AU, Rahman SB. Segmental NF: An uncommon variant of a common disorder. J Coll Physicians Surg Pak 2003; 13: 717-8. Bari AU, Rahman SB. Therapeutic update on cutaneous leishmaniasis. J Coll Physicians Surg Pak 2003; 13 : 471-6.

Bari A U, Iftikhar N, Rahman SB. Bilateral symmetrical herpes zoster in an immunocompetent patient (herpes zoster duplex symmetricus). J Coll Physicians Surg Pak 2003; 13: 524-5. 10. Bari A U, Rahman SB. Zosteriform Lichen Planus. J Coll Physicians Surg Pak 2003; 13: 104-5. 11. Bari AU, Iqbal Z, Sohail M, Rahman SB. Skin priming and efficacy of glycolic acid and salicylic acid in treatment of melasma. J Coll Physicians Surg Pak 2002; 12: 461-4. 12. Raja KM, Khan AA, Hameed A, Rahman SB. Unusual clinical variants of cutaneous leishmaniasis in Pakistan. Br J Dermatol 1998; 139: 111-3.

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Original Article

Dermatological graduates

literacy

among

medical

Muhammad Jahangir, Tariq Zaman, Tariq Rashid Dermatology Department, Allama Iqbal Medical College / Jinnah Hospital. Lahore.

Abstract Background Patients with skin ailments are frequently mismanaged at primary care level.

One reason might be inadequate knowledge of medical graduates about skin diseases. Objective Evaluation of dermatological literacy of our medical graduates. Methods 198 doctors graduating in year 2000 & onwards during 1st year of house job serving in various hospitals of Lahore having no post-graduation clinical experience in dermatology were enrolled. They attempted a questionnaire consisting of matching, true/false, and single best response pertaining to common dermatoses. Those securing more than 50% marks were considered successful. Results Of 198 medical graduates, only 52 (26%) could get more than 50 % marks. Misconceptions were frequent, 54% thought marriage cures acne, 60% considered that calcium deficiency causes pityriasis alba. Conclusion Dermatological knowledge of medical graduates is highly inadequate. Furthermore, misconceptions are frequent. Key words Dermatological literacy, medical graduates

Introduction Skin diseases are widespread in the community. In USA and UK the prevalence of skin diseases is estimated as 33% and 25% 1 respectively. Pakistan is a developing tropical country and due to poor hygiene, over crowding and poverty certain skin diseases especially various cutaneous infections and infestations are more common. Though the exact statistics are not available the prevalence of skin diseases is likely to be much higher than the developed world. Misdiagnosis and

Address for correspondence Muhammad Jahangir, Professor of Dermatology, Allama Iqbal Medical College / Jinnah Hospital. Lahore.

mismanagement of even common skin diseases is not infrequent at primary health care level. This prolongs the sufferings of patients, wastes their precious working hours and financial resources. It also puts extra burden on the secondary and tertiary health care facilities. One reason of t is h scenario might be inadequate knowledge and skills of primary health care physicians about dermatology. To objectively assess this issue a study was planned to evaluate dermatological knowledge of fresh medical graduates. Methods This cross-sectional and descriptive study was conducted in dermatology department,

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Muhammad Jahangir et al.

Allama Iqbal Medical College and Jinnah Hospital, Lahore in August 2003. A questionnaire consisting of matching (02), true/false (06) and single best (15) questions of easy to moderate difficulty index, pertaining to common dermatoses was devised by a panel of three teachers of dermatology. One hundred and ninety eight house officers of various hospitals of Lahore (Jinnah, Mayo, Services, Ganga Ram and Lahore General Hospitals) were included in the study. Those graduated before the year 2000 or having any experience in dermatology were excluded. The questionnaire was solved by all the enrolled doctors. The answers were checked according to the key and marks awarded. The same questionnaire was given to 30 non-doctors. There was no negative marking but the hit and trial benefit was compensated by subtracting 50% of the average score obtained by nondoctors from the marks of doctors. Those securing more than 50% marks were considered successful. All the data was tabulated and analyzed in a database. Results Majority of the enrolled doctors graduated in the years 2002-03 (Table 1). Most of them graduated from the medical colleges of the Punjab (Table 2). Only 67(34%) and 71(36%) participants have adequate attendance ( 75%) in dermatology lectures and ward training during their graduation, according to their response in the questionnaire (Table 3). Only 52 (26%) could get passing marks (more than 50%) [Table 4]. Scores of individual items showed gross misconceptions and inadequacy of basic dermatological

Table 1 Graduation year of medical graduates Year No of medical graduates ( n = 198 ) 2003 113 2002 58 2001 20 2000 07 Table 2 College of graduation (n=198) Name of the College No of medical graduates Allama Iqbal Med. 49 College, Lahore Fatima Jinnah Med. 44 College, Lahore King Edward Med. 23 College, Lahore Punjab Med. College, 22 Lahore Nishtar Med. College, 17 Multan Quaid-e-Azam Med. 15 College, Bahawalpur Miscellaneous Colleges 28 Table 3 Dermatology attendance (n=198) Attendance Lectures Ward % No. (%) No. (% ) 0­24 % 42 (21) 67 (34) 25­49 % 34 (17) 24 (12) 50­74 % 55 (28) 36 (18) 75­100 % 67 (34) 71 (36) Table 4 Scores of medical graduates Score Number of medical graduates % No. % 0-25 31 16 26-50 115 58 51-75 51 26 76-100 1 <1

knowledge. For example, in response to questions "Papule is a fluid filled lesion", "Plaque is palpable", "Scales are dried exudates", and "In scabies fomites are more important than direct contact", 48%, 58%, 77% and 68% doctors replied incorrectly. Majority thought that marriage cures acne (54%) and calcium deficiency is the cause of pityriasis alba (60%). Regarding treatment of acne, a big

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majority (78%) considered corticosteroids as treatment for acne. Discussion In a questionnaire survey conducted in Karachi by Rathi et al.2 only 36% of general practitioners had a satisfactory level of awareness about various aspects of scabies, highlighting inadequate knowledge of general practitioners about one of the most common skin diseases in Pakistan. Results of our study also showed that knowledge of fresh medical graduates about common dermatoses was highly inadequate (only 26% could secure >50 % marks). The reasons of this scenario are multifold. Dermatological teaching and evaluation is highly inadequate both in content and methodology in all the medical colleges in Pakistan. Number of lectures and duration of clinical attachment is much below the minimum requirements. There is no compulsory question pertaining to dermatology in theory paper in final year examination and dermatologist does not frame the question. Students are not assessed clinically in dermatology through either short or long cases and/or clinical slides. Furthermore attendance in dermatology is not given due weightage. Due to this, many students never attend dermatology lectures and wards. This is also evident in our study where majority of the doctors had unsatisfactory attendance in dermatology during their graduation (Table 3). Also problem-based learning (PBL) and other modern learning methods have not been introduced in dermatology teaching. In contrast to this scenario, in the new curriculum for undergraduate medical

education in UK,3 PBL methodology has been adopted for teaching dermatology and active contribution of dermatologists in teaching of basic science has been stressed. Students get opportunities to see dermatology patients even in 1st and 2nd year of their training. They have to pass theory paper in final year examination and clinical examination in dermatology at the end of clinical attachment. Burge 4 also stressed in his article about curriculum planning in dermatology that medical undergraduates should have opportunities to actively participate in dermatology clinics under appropriate supervision. In our study, participant's knowledge of dermatology was highly inadequate e.g. 78% considered corticosteroids as treatment for acne. Misconceptions about skin ailments were frequent. 54% felt that marriage cures acne, and 60% had the feeling that calcium deficiency causes pityriasis alba. The impact of inadequate knowledge and misconceptions ultimately affects the rights of skin patients. Misery and suffering of patients is enhanced due to inadequate primary care. This also leads to increased load on tertiary health care facilities.5 A study by Brajac et al. 6 in Croatia shows that overall knowledge of family physicians pertaining to the causes, natural course and therapy of acne was very low. The overall score of correct answers was 15%, 6%, and 21%, respectively for questions pertaining to causes, natural course and antibiotic therapy of acne. To address this devastating situation of dermatologic literacy among medical graduates, it is need of the time to improve

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dermatology teaching in medical colleges in the best interest of skin patients. Conclusion Dermatological knowledge of medical graduates is highly inadequate and misconceptions are frequent. Decision makers should pay attention to address this situation. Further studies are required to highlight this situation & its impact on patients suffering from skin ailments. Suggestions are also required about ways & means to enhance dermatology literacy among medical graduates.

References 1. Weinstock MA, Chren MM. The Epidemiology and Burden of skin diseases. In: Freedberg IM, Eisen AZ, Wolff K et al., eds. Fitzpatrick's Dermatology in

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3.

4.

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6.

General Medicine, 6th edn. New York: McGraw-Hill, 2004; 7-8. Rathi SK, Rathi HS, Lakhani H, Hansotia MF. Awareness about scabies among general medical practitioners (GPs) of Karachi, Pakistan. J Pak Med Assoc 2001; 51: 370-2. Burge S for British Associations of University Teachers of Dermatology. Teaching dermatology to medical students: a survey of current practice in UK. Br J Dermatol 2002; 146: 295-303. Burge SM. Teaching dermatology. Clin Exp Dermatol 2004: 29 : 20610. Zaman T, Jahangir M, Asghar HA, Shafique N. Utilization of tertiary care centres ­ the actual picture: a study of 1500 patients presenting to dermatology department, AIMC / Jinnah hospital, Lahore. J Pak Assoc Dermatol 2001; 11:13-18. Brajac I, Bilic -Zulle L, Tkalcic M et al. Acne vulgaris: myths and misconceptions among patients and family physicians. Patient Educ Couns 2004; 54: 21-5.

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Original Article

Hematological abnormalities in adult patients of chicken pox

Arfan ul Bari, Simeen ber Rahman* Consultant Dermatologist, PAF Hospital Sargodha *Dermatology Department, Military Hospital Rawalpindi, Pakistan

Abstract Background Chicken pox (Varicella) is a highly communicable viral disease that occurs most

often in children but it can occur at any age and can prove more fatal in adults, due to its complications like pneumonia, thrombocytopenia and neurological abnormalities. Objective The study was aimed to see hematological abnormalities in chicken pox patients. Patients and methods Sixty patients of both sexes, aged between 15-50 years were included in the study. Blood complete picture (CP) including platelet count was done in all cases on first presentation of the disease. A second blood CP was performed after two weeks duration. Blood hemoglobin (Hb), total leukocytes count (TLC) and platelets count (PC) were recorded and then compared with age and sex matched healthy individuals. Results Patients with chicken pox were found to have normal Hb and TLC but relatively lower platelet count as base line finding. A slight change was seen after two weeks in Hb and TLC while a significant improvement was observed in platelets ( p<.05). When compared with healthy individuals, it was only the platelet counts that were significantly different (p<.001). Conclusion Anemia is not a feature of chicken pox but a relative leucopenia can be expected as in any other viral infection. It is thrombocytopenia that is found more significantly in chicken pox, probably caused by production of antiplatelet autoantibodies in these patients. Platelet specific autoantibodies are probably the cause of thrombocytopenia in patients of chicken pox and we should have a closer look on platelet count in such patients. Key words Chicken pox, varicella, varicella-zoster virus, thrombocytopenia

Introduction Chickenpox (varicella) is an acute, contagious disease, characterized by a generalized exanthem consisting of vesicles that occur in successive crops and that rapidly evolve into pustules, crusts, and scabs. Chicken pox is a manifestation

Address for correspondence Squadron Leader Dr. Arfan ul Bari, Consultant Dermatologist, PAF Hospital, Sargodha. Ph (off) # 0451-5553307 Ph (res) # 0451-5553308 Email: [email protected]

of primary infection with the varicella zoster virus. After the acute infection subsides, the virus like other herpesviruses, persists in a latent form. Humans are the only source of infection for this highly contagious virus. Person-toperson transmission occurs primarily by direct contact with patients with varicella or zoster, occasionally by airborne spread from respiratory secretions and rarely from zoster lesions. In utero infection can also occur. Introduction of a varicella -zoster virus infection into a household usually results in infection of nearly all susceptible

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persons. Nosocomial transmission is welldocumented in pediatric units, but transmission is extremely rare in newborn nurseries. Immunity is generally life long. Symptomatic reinfection is rare in healthy persons, although aymptomatic reinfection does occur.1-4 About 90% of reported cases of chickenpox occur in children younger than 14 years of age, but varicella in adolescents and young adults may be becoming more common. 5 Varicella is most common during the late winter and early spring. 6 Aymptomatic primary infection is unusual. Immunocompromised individuals with either primary (varicella) or recurrent (zoster) infection are at increased risk of severe disease. Since the incubation period for varicella is 10 to 21 days, those cases beginning in the first 10 days of life are considered to have been acquired in utero. Chickenpox is heralded by the approximately simultaneous occurrence of fever and rash. The rash is characteristically centripetal, beginning on the face or scalp and spreading rapidly to the trunk, but with relative sparing of extremities. It begins as red macules but progress quickly to vesicles and crust. Itching is the rule. There is a tendency for new lesions to occur in crops.1-4,7 Most childhood infections are benign; however, the disease may have serious sequelae in adults. Pneumonia can complicate up to 20% of cases, with mortality rates reaching 40%. Other complications include encephalitis, myocarditis, pericarditis, adrenal insufficiency, glomerulonephritis, hepatic dysfunction, and thrombocytopenic purpura.1,5,8 -13 Varicella is usually a clinical diagnosis. Laboratory tests are available for confirmation, but they are not always

required. The white blood cell (WBC) count may be normal, low, or mildly elevated. Marked leukocytosis suggests a secondary infection. Culture of the base of the vesicle, direct electron microscopy, and immunofluorescence staining of the base of the lesion may be performed for detection of V-Z virus but usually are not necessary.1,3,14,15 Although a positive history of chickenpox is a good indicator of immunity, a negative history of clinic al disease is unreliable. Treatment of varicella is generally supportive. Warm soaks and oatmeal or cornstarch baths may reduce itching and provide comfort. Topical calamine lotion may produce soothing and drying of the skin lesions. Systemic antiviral (acyclovir) is recommended only in immunocompromised individuals or in patients with varicella complications.1,8,16 For susceptible individuals, passive immunization with VZIG is effective against varicella if given within 96 hours of exposure.17 The prognosis of uncomplicated varicella is excellent. The mortality rate of adult varicella pneumonia is quite high in immunocompetent as well as in immunocompromised patients.8,11 Patients and methods A total of sixty patients of both sexes, aged between 15-50 years were included in the study. Majority of patients were the serving persons of the armed forces and their families. After taking thorough history of illness, duration and nature of the rash, blood complete picture (CP) including platelet count was done in all cases on first presentation. Most of the patients were admitted in the hospital and

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were treated as indoor patients in isolation ward. A second blood CP was performed on resolution of the lesions (after about two week's duration). Blood hemoglobin (Hb), total leukocytes counts (TLC) and platelets counts (PC) were recorded on both occasions. Blood CP was also performed in thirty, otherwise healthy individuals and the same parameters (Hb, TLC, and PC) were recorded in these unaffected, healthy persons. The results were compared in both the groups and statistically analyzed by using student t test. Results Patients belonged to a heterogeneous population. There were 52 males and 8 females. Majority (48) were between 2030 years of age. The average age was 26.7 years. All of them reported 1-3 days after appearance of first rash. On base line investigations, mean Hb was 13.4 g/dl, TLC=6.1x109 /l and platelets were 159.6 x 10 9 /l. After resolution of the lesions (two weeks after initial presentation) the relative findings were 14.1 g/dl, 7.0x109 /l and 198x109 /l. Hb and TLC did not show any significant change; however, the improvement in platelet count was significant (p<0.05). The mean findings in age and sex-matched healthy individuals were; Hb = 12.8 g/dl, TLC = 7.5x109 /l and PC=250.4x109 /l. On comparison, Hb and TLC were again in the same range but PC was significantly low (p<0.001) in patients of chicken pox (both in the beginning as well as after the resolution of the disease.

Discussion Varicella vir us is transmitted by the respiratory route through droplets and is highly contagious. Approximately 90% of persons without antibodies develop disease after exposure. Infected patients are contagious from 1 or 2 days before the lesions develop until all lesions are covered with scabs. After an incubation period of 10 to 21 days, a prodrome develops that consists of systemic symptoms such as headache, fever, and malaise. One or two days later, a maculopapulo-vesicular rash develops. The rash follows a classic course, with several waves of lesions cropping up every 2 to 3 days. The entire course of the disease lasts 6 to 10 days. The body combats the primary infection with a cell-mediated antibody response. IgG, IgM, and IgA are produced within 2 to 5 days after infection and reach a maximum after 2 to 3 weeks.18 The IgG crosses the placenta to provide passive immunity to the fetus. Although there can be significant variation in the number of lesions, all primary infections are believed to confer immunity. Rare reports exist in the literature regarding the development of recurrent clinical 19 chickenpox. Most childhood infections are benign; however, the disease may have serious sequelae in adults. Pneumonia can complicate up to 20% of cases, and can be deadly. Varicella encephalitis is believed to be an autoimmune phenomenon and fortunately is rare. Other complications include myocarditis, pericarditis, adrenal insufficiency, glomerulonephritis, hepatic dysfunction, and thrombocytopenic 8-13 purpura. Post infectious, immunemediated thrombocytopenia may result in

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bleeding complications 1-2 weeks after illness.20 Purpura fulminans is a rare but life threatening complication of varicella reported in children and is caused by autoimmune protein S deficiency. 21 Anemia is generally not there, but relative leucopenia can be seen in patients of chicken pox as expected in almost all of the other viral infections but a significant thrombocytopenia is seen only in few viral infections. In one study, a subclinical thrombocytopenia was revealed in 55% of children affected by measles, in 25% of mumps, in 45% of varicella, in 30% of german measles and in 55% of infectious mononucleosis.22 This was supposed to be due to production of antiplatelet antibodies in these viral infections. In another study serum IgG or, predominantly, IgM antibody binding to electrophoretically separated normal platelet membrane protein antigens were detected by immunoblotting in five children with thrombocytopenia associated with varicella. Glycoproteins GPIb, GPIIb, GPIIIa, and other 25-260 kilodalton (kDa) proteins were identified as target antigens, suggesting a transient autoimmune mechanism causing thrombocytopenia.23 Platelet surface glycopr otein V (GPV) was found to be the target antigen in autoimmune thrombocytopenia in another study. 24 Relative leucopenia seen in our patients was not statistically significant when compared with matched healthy group. We also encountered relative thrombocytopenia in the vast majority of our cases but it was not dangerously low to herald any episode of bleeding. PC below 100 was seen in two patients who were rather closely monitored but in the

end they also showed improvement in count as other patients. Conclusion Transient thrombocytopenia as an autoimmune phenomenon is a frequent occurrence in patients of chicken pox and can rarely be a fatal complication. Treating physician should have a closer look on platelet counts in such patients. References

1. Chen TM, George S, Woodruff CA, Hsu S. Clinical manifestations of varicella-zoster virus infection. Dermatol Clin. 2002; 20: 267-82. Grose C. Variation on a theme by Fenner: the pathogenesis of chickenpox. Pediatrics 1981; 68: 7357. McCrary ML, Severson J, Tyring SK. Varicella zoster virus. J Am Acad Dermatol 1999; 41: 1-14. Whitney RJ. Varicella -zoster virus infections. In: Galasso GJ, Whitley RJ, Merigan TC, eds. Antiviral agents and viral diseases of man. New York: Raven Press; 1990. p. 235-71. Preblud SR. Varicella: Complications and costs. Pediatrics 1986; 78: 72833. Lin F, Hadler JL. Epidemiology of primary varicella and herpes zoster hospitalization: the pre varicella vaccine era. J Infect Dis 2000; 181: 1897-905. Rockley PF, Tyring SK: Pathophysiology and clinical manifestations of varicella zoster virus infections. Int J Dermatol 1994; 33: 227-32. Manfredi R, Chiodo F, Titone L et al. Chickenpox complications among immunocompetent hospitalized children in Italy. AcyclovirChickenpox Italian Study Group. Pediatr Med Chir 1997; 19: 99-104. Bovill B, Bannister B. Review of 26 years' hospital admissions for

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14. 15.

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chickenpox in North London. J Infect 1998; 36: 17-23. Rodriguez Borregan JC, Dominguez Artiga MJ, Minambres E et al. Varicella pneumonia in adults: 30 cases. Ann Med Intern 2003; 20: 6126. Paytubi C, Negredo E, Ferrer S et al. Varicella pneumonia in the adult. Study of 9 cases. Ann Med Intern 2001; 18: 312-6. Kooter AJ, Van der Linden PW, De Klerk C. Acute idiopathic thrombocytopenic purpura in adults following viral infection: report of two cases. Neth J Med 2002; 60: 1746. Kaneda K, Kojima K, Shinagawa K et al. An adult patient with varicella preceded by acute thrombocytopenia. Rinsho Ketsueki 2001; 42: 1142-4. Arvin AM. Varicella zoster virus. Clin Microbiol Rev 1996; 9: 361-81. Georges P, ed: Varicella-Zoster infections. In: 1997 Red Book Report of the Committee on Infectious Diseases, 24th edn. Geneva: WHO; 1997 573-85. Whitley RJ. Therapeutic approaches to varicella-zoster virus infection. J Infect Dis 1992; 166: S51-S57. Centers for Disease Control and Prevention: Recommendations of the immunization practices advisory committee: Varicella-zoster immune globulin for the prevention of chicken pox. MMWR 1984; 33: 84. Cradock-Watson JE, Rideholgh MKS, Bourne MS: Specific immunoglobulin

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responses after varicella and herpes zoster. J Hyg (London) 1979; 82: 319. Martin KA, Junker AK, Thomas EE et al. Occurrence of chickenpox during pregnancy in women seropositive for varicella-zoster virus. J Infect Dis 1994; 170: 991. Feusner JS, Slichter SJ, Harker LA. Mechanism of thrombocytopenia in varicella. Am J Hematol 1979; 7: 25564. Kurogol Z, Vardar F, Ozkinay F et al. Lupus anticoagulant and protein S deficiency in otherwise healthy children with acute varicella infection. Acta Paediatr 2000; 89: 1186-9. Tucci PL, Tucci F, Peruzzi PF. The behaviour of platelets in some viral infectious diseases in childhood. Ann Sclavo 1980; 22: 431-7. Winiarski J. Platelet antigens in varicella associated thrombocytopenia. Arch Dis Child 1990; 65: 137-9. Mayer JL, Beardsley DS. Varicellaassociated thrombocytopenia: autoantibodies against platelet surface glycoprotein V. Pediatr Res 1996; 40: 615-9. Varicella zoster virus. In: Fields BN, Knipe DM, eds. Virology, 2nd edn. New York: Raven Press; 1990. p. 2011-54. Resnick SD. New aspects of exanthematous diseases of childhood. Dermatol Clin 1997; 15: 257-66.

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Original Article

The effect of itraconazole pulse therapy on quality of life in Pakistani patients of distolateral subungual onychomycosis

Shahbaz Aman, Talat M. Akbar, Ijaz Hussain, Muhammad Jahangir, Tahir S. Haroon Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore, Pakistan

Abstract Background Distal and lateral subungual onychomycosis (DLSO) is the most common

clinical type of onychomycosis. The disease causes little physical handicap but it has a devastating effect on quality of life (QOL) particularly in our set up. Objective The purpose of the study was to assess the effect of itraconazole pulse therapy on quality of life in Pakistani patients with DLSO. Methods Sixty-two patients, 47 males and 15 females suffering from DLSO, age range 19 to 55 years, who were themselves able to understand and fill the questionnaire related with general and disease-specific QOL in English or Urdu version, were enrolled in the study. The total score ranged from 0-60. The higher the score, the greater was the impact on QOL. The patients were subjected to itraconazole pulse therapy and each pulse consisted of 200 mg twice a day for 7 days, followed by a drug-free interval of three weeks. Two pulses were given for fingernail onychomycosis and three pulses for toenail infection. The pre- and posttrial data was analyzed before and after therapy in 46 finger- and 16 toenail cases of DLSO. Results The disease caused psychosocial problems (92%), economic problems in treatment (89.4%), difficulty in cutting nails (62.9%), physical contact problems with hands (60.8%), discomfort in wearing shoes and walking (56.2%), pain (33.8%), disturbance of work with hands (30.4%) and affected performance in sports (22.5%). After itraconazole pulse therapy, these problems decreased to 12.9%, 14.5%, 6.45%, 6.4%, 12.5%, 4.8%, 6.45% and 3.2%, respectively. The mean pretreatment score in patients with finger- and toenail disease was 32+3.4 and 29+4.5, respectively. The score dropped to 4.3+5.4 and 4.4+5.6 (P<0.05) after itraconazole therapy at last follow-up 32 weeks and 48 weeks for finger- and toenail disease, respectively. Fingernail disease has affected QOL more than toenail disease and longer duration of disease, greater involvement of individual nails and greater number of nails involved was also associated with more serious impact on QOL. Females were found to be more psychologically upset than males. Conclusion Itraconazole pulse therapy significantly improves the QOL in disto-lateral subungual onychomycosis of both finger- and toenails in our patients. Key words Onychomycosis, quality of life, itraconazole

Introduction Onychomycosis is the major cause of nail disease in whic h the affected nails become

Address for correspondence Dr. Shahbaz Aman, 2-C Hearn Road, Islampura, Lahore, Pakistan Ph # 92 42 7226045 Email: [email protected]

discolored, thickened and friable.1 Distal and lateral subungual onychomycosis (DLSO) is the most common clinical type of onychomycosis.2,3 This is a chronic disease which can have a severe impact on patient's physical and psychological wellbeing. 4 It can limit the mobility and affect peripheral circulation. The disease may also precipitate recurrent thrombophlebitis

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and cellulitis in the legs.4 The disease is resistant to topical treatment and to achieve resolution, an effective oral antifungal therapy is essential. 5 Owing to its broad-spectrum keratophilic nature and long tissue half-life, itraconazole is a widely used oral antimycotic in onychomycosis. Various studies show an intermittent pulse therapy of itraconazole for onychomycosis to be effective.5,6 Quality of life (QOL) is defined as capacity to perform the daily activities appropriate to person's age and major social role.7 The role could be paid employment, schooling, house work or self care. Several indices are available in the form of questionnaires to measure the extent of disability caused by skin diseases.7 Due to protracted course of illness, the patients with onychomycosis are bothered in numerous ways e.g. nail discoloration, disfigurement, pain and embarrassment.4,8-10 The psychosocial consequences are probably more common than the physical. 4 The present study "Quality of life in distolateral onychomycosis: pre- and postitraconazole therapy" was conducted to quantify the level of handicap experienced by Pakistani patients with DLSO before and after itraconazole pulse therapy. Patients and methods This was a questionnaire-based study. The study protocol and questions were approved by the Institutional Review Board Committee (IRBC). The study was carried out at the Department of Dermatology, King Edward Medical

College/Mayo Hospital, Lahore during the period from June, 1996 to December, 1998. A full medical history and clinical assessment of onychomycosis with informed consent was taken. Sixty seven patients of either sex but of more than 18 years of age with disto-lateral subungual onychomycosis of finger- and/or toenails who could themselves complete the questionnaire in English or Urdu (National language in Pakistan) version were enrolled in the screening period. Mycologically confirmed (positive microscopy plus fungal culture) cases were included in the study. Those patients were excluded who had involvement of the proximal region of the nail plate i.e. nail matrix or had psoriasis, dermatitis of nail fold, diabetes, peripheral vascular disease/arterial insufficiency and severe general underlying disease. Those patients were also excluded who used oral antifungal therapy within 2 months prior to screening while topical anti-fungal therapy was stopped at screening. The subjects who were receiving concurrent rifampicin, phenytoin, digoxin, oral anticoagulants, cyclosporin, astemizole, terfenadine, midazolam, cisapride or history of drug allergy or hypersensitivity to an azole antifungal drug were also excluded. Pregnant and lactating females, patients with abnormal liver functions and immunosuppression, either by disease or treatment-induced or patients with evidence of bacterial paronychia were omitted, too. The patients who fulfilled the inclusion and exclusion criteria were subjected to itraconazole pulse therapy, 200 mg twice a day for 7 days, followed by a drug-free

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interval of three weeks. Two pulses were given for fingernail and three pulses for toenail onychomycosis. Patients were followed up to six months after stopping the 2 -pulses in fingernails and 9 months after stopping the 3-pulses in toenails, respectively. No antimycotic therapy was allowed during the follow-up period. The patients were evaluated for QOL at 0 and 32 weeks for fingernails while 0 and 48 weeks for toenails. All the patients were instructed to fill a health related quality of life (HRQOL) questionnaire (Table 1) that included general and disease-specific items measuring the impact of disease on daily activities, appearance and problems associated with this infection at base-line and last follow-up (32 & 48 weeks) after treatment in finger- and toenail infection, respectively. The questionnaire consisted of 15-questions covering 7 different domains of QOL e.g. psychosocial and feelings (Q1-5), socio-economic aspect (Q6), psychological (Q7-8, 12-13), leisure activities/sports (Q9), physical (Q10-11), personal relationship (Q14a) and daily activities (Q14b,-15b). The patients were asked to score, on a scale from 0 to 4, for each of 15 questions, how they felt their lives have been affected by the disease. The response for each question could be 0= not at all, 1= yes, but not bothersome, 2= yes, somewhat bothersome, 3= yes, a lot bothersome, 4= yes, extremely bothersome. The total score ranged from 0 to 60 for all the items of questionnaire. The higher the scores, the poorer was the quality of life.

Table 1 Health related quality of life questionnaire used in the study 1. People find it unpleasant to look at my nails. 2. (a) I feel uncomfortable by shaking hands because of my nail problem. (b) I feel disheartened because of my nail problem. 3. I am embarrassed when going out to eat or to a party. 4. I have to explain to others what is wrong with my nails. 5. Others are afraid of catching mycosis from me. 6. It costs a lot of money to treat my nail disease. 7. I tend to hide my nails. 8. I worry that my nail problem is contagious. 9. I am limited in my performance when doing sports activities due to nail problem. 10. I have pain in my fingers/toes and nails. 11. I have difficulty in cutting my nails. 12. I feel, I will never manage to get rid of my nail problem. 13. I can't forget that I have this nail problem. 14. (a) I feel that people avoid physical contact with me because of my nail problem. (b) I can't wear shoes, due to my nail problem. 15. (a) I find it difficult to work with my hands. (b) I limit my walking, I do because of my nail problem.

Patients were followed-up after pulse treatment and no antimycotic therapy was allowed during the follow-up period. Nail dust samples were also taken for microscopy and fungal culture. Final evaluation at 32 weeks for fingernail and 48 weeks for toenail infection (last followup) was done by analyzing the data collected and marked by the patients themselves. Paired and unpaired student t test was used for comparison between males and females pre- and post-treatment scores for finger- and toenail patients, respectively. A p value of <0.05 was considered significant.

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Results Of 67 enrolled patients, there were two delayed exclusions and three were lost to follow up, so there were 62 evaluable patients. Of 62 patients, 47 were males and 15 females (mean age 27.6 years, range 19-55 years). Fingernails were affected in 46 cases whereas 16 had toenail infection. Fifty-one patients had dermatophyte onychomycosis while 11 were suffering from candida onychomycosis. The mean pretreatment score in patients with finger- and toenail disease was 32+3.4 and 29+4.5, respectively. The score dropped to 4.3+5.4 and 4.4+5.6 (p<0.05) after itraconazole therapy at final evaluation. Figures 1 and 2 show the mean pre- and post-treatment score in individual questions in finger- and toenail disease. The problems noted at baseline were psychosocial problems (92%), economic problems in treatment (89.4%), difficulty in cutting nails (62.9%), physical contact problems with hands (60.8%), discomfort in wearing shoes and walking (56.2%), pain (33.8%), disturbance of work with hands (30.4%) and affected performance in sports (22.5%). After pulse therapy these problems decreased to 12.9%, 14.5%, 8%, 6.4%, 12.5%, 4.8% and 3.2%, respectively (Figure 1 and 2). The patients suffering physical handicap in daily routine work were house- hold females (n=8), farmers (n=2), gardeners (n=2), teachers (n=1) and tailors (n=1). The psychosocial problems like more self-consciousness, embarrassment and avoidance of social interaction with close relatives and friends

were noted due to unsightly appearance of diseased nails.

ugly

The pretreatment mean score in females (34+3.2) was higher than males (30+3.9) and they were found to be more psychologically upset. There was no difference between the pretreatment scores of married and unmarried patients and different age groups but patients with disease of more than 6 months duration were seen to be more psychologically disturbed as compared with patients of disease with short duration. It was also noted that the greater involvement of individual nails and the more number of nails involved were associated with more negative impact on QOL. Fingernail disease was found to have much more impact on QOL than toenail disease. The mean pretreatment score for pain in females was higher than males ( p<0.05). At the last follow-up, after the therapy, patients reported fewer problems including embarrassment or self-consciousness, the desire to keep their nails concealed and avoidance of contact by others. Discussion Onychomycosis is a public health concern causing cosmetic and functional disability.4,9,11 Both finger- and toenail disease can cause pain, psychosocial distress and has the potential to be a continuous source of infection for others.14,11 Fingernail disease may cause difficulty in manipulation and deterioration in fine touch sensitivity while toenail infection may lead to difficulty in walking, wearing shoes and sustained standing. 14,11,12 Psychosocial

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3

2.5 2 Mean score of individal 1.5 questions 1 0.5 0 Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14 Q15

before treatment

after treatment with itraconazole pulse therapy

Figure 1 Question response in fingernail infection (n=46)

3 2.5 2 Mean score of individual 1.5 questions 1 0.5 0 Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14 Q15

before treatment

after treatment with itraconazole pulse therapy

Figure 2 Question response in toenail infection (n=16)

limitations result from reactions of relatives, friends and others to the visible impairment in affected nails.8 Therefore, medically confirmed onychomycosis should be treated. The disease specific questionnaire was used in 62 confirmed cases of DLSO to highlight specific areas of their life affected by disease. The variables that

influence the QOL include physical (mobility, pain, sexual), role (daily activities, work), mental (anxiety, depression & attention) and social (leisure activities) parameters.17,13,14 The mean pretreatment score in patients with fingerand toenail disease was higher before pulse therapy which dropped significantly (p<0.05) after itraconazole therapy at last follow-up. The difference between mean

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pretreatment score for females and males was statistically significant (p<0.05). The present study showed that the disease had affected quality of life via social and mental stigma and disrupted daily activities similar to other studies.9,11,12 Our study also revealed that DLSO leads to more self-consciousness and embarrassment in persons similar to most of other studies.9,15-17 Physical activities such as sports and house-hold work were affected little as compared to psychosocial impact similar to other studies. Most of the patients in the study also reported that the disease lead to some problems associated with physical contact with life partner or other relatives. The physical appearance was an important determinant in our study. The effect of disease is more on psychosocial than physical functioning similar to other reported data.4,10,12 The data indicate that female patients doing household work or males associated with fine technical work reported mild to moderate pain. Fingernail disease was found to have much impact on QOL than toenail disease because of cosmetic considerations or technical work done with the fingers than toes.4,12 The present study confirmed the psychological and physical effects of the disease on quality of life and the use of itraconazole pulse therapy resulted in superior patient outcomes regarding disease and quality of life. Patients reported satisfaction with the treatment program was significantly higher. In the end, dermatologists should be alert to the negative impact of disease and

should try effective remedy for this problem. Patients with high score may also benefit from counseling and/or contact with psychologist, so that appropriate psychological intervention can be made in addition to drug treatment. References

1. Joish VN, Armstrong EP. Which antifungal agent for onychomycosis? A pharmacoeconomic analysis. Pharmacoeconomics 2001; 19: 983-1002. 2. Andre J, Achten G. Onychomycosis. Int J Dermatol 1987; 26: 481-90. 3. Zaias N. Onychomycosis. Dermatol Clin 1985; 3: 445-60. 4. Scher RK. Onychomycosis: A significant medical disorder. J Am Acad Dermatol 1996; 35: S2-5. 5. Barranco V. New approaches to the diagnosis and management of onychomycosis. Int J Dermatol 1994; 33: 292-9. 6. Richard B, Odom R. New therapies for onychomycosis. J Am Acad Dermatol 1996; 35: S26-30. 7. Doward LC, McKenna SP. Evolution of quality of life assessment. In: Rajagopalan R, Sheretz EF, Anderson TR, eds. Care Management of Skin Diseases. New York: Marcell Dekker 1998: 9-94. 8. Lubeck DP, Gause D, Schein JR et al. A health-related quality of life measure for use in patients with onychomycosis: A validation study. Qual Life Res 1999; 8 : 121-9. 9. Lubeck DP, Patrick DL, McNulty P et al. Quality of life of persons with onychomycosis. Qual Life Res 1993; 2: 341-8. 10. Shaw JW, Joish VN, Coons SJ. Onychomycosis: health-related quality of life considerations. Pharmacoeconomics 2002; 20: 2336. 11. Elewski BE. Onychomycosis: Treatment, quality of life and

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economic issues. Am J Clin Dermatol 2000; 1: 19-26. 12. Millikan LE, Powell DW, Drake LA. Quality of life for patients with onychomycosis. Int J Dermatol 1999; 38 (Suppl. 2): 13-6. 13. Lubeck DP. Measuring healthrelated quality of life in onychomycosis. J Am Acad Dermatol 1998; 38: S64-68. 14. Turner RR, Testa MA. Measuring the impact of onychomycosis on patient quality of life. Qual Life Res 2002; 9: 39-53.

15. Stier DM, Gause D, Joseph WS et al. Patients satisfaction with oral versus nonoral therapeutic approaches in onychomycosis. J Am Podiatr Med Assoc 2001; 91: 521-7. 16. Scher RK. Onychomycosis is more than a cosmetic problem. Br J Dermatol 1994; 130 (Suppl. 43): 15. 17. Drake LA, Scher RK, Smith EB et al. Effect of onychomycosis on quality of life. J Am Acad Dermatol 1998; 38: 702-4.

Editor's note From the October-December, 2004 issue of JPAD, the `QUIZ' section has been replaced by `PHOTODERMDIAGNOSIS' section and it is edited by Dr. Amor Khachemoune, MD. The manuscripts should be submitted to: Dr. Amor Khachemoune, MD. 1440 Beacon St # 508, Brookline MA 02445, USA. E-mail: [email protected]

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Original article

Study on the histopathology of chronic arsenicosis

M.S. Sikder, M.H. Rahman, A.Z.M. Maidul, M.S.U. Khan , M.M. Rahman Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh * Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, Bangladesh

* *

Abstract Background Arsenicosis is epidemic in Bangladesh. The associated cutaneous changes have

high malignant potential. Objectives To assess the spectrum of histopathological changes in arsenical keratoses. Patients and methods A total of 70 arsenicosis patients (arsenic exposure group) and 20 clinically healthy patients (control group) who showed typical features of cutaneous manifestations were selected in this study. Skin biopsies from randomly selected patients were taken for undertaking histopathological studies. Results In the arsenicosis group and control group different istoloicl cnes were hypekeratois (100% vs. 20%) [p <0.001], parakeratosis (97% vs. 10%) [p<0.001], acanthosis (95.7% vs. 1%) [p<0.001], papillomatosis (74% vs. 0%) [p<0.001], basal pigmentation (42% vs. 4%), and dysplsia and malinant canes (5% vs. 0%), respectively. were seen in, 97%, 95.7%, 74%, 42% and 5% of cases, respectively. Conclusion In Bangladesh, long term arsenic exposure could increase the risk of certain kinds of cancers, some of them still unknown. It is therefore stressed that basic researches in histopathology of arsenic keratosis is patients particularly important in making the diagnosis . Key words Arsenicosis, histopathology

Introduction The `epidemic' occurrence of arsenicosis among people who have chronic exposure to arsenic through domestic consumption of contaminated ground water has been well reported in Bangladesh. The number of arsenicosis patients is increasing alarmingly

1-7 8

exposure to arsenic continues, the morbidity and mortalit y due to arsenical carcinomas

9

would rise.

10

Elder indicated that the histopathological study could be taken to be a "gold standard" for most dermatological diagnoses and

11

day by day. Ahmad et al. reported that about 6.6 % of the arsenicosis patients had neoplastic (cancerous and precancerous) skin lesions. Experts fear that, if the

Address for Correspondence Dr. M.H. Rahman, Department of Dermatology & V.D. BSMMU (PG- Hospital) Dhaka, Bangladesh Email: [email protected]

Kirkham elucidated important histological features on arsenical keratosis and carcinoma. The present study was therefore undertaken to establish the relationship of histopathological findings with clinical arsenicosis, in Bangaldesh.

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Patients and methods A total of 70 arsenicosis patients (arsenic exposure group) and 20 healthy persons (control group) were included in this study. The patients selected had history of consumption of arsenic -contaminated water and showed typical features of cutaneous manifestations. Melanosis and keratosis are the two important skin lesions, which appear in almost all cases of arsenicosis. Since melanosis is not always associated with keratosis, but keratosis is always associated with melanosis, therefore biopsies were tken randomly from patients with keratosis. Skin biopsies were also obtained from 20 healthy individuals (controls) for comprison. Data obtained were statistically analyzed using X (Chi-square) test and Epi-info package system. Results Hhistopathological findings in 70 arsenicosis patients and 20 healthy controls are represented in Table 1 and Figure 1. The dermatological manifestations are shown in Figures 2-5 whereas Figure 6 shows histopathological changes. Discussion The occurrence of cancer and precancerous skin lesions due to arsenic toxicity is well

12

Table 1 Histopathological findings of chronic arsenicosis Findings Patients Controls P value (n= 70) (n= 20) Hyperkeratosis Parakeratosis Acanthosis Papillomatosis Basal pigmentation Dysplasia & malignant changes 70 (100%) 68 (97%) 67(95.7%) 52 (74%) 30 (42.8%) 5 (7%) 4 (20%) 2 (10%) 1 (5%) 0 (0%) 4 (20%) 0 (0%) <0.001 <0.001 <0.001 <0.001 >0.05 >0.1

2

rete ridges. In arsenical keratosis of the palms and soles, one may find, in some instances, only hyperkeratosis and acanthosis without evidence of nuclear atypicality. However, when one cuts deeper into the tissue block atypicality may become

11

apparent. Arsenical keratosis can be classified into

7

two types: (1) a benign type with no cell atypia or with milder cellular atypia and (2) a malignant type consisting of lesions of Bowen's disease, basal cell carcinoma or squamous cell carcinoma. Skin histopathological findings of the present

16

documented. Malignant lesions due to chronic arsenic exposure through contaminated water have been reported from different parts of the world including

9,13,14,15

Bangladesh. Histological exami-nation of arsenical keratosis typically reveals hyperkeratosis with or without parakeratosis, acanthosis and enlargement of

study agree with the study of Dhar et al. They showed that hyperkeratosis, parakeratosis, acanthosis, papillomatosis hypergranulosis and dysplastic changes were the most important and constant findings while basal pigmentation and dermal changes were inconstant findings. Similar result was also obtained from our study, which revealed that hyperkeratosis, parakeratosis and acanthosis were the most constant features in comparison to the control group (p<0.001). However, basal pigmentation replace dysplasia and malignant changes were inconstant findings

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at p>0.05 and >0.1 level respectively.

8

Ahmad et al. observed that in

Figure 3 Palmo -plantar keratoderma. Figure 1 Comprison of different histologicl chnges in the study group nd control group.

Figure 4 Squamous cell carcinoma on the back of the heel.

Figure 2 Rain drop pigmentation over the trunk.

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Figure 5 Bowen's disease on the sole of the foot.

Moreover, arsenic seems to block predominantly DNA polymerase by attaching itself to sulfahydryl groups. The damaging effect of arsenic on DNA has been thought to explain its carcinogenic

11,17

effect. Conclusion More fundamental research in relation to the pathogenesis is particularly important in case of prolonged arsenic intake, since the available reports in Bangladesh demonstrate the existence of an arsenic -exposureresponse relationship between magnitude of arsenic exposure and incidence of skin cancer and other manifestations, including keratosis and hyperpigmentation. References

1. Maidul AZM. Chronic arsenic toxicity and skin problem in Bangladesh. Bang J Dermatol Venereol Leprol 1997; 14: 12. Smith AH, Lingas EO, Rahman M. Contamination of drinking water by arsenic in Bangladesh: A public health emergency. Bull WHO 2000; 78: 1093110. Calderon RL, eds. Arsenic exposure and health effects. New Yo rk: Elsevier Science; 2001. Ahmed K. Report highlights widespread arsenic contamination in Bangladesh. Lancet 2001; 358: 133-5. Anwar J. The poor in Bangladesh suffer. Effects and treatment of arsenic poisoning. International Workshop on Arsenic Mitigation. Dhaka, 14-16 January, 2002. McLellan F. Arsenic contamination affects millions of Bangladesh. Lancet 2002; 358: 1127-30. Saha, KC, ed. Arsenicosis in West Bengal. Kolkata: Prakashani; 2002. Ahmad SA, Sayed MHS, Khan MH et al. Arsenicosis: neoplastic manifestation. J Prevent Soc Med 1998; 17: 110-5.

Figure 6 Histopathological changes in chronic arsenicosis.

Bangladesh about 6.6% of the arsenicosis patients had precancerous skin lesions and a very few (0.8%) had cancerous skin lesions. The investigators apprehended that if the arsenic exposure to drinking water continues the morbidity and mortality due to cancerous and precancerous lesions would be quite

3

high. Rahman and Axelsen discussed arsenic kinetics in human health. They were of the opinion that the future magnitude of arsenic -caused skin cancer in Bangladesh is uncertain, but skin cancers have been reported in Taiwan, Chile, Mexico and elsewhere. The main cause of death due to chronic ingestion of arsenic in drinking water is internal cancers. Pulmonary cancer in vineyard workers exposed to an arsenic insecticide, and villagers exposed to arsenic containing drinking water has been reported

18,19

2.

3.

4.

in earlier studies. In the latter series the onset of pulmonary cancer started 30 years after the arsenic exposure. That skin cancers are not fatal with appropriate treatment was the conclusion of the above researchers. Experimental studies in vitro concerning the effects of inorganic arsenic on human epidermal cells have revealed that arsenic depresses premitotic DNA replication.

5.

6.

7. 8.

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9.

Sikder MS. Dermatological manifestations of chronic arsenic toxicity (MD thesis ). Department of Dermatology and Venereology, BSMMU, Dhaka; 1999. 10. Elder D, ed. Lever's Histopathology of

th

15.

the Skin, 8 edn. Philadelphia: LippinRaven; 1997. p. 1-2. 11. Kirkham N. Tumors and cysts of the epidermis . In: Elder D, ed. Lever's

th

16.

Histopathology of the Skin, 8 edn. Philadelphia: Lippin-Raven; 1997. p. 685-746. 12. National Research Council. Arsenic in Drinking Water. Washington: National Academy Press; 1999. 13. Tseng WP, Chu HM, How SW et al. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Nutrl Cancer Inst 1968; 40, 453-63. 14. Cebrian ME, Albores A, Anguila, M, Blakely E. Chronic arsenic poisoning in

17.

18.

19.

the north of Mexico. Human Toxicol 1983; 2: 121-33. Smith AH, Goycolea M, Haque R Biggs ML. Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water. Am J Epidemiol 1998; 147: 660-69. Dhar RK, Biswas BK, Samanta G et al Groundwater arsenic calamity in Bangladesh. Curr Sci 1997; 73: 48-59. Jung EG, Trachsel B. Molekulärbiologische untersuchungen zur arsencarcinogenese. Arch Klin Exp. Dermatol 1970; 237: 819-23. Fierz U. Katamnestische Untersuchungen über die Nebenwirkungen der Therapie mit anorganischen Arsen bei Hautkrankheiten. Dermatologica 1965; 131: 412-5. Yeh S. Skin cancer in chronic arsenicism. Hum Pathol 1973; 4: 46985.

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Histopathological spectrum of leishmaniasis...

Asher Ahmed Mashood et al.

Original Article

Histopathological spectrum of cutaneous leishmaniasis in North West Frontier Province

Asher Ahmed Mashhood, Iqbal Khan*, Shagufta Nazir* Department of Dermatology, Combined Military Hospital, Peshawar * Department of Pathology, Combined Military Hospital, Peshawar

Abstract Objectives The objective of the study was to determine various histological spectrum of

cutaneous leishmaniasis in NWFP and to detect if there were any other useful histological findings in addition to the detection of amastigotes, which could help in the diagnosis. Materials and methods Total number of patients included in the study was 36. These patients were referred from various areas of NWFP. All except one were males. Their age ranged between 8 -60 years. The duration of illness was from 3 -32 weeks. A skin biopsy was performed from the most typical lesion from each patient. The biopsy slide was stained with H&E stain and viewed under a microscope by a single expert. The histopathological findings were noted in accordance to uniform criteria. Results The confirmation of the diagnosis was done by the detection of amastigotes (LT bodies) in the slides. They were detected in 11 out of 36 patients (30.55%). The other most significant finding detected in all the slides was the presence of a mixed inflammatory cell infiltrate in the superficial dermis. Conclusion It is concluded that the chances of picking up of amastigotes in the biopsy slides in not high. Hence, the presence of dense mixed inflammatory cell infiltrate in superficial dermis must be considered as a diagnostic feature in the absence of LT bodies. Key words Cutaneous leishmaniasis, histopathology, LT bodies

Introduction Definitive diagnosis of Leishmania infection is necessary before the start of chemotherapy. The laboratory diagnosis of cutaneous leishmaniasis requires demonstration of parasites in smear, biopsies, or by isolation of the organism in culture medium or in experimental animal. Many other methods for demonstration of

Address for Correspondence Maj. (Dr) Asher Ahmed Mashood, Consultant Skin Specialist, CMH, Peshawar Email: [email protected] Tel # 091-2016154, 091-271779

parasite (histochemical and immunohistochemical) or for detecting antibodies against le ishmania (serologic) have been described. Many advances have been made in these areas, but the methodology and the technology involved in immunohistochemistry and serology remain outside the reach of the standard laboratories. Both in developed and less developed countries, the laboratories still rely on demonstration of parasites in the smear stained with Giemsa and on biopsy specimens processed and stained with haematoxylin and eosin (H&E).1

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Skin biopsy for histopathology is the most frequently performed investigation in Pakistan. The positive report requires the presence of amastigotes in the slides. The chances of picking up amastigotes in histopathology slides are not high, so it is important to identify other histopathological findings as well which can contribute to the diagnosis. Materials and methods Study design This was a non-interventional, descriptive study. Objectives of the study There were two objectives of this study: 1. Firstly, to detect various histopathological features in the patients of cutaneous leishmaniasis in North West Frontier Province, and to see if the results are similar or different from the results from other studies. 2. Secondly, to determine if there are any other histopathological findings in addition to the detection of LT bodies in the definitive diagnosis. Study population The study population comprised army personnel and their relatives who were referred to the skin department of Combined Military Hospital, Peshawar, from Kohat, Bannu, DI Khan, and North and South Waziristan agencies. Total number of patients included in the study was thirty-six (n=36). All the patients except one were males. Their ages ranged between 8-60 years (Mean 31.97 years). The duration of

the disease was from 3-32 weeks (Mean 10 weeks). The centre of trial was skin and histopathology department of Combined Military Hospital, Peshawar. Inclusion criteria The study included patients of all ages with one or more nodular, ulcerated or crusted plaques over exposed areas of the body since at least 3 weeks (presence of satellite lesions or sporotrichoid spread further supported the diagnosis). A history of contact of the disease in a known endemic area was also considered as one of the inclusion criterion. Exclusion criteria The study excluded very young and very old patients, patients who did not agree to be included in the trial and the patients with a doubtful clinical lesion. Those patients who had no history of travel to an endemic area and those who received some definitive treatment for their disease were also excluded. Record keeping A typed pro forma was prepared, which was used for every patient. It included name, age and sex of the patient, the duration of illness, area of contact of the disease and the histopathological findings in accordance with uniform criteria. Histopathological examination Skin biopsy was performed from the edge of the most representative lesion in every patient. The specimen was sent to histopathology department in formalin. The formalin-fixed specimens were paraffin embedded after going through a series of processing i.e. fixation, dehydration,

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clearing and impregnation. The section cutting was done by rotatory microtome (Model AS-325 Shandon), followed by haematoxylin and eosin staining. The slides when prepared were examined by a single microscope (Model CH-20 Olympus), and by only one histopathologist in consultation with a dermatologist. Results Following were the results of this study: 1. Leishmania trophozoite (LT) bodies were picked up in the histopathology slides in 11 out of 36 patients (30.5% yield). 2. A feature seen in all histopathology slides was the presence of dense, mixed inflammatory cell infiltrate, composed of lymphocytes, histiocytes and plasma cells in the superficial dermis (100% yield). 3. Neutrophils were a part of this infiltrate in the histopathology slides of 26 patients (72.2%). Among these 26 slides, neutrophilic abscesses were seen in 14 patients (38.9%). 4. Epidermal ulceration was seen in histopathology slides of 28 patients (77.8%), almost always associated with the presence of neutrophils in the infiltrate. 5. Epidermal hypertrophy was seen in all the slides (100%). 6. Epithelioid cells were in histopathology slides of 20 patients (55.5%), and epithelioid cell granulomas in 16 patients (44.4%). Langhans giant cells were noted as a part of granulomas in 11 patients (30%) and caseation necrosis

within the granulomas in 7 (19.4%) patients. Clinico-pathological correlation In wet and ulcerated lesions, the infiltrate was mainly mixed, and there were more chances of picking up of amastigotes in the histopathological slides. In dry and nodular lesions, the infiltrate was again mixed but there was a greater tendency of granulomas formation with less chances of picking up amastigotes. Histological patterns Four definitive histological patterns were identified in this study. These were: 1. Mixed inflammatory cell infiltrate with LT bodies and no granulomas (7 [19.5%] patients) [Figure 1]. 2. Mixed inflammatory cell infiltrate with LT bodies and presence of epithe lioid cell granulomas (4 [11.1%] patients). 3. Mixed inflammatory cell infiltrate, with no LT bodies and the presence of epithelioid cell granulomas (12 [36.1%] patients) [Figure 2]. 4. Mixed inflammatory cell infiltrate with no LT bodies and no granulomas (13 [33.3%] patients) [Figure 3]. Discussion From a specific area of the country, 4 definitive patterns emerged. In a previous study published in Pakistan,2 the histopathological findings were also placed in four groups. In two of the groups (76% of the patie nts), there was mixed inflammatory cell infiltrate, in 12% there was chronic inflammatory infiltrate without granuloma

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tuberculoid pattern or pure mononuclear infiltrate. Despite the fact that histopathological examination of skin biopsy is the most frequently performed investigation in the patients of leishmania sis, the chances of picking up LT bodies are not high. In our study LT bodies were detected in 11 out of 36 patients (30.5%). The results in other studies are much the same a ours. Bhutto et al.3 detected LT bodies in 365 o of 1210 ut patients registered (diagnostic yield was 30.2%). Sharquie et al.4 found amastigotes in 18 out of 60 patients (30% yield). In the study by Weigle et al.5 23 slides were positive for LT bodies among the total 165 patients (13.9% yield). Azedah et al.6 detected amastigotes in 64 out of 117 slides (54.7% yield) and Simeen et al.7 reported 76% yield by picking up amastigotes in 38 out of 50 examined slides. This comparison is graphically shown in Figure 4. After seeing the above comparisons the first question which aarises is that if the percentage yield of amastigotes in skin biopsy is so low, is such an invasive procedure, which is also costly in our setting, justifiable in the diagnosis? Secondly, in the absence of demonstrable LT bodies can there be any other histological feature, which can contribute to the confirmation of the diagnosis of cutaneous leishmaniasis? Features like epidermal hyperplasia, epidermal ulceration, granuloma formation, Langhans cells and mononuclear or polymorphonuclear infiltrate occurs in other related diseases e.g. lupus vulgaris, dermatophyte infection, etc. A feature that

Figure 1: Mixed inflammatory cell infiltrate with LT bodies and no granuloma.

Figure 2 Mixed inflammatory cell infiltrate with epithelioid cell granulomas and no LT bodies.

Figure 3 Mixed inflammatory cell infiltrate consisting of Lymphocytes, neutrophils, plasma cells and histiocytes . There are no LT bodies or granulomas.

and in 12 % there were only tuberculoid granulomas. In our study, there was no pure

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Percentage of picking up of amastigotes 80.00% 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% Sharquie et al (4) Azedah et al (6) This study

granulomatous disease; hence, this should be taken as a diagnostic feature in the absence of LT bodies. References

Percentage of picking up of amastigotes

1.

2.

3.

Figure 4 Comparison of percentage of picking up of amastigotes in various studies

was present in all the slides in our study, no matter what the duration of the illness, was the presence of a dense and superficial mixed inflammatory cell infiltrate comprising of mainly lymphocytes, plasma cells and histiocytes. Neutrophils and epithelioid cells were also a part of this infiltrate in most of the cases. Hence, this mixed inflammatory infiltrate must be taken as a definitive diagnostic feature in the absence of demonstrable LT bodies. Conclusion Chances of picking up amastigotes in histopathology slides are not very high. A constant finding in our study was the presence of a dense mixed inflammatory cells infiltrate in the superficial dermis. This feature is not present in any other chronic

4.

5.

6.

7.

Palma G, Gutierrez Y. Laboratory diagnosis of Leishmania. Clin Lab Med 1991; 11: 909-22. Simeen BR, Arfan UB. Histopathological patterns of Cutaneous leishmaniasis with clinical correlation seen in Pakistan. Pak Armed Forces Med J 2003; 53: 142-7. Bhutto AM, Soomro RA, Nonaka S, Hashiguchi Y. Detection of new endemic areas of cutaneous leishmaniasis in Pakistan: a 6year study. Int J Dermatol 2003; 42: 543-8. Sharquie KE, Hassen AS, Hassen SA, Al-Hamamil A. Evaluation of diagnosis of cutaneous leishmaniasis by direct smear, culture and histopathology. Saudi Med J 2002: 23: 925-8. Weigle KA, de Davalos M, Heredia P et al. Diagnosis of cutaneous and mucocutaneous leishmaniasis in Colombia: a comparison of seven methods. Am J Trop Med Hyg 1987; 36: 48996. Azadeh B, Samad A, Ardehali S. Histological spectrum of cutaneous leishmaniasis due to Leishmania tropica. Trans R Soc Trop Med Hyg 1985; 79: 631-6. Simeen BR, Arfan UB. Laboratory profile in patients of cutaneous leishmaniasis from various regions of Pakistan. J Coll Physicians Surg Pak 2003; 13: 313-6.

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Original Article

Topical calcipotriol in the treatment of chronic plaque psoriasis in Bangladeshi skin

Agha Masood Choudhury, AZM Maidul Islam, SMMMA Ahad Department of Dermatology & Venereology, Bangabandhu Sheikh Mujib Medical University Dhaka-1000, Bangladesh

Abstract Background Calcipotriol (DAIVONEX ) ointment has been shown to be effective in the

treatment of chronic plaque psoriasis. Objective To assess the efficacy and safety of calcipotriol ointment (50µg/g) in the treatment of chronic plaque psoriasis. Patients and methods A total of 61 patients (39 males, 22 females, age range from 18 to 76 years) of chronic plaque psoriasis were enrolled in an open prospective trial. 51 completed the study. Calcipotriol ointment was applied twice daily for up to 6 weeks on lesional area, following a 2 weeks washout phase with liquid paraffin. Efficacy, as measured by the Psoriasis Area and Severity Index (PASI), and safety were assessed at 2, 4 and 6 weeks. Results Reduction of PASI was statistically highly significant at all visits. The mean PASI fell in 6 weeks from 10.47 to 2.18 (P<0.001). Analysis of patient assessment at 6 weeks showed total clearance in 8% of patients and marked improvement in 71% of patients. The serum calcium level remained unchanged. Conclusion Topical application of 50µg/g calcipotriol ointment was found to be effective and safe in the treatment of chronic plaque psoriasis. Key words Calcipotriol (DAIVONEX), psoriasis treatment, PASI

Introduction Calcipotriol is a synthetic analogue of vitamin D3 which has a high binding affinity to the cellular receptor for calcipotriol1; is a potent regulator of cell differentiation and an inhibitor of cell proliferation in human keratinocytes.2 It is effective as a topical treatment for chronic plaque psoriasis.3,4 It is as effective as or

Address for Correspondence Dr. Agha Masood Choudhury, Associate Professor, Department of Dermatology & Venereology, Bangabandhu Sheikh Mujib Medical University, Dhaka-1000, Bangladesh. Ph# 88-02-9672100(off), 9343583 (Res) E-mail: [email protected]

even more effective than, 0.1% betamethasone 17-valerate ointment5,6 and more effective than short contact dithranol therapy in plaque psoriasis.7 The aim of the present study was to assess the therapeutic efficacy, topical and systemic safety, and tolerance of twice daily application of 50µg/g calcipotriol ointment in the treatment of chronic psoriatic plaque in Bangladeshi skin. Patients and methods A prospective, non-controlled, open clinical trial of calcipotriol ointment

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(50µg/g) was conducted in the department of Dermatology and Venereology, Bangabandhu Sheikh Mujib Medical University, formerly Institute of Postgraduate Medicine & Research, Dhaka, Bangladesh, during July 1999 to June 2000. Sixty one outpatients (39 males, 22 females), aged 18-76 years (mean age 41.10), suffering from chronic plaque psoriasis were enrolled and fifty one completed the study. Patients were required to provide signed consent. The exclusion criteria were: acute guttate, pustular or erythrodermic psoriasis, unstable psoriasis during the washout period, systemic antipsoriatic treatment or ultraviolet therapy during the 16 weeks preceding the study, pregnancy, wish to become pregnant during the study period or lactating mother, concurrent medication with > 400 i.u. vitamin D daily, calcium tablets, or any other medication which could affect the course of the disease (e.g. lithium, beta-blockers, captopril, thiazide diuretics), abnormal renal and hepatic function and hypercalcemia . The first phase of the study was a 2-week wash-out period during which patients applied white soft paraffin as an emollient twice a day. If the psoriasis remained stable, patients then proceeded with topical application of calcipotriol ointment twice daily for up to 6 weeks on lesional area except the head and skin folds. The maximum amount allowed was 100gm/week. Low potency topical steroids were advised for treatment of lesions on head or skin folds. Patients were assessed at entry into the study and every two weeks during the treatment phase. At each visit, the investigator assessed the extent (graded 0-6) and severity of the psoriasis (graded 0-4) with

Table 1 Parameters assessed in this study Assessment of extent of psoriasis 0. No involvement 1. < 10% 2. 10-29% 3. 30-49% 4. 50-69% 5. 70-89% 6. 90-100% Assessment of severity of psoriasis (erythema, thickening, scaling) 0. Absent 1. Slight 2. Moderate 3. Severe 4. Very severe Overall efficacy assessment 1. Worse 2. No change 3. Minimal improvement 4. Moderate improvement 5. Marked improvement 6. Cleared Assessment of acceptability 1. Very poor 2. Poor 3. Acceptable 4. Good 5. Excellent

scaling by means of a modified Psoriasis Area and Severity Index (PASI)8 scoring system (Table 1). The areas assessed were trunk and limbs. The head was excluded from the assessment. Overall efficacy assessment was undertaken by the investigator and the patie nt, after 2, 4 and 6 weeks treatment using a six point scale (Table 1). An overall cosmetic acceptability assessment was made by the patient at week 6 (graded 1 Table 1). -5; Blood samples for serum calcium levels were estimated on entry and at the end of treatment.

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Results Sixty one patients entered the study (39 males, 22 females). The mean age was 41.1 (range 18 to 76 years). Ten patients withdrew from the study (4 defaulted, 3 unacceptable responses, 3 adverse events). There was a statistically significant reduction in the mean (+SD) PASI which fell from10.47 + 4.24 at the start of treatment to 2.18 + 0.54 at the end of treatment (p<0.001). Among patients who completed the study, total clearance of psoriasis (PASI score reduced to zero from baseline) at the end of treatment occurred in 8% of patients. Marked, moderate and minimal improvement was observed respectively in 71%, 9%, and 7% of patients (Figure 1). Worsening of psoriatic lesions in 3% and no change in psoriatic lesions in 2% of patients were found (Figure 1). Cosmetic acceptability of calcipotriol ointment was found to be good or excellent in 88% of patients. Fifteen patients reported adverse events, the most common being local irritation (8 patients) which was mild and transient. Calcium level remained normal in all patients after completion of treatment. Discussion Twice daily 50µg/g calcipotriol ointment for 6 weeks resulted in total clearance of psoriasis (PASI score reduced to zero from baseline) at the end of treatment occurred in 8% of patients. Our results showed that there was marked improvement of lesions in approximately 71% patients (Figure 1). These results are similar to those obtained previously. 2,3,4 There was a highly significant reduction in the mean PASI at

Table 2 PASI score during the 6 weeks of treatment phase Baseline 10.47 + 4.24 2 weeks 5.92 + 3.12 4 weeks 3.15 + 1.42 6 weeks 2.18 + 0.54 Data are expressed as mean +SD. Differences between treatments are statistically significant, p <0.001(paired t test).

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1

No change Worse Total clearance Minimal improvement Moderate improvement Marked improvement

Figure 1 Investigator's overall efficacy assessment at the end of 6 weeks of treatment.

12 10.47 10

§ =P<0.001

5.92

8

PASI 6

4 3.15 2 2.18

0 Before Treatment 2 week 4 week 6 week

Figure 2 Mean PASI (+ standard error of the mean) before and during treatment.

217

Topical calcipotriol in the treatment of psoriasis

Agha Masood Choudhary et al.

each visit, compared with baseline. The most rapid reduction occurred in the first 2 weeks of treatment (Figure 2 and Table 2) which is comparable with other studies.9,10 Maximal reduction in mean PASI found at 6 weeks which was also noticed by other researchers.6,7,11 No serious adverse events were reported or observed. Some irritation of lesional and perilesional skin was not uncommon. In our study, irritation occurred in approximately 16% of patients which was also reported in other studies.6,7 Worsening of psoriasis while on treatment in three and no change in psoriatic lesions were found in one patient (Figure 1). In the present study, ten patients withdrew from the study; four defaulted, three were unacceptable responses and three had adverse events. At the end of treatment, overall acceptability was good or excellent in 88% of patients. Serum calcium level remained within the normal range in all patients in our study and no significant change in serum calcium le vels were also reported in numerous studies.1,3,5,6,9,12,13 Studies with calcipotriol have shown that application of up to 100g (50µg/g) per week carries no risk of hyperglycemia . In conclusion, this open study demonstrated that twice-daily application of 50µg/g calcipotriol ointment is safe and well tolerated in the treatment of chronic plaque psoriasis. Acknowledgement This study was supported Pharmaceuticals products, Bangladesh. by Leo Dhaka,

References

1. Binderup L, Bramm E. effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988; 37: 889-95. Kragballe K. MC 903. a noncalciotropic vitamin D3 analogue stimulates differentiation and inhibits proliferation of cultured human keratinocytes. J invest Dermatol 1988; 91: 383 (Abstr). Kragballe K, Beek HI, Segaard H. Improvement of psoriasis by a topical vitamin D3 analogue (MC 903) in a double blind study. Br J Dermatol 1988; 119: 223-30. Kragballe K. Treatment of psoriasis by the topical application of novel vitamin D 3 analogue (MC 903). Arch Dermatol 1989; 125: 1647-52. Kragballe K, Gjertsen BT. De Hoop D et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337: 1936. Cunliffe WJ, Berth-Jones J, Claudy A et al. Comparative study of calcipotriol (MC 903) ointment and betamethasone 17valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol 1992; 26: 736-43. Berth-Jones J, Chu AC, Dodd WAH et al. A multicentre parallel group comparison of calcipotriol ointment and short contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol 1992; 127: 266-71. Frederiksson T, Petterson U. Oral therapy with a new retinoid. .Dermatologica 1978; 157: 23844. Darley CR, Cunliffe WJ, Green CM et al. Safety and efficacy of calcipotriol ointment (DOVONEX) in treating children with psoriasis vulgaris. Br J Dermatol 1996; 135: 390-3.

2.

3.

4.

5.

6.

7.

8.

9.

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10. SN Tham, KC Lun, WK Cheong. A comparative study of calcipotriol ointment and tar in chronic plaque psoriasis. Br J Dermatol 1994; 131: 673-7. 11. Dwyer C, Chapman RS. Calcipotriol and hypercalcemia. Lancet 1991, 338: 764-5. 12. Dubertrat L, Wallach D. Souteyrand P et al. Efficacy and

safety of calcipotriol (M C 903) ointment in psoriasis vulgaris. J Am Acad Dermatol 1992; 27: 983-8. 13. Klaber MR, Hutchinson PE, Holden C et al. Long term treatment of psoriasis with calcipotriol. Br J Dermatol 1992; 127 (Suppl. 40):17 (abstract).

219

Spectrum of cutaneous infections in patients of leukemia

Tariq Zaman et al.

Original Article

Spectrum of cutaneous infections in patients of leukemia

Tariq Zaman, Muhammad Jahangir, Muhammad Abbas Raza*, Tahir Saeed Haroon** Dermatology Department, Allama Iqbal Medical College/Jinnah Hospital. Lahore. * Department of Medicine, King Edward Medical College/Mayo Hospital. Lahore. Department of Dermatology, King Edward Medical College/Mayo Hospital. Lahore.

Abstract Background Cutaneous infections are common in patients of leukemia due to

immunosuppression caused by the disease itself and its therapy. Objectives This study was aimed to analyze the incidence, types and clinical presentations of various cutaneous infections in different types of leukemias in this part of the world. Patients and methods This observational, descriptive and cross sectional study was carried out in department of dermatology, King Edward Medical College & Mayo Hospital, Lahore. Two hundred and fifty diagnosed patients of leukemia were enrolled from pediatrics, oncology, dermatology and medical units of Mayo Hospital, Lahore. Detailed dermatological examination was performed and the cases having any skin infection were further investigated. The incidence and morphological patterns of various cutaneous infections in leukemia were analyzed. Results Out of the 250 enrolled patients, cutaneous infections were present in 177 (71%) patients. Out of these 177 patients, 101(57%) were male while 76(43%) were female. The age ranged from 2 years. Infections of skin were more common in acute as compared to -76 chronic leukemias (p < 0.01). Candidiasis was the commonest infection (72%) seen, while bacterial, viral and dermatophytic infections were present in 31%, 35% and 12% of the patients, respectively. Scabies was found in 12%. More than half of the patients (54%) had two or three types of concomitant i fections. Bacterial infections were more frequent in n myelogenous leukemias (p < 0.001), while candidal and dermatophytic infections were more common in lymphocytic leukemias (p<0.001 and < 0.05, respectively). Dissemination, higher grade of severity and atypical morphology was frequently seen with these infections. Conclusions The incidence of cutaneous infections in leukemic patients is very high and these are more common in acute as compared to chronic leukemia. Candidiasis is the commonest infection. Bacterial infections are more frequent in myelogenous leukemias, whereas superficial fungal infections are more in lymphocytic leukemias. Infections with higher degree of severity, dissemination and atypical morphology are common. Key words Leukemia, cutaneous infections.

Introduction Cutaneous manifestations of leukemia are divided into specific and nonspecific.

Address for Correspondence Dr. Tariq Zaman, 210 GT Road, Baghban Pura, Lahore Email: [email protected] 220

Specific lesions are due to metastatic infiltration of neoplastic cells in the skin but these cells are not present in the nonspecific lesions.1 Nonspecific (non-metastatic) dermatologic manifestations are more frequent than the specific ones and infections form the bulk of such manifestations.2 Severe scabies and

Journal of Pakistan Association of Dermatologists 2004; 14: 220-227.

bacterial, viral, and fungal infections are very common in immunosuppression, and patients of leukemia are especially vulnerable to these infections.3,4 In addition to the higher incidence, the infections in these patients also have atypical morphology. These are usually of severe degree, disseminated, recurrent and with unusual presentations. Infection is the leading cause of death in patients with leukemia.5 The diversity in types and morphology of cutaneous infections in these patients often pose a significant diagnostic challenge. Familiarity with the clinical spectrum of these infections is necessary for prompt clinical evaluation and aggressive therapy to alleviate morbidity and mortality associated with these immunosuppressed patients. This study was carried out to analyze the incidence, types and clinical presentations of various cutaneous infections in different types of leukemias in this part of the world. Patients and methods

Relevant findings of history, general physical and systemic examination of each patient were recorded on a predesigned pro forma. A thorough dermatological examination, including skin, mucosae and adenexa was carried out. Suspected cases of cutaneous infections were further worked up. Detailed clinical features of all the cutaneous lesions in every patient were recorded. Diagnosis of cutaneous infections was established by clinical features and relevant investigations like scraping, smear, culture, histopathology, etc. All the data collected was tabulated and analyzed in a database. Statistical analysis All categorical variables were described as percentages and the only continuous variable, the age, as mean +/-SD (standard deviation). Odds ratios were calculated for risk of various infections in different groups of leukemia. Chi-square statistics was applied to test the significance of differences between categorical variables. Statistical significance was defined as p< 0.05. Results

This observational, descriptive and cross sectional study was planned and conducted in dermatology department, King Edward Medical College/Mayo Hospital, Lahore. Cases with established diagnosis of any type of leukemia were included. The patients were enrolled from pediatrics, oncology, dermatology and medical units of Mayo Hospital, Lahore. Two hundred and fifty patients of either sex and any age, fresh as well as on therapy, were registered for the study.

Cutaneous infections were present among 71% (177) of the 250 enrolled cases of different types of leukemia (Table 1). Out of these 177 patients, 101 (57%) were male and 76 (43%) were female with male to female ratio of 1.3:1. Eighty-three (47%) were children (<12 years) with mean age of 7.3 years (SD +/- 2.2) and the rest 94 (53%) were adults (>12 years) with mean age of 40.9 years (SD +/- 13.9). Overall age ranged from 2-76 years (Table 2).

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Tariq Zaman et al.

Type of leukemia AML ALL CML CLL Total

Total patients 77 118 42 13 250

Patients with infections No. (%) 56 (73) 91 (77) 23 (55) 7 (54) 177 (71)

Table 1 Cutaneous infections in leukemia AML: acute myelogenous leukemia, ALL: acute lymphoblastic leukemia, C ML: chronic myeloid leukemia, CLL: Chronic lymphocytic leukemia,

Table 2 Demographic data Parameters AML (n = 56) No. (%) ALL (n = 91) No. (%) CML (n = 23) No. (%) CLL (n = 7) No. (%) Total (n = 177) No. (%)

Age <12 Yrs. (%) 14 (25) 66 (73) 3 (13) 0 (0) 83 (47) > 12 Yrs. (%) 42 (75) 25 (27) 20 (87) 7 (100) 94 (53) Sex Male (%) 31 (55) 57 (63) 9 (39) 4 (57) 101 (57) Female (%) 25 (45) 34 (37) 14 (61) 3 (43) 76 (43) M:F 1.22:1 1.68:1 1:1.55 1.33:1 1.32:1 AML: Acute myelogenous leukemia, ALL: Acute lymphoblastic leukemia, CML: chronic myeloid leukemia, CLL: Chronic lymphocytic leukemia Table 3 Types of cutaneous infections in different leukemias Type of infection AML ALL CML CLL Total (n = 56) (n = 91) (n = 23) (n = 7) (n = 177) No. (%) No. (%) No. (%) No. (%) No. (%) Bacterial 23 (41) 17 (19) 14 (64) 1 (14) 55 (31) Viral 22 (39) 31 (34) 7 (30) 2 (29) 62 (35) Superficial fungal infections 32(57) 82(90) 11(48) 7(100) 132(75) Candidal 32 (57) 77 (85) 11 (48) 7 (100) 127 (72) Dermatophytic 4 (7) 14 (15) 1 (4) 2 (29) 21(12) Pityriasis versicolor 0(0) 3(3) 2(9) 1(14) 6(3) Scabies 8 (14) 9 (10) 5(22) 0 (0) 22 (12) AML: Acute myelogenous leukemia, ALL: Acute lymphoblastic leukemia, CML: chronic myeloid leukemia, CLL: Chronic lymphocytic leukemia

Cutaneous infections were more common in acute leukemias (AML + ALL = 75%) as compared to chronic leukemias (CML + CLL = 55%) and the difference is statistically significant (p<0.01). The odds ratio for risk of infection for acute leukemia is 1.263 and for chronic leukemia is 0.496 (Figure 1). Superficial fungal infections (candidiasis, dermatophytosis or pityriasis versicolor) were present in 132 (75%) of the 177 patients of leukemia with cutaneous infections. Among this group candidiasis

80 70 60

% of patients

OR = 1.263

OR = 0.496

50 40 30 20 10 0

Acute leukemia Chronic leukemia p< 0.01

OR = Odds ratio for risk of infection

Figure 1 Cutaneous infections: acute vs. chronic leukemias (n=250)

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Journal of Pakistan Association of Dermatologists 2004; 14: 220-227.

Three infections 12%

Single infection 46%

Two infections 42%

Figure 2 Concomitant cutaneous infections (n=177)

Figure 5 Kaposi's varicelliform eruption

Figure 3 Concomitant infections, candidiasis and herpes simplex

Figure 6 Disseminated dermatophytosis

Figure 4 Severe alopecia

folliculitis

with

scarring

Figure 7 Generalized pityriasis versicolor

(cutaneous or mucocutaneous) was the most prevalent, being present in 72% of the cases, whereas 12% had dermatophytosis and only

3% had pityriasis versicolor. Bacterial and viral infections were also common and affected 31% and 35% of the cases

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Tariq Zaman et al.

Table 4 Type of infections - myelogenous vs. lymphocytic leukemias Myelogenous leukemia Lymphocytic leukemia Type of infection (AML + CML) (n = 79) (ALL + CLL) (n=98) No. % Odds No. % Odds Ratios ratios Bacterial 37 47 1.954 18 18 0.499 Viral 29 37 1.076 33 34 0.942 Superficial fungal infections 43 54 0.407 89 91 3.371 Candidal 43 54 0.516 84 86 2.107 Dermatophytic 5 6 0.502 16 16 1.449 Pityriasis versicolor 2 3 4 4 Scabies 13 17 1.138 9 9 0.712 Table 5 Types of bacterial, viral and dermatophytic Infections No. of patients Bacterial infections (n = 55) Furuncles 18 Impetigo 12 Folliculitis 8 Pyoderma 8 Cellulitis 6 Carbuncle 3 Viral infections (n = 62) Herpes simplex Herpes zoster Varicella Verruca vulgaris Verruca plana Molluscum contagiosum Dermatophytic infections (n = 21) Tinea corporis Tinea unguium Tinea cruris Tinea capitis Tinea pedis Tinea faciei

p value

<0.001 0.674 <0.001 <0.001 <0.05 0.145

%

33 22 15 15 11 5

21 14 9 8 6 4

34 23 15 13 10 6

8 7 5 4 4 4

38 33 24 19 19 19

Table 4 along with the statistical analysis showing odds ratios for risk of infection and p value for each group. Bacterial infections were more frequent in myelogenous as compared to lymphocytic leukemias and the difference was highly significant (p<0.001). Conversely, superficial fungal infections (as a group) were more common in lymphocytic leukemias, again with a highly significant difference (p<0.001). And within this group, candidia sis and dermatophytic infections individually were also significantly more in lymphocytic leukemia with p value of <0.001 and <0.05 respectively, whereas statistical difference was not calculated for pityriasis versicolor due to small sample size. The difference in two groups of leukemias is not statistically significant for viral infections and scabies (value of p is 0.674 and 0.145, respectively). Among the bacterial infections furunculosis and impetigo were more common, however, folliculitis, nonspecific pyoderma, cellulitis and carbuncles were also seen (Table 5). In most of the patients they were very severe, widespread and involved multiple areas of the skin (Figure 4). Herpes simplex and herpes zoster were common viral infections seen ( Table 5). In herpes simplex severe local disease was frequent and hemorrhagic and necrotic lesions were seen in some

respectively. Scabies was seen in only 12% of the patients (Table 3). More than half of the patients (54%) had multiple types of infections (bacterial, viral, superficial fungal, scabies, etc.). Out of these 42% had two and 12% had three types of concomitant infections (Figures 2 and 3). Frequencies of various infections in myelogenous vs. lymphocytic leukemias are summarized in

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patients. One case presented as Kaposi's varicelliform eruption (Figure 5). Extensive necrosis and ulceration along with involvement of greater number of adjacent dermatomes was a common finding in herpes zoster. Generalized cutaneous dissemination was also seen in four cases. One patient with CML had bilateral herpes zoster. In most of the patients of viral warts and molluscum contagiosum, the lesions were numerous and persistent and sometimes with atypical morphology. Almost all the clinical types of dermatophytic infections were seen but tinea corporis and tinea unguium were most common (Table 5). Multiple lesions and widespread local dissemination was frequent (Figure 6). Nine cases had dermatophytic infection on multiple sites of the body. Generalized pityriasis versicolor was present in one patient of CML (Figure 7). Majority of the patients had oral candidiasis, however, vaginal involvement, intertrigo, paronychia and onychia were also frequent. Extensive local disease along with involvement of more than one site was common. Scabies in most of the patients was very severe and often secondarily i fected. n Two cases of crusted (norwegian) type were also seen. Discussion Immunosuppression in leukemia results from the depletion of immunocompetent cells, primarily due to premature/abnormal leukocytes of the lineage involved6 and secondarily from the marrow failure due to the infiltration by these malignant leukocytes. It is further aggravated by the cytotoxic therapy. In this background, primary cutaneous infections and systemic

infections with secondary skin involvement are common complications.7-9 The incidence of various cutaneous infections in our patients was 71% (Table 1). Moreover, 54% of the patients had more than one type of infections (Figure 2). In addition to immunosuppression, poor hygiene, limited diagnostic facilities, inadequate isolation and exposure to nosocomial infections may be the contributory factors for this high incidence in our setting. Cutaneous and mucocutaneous candidiasis was the commonest infection (72%) encountered in this study (Table 3). This is in agreement with the previous reports regarding immunosuppressed patients in the literature.7,10,11 This is due to the fact that the medical condit ions that cause defects in cellmediated immunity or neutropenia, and chronic immunosuppressive therapy can predispose the patients to candidal infection. 12 Although less serious than systemic candidiasis, mucocutaneous candidiasis is a common complication observed in immunosuppressed patients.13,14 In acute leukemias the production of immature cells is very high as compared to chronic leukemias. This increased load of neoplastic cells causes greater degree of marrow infiltration at the expense of normal hemopoietic elements including 15 leukoctytes. The resulting greater overall immunosuppression in acute leukemias may be responsible for the statistically significant difference between the frequencies of cutaneous infections in acute (75%) vs. chronic (55%) leukemias (Figure 1). In disorders of phagocytosis, bacterial infections are characteristically more common. 16 The significantly high incidence

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Tariq Zaman et al.

of bacterial infections found in myelogenous leukemias as compared to lymphocytic leukemias in our study ( Table 4) may be due to defective phagocytic defence function in leukemias of myeloid series. Fungal and viral infections are predominant in conditions with deficient cell-mediated immunity. 11 The greater impairment of cellular immunity in lymphocytic leukemias may have given rise to significantly higher incidence of candidiasis and dermatophytic infections in lymphocytic leukemias than the myelogeneous ones (Table 4). The lack of statistically significant difference regarding viral infections, among the two groups in this study, can not however be explained on such basis. In immunocompromised patients the classic clinical findings are distorted. There are unusual presentations of common infections or infections with atypical and opportunistic pathogens. In leukemia, infections are usually of severe degree, disseminated and with atypical presentation & protracted course. They are acute and fulminant or chronic and recurrent, with only partial response to conventional treatment.2,3,4,17-24 Similar morphological profile of various infections was encountered in this study as well, e.g. widespread and severe bacterial and fungal infections, disseminated and necrotic herpes simplex and zoster, Kaposi's varicelliform eruption, bilateral herpes zoster, generalized and atypical viral warts and molluscum contagiosum, crusted scabies, etc. In conclusion, the cutaneous infections very high and they acute leukemia as incidence of various in leukemic patients is are more common in compared to chronic

leukemia. Candidiasis is the commonest infection. Bacterial infections are more frequent in myelogenous leukemias, whereas superficial fungal infections are more in lymphocytic leukemias. Infections with higher degree of severity, dissemination and atypical morphology are common. References

1. Zaman T, Pal SS, Khurshid K et al. Leukemia cutis ­ the specific cutaneous lesions of leukemia: a clinical study of 250 patients. Ann King Edward Med Coll 1999; 5: 255-8. Stawiski MA. Skin manifestations of leukemias and lymphomas. Cutis 1978; 21: 814-8. McLean DI, Haynes HA. Cutaneous manifestations of internal malignant disease: Cutaneous paraneoplastic syndromes. In: Freedberg IM, Eisen AZ, Wolff K et al., eds. Fitzpatrick's Dermatology in th General Medicine, 6 edn. New York: McGraw-Hill; 2003. p. 17867. Muller SA, Herrmann EC, Winklemann RK. Herpes simplex infections in haematologic malignancies. Am J Med 1972; 52; 102-14. Chang HY, Rodriquez V, Narboni G et al. Cause of death in adults with acute leukemia. Medicine 1976; 55: 259-68. Kavanaugh DY, Carbone DP. Immunologic dysfunction in cancer. Hematol Oncol Clin North Am 1996; 10: 927-31. Emmanouilides C, Glaspy J. Opportunistic infections in oncologic patients. Hematol Oncol Clin North Am 1996; 10: 841-6. Euvrard S, Kanitakis J, Cochat P et al. Skin diseases in children with organ transplants. J Am Acad Dermatol 2001; 44: 932-9. Gulec AT, Demirbilek M, Seckin D et al. Superficial fungal infections

2.

3.

4.

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10.

11.

12.

13.

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15.

in 102 renal transplant recipients: A case-control study. J Am Acad Dermatol 2003; 49: 187-92. Kontoyiannis DP, Rubin RH. Infection in the organ transplant recipient: An overview. Infect Dis Clin North Am 1995; 9: 811-5. Patel R, Paya CV. Infections in solid organ transplant recipients. Clin Microbiol Rev 1997; 10: 86-9. Wright WL, Wenzel RP. Nosocomial candida: Epidemiology, transmission, and prevention. Infect Dis Clin North Am 1997; 11: 411-5. Conant MA. Fungal infections in immunocompromised individuals. Dermatol Clin 1996; 14: 155-65. Epstein JB, Polsky B. Oropharyngeal candidiasis: a review of its clinical spectrum and current therapies. Clin Ther 1998; 20: 40-3. Allan NC, Ludlam CA. Diseases of blood. In: Edwards CRW, Bouchier IAD, eds. Davidson's Principles and Practice of Medicine, 16th edn. Edinburgh: Churchill Livingstone; 1991. p. 629-78.

16. White CJ, Gallin JI. Phagocyte defects. Clin Immunol Immunopathol 1986; 40: 50-61. 17. Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996; 9: 361-5. 18. Aston DL, Cohen A, Spindler MA. Herpesvirus hominis infections in patients with myeloproliferative and lymphoproliferative disorders. Br Med J 1972; 4: 462-5. 19. Cormia FE, Domonkos AN. Cutaneous reactions to internal malignancy. Med Clin North Am 1965; 49: 655-80. 20. Feldman S, Cox F. Viral infections and haematological malignancies. Clin Haematol 1976; 5: 311-28. 21. Bouwes JNB, Berkhout RJ. HPV infections and immunosuppression. Clin Dermatol 1997; 15: 427-33. 22. Birthistle K, Carrington D. Molluscum contagiosum virus. J Infect 1997; 34: 21-3. 23. Piette WW. An approach to cutaneous changes caused by haematological malignancies. Dermatol Clin 1989; 7: 467-79. 24. Orkin M. Scabies: What's new? Curr Probl Dermatol 1995: 22: 105-7.

227

Urticaria: a threat to betel consumers

Javed Anwer et al.

Original Article

Urticaria: a threat to betel consumers

Javed Anwer, Pervaiz Iqbal, Noor Muhammad Ursani Department of Dermatology L.U.H.M.S. Jamshoro.

Abstract Background Chronic urticaria is a common dermatosis with a multifactorial etiology

including ingestants. The incidence of chronic urticaria has doubled during the last decade. Chewing of betel is common in Hyderabad. Objective To determine the relationship of betel to chronic urticaria as an underlying cause in the local population. Patients and methods During one year, patients of chronic urticaria at our department were investigated to find out the underlying cause. Results Out of 2625 total cases of urticaria, 943 (35.9%) were found to be habitual betel nut (supari) and pan (betel leaf) and gutka (betel leaf and lime) chewers. Ninety two of 95 volunteers got relief of their signs and symptoms on abstinence from betel. Eighty five of them reported relapse of the disease rechallenge with the suspicious substance confirming the cause-effect relationship Conclusion The observations suggest that intake of betel in the form of sweetened supari and pan masala and gutka correlates with chronic urticaria. Key words Chronic urticaria, betel

Introduction Urticaria and/or angioedema is a common reactive phenomenon and according to an estimate about 20% of the people suffer from urticaria at sometime or other during their life time.1 Acute urticaria may be severe but brief and less concerned with dermatologists. When urticaria persists for longer than six to twelve weeks it is considered chronic in nature.2 Dermatologists are more concerned about chronic urticaria because of its challenging etiology which remains obscure in more

Address for Correspondence Dr. Pervaiz Iqbal, Dermatology Department, LUMS, Hyderabad

than 75 percent of the cases.3 An association with systemic illnesses like mycobacterial infections, chronic sinusitis, dental abscess, SLE, leucocytoclastic vasculitis and thyroid disorders has been found.4 In women vaginal candid iasis and tric homonal infections are frequently associated. Urticaria is also induced by physical stimulus such as temperature, sunlight and physical pressure. Specific hypersensitivity to aeroallergens, idiosyncratic reactions to drugs or food chemicals and additives may provoke urticaria i some individuals but in majority n other intrinsic or unknown factors dominate. Whatever the cause, the pathogenesis of urticaria shares the common mechanism irrespective of the etiology. 5

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Journal of Pakistan Association of Dermatologists 2004; 14: 228-231.

Reviewing the profile of Skin Diseases among all the patients visiting the out patient department of Dermatology at Liaquat University of Medical and Health Sciences Hyderabad & Jamshoro during 10 years period extending from January 1991 to December 2000, the incidence of urticaria doubled (personal observation). Considering the rising figures, the present study was planned at the outpatient department from January Ist 2002 to December 31st 2002. The main objective of this study was to sort out major factors. Materials and methods This observationa l study comprised of all patients, having chronic urticaria, who visited outpatient Department of Dermatology, Liaquat University of Medical and Health Sciences Jamshoro/Hyderabad included during the year 2002. 2625 (5.8%) of total cases having signs and symptoms of urticaria for more than 10 weeks duration, labeled as chronic urticaria , were scrutinized in detail. Table 1 shows the study population according to age and sex. Detailed personal history in relation with respiratory, urinary and gastrointestinal systems was particularly taken. Attention was paid to medication specially NSAIDS, alcohol or any drug addiction. Mouth, nose and throat of each individual was examined thoroughly to assess the effects of smoking and other dietry and chewing materials specially supari (betel nut), pan (betel leaf) and gutka (betel leaf and lime). In case of habitual users, the duration and quantity of daily intake was also noted to assess their relation to signs, symptoms and chronicity of the urticaria.

Table 1 Age & sex distribution of patients of chronic urticaria (n=2625). Age Male Female (years) No. (%) No. (%) 0-10 48 (1.8) 35 (1.3) 11-20 142 (5.5) 133 (5.1) 21-30 356 (13.6) 292 (11.1) 31-40 278 (10.6) 461 (17.4) 41-50 149 (5.8) 383 (14.6) 51-60 85 (3.3) 138 (5.2) >61 68 (2.6) 57 (2.1) Total 1128 (43.2) 1497 (56.8)

Complete blood counts, ESR, detailed urine and stool examinations were carried out in every case. Ultrasound abdomen and chest and sinus roentgenogram were done in a number of cases. Those with acid-peptic disease were also screened for Helicobacter pylori. Thyroid scan and thyroid function tests in ten cases were performed. All thyroid investigations were within normal limits. Skin biopsy was suggested in four cases whose weal persisted more than 48 hours and did not respond to antihistamines, all four had urticarial vasculitis. Results In our study of 2625 chronic urticaria cases, we observed chronic urticaria to be more common in 30-50 years of age in both sexes. 90% of the patients belonged to lower socioeconomic group. In 35.9% (943) cases of chronic urticaria, we observed excessive use of betel ingredients in some form, especially gutka, suparai and pan masala . History of two or more years intake of these substance was noted. On further questioning more than 85% revealed history of vague lower abdominal pain, nausea, irregular bowel habit, constant mild cough and sore throat and occasional palpitation. 23% of affected persons reported improvement in

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Urticaria: a threat to betel consumers

Javed Anwer et al.

urticaria when they did not take gutka in ample quantity. Other causative factors were detected in 5.6% (147) cases (apart from those induced by betel ingredients). These were inadequately treated chronic recurrent infections e.g. as urinary tract infections with embedded urinary calculi, sinusitis with deflected nasal septum, Helicobacter pylori infections and otitis media, dermatophytosis, dental carries and gingivitis, malignancies, viral hepatitis, fish and pickle among dietary products. Rechallenge with betel Out of these 943 cases of betel ingredients related sufferers, we randomly selected 95 patients, who voluntarily stopped taking supari, pan m asala and gutka, as per our advice. 92 of these 95 volunteers got relief within 15 days. After a month they were rechallenged with the suspected material under study, and within 20 days, 85 volunteers developed urticarial rashes again. Discussion: The most important and challenging aspect of the urticaria is determination of the underlying cause which is very difficult in the majority of chronic urticaria cases. A pre-requisite in the investigation of chronic urticaria is the establishment of a pattern of occurrence that is onset, duration and course of disease.6 A varying pattern of onset suggest that the source of challenge to the individua l is from some external factor such as one found in the allergic, exogenous and physical causes of urticaria. A constant pattern of onset suggests habitual exposures to an exogenous challenge, such as common

food or a cause within the patient as one occurring in certain underlying infections, collagen disorders etc. In 60% cases of chronic urticaria, a specific cause is not found, despite the best efforts. Multiple and exhaustive sessions for comprehensive history, foods, hobbies, medication, dairy, complete blood count, repeated routine investigations particularly for UTI and GIT infections and a trial of food additive-free diet are some of the appropriate approaches. Ingested allergens undoubtedly play a role in the symptoms of some patients, both atopic and non-atopic and gastrointestinal signs such as lip swelling, vomiting, diarrhea, pruritus ani were associated, as well. Our study revealed betel use to be the major cause in 35.9% of cases. This important finding was confirmed by rechallenge. Betel chewing has been important social activity in many countries for millennia. It serves many cultural roles, is mild psychostimulant and is thought to be addictive. Betel chewing is a social and cultural component of Pakistani society, as well. About 20% of the three million population living in Hyderabad chew betel, during most of working hours, despite, being fully aware of at least one malignant outcome that is the oral cancer. Betel is associated with oral submucosal fibrosis (OSF), leukoplakia and oral squamous cell carcinoma.7 OSF is often accompanied by mucosal leukoplakia and loss of lingual papillae.8 OSF is regarded by many researchers as a precancerous condition. 9-11 Perleche and lichen planus-like lesions have also been observed in betel chewers.12,13 Gutka is a mixture of leaf (Piper betel), nut of areca palm tree,

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Journal of Pakistan Association of Dermatologists 2004; 14: 228-231.

catechue-a spice obtained from Accacia catechu, lime (calcium hydroxide) and tobacco. All these ingredients are of poor quality (even fungus affected) which are dubbed for a few days to soften. Some flavouring substances are added finally before packing and marketing. Because of its moderate psychostimulating effect and comparatively low price, a vast majority of labourers, their working female members, children and elderly persons chew this admixture, virtually during all working hours. Mothers are known to give their infants premasticated liquid. Betel lime and areca nut are two main carcinogenic betel components. The active ingredient of areca nut is arecoline, an alkaloid with acetylcholine-like properties. Arecoline can cause bronchoconstriction and may trigger asthma.14 The cholinergic activity may be the underlying mechanism for urticarial rash. Much is being published in the newspapers against consumption of pan and supari but still there is a need of an awareness campaign by social and health organizations in our country, particularly. Indian Ministry of Health and Family Welfare requires warning labels on packets of supari, and pan masala stating that the products are injurious to health.15 In Mumbai, the local government has imposed a ban on public spitting of betel as part of efforts to tidy up the city.16 Though, we have noticed an association between urticaria and betel consumption; however, further research is warranted to reconfirm this relationship. References

1. Hafeez ZH. Role of diet in allergic dermatoses. J Pak Med Assoc 1998; 48, 185-7.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12. 13.

14.

15. 16.

Leznoff A. Helping the patients with chronic urticaria. Allergy 1998; 2: 7-10. Monroe EW. Chronic urticaria: review of non-sedating antihistamines in treatment. J Am Acad Dramatol 988; 19:843-50. Leznoff A, Sussman G. Syndrome of idiopathic urticaria and angioedema with thyroid autoimmunity. J Allergy Clin Immunol 1989; 84 : 66-71. Heddle RJ, Gillis D. Common allergic skin conditions. Aust Four Physicians 1993; 22: 126-9. Champion RH. Urticaria: then and now. Br J Dermatol 1988; 119: 427-36. Norton SA. Betel consumption and consequences . J Am Acad Dermatol 1998; 34: 876-81. Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Med Oral Surg Oral Pathol 1966; 22: 764-9. Pindborg JJ, Murti PR, Bhonsle RB et al. Oral submucus fibrosis as a precancerous condition. Scand J Dent Rs 1984; 89: 270-4. Murti PR, Bhonsle RB, Pindborg JJ et al. Malignant transformation rate in oral submucous fibrosis over a 17 year period. Community Dent Oral Epidimol 1985, 13:340-1 Gupta PC, Pindborg JJ, Mehta FS. Comparison of carcenogenicity of betal liquid with and without tobacco. An epidemiological review. Ecol Dis 1982; 4 : 213-9. Singh G. Betal chewer perleche. Br. J Dermatol 1973; 89: 98-102. Daftary DK, Bhonsle RB, Murti, Pindborg JJ. Mehta FS. Oral lichen planus like lesion in Indian Betel tobacco chewers. Scand J Dent Rev 1980; 88: 244-9. Taylor RFH, Al Jarat N, John LME et al. Betel-nut chewing and asthma. Lancet 1992; 339:1134. Mangla B. Indian betel nut warning. Lancet 1993; 376: 267-9. Kumar S. Indians pit their wit against spitters. Lancet 1997; 394: 345-7.

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Nitric oxide may directly induce psoriasis...

M. R. Namazi et al.

Review Article

Nitric oxide may directly induce the psoriatic disease process via suppression of keratinocyte apoptosis and induction of keratinocyte hyperproliferation

M.R. Namazi, R. Salmanpour, F. Handjani, F. Jowkar Dermatology Department, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract Nitric oxide (NO) has been supposed to induce the psoriatic disease process indirectly

through increase of release and also effects of substance P and calcitonin gene-related peptide. This paper discusses the potential direct roles of NO by induction of keratinocyte hyperproliferation and suppression of keratinocyte apoptosis. NO has been shown to exert a biphasic effect on keratinocytes based on its concentration: increasing proliferation and decreasing differentiation of keratinocytes at low concentrations but producing the reverse effects at high concentrations (500µm). Therefore, NO, having a maximum concentration of about 0.01µm in the psoriatic lesions, more likely induces keratinocyte hyperproliferation rather than suppressing it. Low production of NO in psoriasis occurs in the face of high overexpression of inducible nitric oxide synthase (iNOS) mRNA and protein and may be due to a) overexpression of arginase 1, which regulates iNOS activity by competing for the common substrate L-arginine, b) overexpression of calcitonin gene-related peptide, which inhibits iNOS activity, c) NO's regulatory effect on its own production by binding to heme which mediates iNOS dimerization, and d) NO's inhibition of the release of nerve growth factor which in synergy with TNF- induces iNOS. Noteworthy, neopterin and cutaneous polyamines, which are also overexpressed in the psoriatic lesions, contribute further to the low production of NO via suppression of the expression of iNOS gene. Based on the observations that psoriatic keratinocytes are resistant to the induction of apoptosis and that NO, at low concentrations, is capable of suppressing apoptosis, this author suggests the apoptosis -suppressant effect of NO as another potential role for NO in inducing the psoriatic disease process. Key words Apoptosis, calcitonin gene-related peptide, keratinocyte, nitric oxide, neopterin, nerve growth factor, psoriasis.

An important development in the understanding of the pathogenesis of psoriasis has been the discovery that psoriatic plaques actively produce nitric oxide (NO).

Address for Correspondence Dr. M.R. Namazi P.O.Box 71955-687 Shiraz, Iran E-mail: [email protected]

Kolb­Bachofen et al.1 first showed that epidermal keratinocytes in psoriatic plaques produce the enzyme "inducible nitric oxide synthase (iNOS)", and Weller et al.2 showed that NO synthesis is indeed increased in psoriasis. The production of NO is about 100 times higher in psoriatic plaques than the skin of normal persons.3 These observations are highly suggestive of a role for NO in the development of psoriasis.

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Giustizieri and coworkers4 have shown that nitric oxide donors suppress chemokine production by keratinocytes in vitro and in vivo. This work as well as the finding that NO farvors a Th2 over a Th1 response, while psoriasis is characterized by a Th1­ type cytokine pattern,5 may lead to the proposal that NO exerts regulatory effects on psoriatic disease process, rather than producing it. However, it has been shown that NO exerts a biphasic effect on keratinocytes based on its concentration: increasing proliferation and decreasing differentiation of keratinocytes at low concentrations but producing the reverse effects at high concentrations (= 500 µM).6 It is estimated that in the psoriatic lesions, NO concentrations are about 0.00005 µM near the skin surface and increase to a maximum of about 0.01 µM in the middle of the rete pegs.7 Taken together, though it is still difficult to reconcile the paradoxical effects of NO on keratinocytes and on the immune system, it seems more likely that NO, in concentrations produced in psoriasis, induces keratinocyte hyperproliferation rather than inhibiting it. Moreover, since high concentrations of NO are keratinocytostatic, it is not astonishing that both NO scavengers and NO donors be of value in the treatment of psoriasis. The efficacy of anthralin in treating psoriasis could therefore be explained partly by its induction of iNOS.8 Conclusively, though NO concentration is elevated in psoriasis, it is still too low to exert antiproliferative effects, rather, it induces keratinocyte hyperproliferation. Inducible NOS (iNOS) mRNA and protein are highly overexpressed in psoriatic lesions,

however, arginase 1, which participates in the regulation of iNOS activity by competing for the common substrate Larginine, is also overexpressed in the lesions, being co-expressed with iNOS.9 Furthermore, calcitonin gene-related peptide (CGRP), which is overexpressed in the psoriatic lesions,10 is capable of inhibition of iNOS activity and therefore decreasing NO concentration.11,12 Given that NO is known to increase the release of CGRP,10 NO could be supposed to control its own production indirectly through effecting the overexpression of CGRP. The dimerization of iNOS, mediated by the binding of iron protoporphyrin IX (heme) to the oxygenase domain of iNOS, is essential for its activation. Since NO binding to heme renders it insoluble, the iron released from the oxygenase domain prevents dimerization of iNOS proteins and uncouples already formed iNOS dimers. NO may thus directly regulate its own production.11 Nerve growth factor (NGF), which is overexprssed in the psoriatic lesions,13 is known to induce iNOS in synergy with tumor necrosis factor-alpha (TNF-),14 which is also overexpressed in the lesions. NO is known to inhibit the basal nerve growth factor release through increase of cGMP levels 16 and hence indirectly controls its own production. Neopterin, a compound belonging to the unconjugated pteridines group, is mainly synthesized by monocytes/macrophages upon stimulation with Th1-deriven IFN-gamma. Neopterin has been proposed to inhibit the NO-induced apoptotic cell death via suppression of cytokine-induced NO synthesis, say, via suppressing the iNOS gene expression.17 Therefore, neopterin has been supposed to encourage tumor cell growth and proliferation.17,18 It has been demostrated that

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M.R. Namazi et al.

serum and urinary neopterin levels are elevated in psoriatics.19 Thus, neopterin may also be partly responsible for the low NO concentration in the psoriatic lesions. Moreover, cutaneous polyamines, which are known to be increased in psoriasis,20 further decrease the concentration of NO through suppression of iNOS gene expression. 21 Morhenn10 proposed that NO could trigger keratinocyte hyperproliferation through stimulation of guanylate cyclase in the keratinocytes, thereby producing cyclic guanosine monophosphate (cGMP) nucleotide which is supposed to be a potential mitogen for keratinocytes. However, this view was opposed by some workers, as some studies suggest that cGMP arrests keratinocyte proliferation and promotes differentiation, possibly by cGMPgated Ca+2 channel activation. Therefore, no mechanism has been established for NOinduced keratinocyte hyperproliferation until very recently; that it has been proposed that NO may induce the psoriatic disease process indirectly through its ability in augmenting both the release and effects of CGRP and substance P, which are considered to play important roles in the pathomechanism of psoriasis.10 The discussion presented in this paper supports the Morhenn's hypothesis further through ascribing a direct role to NO in inducing keratinocyte hyperproliferation. Further support for the proposed role of NO in inducing the psoriatic disease process could be provided by considering the NO's ability in suppressing apoptosis: Traditionally, psoriasis has been viewed as a hyperproliferative disorder of keratinocytes. An important breakthrough in the understanding of the pathomechanism of

psoriasis was the finding that keratinocytes derived from psoriatic plaques have a prolonged capacity to resist induction of apoptosis compared with normal-skinderived keratinocytes.22 This may contribute to the disease process in which there is marked accumulation of cells in the epidermis accompanied by a thickened stratum corneum. Of note is that the antiapoptotic Bcl x receptor, a member of the Bcl 2 family, is overexpressed in basal psoriatic keratinocytes.13 Apoptotic cell death can result either from developmentally controlled activation of endogenous execution programs or from transduction of death signals triggered by a wide variety of exogenous signals. One major path in the cell suicide program requires the activation of cysteine proteases of the interleukin-1 -converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like family. These proteases play a pivotal role not only in TNF-alpha and APO-1/Fas-triggered apoptosis, but turn out to be of general importance in the apoptoticsignalling cascade.23 Though high concentrations of NO (>300 µM) trigger apoptosis through direct DNA damage or inhibition of cellular enzymes by binding to their iron-sulphur moieties, it has been shown that NO, at low concentrations (< 50 µM), is capable of suppression of apoptosis, independent of elevation of cGMP levels and via inhibition of interleukin-1 -converting enzyme (ICE)like and cysteine protease protein (CPP)-32like proteases by S-nitrosylation of the functionally essential cysteine groups conserved among ICE/CPP-32-like 23 proteases. Furthermore, NO is known to

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exert antiapoptotic effect through increasing the expression of protective genes such as heat shock protein and Bcl-224and also through cGMP-dependent inhibition of acid sphingomyelinase which contributes to activation of the initiator capsase-8 and early DNA fragmentation.25 Therefore, it could b concluded that NO, e having an estimated maximum concentration of 0.01 µM in the psoriatic lesions, may induce the psoriatic disease process not only through induction of keratinocyte hyperproliferation but also via suppression of keratinocyte apoptosis. References

1. Kolb-Bachofen V, Feshel K, Michel G, Ruzicka T. Epidermal keratinocyte expression of inducible nitric oxide synthase in skin lesions of psoriasis vulgaris. Lancet 1994; 344: 139-42. Weller R, Ormerod A, Benjamin N. Nitric oxide generation measured directly from psoriatic plaques by chemiluminescence. Br J Dermatol 1996; 134: 569-74. Weller R, Ormerod A. Increased expression of nitric oxide synthase. Br J Dermatol 1997; 136: 132-48. Giustizieri ML, Albanesi C, Scarponi C et al. Nitric oxide donors suppress chemokine production by keratinocytes in vitro and in vivo. Am J Pathol 2002; 161: 1409-19. Weller R. Nitric oxide, skin growth and differentiation: more questions than answers? Clin Exp Dermatol 1999; 24: 388-91. Krischel V, Bruch­Gerharz D, S uschek C et al. Biphasic effect of exogenous nitric oxide on proliferation and differentiation in skin derived keratinocytes but not fibroblasts. J Invest Dermatol 1998; 111: 286-91. Sarill NJ, Weller R, Sherratt JA. Mathematical modelling of nitric oxide regulation of rete peg formation in psoriasis. J Theor Biol 2002; 214: 1-16.

8.

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11.

12.

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6.

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7.

19.

Ross R, Reske-Kunz AB. The role of NO in contact hypersensitivity. Int Immunopharmacol 2001; 1: 1469-78. Bruch-Gerharz D, Schnorr O, Suschek C et al. Arginase 1 over-expression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation. Am J Pathol 2002; 162: 203-11. Namazi MR. A complementary note on the Morhenn's hypothesis on the pathomechanism of psoriasis. Immunol lett 2003; 85: 223-30. Taylor AW, Yee DE, Streilein JW. Suppression of nitric oxide generated by inflammatory macrophages by calcitonin-gene related peptide in aqueous humor. Invest Ophthalmol Vis Sci 1998; 39: 1372-8. Namazi MR. Decreased concentration of nitric oxide in psoriatic lesions is not entirely cuased by overexpression of arginase I: Introducing calcitonin generelated peptide as another culprit. Am J Pathol (In press). Pincelli C, Marconi A. Autocrine nerve growth factor in human keratinocyte. J Dermatol Sci 2000; 22: 71-9. Macdonald NJ, Taglialatela G. Tumor necrosis factor-alpha and nerve growth factor synergistically induce iNOS in pheochromocytoma cells. Neuroreport 2000; 11: 3458-6. Namazi MR. Nicotinamide: a potential addition to the antipsoriatic weaponry. FASEB J (In press). Xiong H, Yamada K, Jourdi H et al. Regulation of nerve growth factor release by nitric oxide through cyclic GMP pathway in cortical glial cells. Mol Pharmacol 1990; 56: 339-47. Rieder J, Lirk P, Hoffmann G. Neopterin as a potential modulator of tumor cell growth and proliferation. Med Hypotheses 2003; 60: 531-4. Reider J, Amann A, Schlosser M. Suppressive effects of neopterin on inducible nitric oxide synthase gene expression in ovarian carcinoma cells in vitro. Pteridines 2001; 12: 1-8. Sanchez-Regana M, Catasus M, Creus L, Umbert P. Serum neopterin as an objective marker of psoriatic disease activity. Acta Derm Venereol 2000; 80: 185-7.

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M.R. Namazi et al. interleukin-1 -converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like protease. J Exp Med 1997; 4: 601-7. 24. Chung HT, Pae HO, Choi BM et al. Nitric oxide as a bioregulator of apoptosis. Biochem Biophys Res Common 2001; 282: 1075-9. 25. Barasacchi R, Perrotta C, Sestili P et al. Cyclic GMP-dependent inhibition of acid sphingomyelinase by nitric oxide: an early step in protection against apoptosis. Cell Death Differ 2002; 9: 1248-55.

20. Lowe NJ, Breeding J, Russel D. Cutaneous polyaminas in psoriasis . Br J Dermatol 1982; 107: 21-5. 21. Baydoun AR, Morgan DML. Inhibition of ornithine decarboxylase potentiates nitric oxide production in LPS-activated J774 cells. Br J Pharmacol 1998; 125: 1511-6. 22. Wrone-Smith T, Mitra RS, Thompson CB et al. Keratinocytes derived from psoriatic plaques are resistant to apoptosis compared with normal skin. Am J Pathol 1997; 151: 1321-29. 23. Dimmeler S, Haendeler J, Nehls M, Zeiher AM. Suppression of apoptosis by nitric oxide via inhibition of

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Journal of Pakistan Association of Dermatologists 2004; 14: 237-243.

Review Article

Herpes zoster: management

complications

and

Jayakar Thomas Senior Consultant ­ Dermatology, Apollo Hospitals, Chennai & Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India

Abstract Herpes zoster is a common viral infection caused by varicella-zoster virus. Clinically it is

characterized by painful vesico-bullous eruption in a dermatomal distribution. Systemic involvement occasionally occurs, especially in immunosuppressed hosts. Post-herpetic neuralgia is the most dreadful complication. The present review addresses the complications and management of this common ailment in routine and under special circumstances. Key words Herpes zoster

Introduction Herpes zoster (HZ) is a manifestation of the reactivation of varicella -zoster virus (VZV). Following initial infection, the virus remains latent in the dorsal sensory ganglia until it reactivates and replicates. It is characterized by the presence of dermatomal pain, and usually a papulovesicular rash also in a dermatomal distribution, although the rash is not always accompanied by pain and vice versa (zoster sine herpete ). The rash typically resolves within 2-4 weeks, although this can take significantly longer in immunocompromised individuals. Virus replication and transmission in nerves and ganglia, together with the subsequent development of skin rash, contribute to the prodromal and acute-phase pain of HZ. Subsequent to this, there can be chronic pain. Thus, pain associated with HZ is typically compartmentalized into three phases ­ prodromal, eruptive or rash, and

Address for Correspondence

Dr. Jayakar Thomas 2, West Mada Church Road, Royapuram, Chennai 600013, India

post-herpetic neuralgia (PHN). Other complications of herpes zoster may be addressed as dermatological, neurological, ophthalmologic, etc and are discussed in the text to follow. Prevention and management of complications, particularly PHN are the main objectives of therapy. In addition, treatment of HZ aims to increase the rate of healing of skin lesions. The continued application of mathematical modeling and detection techniques, such as polymerase chain reaction, will increase understanding of the pathogenesis and risk factors involved and provide the potential to develop new treatment methodologies to manage zoster associated pain (ZAP). Complications Zoster-associated complications are varied and affect different systems in the body having a negative impact on the quality of the patient's life. Those more likely to be at high risk of developing complications include: · At the extremes of age (although HZ is not very common in children)

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Herpes zoster: complications and management

Jayakar Thomas

· · · · · · ·

With untreated HZ Individuals with AIDS Patients with malignancies Bone marrow transplant recipients Solid organ transplant recipients Patients receiving high-dose corticosteroids Children with leukemia

and low CD4 cell counts. These are seen as hyperkeratotic papules, ecthymatous lesions, and large punched-out ulcers with a central black eschar and a peripheral rim of vesicles.1,2 Neurological Physicians should be aware of the existence of rare but serious neurological complications of HZ, such as delayed contralateral hemiparesis, chronic VZV encephalitis, myelitis, polyradiculitis, and numerous cranial and peripheral nerve palsies (including Bell's palsy and Ramsay Hunt syndrome). Direct VZV invasion of the cerebral arteries along intracranial branches of the trigeminal nerve, resulting in infla mmation of the internal carotid artery or one of its branches on the same side as the HZ rash, is thought to be the pathogenesis of delayed contralateral hemiparesis. The typical presentation is headache and hemiplegia occurring in a patient with a recent history of HZ ophthalmicus. Examination of cerebrospinal fluid (CSF) reveals mononuclear cell pleocytosis and increased protein. Arteriography is usually diagnostic and demonstrates inflammation, narrowing, and thrombosis of the proximal branches of the anterior or middle cerebral artery. 3, 4 Chronic VZV encephalitis is seen almost exclusively in patients with conditions involving depressed cellular mediated responses. It occurs months after an episode of HZ, making diagnosis problematic. The clinical presentation comprises headache, fever, altered mental status, seizures, and focal neurological defects (including aphasia, hemiplegia, and reduced visual

These individuals have an increased probability of cutaneous and visceral dissemination, VZV pneumonia, encephalitis, and hepatitis. Dermatological Bacterial infections with staphylococcal and streptococcal organisms are by far the commonest local complications as evidenced by the appearance of pustules, hemorrhagic crusting and necrosis of involved skin. Eventual scarring occurs in almost all patients and tends to be permanent in around 75%, the incidence increasing proportionately with the age at which HZ occurs. The scars may be pitted or non-pitted, pigmented or depigmented, atrophic or hypertrophic, and anesthetic or hyperesthetic. A number of unrelated dermatological conditions such as sarcoid granuloma, reactive perforating collagenosis, pseudolymphoma, xanthoma, and epitheliomas have been described. However, koebnerization-associated dermatoses such as psoriasis, lichen planus and molluscum contagiosum are more common. An unusual presentation of HZ in the immunocompromized is atypical generalized zoster that begins with a limited area of involvement in the primary dermatome, quickly followed by generalized cutaneous dissemination. Atypical lesions can occur in individuals with HIV infection

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Journal of Pakistan Association of Dermatologists 2004; 14: 237-243.

fields). Magnetic resonance imaging reveals plaque-like lesions in the white matter with hemorrhagic infarcts of cortical and subcortical gray and white matter. VZV DNA has been amplified by polymerase chain reaction from the CSF of these patients. The clinical course is often deterioration and death in up to half of cases although anecdotal reports suggest benefit from high-dose aciclovir therapy. 5,6 Ophthalmologic No case of herpes zoster opthalmicus (HZO) can be managed without the specialist advice of an ophthalmologist. HZO is observed in around 20% of patients with HZ and up to 90% of these may experie nce ocular complications if left untreated. These complications include conjunctivitis, scleritis, and episcleritis, ocular motor palsies, epithelial keratitis, stromal infiltrates, anterior uveitis, and acute retinal necrosis (ARN). Since the advent of AIDS, a more aggressive form of ARN referred to as rapidly progressive herpetic retinal necrosis (RPHRN) has been identified. The signs and symptoms include pain, photophobia, iritis, vitritis, uveitis, viteous precipitates, vascular sheathing, large white plaques in retinal periphery, and necrotizing spreading retinal lesions. About 80% of these cases progress to become bilateral in 5-20 days. Intravenous antiviral therapy with aciclovir, followed by oral famciclovir, or valaciclovir should be considered in these cases.7,8 Abdominal herpes zoster A serious manifestation of HZ in the immunocompromised individual is abdominal HZ. Patients present with severe, unexplained abdominal pain that may

precede the appearance of cutaneous rash by hours or days. The dia gnosis of HZ is usually not considered until the typical skin vesicles begin to appear in a thoracic dermatome. Abdominal HZ is associated with a high mortality rate, even when appropriate antiviral therapy is administered. Autopsy studies have revealed a high frequency of abdominal visceral involvement in patients with abdominal HZ. Polymerase chain reaction detection of VZV in peripheral blood mononuclear cells and whole blood has been used in a few cases to make the diagnosis of visceral VZV before the appearance of the rash. 9, 10 Zoster associated pain (ZAP) The most debilitating symptom of HZ is the associated pain, which may be both acute and chronic in nature and can persist for months or even years. This has a major impact on the patient's quality of life and once established, can be difficult to manage effectively, making this the most compelling reason for early treatment of HZ. Analysis of several studies indicates that antiviral treatment initiated within 72 hours of rash onset increases the rate of rash healing and also speeds the resolution of ZAP in many patients. Although the pain experienced during the acute phase usually resolves as the rash heals, chronic pain can persist for prolonged periods. The term post-herpetic neuralgia (PHN) has been variously used to describe: · Pain that persists or occurs after resolution of the cutaneous rash · Pain persisting more than 30 days after rash onset · Pain at 3 months after the acute -6 episode.

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Herpes zoster: complications and management

Jayakar Thomas

The three main risk factors that predict PHN are: · Advancing age · Presence of a prodrome · Acute pain severity Other hypothetical factors predictive for PHN include viremia, rash severity, and adverse psychosocial factors. With lack of good prospective population-based studies the incidence of PHN is unclear. However retrospective population-based studies report that, in the absence of therapy, 65-75% of patients with HZ develop pain persisting for more than 4 weeks. Thus there is a continuum of pain ­ from the pain of the prodrome through to the persisting pain. This continuum is referred to as zoster associated pain (ZAP).11,12 HZ and pregnancy HZ during pregnancy does not increase the risk of severe ZAP. Therefore, there is no argument to support oral antiviral therapy in such a condition. Long-term safety data on aciclovir and the experience of genital herpes management with aciclovir during pregnancy might suggest that this drug has a good tolerability profile. Clinicians caring for women of childbearing age should be aware of the various aspects of HZ. Determining the VZV serological status as part of the antenatal laboratory work-up helps predetermine the likelihood of developing HZ. Women with no history of varicella should undergo serological testing and susceptible women should be vaccinated. Vaccination will reduce the risk of severe maternal morbidity caused by varicella -related complications that can occur during

pregnancy and obviate the need for varicella -zoster immunoglobulin (VZIG) prophylaxis during pregnancy. Pregnant women with no history of varicella should not be vaccinated while pregnant but should undergo serological testing to determine susceptibility. Vaccination of susceptible women of childbearing age may potentially also prevent congenital varicella syndrome, neonatal varicella, or childhood HZ.13 Pediatric aspects Herpes zoster occurs rarely in children. The main risk factors for childhood HZ are the occurrence of varicella during the first year of life, or maternal varicella infections during pregnancy (either chicken pox or herpes zoster). Other factors are subclinical, unrecognized, or pauci lesional chicken pox. Prodromal, acute, and persistent pain is almost non-existent in childhood. The attending pediatrician, however, should be vigilant on potential development of encephalitis, hepatitis, and pneumonitis and more so in the immune challenged as in the case of children with leukemia. 14 Management A complete review of literature on management of HZ is not within the scope of this article. As such only the key points are discussed. Barriers to the treatment of HZ may include the following: · Lack of clear initial symptoms due to the variable nature of prodromal pain · Time taken to obtain a consultation once rash appears due to waiting lists and appointment systems, and patient's fear of illness- especially in the elderly

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· ·

·

Time between consultation and dispensing of prescription Lack of awareness by some physicians of the suffering experienced by patients with HZ Perception among some physicians that treatments are expensive

longer than 72 hours and in whom clinical examination reveals new vesicle formation (indicative of ongoing virus replication). Similarly, if risk factors for severe or protracted pain are present at presentation, antiviral therapy should be initiated irrespective of time since rash onset. 16 Tricyclic antidepressants, such as amitriptyline (25 mg once daily; 10 mg in the frail and elderly, elevated every few days to a dose that is effective without severe side-effects), particularly if initiated early in the clinical course of HZ, can relieve the acute pain associated with the disease and have the potential to prevent the development of PHN. Sympathetic nerve blocks have been studied in several trials, most of which were uncontrolled and lacked comparative groups. Thus, it is difficult to draw any conclusions about the efficacy of this intervention in HZ.

In general patients with HZ should receive antiviral therapy to limit viral replication and, thereby, minimize the acute pain associated with HZ, help prevent PHN, prevent complications, and speed the resolution of rash.

It is important that patients with HZ are encouraged to present to physicians as early as possible for prompt medical care. Both public and medical education efforts are required to achieve this.15 In many individuals, HZ comprises rash and pain of relatively short duration. However, in some individuals, especially the elderly, HZ is associated with complications and prolonged pain. The aims of treatment are to minimize the duration and severity of pain and to prevent the complications. General measures include bed rest, antibiotics, analgesics, and topical astringents. Antiviral therapy for immunocompetent adults over 50 years of age with HZ is a specific measure that is routinely recommended, particularly if it can be instituted within 72 hours of lesion onset. Because of their improved pharmacokinetic profiles and simpler dosing regimens, valaciclovir (1000 mg three times a day) or famciclovir (250 mg or 500 mg three times a day) have replaced aciclovir (800 mg five times a day) as the preferred oral treatment. However, intravenous aciclovir seems the only available option in the treatment of HZ in immunocompromised individuals and in those who suffer from major complications discussed earlier. There is some evidence that antiviral therapy should be considered for patients whose rash has been present

Corticosteroids and HZ It is recommended that physicians consider the use of oral steroids to reduce inflammation that may be contributing to ZAP. Some recommend corticosteroids for the treatment and prevention of ocular disease caused by HZ. The literature concerning the use of corticosteroids for HZ either provides conflicting results or includes recommendations based on clinical experience rather than clinic al trials. With the concern over possible dissemination, adverse effects, and questionable efficacy, a careful examination of medical literature is

241

Herpes zoster: complications and management

Jayakar Thomas

warranted to determine the place of corticosteroids in the management of HZ.17 Potential of vaccine to prevent HZ The availability of a safe and effective varicella vaccine prevents the opportunity to determine whether it may also be effective for preventing HZ in the elderly. The initial suggestion that vaccination may reduce the likelihood of HZ was prompted by a study in children with leukemia who received VZV OKA vaccine. Among these, the incidence of HZ was lower than in children who had experienced natural VZV infection. 18 Conclusion Herpes zoster is a disease that can most often impair the quality of the patient's life. The pain associated with it is the most compelling cause for concern. HZ is a prototype of a disease which needs newer therapeutic approaches for which research in the following directions are recommended: · Improved and predictive animal models are needed for the study of acute disease and of latent VZV infection and to assess the effect of potential new drugs for the treatment of varicella and HZ. It is recommended that the development of suitable small animal models for studying VZV infection be continued. Although VZV reactivates in the dorsal root ganglia, it is unclear whether or not there are potential sites of reactivation. It is important to ascertain whether virus can reactivate in other sites and whether this reactivation can boost the

·

immune response. Further investigation of the hypothesis that reactivation occurs in peripheral blood mononuclear cells is recommended, as this would offer the chance of regularly monitoring reactivation and of predicting the onset of HZ. Continued research is recommended to obtain a better understanding of VZV latency, and, in particular, knowledge of the viral antigens expressed during that period. This may allow the development of approaches to prevent the reactivation of the virus and thus the onset of herpes zoster.

References

1. Requena L, Kutzner H, Escalonilla P et al. Cutaneous reactions at sites of herpes zoster scars; an expanded spectrum. Br J Dermatol 1998; 138: 161-8. Nico BMS, Bergonse FN, Godoy BM. Molluscum contagiosum in herpes zoster scars. Int J Dermatol 2001; 40: 521-4. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ et al. Neurologic complications of the reactivation of varicella-zoster virus. N Eng J Med 2000; 342: 635-45. Melanson M, Chalk C, Georgevich L. Varicella-zoster virus DNA in CSF and arteries in delayed contralateral hemiplegia: evidence for viral invasion of cerebral arteries. Neurology 1996; 47: 569-70. Horten B, Price RW, Jiminez D. Multifocal varicella-zoster virus leukoencephalitis temporally remote from herpes zoster. Ann Neurol 1981; 9: 251-66. Gray F, Mohr M, Rozenberg F. Varicella-zoster virus encephalitis in acquired immunodeficiency syndrome: a report of four cases. Neuropathol Appl Neurobiol 1992; 18: 502-14.

2.

3.

4.

·

5.

6.

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Journal of Pakistan Association of Dermatologists 2004; 14: 237-243.

7.

Marsh RJ, Cooper M. Ophthalmic herpes zoster. Eye 1993; 7: 350-70. 8. Womack LW, Liesgang TJ. Complications of herpes zoster ophthalmicus. Arch Ophthalmol; 1983; 101: 42-5. 9. Stemmer SM, Kinsman K, Tellschow S et al. Fatal noncutaneous visceral infection with varicella-zoster virus in a patient with lymphoma after autologous bone marrow transplant. Clin Infect Dis 1993; 16: 497- 9. 10. Rogers SY, Irving W, Harris AW et al. Visceral varicella zoster infection after bone marrow transplantation without skin involvement and the use of PCR for diagnosis. Bone Marrow Transplant 1995; 15: 805-807. 11. Whitley RJ, Weiss HL, Soong SJ et al. Herpes zoster: risk categories for persistent pain. J Infect Dis 1999; 179: 9-15. 12. Whitley RJ, Shukla S, Crooks RJ. The identification of risk factors associated with persistent pain following herpes zoster. J Infect Dis 1998; 178: 571-5.

13. Enders G, Miller E, Cradock-Watson J, et al. Consequences of varicella and herpes zoster in pregnancy: a prospective study of 1739 cases. Lancet 1994; 343: 1548-51. 14. Guess HA, Broughton DD, Melton LJ et al. Epidemiology of herpes zoster in children and adolescents: a populationbased study. Pediatrics 1985; 76: 512-7. 15. Smith KJ, Roberts MS. Cost effectiveness of newer antiviral agents for herpes zoster: is the evidence spotty? J Infect Dis 1998; 178 (Suppl 1): 585-590. 16. Nikkels AF, Fierard GE. Oral antivirals revisited in the treatment of herpes zoster. Am J Clin Dermatol 2002; 3: 591-8. 17. Santee JA. Corticosteroids for herpes zoster. Am J Clin Dermatol 2002; 3: 518-24. 18. Takahashi M. Current status and prospects of live varicella vaccine. Vaccine 1992; 10: 1007-14.

243

Cutaneous mucinoses: an overview

Aefan ul Bari

Review Article

Cutaneous mucinoses: an overview

Arfan ul Bari PAF Hospital Sargodha

Abstract The cutaneous mucinoses are a group of connective tissue disorders characterized by the

deposition of mucin, either focally or diffusely, in the interstices of the dermis. The diseases may occur as a primary (metabolic) event or as a secondary (catabolic) process in certain dermatoses such as lupus erythematosus and dermatomyositis. Systemic abnormalities are seen with most of these disorders. A brief review and classification of the disorders included in this group is given here. Key words Cutaneous mucinoses, dermal mucinoses, mucin, connective tissue disorders.

The cutaneous mucinoses are a heterogeneous group of diseases so named because of the variable amount of mucin accumulation in the skin or within the hair follicle. Mucin is jelly-like acid mucopolysacharide (glycosaminoglycan) of the ground substances and probably plays a role in extravascular exchange of metabolites. It is produced by fibroblasts and is composed of hyaluronic acid bound to heparin and chondroitin sulphate.1,2 We divide the cutaneous mucinoses into two groups: the distinctive cutaneous mucinoses in which the mucin deposit is a distinctive histopathologic feature that manifests as a clinically specific lesion (also called the metabolic or primary group), and the diseases associated with histopathologic mucin deposition as an additional finding (also called the catabolic or secondary group). The former are further divided into degenerative-inflammatory mucinoses,

Address for Correspondence Squadron Leader Dr. Arfan ul Bari Consultant Dermatologist, PAF Hospital, Sargodha Ph (off) # 0451-5553307 Ph (res) # 0451-5553308 Email: [email protected]

which may be either dermal or follicular, and into neoplastic -hamartomatous mucinoses. Histopathologic diagnosis is particularly difficult for dermal mucinoses and requires clinicopathologic correlation. Three histologic clues, namely the pattern of mucin distribution (diffuse or focal), the level of mucin deposit in the dermis and some additional findings may help diagnosis. Follicular mucinoses have the easiest pattern to recognize histologically. Neoplastic -hamartomatous cutaneous mucinoses include mucinous nevus, a benign hamartoma, and myxoma, which is a benign tumor to be differentiated from reactive cutaneous focal mucinosis.1-4 Histologically, mucins are stained with alcian blue at pH 2.5 (blue),mucicarmine (red), colloidal iron (blue green) and the colouration depends on the number and nature of the acid groups. They are also stained metachromatically with toluidine blue, methyline blue and thionine.5,6 Periodic acid-schiff (PAS) stains heparin but not hyaluronic acid. On the basis of histological site and pattern of mucin deposition and extent of involvement, cutaneous mucinoses may also be divided into focal, follicular and

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Journal of Pakistan Association of Dermatologists 2004; 14: 244-247.

diffuse. Focal mucinoses are localized benign forms that are usually not associated with other organ involvement. Follicular mucinosis is generally considered with cutaneous lymphomas. Diffuse cutaneous mucinoses differ from local mucinoses by greater cutaneous involvement, systemic organ dysfunction from mucin deposition and associated extra-cutaneous disease not related to mucin deposition. The full description of clinicopathological and diagnostic features in case of individual disorders is beyond the scope of this article, therefore, only the major mucinoses are listed and classified below and only treatment aspect has been touched briefly in the end. Clinicopathological classification3,4,7-10 A. Primary (metabolic) mucinoses These include cutaneous mucinoses in which the mucin deposit is a distinctive histopathologic feature that manifests as a clinically specific lesion and occurring as a primary pathology. This group is further divided into diffuse, focal and follicular on the basis of histological pattern and extent of involvement. (i) Diffuse These generally comprise of disorders with diffuse cutaneous involvement associated with variable systemic organ involvement such as endocrine system. · Generalized myxedema · Pretibial myxedema · Reticular erythematous mucinosis · Scleredema · Scleromyxedema · Diffuse papular mucinosis · Lichen myxedematosus

Self-healing juvenile cutaneous mucinosis · Cutaneous mucinosis of infancy · Papular and nodular mucinosis associated with lupus erythematosus (tumid LE) · Papular mucinosis of the toxic oil syndrome (ii) Focal Focal mucinoses are localized benign forms and generally, are not associated with other organ involvement · Acral persistent papular mucinosis · Cutaneous focal mucinosis · Oral focal mucinosis · Digital mucous cyst · Mucocele · Cutaneous myxoma · Nevus mucinosis (Hunter syndrome) (iii) Follicular forms These are characterized clinically by infiltrated scaly plaques with loss of hair and histologically by mucin deposition in sebaceous glands and the outer root sheath of hair follicles. The cases may or may not be associated with lymphomas. · Alopecia mucinosa (follicular mucinosis) · Urticaria -like follicular mucinosis B. Secondary (catabolic) mucinoses This group includes the diseases in which dermal mucinosis may, to a greater or lesser extent, be associated with otherwise typical histopathological features of that disease. · Lupus erythematosus · Dermatomyositis · Granuloma annulare · Jessner's lymphocytic infiltrate

·

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Cutaneous mucinoses: an overview

Aefan ul Bari

· · ·

· ·

Degos disease (malignant atrophic papulosis) Hereditary progressive mucinous histiocytosis Papula r mucinosis in L-tryptophaninduced eosinophilia -myalgia syndrome Mucinosis accompanying mesenchymal and neural tumours Mucopolysaccharidoses

Conclusion The cutaneous mucinoses are a complex group of dermatologic diseases with local, follicular, or diffuse disease. The diffuse cutaneous mucinoses are remarkable not only for their dermal disease, but also for the numerous systemic manifestations. Because of the variability of associated systemic manifestations, some with substantial morbidity and mortality, it is important for the clinical dermatologist to be able accurately to diagnose and differentiate various diffuse cutaneous mucinoses. References

1. Truhan AP, Roenigk HH Jr. The cutaneous mucinoses. J Am Acad Dermatol 1986; 14: 1-18. Rongioletti F, Rebora A. Cutaneous mucinoses. Ann Dermatol Venereol 1993; 120: 75-87. Jackson EM, English JC 3rd. Diffuse cutaneous mucinoses. Dermatol Clin. 2002; 20: 493-501 Stephens CJM, McKee PH, Black MM. The dermal mucinoses. Adv Dermatol 1993; 8: 201-27. Rongioletti F, Rebora A. The new cutaneous mucinoses: A review with an up-to-date classification of cutaneous mucinoses. J Am Acad Dermatol 1991; 24: 265-70. Scott JE, Dorling J. Differential staining of acid glycosaminoglycans by alcian blue in salt solutions. Histochemie 1965; 5: 221-3. Rongioletti F, Rebora A. Cutaneous mucinoses: microscopic criteria for diagnosis. Am J Dermatopathol 2001; 23: 257-67. Jeremy E R. Papular mucinosis. Dermatology Online Journal 2001; 7: 13. Clark BJ, Mowat A, Fallowfield ME, Lee FD. Papular mucinosis. Papular mucinosis: is the inflammatory cell infiltrate neoplastic? The presence of monotypic plasma cell population

Treatment11-16 Treatment of most of the cutaneous mucinoses remains unsatisfactory and no uniformly effective therapy exists, although several treatments are routinely used. Topical therapy is generally of no benefit. There have been occasional reports of spontaneous resolution of localized lesions. Clearance of lesions has been reported with melphalan and cyclophosphamide alone or in combination with prednisone. Both isotretinoin and etretinate have been associated with improvement. Interferonalpha, cyclosporine, PUVA photochemotherapy, electron-beam therapy, IVIg, and dermabrasion have also been attempted with variable succes. Isolated cases document the beneficial responses of dapsone, indomethacin, and interferons. Pulsed dye laser has been found successful in treating reticular erythematous mucinosis in one report. The overall prognosis for extensive disease is poor. Because of the variable course of the disease and the likelihood of spontaneous resolution, therapeutic efficacy is difficult to prove.

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3.

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5.

6.

7.

8.

9.

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10.

11.

12.

13.

demonstrated by in situ hybridization. Br J Dermatol 1996; 135: 467-70. Bata-Csorgo Z, Husz S, Foldes M, Korom I, Molnar K, Morvay M, et al. Scleromyxedema. J Am Acad Dermatol 1999; 41: 343-6. Sperber BR, Allee J, James WD. Selfhealing papular mucinosis in an adult. J Am Acad Dermatol. 2004; 50: 121-3. Caputo R, Grimalt R, Gelmetti C. Selfhealing juvenile cutaneous mucinosis. Arch Dermatol 1995; 131: 459-61. Howden SM, Herndon JH Jr, Freeman RG. Lichen myxedematosus: a dermal infiltrate disorder responsive to

cyclophosphamide therapy. Arch Dermatol 1975; 111: 1325-30. 14. Tschen JA, Chang JR. Scleromyxedema: treatment with interferon alpha. J Am Acad Dermatol 1999; 40: 303-6. 15. Liiter RK. Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg). J Am Acad Dermatol 2000; 43: 403-6. 16. Greve B, Raulin C. Treating REM syndrome with the pulsed dye laser. Lasers Surg Med 2001; 29: 248-51.

247

Ehlers-Danlos syndrome- a not so rare entity

Asher Ahmad Mahood

Case Report

Ehlers-Danlos syndrome- a not so rare entity

Asher Ahmed Mashhood Department of Dermatology, CMH Peshawar Cantt

Abstract The patient was a young girl who presented with 5 years history of excessive joint mobility,

difficulty in wound healing and formation of thin scars over the extensor aspects of the limbs. There was no history of any bleeding tendency, joint subluxation or eye complaints. On examination, the skin was soft and hyperextensible and the joints exhibited a great range of mobility. There were multiple paper-thin scars over the extensor aspects of elbows, knees and shins. There was a `molluscoid pseudotumour' over her right elbow. The patient was diagnosed as a case of EDS type I on the basis of history and clinical examination. The tumour was excised and the histopathology report was consistent with the diagnosis of molluscoid pseudotumour. She was prescribed Tab Vitamin C 500mg daily. The patient and the parents were explained about the disease, its prognosis and complications. Key words Ehlers-Danlos syndrome

Introduction Case report Ehlers-Danlos syndrome (EDS) is a group of generalized disorders of connective tissue. It is characterized by fragility of the skin and blood vessels, hyperextensibility of the skin and joint hypermobility.1 At least 10 clinical types have been defined, although some patients fail to fit neatly into one category. This is the first case report of EDS appearing in Pakistani literature. The purpose of this case report is to present the key features of this syndrome and to briefly discuss the features of other types of the syndrome. It is a rare syndrome and a clear knowledge of the disease and its complications is must for all the practicing dermatologists.

Address for Correspondence Maj. (Dr) Asher Ahmed Mashhood Classified Dermatologist CMH Peshawar Cantt Email: [email protected]

A 10-year-old girl reported in Skin OPD of Combined Military Hospital, Peshawar with five years history of hypermobility of all the joints of her body and difficulty and delay in wound healing. The wounds healed by leaving large scars. There was also a history of a soft, nodular and painless mass over her right elbow since last one month. There was no history of any bruising or bleeding tendency, periodontal disease, varicose veins, hernias or any ocular complaint. The patient was 2nd among the two brothers and two sisters. Rest of the family members were all healthy. On general physical examination, the girl was of thin and lean build. She was well oriented in time and space. Her vital signs were all stable. Her systemic examination revealed no abnormality, however all of

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Journal of Pakistan Association of Dermatologists 2004; 14: 248-252.

Figure1 Skin is hyper extensible but springs back to its position when released.

Figure 3 A soft, nodular, skin-coloured growth over the right elbow. Note the extensive pronation of the right forearm.

was made. Excision biopsy of the soft nodular growth was made and the histopathology revealed a mixture of fat cells and mucoid material in a fibrous stroma. The parents were explained at length about the disease, its mode of inheritance, possible complications and the prognosis. The patient was placed on Tab Vitamin C 500mg/day and instructed to pay regular visits to the Skin OPD. The Ehlers-Danlos syndrome is a heterogeneous group of generalized connective tissue disorders, the major manifestations of which are skin fragility, skin hyperextensibility, and joint hypermobility. The clinical and molecular definition of more than ten types of EDS has, more than ever, emphasized the importance of correct diagnosis because the natural history and mode of inheritance differ among the types.2 This disorder affects approximately 1 in 5,000 live births, including males and females of all racial and ethnic groups.3 Specific biochemical abnormalities involving the collagen fibers are identified in several types, although type IX also affects elastin metabolism4 and type X has a defect in fibronectin.5 Table 1 provides

Figure 2 Multiple paper-thin scars over her right knee and front of her leg.

her joints showed hypermobility. The skin examination revealed hyperextensible skin, which was not lax (Figure 1). There were multiple paper-thin scars over her both forearms and legs, especially over the knees and shins (Figure 2). There was a 2x2 cm soft, nodular, skin-coloured growth over her right elbow, which was not tender (Figure 3). Discussion Based upon the history and clinical appearance the diagnosis of EDS type-I

249

Ehlers-Danlos syndrome- a not so rare entity

Asher Ahmad Mahood

Table 1 Current classification of Ehlers-Danlos syndrome Types I Gravis* Clinical features Soft, hyper extensible skin; easy bruising; thin, atrophic scars; hypermoblie joints; varicose veins; prematurity of affected newborns Similar to EDS type I but less severe Soft skin; large and small joints are hyper mobile Thin, translucent skin with visible veins; easy bruising; absence of skin and joint extensibility; arterial, bowel and uterine rupture Similar to EDS type II Soft skin, muscle hypotonia; scoliosis; joint laxity; hyperextensible skin Congenital hip dislocation, severe joint hyper mobility; soft skin with normal scarring Inheritance AD Biochemical Defect Mutation in pro1(V) or pro2(V) chains of type V collagen (COL5A1, COL5A2) in some families Same as EDS I Not known Mutations in COL3A1; abnormal type III collagen synthesis, secretion or structure Not known Lysyl hydroxylase deficiency; mutations in PLOD gene Deletion of exons from type I collagen gene that encodes amino-terminal propeptide cleavage site of COL1A1 (type VIIA) or COL1A2 (type VIIB) Recessive mutations in type I collagen N-peptidase (type VIIC) Not known

II Mitis* III Familial hypermobile IV Arterial

AD AD AD

V X-linked^ VI

XLR AR

VII Arthrochalasia multiplex Type VIIA, B

AD (type VIIA, B)

VII Type VIIC VIII Periodontal #

Severe skin fragility; sagging, redundant skin Generalized periodontitis; soft hyperextensible skin; chronic purple-hued scarring over shins Soft lax and hyper extensible skin; short arms; limited pronation/ supination, occipital horns, broad clavicles; bladder diverticula; inguinal hernia Similar to EDS type II, with abnormal clotting studies

AR (type VIIC) AD

IX X-linked cutis laxa ±

XLR

Defect in lysyl oxidase

X^

AR

Proposed defect in fibronectin

* In proposed new classification, merged as a single entity, ^ Found only in a single family, # May be a variant of EDS type I/II rather than a distinct entity, ± Probably not a separate entity. Related to Menkes syndrome, Note: AD - autosomal dominant, A R - autosomal recessive, XLR - X linked recessive

the currently acceptable classification, known biochemical defects; brief clinical features and modes of inheritance in different types of EDS. EDS type-I is the commonest variety of this syndrome. It is inherited as an autosomal dominant trait. In both the types I and II syndromes, it is suspected that

there are some genetic abnormalities that result in abnormal type I collagen fibril structure because electron micrographs have detected abnormally thick type I collagen fibrils.6 In the skin of some patients with EDS I and II, the fiber bundles are abnormally small. Linkage studies have excluded type I collagen genes themselves as the genetic defect in

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some families with EDS types I and II.7 Interest in type V collagen as a candidate molecule in EDS came about because type V collagen and type I collagen molecules form heterotypic collagen fibrils.8 There are now several published reports of linkage to COL5A1 and/or mutations in the coding regions of proa1(V) chains in EDS families.9,10 There is also an evidence of locus heterogeneity, because mutations in the triple -helical domain of proa2(V) chains of type V collagen can also cause the classic EDS type I/II phenotype.11 Skin in EDS type I is soft, velvety and can be stretched easily, and when released springs back immediately to its original position. The skin is not otherwise lax, until later in life, when redundant folds form at the elbow. The dermis is fragile and is easily bruised. Striae do not develop. Scars after trauma or surgical procedures are thinned and atrophic and may stretch considerably after healing, having a characteristic "cigarette paper" appearance. Sutures may tear out repeatedly. Blue-grey spongy tumours, "molluscoid pseudotumours" are formed on extensor surfaces of joints, in the foot or on shins. Joints are hyper mobile, which may cause pain while walking. Furthermore, joint hyper mobility may leads to subluxation of large joints, scoliosis, pes planus (flat foot) and rd osteoarthritis in 3 or 4th decade. Muscle tone is often poor leading to diaphragmatic eventration and gastric torsion.12 Other complications include varicose veins, prematurity due to rupture of fetal membranes, mitral valve prolapse, dilatation and rupture of ascending aorta or proximal pulmonary artery. As physical

and mental developments are normal, life expectancy is not reduced. The diagnosis is made primarily on the basis of a detailed history and clinical examination. The laboratory diagnosis can be done only in specialized laboratories working on molecular biology of collagen. The treatment is highly unsatisfactory. Some benefit may be achieved by giving oral ascorbic acid in a dose of 500-3000 mg daily. It is found that 4 grams of vitamin C daily produce a significant improvement in the quality of newly synthesized collagen but do not alter the pre-formed collagen.13 Suture should be buttressed and tension avoided. However re-excision of ugly scars gives a good cosmetic result.14 Conclusion Ehlers-Danlos syndrome is not a commonly encountered disease. A clear understanding of the key feature of this syndrome is vital for the diagnosis and knowledge of its complications and prognosis is important to satisfy the patients and their relatives. References

1. Beighton P, ed. The Ehlers-Danlos syndrome. London: Heinemann; 1970. Byers PH. Ehlers-Danlos syndrome: recent advances and current understanding of the clinical and genetic heterogeneity. Invest Dermatol 1994; 103: 47S-52S. Whitelaw SE. Ehlers-Danlos syndrome, classical type: case management. Pediatr Nurs 2003; 29: 423-6.

2.

3.

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Ehlers-Danlos syndrome- a not so rare entity

Asher Ahmad Mahood

4.

5.

6.

7.

8.

9.

Christiano AM, Uitto J. Molecular pathology of the elastic fibers. J Invest Dermatol 1994; 103: 53S-57S. Arneson MA, Hammerschmidt DE, Furcht LT. A new form of EhlersDanlos syndrome: fibronectin corrects the defective platelet function. JAMA 1980; 244: 144-7. Hausser I, Anton-Lamprecht I. Differential ultrastructural aberrations of collagen fibrils in Ehlers-Danlos syndrome types I­IV as a means of diagnostics and classification. Hum Genet 1994; 93: 394-403. Sokolov BP. Exclusion of COL1A1, COL1A2, and COL3A1 genes as candidate genes for Ehlers-Danlos syndrome type I in one large family. Hum Genet 1991; 88: 125-32. Birk DE et al: Collagen type I and type V are present in the same fibril in the avian corneal stroma. J Cell Biol 1988; 106: 999-1007. Wenstrup RJ et al: A splice-junction mutation in the region of pro? 1(V) a

10.

11.

12.

13.

14.

chains results in the gravis form of the Ehlers-Danlos syndrome (type I). Hum Mol Genet 1996; 5: 1733-9. Nicholls AC et al: An exon skipping mutation of a type V collagen gene (COL5A1) in Ehlers-Danlos syndrome. J Med Genet 1996; 33: 940. Michalickova K. Mutations of the a ? 2(V) chain of type V collagen impair matrix assembly and produce EhlersDanlos syndrome type I. Hum Mol Genet 1998; 7: 249-56. Phadke JG. Ehlers-Danlos syndrome with surgical repair of penetration of diaphragm and torsion of stomach. J R Soc Med 1979; 72: 781-3. Ringsdorf WM Jr, Cheraskin E. Vitamin C and human wound healing. Oral Surg Oral Med Oral Pathol 1982; 53: 231-6. Reidy JP. Cutis hyperelastica (EhlersDanlos) and cutis laxa. Br J Plast Surg 1963; 16: 84-94

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Case Report

Acral persistent papular mucinosis: A rare variant of cutaneous mucinosis

Arfan ul Bari, Muhammad Rashid*, Simeen ber Rahman** Dermatology Department, PAF Hospital Sargodha *ENT Department, PAF Hospital Sargodha ** Dermatology Department, Military Hospital, Rawalpindi, Pakistan

Abstract Acral persistent papular mucinosis (APPM) is a distinctive form of dermal mucinosis not

associated with systemic diseases. We report such a case in a sixty years old male who presented with few small papular lesions over both of his ears. These were managed successfully with excision and cryosurgery. Key words Papular mucinosis, myxedematosus

acral

persistent

papular

mucinosis,

scleromyxedema,

lichen

Introduction Papular mucinosis is one of the cutaneous deposit diseases that presents as fleshcolored dermal papules mostly on the acral parts of the body. There is confusion with regard to the terminology of this entity in the literature. Localized form of the disease has been called papular mucinosis or lichen myxedematosus and generalized, confluent papular forms with sclerosis are known as scleromyxedema.1,2 Although papular mucinosis is frequently used as a synonym for all three forms, but more appropriately it should be restricted to only mild cases. Acral persistent papular mucinosis is now considered to be a separate entity. This acral condition is

Address for Correspondence Squadron Leader Dr. Arfan ul Bari Consultant Dermatologist, PAF Hospital, Sargodha Ph (off) # 0451-5553307 Ph (res) # 0451-5553308 Email: [email protected]

rare, affects adults of both sexes equally and appears between ages 30 and 80. It is chronic and may be progressive. The primary lesions are waxy, 2-to-4-mm, dome-shaped or flat-topped papules. Frequently, they may coalesce into plaques or appear in a linear array. Less frequently, urticarial, nodular, or sometimes annular lesions may be appreciated. The dorsal aspect of the hands, face, elbows, and extensor portions of the extremities are most frequently affected. Mucosal lesions are absent. The coalescence of papules on the face, particularly of the glabella, results in longitudinal folding and may give the appearance of a leonine facies.1-4 In scleromyxedema, large parts of the body may be involved; the skin shows erythematous, scleroderma-like induration that is accompanied by reduced mobility of the lips, hands, arms, and legs. Systemic manifestations have been described (myopathy, polyarthritis, esophageal aperistalsis, and hoarseness)

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Acral persistent papular mucinosis: a rare variant of cutaneous mucinosis

Arfan ul Bari et al.

and visceral involvement may be fatal. Laboratory studies in mild acral forms are usually normal but may show an abnormal paraprotein, usually of the IgG-8 type in scleromyxedema and more generalized forms of the disease. This underlying suggestion of a plasma-cell dyscrasia prompts examination of the bone marrow, which may be normal or show increased numbers of plasma cells or even myeloma.1-3,5,6 Histologic examination of papular mucinosis shows dermal deposition of mucin, best depicted with alcian blue or colloidal iron stains. There is an increase in the number of fibroblasts and dermal fibrosis. Mild localized form may heal spontaneously.7 Other treatment options include potent topical steroids, dermabrasion, cryosurgery and local surgical excision. In case of more generalized forms, clearance of lesions has been reported with melphalan and cyclophosphamide alone or in combination with prednisone. Both isotretinoin and etretinate have been associated with improvement. Interferonalpha, cyclosporine, PUVA photochemotherapy, electron-beam therapy, IVIg have also been tried.1,2,5,6,8,9 The prognosis is good in case of limited cutaneous disease but for extensive disease, it is generally poor. The purpose of reporting this case was to highlight this rare cutaneous deposit disorder. Case report A 60-year-old, otherwise healthy man reported with a two year history of 3 -4, firm, skin colored papules on each ear. These were painless and non itchy. He did

Figure 1 Small skin-coloured papules on left ear.

Figure 2 Small skin-coloured papules on right ear.

Figure 3 Histopathology showing upper a nd mid dermal mucin deposits separating collagen fibers and fibroblasts.

not notice similar lesions elsewhere over the body. On examination, 3-4, 0.1 to 0.4cm, firm, skin-colored papules were noted on outer aspects of each ear (Figures 1 and 2). Laboratory investigations including; blood complete picture, serum glucose, serum cholesterol, liver and renal

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function studies were all within normal range. A serum protein electrophoresis was also normal. Excision biopsy of two larger lesions on both sides was done and it revealed upper and mid dermal deposits of mucin associated with a proliferation of plump fibroblasts (Figure 3). On confirmation of diagnosis, the remaining lesions were managed successfully with cryosurgery (by applying liquid nitrogen twice weekly for two weeks). There was no recurrence or new eruption during next six months. Discussion Acral persistent papular mucinosis is rather a rare benign entity, which occurs mostly on dorsum of the hands, face and ears.1,4 In our case the disease was restricted only to the ears. The lesions were few and were symmetrically distributed. These were asymptomatic but patient was concerned about pebbly appearance of the superior margin of the ears and was little apprehensive about the nature of the lesions. After histological confirmation of the lesions, he was reassured about the benign nature of the disease. Generally, this is considered a benign form of dermal mucinosis that has not been associated with any other underlying disease, but there has been an occasional report of its association with paraprotienemia .10 We did not find any such association in our case. Other forms of dermal mucinosis like, lichen myxedematosus and scleromyxedema have been clearly associated with multiple disorders.2,5,6

Conclus ion Acral persistant popular mucinosis should be considered a separate entity and must not be mixed with other mucinoses. References

1. Jeremy E R. Papular mucinosis. Dermatology Online J 2001; 7 : 13. 2. Stephens CJM, McKee PH, Black MM. The dermal mucinoses. Adv Dermatol 1993; 21:293. 3. Clark BJ, Mowat A, Fallowfield ME, Lee FD. Papular mucinosis. - is the inflammatory cell infiltrate neoplastic - the presence of a monotypic plasma cell population demonstrated by insitu hybridization. Br J Dermatol 1996; 135: 467-70. 4. Menni S, Cavicchini S, Brezzi A et al. Acral persistent papular mucinosis in two sisters. Clin Exp Dermatol 1995; 20: 431-3 5. Howden SM, Herndon JH Jr, Freeman RG. Lichen myxedematosus: a dermal infiltrate disorder responsive to cyclophosphamide therapy. Arch Dermatol 1975; 111: 1325-30. 6. Bata-Csorgo Z, Husz S, Foldes M et al. Scleromyxedema. J Am Acad Dermatol 1999; 41: 343-6. 7. Caputo R, Grimalt R, Gelmetti C. Self-healing juvenile cutaneous mucinosis. Arch Dermatol 1995; 131: 459-61. 8. Tschen JA, Chang JR. Scleromyxedema: treatment with interferon alpha. J Am Acad Dermatol 1999; 40: 303-6. 9. Liiter RK. Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg). J Am Acad Dermatol 2000; 43: 403-6. 10. Borradori L, Aractingi S, Blanc F et al. Acral persistent papular mucinosis and IgA monoclonal gammopathy: report of a case. Dermatology 1992; 185: 134-6.

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Malignant melanoma of index finger

Moizuddin et al.

Case Report

Malignant melanoma of index finger

Moizuddin, Azmeenah Valimohd* , Athar Ansari Department of Surgery, Hill Park General Hospital, Karachi. * Department of Oncology, Hill Park General Hospital, Karachi.

Abstract Malignant melanoma is rarely encountered in pigmented skin. Acral melanoma is the usual

type s een in coloured skin. It can present as palmar, solar or subungual melanotic macules. In subungual location, the diagnosis may be delayed. We describe an adult female with acral malignant melanoma in whom the diagnostic delay led to spread of disease to regional lymph nodes. Key words Malignant melanoma

Introduction Malignant Melanoma is an uncommon cancer in Pakistan unlike in the western world where it is the commonest skin cancer. Melanomas of the extremities are rare. Surgical management is a difficult and challenging problem.We report a case of malignant melanoma in a 50 years old female who presented with an ulcerated lesion of her index finger and a mass in axilla. Biopsy confirmed the diagnosis. Surgical removal of the primary lesion and axillary nodal clearance had a successful outcome. Case A 50-year-old lady, resident of Quetta, presented with a history of purulent discharge from her right index finger under the nail with a blackish ulcer. This was initially dealt with by drainage by her family

Address for Correspondence Dr. Moizuddin Consultant Surgeon Hill Park General Hospital, Karachi 256

physician. The condition got worse and a swelling appeared in axilla. Excision biopsy of the nail bed revealed fragments of squamous epithelium with underlying tissue exhibiting a pigmented neoplastic lesion comprising of cells with abundant melanin pigment, prominent nucleoli and marked degree of pleomorphism, these cells invading into the overlying epithelium, suggestive of malignant melanoma. On examination she was an average built, fair skinned woman who was vitally stable. A bleeding ulcer, discharging pus with pigmentation was noticeable at the right index finger under the nail bed. There was a palpable node in the right axilla. Systemic review was within normal limits. Routine preop tests were normal. Radiological metastatic workup including CT scan of chest and abdomen confirmed presence of large right axillary nodes measuring 4.1x 3.1 cms. No infiltrate, mass or consolidation was seen in either lung. Mediastinal and hilar lymphadenopathy was absent. Abdomen was normal with absence of any

Journal of Pakistan Association of Dermatologists 2004; 14: 256-258.

Figure 1 A bleeding ulcer with discharging pus and pigmentation affecting the right index finger.

Figure 2 Dissection of right axilla showing a large black nodal mass

lesion in liver, gallbladder, spleen, pancrease, adrenals, kidneys, urinary bladder and the uterus. No evidence of abdominal or pelvic lymphadenopathy was present. Surgical treatment included disarticulation of right index finger at metacarpophalangeal joint and axillary dissection with removal of large black n odal mass (Figure 2). The patient had smooth post-op recovery. Biopsy later confirmed Stage III malignant melanoma. Discussion John Hunter (1728-1793) first described malignant melanoma in 1787. 1 Jonathan Hutchinson (1828-1913) described a flat-

pigmented brown to black melanocytic naevus with malignant potential that occurs on sun-damaged skin on the face, dorsum of the hands and forearm. 2 The malignant transformation occurs in the fifth to seventh decades. These tumours are the commonest skin cancer in the west in whites and relatively rare in blacks.1-4 The largest study of skin cancer in Pakistan by Mansoor et al.5 reported an incidence of 1.2 % in their series. Another study from Karachi by Yasmeen et al.6 showed an incidence of only 5 cases of malignant m elanoma out of 75 skin tumors, with 2 belonging to extremities. Khursheddi et al.7 had previously reported the first ever case of cutaneous melanoma of the sole of the foot in Pakistan in a 97-yearold woman. This case report adds to the list of this exotic tumor at a site hitherto not reported in local literature. We plan chemotherapy and immunological manipulation with i terferon for the control n of the disease. Wide local excision or amputation (e.g. for subungual lesion) and regional lymph node dissection for clinically positive nodes is the treatment of choice. Palliation may be achieved with radiotherapy, or by using cytotoxic agents systemically or regional perfusion with dacarbazine, cisplatin, and n itrosureas with variable response. Finally we would again emphasise the point that any lesion on the skin, which suddenly shows signs of enlarging, must be biopsied as early as possible. References

1. 2. Marks R. An overview of skin cancer. Cancer 1995; 75 (Suppl 2): 607-12. Pion I.A, Rigel D.S, Garfinkel L et al Occupation and the risk of malignant

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3. 4.

5.

melanoma. Cancer 1995: 75 (Suppl 2): 637-44. Elder DE. Skin cancer. Cancer 1995; 75 (Suppl 1): 245-56. Kopf AW, Salopek TG, Slade J et al. Cutaneous examination for skin cancer. Cancer 1995; 75 (Suppl 2): 684-90. Mansoor Al, Naveed I Kamal F eet A, al. Profile of malignant skin tumours over a five year period at the departement of pathology, KE Medical

6.

7.

College Lahore. Biomedica 1999; 15; 58. Yasmeen N, Saeed S, Kanjee A, Sadiq S. A study of 75 cases of malignant skin lesions. J Pak Assoc Dermatol 2002; 12; 130-4. Khurshaidi N, Soomro R, Moizuddin. Primary cutaneous melanoma of the foot. J Pak Assoc Dermatol 2000; 10: 38-40

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Case Report

Leukemia cutis: an indicator of relapse in a patient with myeloid leukemia ­ a case report

Faria Asad, Mansoor Haider, Sabrina Suhail Paal Department of Dermatology, Unit II, King Edward Medical College/Mayo Hospital, Lahore

Abstract Leukemia cutis is a specific cutaneous lesion of leukemia in which there is deposition of

leukemic cells. We report an adult female with papulonodular lesions on the chest region. A skin biopsy was found helpful in diagnosing the relapse in our patient with haematological remission. Key words Leukemia cutis

Introduction Leukemia cutis is regarded as a dissemination of systemic leukemia to skin and its presence is usually associated with a grave prognosis. The skin lesions in a patient with leukemia can be due to either specific cutaneous leukemic infiltration or other non-specific lesions.1 The specific lesions of leukemia cutis are due to infiltration of the epidermis, dermis or subcutaneous tissue by neoplastic leukocytes or their precursors and can have various presentations. Papules, plaques and nodules are the most common lesions. These are typically firm, erythematous or red brown to purple and can become purpuric with coexistent thrombocytopenia. The other clinical appearances of leukemia cutis may be macules, ulcerative or bullous lesions and

Address for Correspondence Dr. Faria Asad, Assistant Professor of Dermatology, KEMC/Mayo Hospital, Lahore Email: [email protected]

urticaria, erythema annulare centrifugum or guttate psoriasis like etc.2 Nonspecific cutaneous manifestations of leukemia are reactive or paraneoplastic. They may arise from marrow failure like pallor or anemia, purpura and bleeding from mucous membranes secondary to thromobocytopenia. Pruritus and herpes zoster are more frequent findings. Prurigo like papules, erythema multiforme, bullous pemphgoid, hyperpigmentation and nonspecific eczematous eruption have also been observed with leukemia.2,3 Leukemia cutis can be diagnosed by biopsy, but the cell type cannot always be identified with certainity. Specific cell markers are needed for de finite diagnosis.1 The best treatment for both specific and non-specific eruption of leukemia is the cure and control of the underlying systemic disease. When such control can not be achieved by currently available chemotherapy, immunotherapy or

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Faaria Asad and Sabrina Suhail Pal

radiation or where response is slow or incomplete, local treatment in the form of electron beam therapy can be used. 4

was started with combination therapy of cytocin and daunorubicin. The lesions

Case report A 42-year old woman presented at the out patient department of Dermatology Unit II, Mayo Hospital, Lahore with few nodules on the neck and upper trunk for the last 3-weeks. She was asymptomatic. The nodules were erythematous to dark brown, firm with a smooth surface (Figure 1). She had been diagnosed as a case of acute myeloid leukemia three months back for which she was given induction therapy followed by consolidation therapy with high dose of cytosar. Except for the nodules, her skin, nail, hair and mucosae were unremarkable. Systemic examination did not reveal any abnormality. Blood, urine, kidney and liver function tests, ultrsonography, x-ray chest, computerized tomography scans (viscera and bones) were normal and there was no evidence of extramedullary disease. A skin biopsy was taken which showed normal epidermis. The dermis revealed a heterogeneous population of small and large cells with eosinophilic cytoplasm, pleomorphic vesicular nuclei and prominent nucleoli. Immunohistochemical analysis from the biopsy specimen identified that the neoplastic cells belonged to monocytic lineage. A diagnosis of leukemia cutis was made. She

Figure 1 Dusky-red papules and nodules coalescing into plaques over chest.

began to subside after three weeks Discussion Leukemia cutis is a relatively rare condit ion and the exact overall incidence of the disease is unclear. All types of leukemias result from the abnormal development of leukocytes in the bone marrow. Maturational arrest occurs, and a proliferative clonal population of cells results. A variety of defects promote the clonal expansion of leukemic cells. These defects include an abnormal proliferative potential, defective terminal differentiation, and apoptosis. The increased proliferative potential is caused by the activation of oncogenes or the inactivation of tumor suppressor genes. Leukemia cutis is thought to result from a local proliferation of the leukemic cells within the skin. 1

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References In most cases of leukemia cutis, systemic disease precedes the development of skin lesions. However, in as many as 7% of patients with leukemia cutis, localized disease occurs prior to bone marrow infiltration and systemic symptoms (aleukemia cutis or primary extramedullary leukemia [EML]).5 Our patient developed cutaneous lesions when her recent report showed that the marrow was in remission, indicating relapse and need for further therapy. The underlying mechanism is believed to be accumulation of small quantities of myeloblasts in bone marrow and with high tropism for the dermis.6,7 It has been observed that in cases of leukemia cutis combination therapy is more effective than single agent high dose therapy. Our patient was also treated with combination therapy which led to regression of lesions. Dermatology is a visual, specialty and early recognition of diseases especially if malignant, is always helpful in the management and prognosis.

1. Ratram KV, Lkhor CJ, Danie l Su WP. Leukemia cutis. Dermatol Clin 1994; 12:419-31. Zaman T, Pal SS, Khurshid K: Leukemia cutis ­ the specific cutaneous lesion of leukemia: a clinical study of 250 patients. Ann King Edward Medical College 1999; 5: 255-8. Buchner SA. Specific and nonspecific skin manifestations in leukemia. Schweiz Rundsch Med Prax 2002; 91: 1071-7. Gambichler T, Herde M, Hoffmann K. Poor prognosis of acute m yeloid leukaemia associated with leukaemia cutis. J Eur Acad Dermatol Venereol 2002; 16: 177-8. Bachmeyer C, Turc Y, Fraitag S. Aleukemic monoblastic leukemia cutis. Ann Dermatol Venereol 2003; 130: 773-5. Pont V, Miquel FJ, Grau TC. Skin involvement in chronic myelomonocytic leukaemia as a predictor of transformation into acute myeloid leukaemia. J Eur Acad Dermatol Venereol 2001; 15: 260-2. Ognbiyi AO, Shokunbi WA, Fasola FA. Leukaemia cutis in a patient with acute myelogenous leukaemia: case report. East Afr Med J 2003; 80: 6068.

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What caused this patch?

Amor Kachemoune and Shahbaz A. Janjua

Photodermdiagnosis

What caused this patch?

Amor Khachemoune, Shahbaz A. Janjua* Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, United States *Ayza Skin and Research Center, Lalamusa 50200, Pakistan.

The healthy mother of a 6 -month-old girl was concerned about an irregular, pale, relatively large patch on the abdomen of her child. (Figure 1) She reported that the lesion was present at birth, had increased in size with the child's growth, and may have become slightly lighter and more noticeable over the 3 months prior to her presentation. The fathers of the child, as well as 3 siblings, were healthy with no abnormal mucocutaneous findings. There was no history of autoimmune disorders in the family. What would be the main differential diagnosis in this case? How would you approach it? Turn the page for the diagnosis and a brief discussion.

Address for Correspondence Amor Khachemoune, MD, CWS 1440 Beacon Street #508 Brookline, MA 02445 Phone: (617) 879 4713 E mail: [email protected]

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Diagnosis Nevus anemicus

Practical approach in the office Diascopy On diascopy, the borders of the lesions will blanch with pressure due to constriction of the blood vessels in the surrounding normal skin; this will make the lesion indistinguishable from surrounding skin. Friction With a tongue blade, you may make a few strokes across both the lesion and the normal-appearing surrounding skin. You should notice a flare on the skin surrounding the lesion, but not the central pale area of the NA. Heat or ice cube Application of heat or an ice cube will often accentuate the lesion, as the border becomes hyperemic while the lesion stays pale. NA is also more noticeable when there is surrounding vasodilatation due to emotional stress. Wood's lamp Wood's lamp examination does not accentuate NA, and may make the lesion inapparent, unlike true depigmenting disorders. Getting to the roots "pharmacologic nevus" of the term

Discussion

Nevus anemicus (NA), also known as pharmacologic nevus, is a nonmelanotic disorder in which pigmentation remains unaffected. NA usually presents as a unilateral pale area of variable size (3-10 cm) with an irregular or "br oken up" outline on the trunk. It is usually present at birth but often noticed later in life. The trunk is the most common location. It occurs more frequently in females and is usually asymptomatic. Histologically, there are no abnormalities of the melanocytes or melanin content. NA is caused by decreased blood flow through the capillaries in the dermal papillae, due to localized hypersensitivity of the blood vessels to catecholamines. Local blood vessels are very sensitive to endogenous catecholamines, remaining permanently vasoconstricted. 1 So, the paleness in NA is vascular, not pigmentary. In addition to nevus depigmentosus (ND), the differential diagnosis includes other hypopigmented or depigmented disorders, such as hypochromic nevi, ash leaf spots of tuberous sclerosis complex, and vitiligo. An extensive review of the differential diagnosis is beyond the scope of this paper. In the following discussion we will focus on the main differences between NA and ND (Table 1).

The following findings may justify the fact that nevus anemicus is best termed a pharmacologic nevus resulting from increased vascular sensitivity to catecholamines, and suggesting that several pharmacological anomalies may be involved: a. Intralesional injection of bradykinin, acetylcholine, pilocarpine, serotonin, nicotine,

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Table 1 Comparison and contrast of nevus anemicus and nevus depigmentosus Nevus anemicus 1. Congenital patch manifested by skin pallor 2. Most commonly occurs as a single patch on the trunk 3. Caused by a localized vascular hypersensitivity to catecholamines which produces increased vasoconstriction and skin pallor 4. No loss of melanin occurs in the lesion 5. Is a pharmacologic nevus 6. Wood's lamp examination does not accentuate it, rather makes the lesion inapparent 7. Diascopy obliterates the border between lesion and normal skin, because the normal skin becomes blanched. 8. Scratching a line across both the lesion and normal surrounding skin will produce erythema in the normal skin but not within the lesion, similarly application of cold or heat will not produce changes within the lesion 9. Histology normal, and melanocytes are preserved and normally distributed. Nevus depigmentosus 1. Congenital dermatosis that manifests as unilateral, hypopigmented patches 2. Usually occurs in a dermatomal pattern. 3. Caused by a block of transfer of melanosomes from melanocytes to keratinocytes 4. Loss of melanin is present causes the lesion 5. Is an anatomic nevus 6. Wood's lamp examination makes the lesion apparent 7. Diascopy would not obliterate the border between lesion and normal skin. 8. Scratching a line across both the lesion and normal surrounding skin will produce erythema both in the normal skin and within the lesion

9. Histology is abnormal showing loss of melanosomes in the melanocytes.

b.

c.

5-hydroxytryptamine, and histamine fails to induce the anticipated vasodilatation or erythema in the affected area. However, following axilla ry sympathetic block or intradermal injection of pilocarpine (an alpha-blocking agent) vasodilatation and erythema are produced in the lesion. It also has been proposed that an abnormality in endothelial adhesion molecule induction (E selectin expression) may be involved.

site. This phenomenon is known as the donor site dominance. Nevus depigmentosus Nevus depigmentosus (ND) is also called achromic nevus or nevus achromicus. ND is a cutaneous abnormality consisting of a hypopigmented macular lesion which can present as circumscribed irregular, oval, or round or as a unilateral band or streak arranged along one or more Blaschko lines that is present at birth and remains stable over time.2-4 Most lesions measure a few centimeters in diameter and have irregular but well-defined borders. When it is very extensive, it is indistinguishable from hypomelanosis of Ito. The name is a bit of misnomer as the areas of leukoderma are actually hypomelanotic not amelanotic. Wood's light makes the lesion more noticeable.

The donor site dominance In autograft exchange transplantation studies, the skin transplanted within the NA retains characteristics of the donor

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On histopatholgy, melanocytes can be normal or slightly reduced in number in ND. Transfer of the melanosomes from melanocytes to keratinocytes is believed to be abnormal in ND. A few patients with ND have been reported to have associated seizures, mental retardation, pes cavus ipsilateral to the hypopigmentation, and hemihypertrophy. 5,6 However, in a recent review of 50 cases of ND from India,7 no abnormal neurologic features were found. In a more recent article Diepell et al.8 reported the case of a patient with ND associated with nevi flammei affecting two contralateral quadrants, venous insufficiency of the right leg, and asymmetry of the arms. We hope this short review helps our readers differentiate NA from ND. References

1. Mountcastle EA, Diestelmeier MR, Lupton GP. Nevus anemicus. J Am Acad Dermatol 1986; 14: 628-32.

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3.

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Bolognia JL, Pawelek JM. Biology of hypopigmentation. J Am Acad Dermatol 1988; 19: 217-47. Orlow SJ. Congenital and genetic disorders associated with hypopigmentation. Curr Probl Dermatol 1994; 6: 157-84. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54 cases of hypopigmentation and hyperpigmentation along the lines of Blaschko. Arch Dermatol 1996; 132: 1167-70. Sugarman GI, Reed WB. Two unusual neurocutaneous disorders with facial cutaneous signs. Arch Neurol 1969; 21: 242-7. Di Lernia V. Segmental nevus depigmentosus: analysis of 20 patients. Pediatr Dermatol 1999; 16: 349-53. Dhar S, Kanwar AJ, Kaur S. Nevus depigmentosus in India: experience with 50 patients. Pediatr Dermatol 1993; 10: 299-300. Dippel E, Utikal J, Feller G et al. Nevi flammei affecting two contralateral quadrants and nevus depigmentosus: a new type of phacomatosis pigmentovascularis? Am J Med Genet 2003; 119: 228-30.

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ICMJE uniform requirements for journals.

International Committee of Medical Journal Editors (ICMJE): uniform requirements for journals

ICMJE uniform requirements for journals are reproduced here as a part of requirement set by Pakistan Medical and Dental Council for medical journals. This will help the budding authors to prepare their manuscripts minimizing the chances of rejection.

Summary of technical requirements

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Double space all parts of manuscripts. Begin each section or component on a new page. Review the sequence: title page, abstract and key words, text, acknowledgments, references, tables (each on separate pa ge), legends. Illustrations, unmounted prints, should be no larger than 203 × 254 mm (8 × 10 inches). Include permission to reproduce previously published material or to use illustrations that may identify human subjects. Enclose transfer of copyright and other forms. Submit required number of paper copies. Keep copies of everything submitted.

of articles, such as case reports, reviews, and editorials, are likely to need other formats. Authors should consult individual journals for further guidance. Type or print out the manuscript on white bond paper, 216 × 279 mm (8.5 × 11 inches), or ISO A4 (212 × 297 mm), with margins of at least 25 mm (1 inch). Type or print on only one side of the paper. Use double spacing throughout, including for the title page, abstract, text, acknowledgments, references, individual tables, and legends. Number pages consecutively, beginning with the title page. Put the page number in the upper or lower right-hand corner of each page. Manuscripts on disks For papers that are close to final acceptance, some journals require authors to provide a copy in electronic form (on a disk); they may accept a variety of word-processing formats or text (ASCII) files. When submitting disks, authors should: 1. be certain to include a print-out of the version of the article that is on the disk; 2. put only the latest version of the manuscript on the disk; 3. name the file clearly; 4. label the disk with the format of the file and the file name;

Preparation of manuscript The text of observational and experimental articles is usually (but not necessarily) divided into sections with the headings Introduction, Methods, Results, and Discussion. Long articles may need subheadings within some sections (especially the Results and Discussion sections) to clarify their content. Other types

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5. provide information on the hardware and software used. Authors should consult the journal's instructions to authors for acceptable formats, conventions for naming files, number of copies to be submitted, and other details. Title Page The title page should carry 1) the title of the article, which should be concise but informative; 2) the name by which each author is known, with his or her highest academic degree(s) and institutional affiliation; 3) the name of the department(s) and institution(s) to which the work should be attributed; 4) disclaimers, if any; 5) the name and address of the author responsible for correspondence about the manuscript; 6) the name and address of the author to whom requests for reprints should be addressed or a statement that reprints will not be available from the authors; 7) source(s) of support in the form of grants, equipment, drugs, or all of these; and 8) a short running head or footline of no more than 40 characters (count letters and spaces) at the foot of the title page. Authorship All persons designated as authors should qualify for authorship, and all those who qualify should be listed. Each author should have participated sufficiently in the work to take public responsibility for appropriate portions of the content. One or more authors should take responsibility for the integrity of the work as a whole, from inception to published article. Authorship credit should be based only on 1) substantial contributions to conception

and design, or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically for important intellectual content; and 3) final approval of the version to be published. Conditions 1, 2, and 3 must all be met. Acquisition of funding, the collection of data, or general supervision of the research group, by themselves, do not justify authorship. Authors should provide a description of what each contributed, and editors should publish that information. All others who contributed to the work who are not authors should be named in the Acknowledgments, and what they did should be described (see Acknowledgments). Increasingly, authorship of multicenter trials is attributed to a group. All members of the group who are named as authors should fully meet the above criteria for authorship. Group members who do not meet these criteria should be listed, with their permission, in the Acknowledgments or in an appendix (see Acknowledgments). The order of authorship on the byline should be a joint decision of the coauthors. Authors should be prepared to explain the order in which authors are listed. Abstract and Key Words The second page should carry an abstract (of no more than 150 words for unstructured abstracts or 250 words for structured abstracts). The abstract should state the purposes of the study or investigation, basic procedures (selection of study subjects or laboratory animals; observational and analytical methods), main findings (giving specific data and their statistical

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significance, if possible), and the principal conclusions. It should emphasize new and important aspects of the study or observations. Below the abstract authors should provide, and identify as such, 3 to 10 key words or short phrases that will assist indexers in cross-indexing the article and may be published with the abstract. Terms from the Medical Subject Headings (MeSH) list of Index Medicus should be used; if suitable MeSH terms are not yet available for recently introduced terms, present terms may be used. Introduction State the purpose of the article and summarize the rationale for the study or observation. Give only strictly pertinent references and do not include data or conclusions from the work being reported. Methods Describe your selection of the observational or experimental subjects (patients or laboratory animals, including controls) clearly. Identify the age, sex, and other important characteristics of the subjects. Because the relevance of such variables as age, sex, and ethnicity to the object of research is not always clear, authors should explicitly justify them when they are included in a study report. The guiding principle should be clarity about how and why a study was done in a particular way. For example, authors should explain why only subjects of certain ages were included or why women were excluded. Authors should avoid terms such as "race," which

lacks precise biological meaning, and use alternative descriptors such as "ethnicity" or "ethnic group" instead. Authors should specify carefully what the descriptors mean, and tell exactly how the data were collected (for example, what terms were used in survey forms, whether the data were selfreported or assigned by others, etc.). Identify the methods, apparatus (give the manufacturer's name and address in parentheses), and procedures in sufficient detail to allow other workers to reproduce the results. Give references to established methods, including statistical methods (see below); provide references and brief descriptions for methods that have been published but are not well known; describe new or substantially modified methods, give reasons for using them, and evaluate their limitations. Identify precisely all drugs and chemicals used, including generic name(s), dose(s), and route(s) of administration. Reports of randomized clinical trials should present information on all major study elements, including the protocol (study population, interventions or exposures, outcomes, and the rationale for statistical analysis), assignment of interventions (methods of randomization, concealment of allocation to treatment groups), and the method of masking (blinding).

Authors submitting review manuscripts should include a section describing the methods used for locating, selecting, extracting, and synthesizing data. These methods should also be summarized in the abstract.

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Ethics When reporting experiments on human subjects, indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 1983. Do not use patients' names, initials, or hospital numbers, especially in illustrative material. When reporting experiments on animals, indicate whether the institution's or a national research council's guide for, or any national law on, the care and use of laboratory animals was followed. Statistics Describe statistical methods with enough detail to enable a knowledgeable reader with access to the original data to verify the reported results. When possible, quantify findings and present them with appropriate indicators of measurement error or uncertainty (such as confidence intervals). Avoid relying solely on statistical hypothesis testing, such as the use of P values, which fails to convey important quantitative information. Discuss the eligibility of experimental subjects. Give details about randomization. Describe the methods for and success of any blinding of observations. Report complications of treatment. Give numbers of observations. Report losses to observation (such as dropouts from a clinical trial). References for the design of the study and statistical methods should be to standard works when possible (with pages stated) rather than to papers in which the designs or methods were originally reported. Specify any general-use computer programs used.

Put a general description of methods in the Methods section. When data are summarized in the Results section, specify the statistical methods used to analyze them. Restrict tables and figures to those needed to explain the argument of the paper and to assess its support. Use graphs as an alternative to tables with many entries; do not d uplicate data in graphs and tables. Avoid nontechnical uses of technical terms in statistics, such as "random" (which implies a randomizing device), "normal," "significant," "correlations," and "sample." Define statistical terms, abbreviations, and most symbols. Results Present your results in logical sequence in the text, tables, and illustrations. Do not repeat in the text all the data in the tables or illustrations; emphasize or summarize only important observations. Discussion Emphasize the new and important aspects of the study and the conclusions that follow from them. Do not repeat in detail data or other material given in the Introduction or the Results section. Include in the Discussion section the implications of the findings and their limitations, including implications for future research. Relate the observations to other relevant studies. Link the conclusions with the goals of the study but avoid unqualified statements and conclusions not completely supported by the data. In particular, authors should avoid making statements on economic benefits and costs unless their manuscript includes economic data and analyses. Avoid claiming

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ICMJE uniform requirements for journals.

priority and alluding to work that has not been completed. State new hypotheses when warranted, but clearly label t em as such. h Recommendations, when appropriate, may be included. Acknowledgments List all contributors who do not meet the criteria for authorship, such as a person who provided purely technical help, writing assistance, or a department chair who provided only general support. Financial and material support should also be acknowledged. Groups of persons who have contributed materially to the paper but whose contributions do not justify authorship may be listed under a heading such as "clinical investigators" or "participating investigators," and their function or contribution should be described for example, "served as scientific advisors," "critically reviewed the study proposal," "collected data," or "provided and cared for study patients." Because readers may infer their endorsement of the data and conclusions, all persons must have given written permission to be acknowledged. References References should be numbered consecutively in the order in which they are first mentioned in the text. Identify references in text, tables, and legends by Arabic numerals in parentheses. References cited only in tables or figure legends should be numbered in accordance with the sequence established by the first

identification in the text of the particular table or figure. Use the style of the examples below, which are based on the formats used by the NLM in Index Medicus. The titles of journals should be abbreviated according to the style used in Index Medicus. Consult the List of Journals Indexed in Index Medicus, published annually as a separate publication by the library and as a list in the January issue of Index Medicus. The list can also be obtained through the library's web site (http://www.nlm.nih.gov/). Avoid using abstracts as references. References to papers accepted but not yet published should be designated as "in press" or "forthcoming"; authors should obtain written permission to cite such papers as well as verification that they have been accepted for publication. Information from manuscripts submitted but not accepted should be cited in the text as "unpublished observations" with written permission from the source. Avoid citing a "personal communication" unless it provides essential information not available from a public source, in which case the name of the person and date of communication should be cited in parentheses in the text. For scientific articles, authors should obtain written permission and confirmation of accuracy from the source of a personal communication. The references must be verified by the author(s) against the original documents. The Uniform Requirements style (the Vancouver style) is based largely on an

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ANSI standard style adapted by the NLM for its databases. Notes have been added where Vancouver style differs from the style now used by NLM. Articles in Journals 1. Standard journal article List the first six authors followed by et al. (Note: NLM now lists up through 25 authors; if there are more than 25 authors, NLM lists the first 24, then the last author, then et al.) · Vega KJ, Pina I, Krevsky B. Heart transplantation is associated with an increased risk for pancreatobiliary disease. Ann Intern Med 1996 Jun 1; 124 (11): 980-3. As an option, if a journal carries continuous pagination throughout a volume (as man y medical journals do) the month and issue number may be omitted. (Note: For consistency, the option is used throughout the examples in Uniform Requirements. NLM does not use the option.) · Vega KJ, Pina I, Krevsky B. Heart transplantation is associated with an increased risk for pancreatobiliary disease. Ann Intern Med 1996;124:980-3. More than six authors: Parkin DM, Clayton D, Black RJ, Masuyer E, Friedl HP, Ivanov E, et al. Childhood leukaemia in Europe after Chernobyl: 5 year follow-up. Br J Cancer 1996;73:1006- 12. 2. Organization as author The Cardiac Society of Australia and New Zealand. Clinical exercise stress testing. Safety and performance guidelines. Med J Aust 1996; 164: 282-4.

3. No author given Cancer in South Africa [editorial]. S Afr Med J 1994; 84:15. 4. Article not in English (Note: NLM translates the title to English, encloses the translation in square brackets, and adds an abbreviated language designator.) Ryder TE, Haukeland EA, Solhaug JH. Bilateral infrapatellar seneruptur hostidligere frisk kvinne. Tidsskr Nor Laegeforen 1996;116:41-2. 5. Volume with supplement Shen HM, Zhang QF. Risk assessment of nickel carcinogenicity and occupational lung cancer. Environ Health Perspect 1994; 102 Suppl 1: 275-82. 6. Issue with supplement Payne DK, Sullivan MD, Massie MJ. Women's psychological reactions to breast cancer. Semin Oncol 1996; 23 (1 Suppl 2):89-97. 7. Volume with part Ozben T, Nacitarhan S, Tuncer N. Plasma and urine sialic acid in non-insulin dependent diabetes mellitus. Ann Clin Biochem 1995; 32 (Pt 3): 303-6. 8. Issue with part Poole GH, Mills SM. One hundred consecutive cases of flap lacerations of the leg in ageing patients. N Z Med J 1994; 107 (986 Pt 1): 377-8. 9. Issue with no volume Turan I, Wredmark T, Fellander-Tsai L. Arthroscopic ankle arthrodesis in rheumatoid arthritis. Clin Orthop 1995; (320):110-4. 10. No issue or volume Browell DA, Lennard TW. Immunologic status of the cancer patient and the effects of

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blood transfusion on antitumor responses. Curr Opin Gen Surg 1993: 325-33. 11. Pagination in Roman numerals Fisher GA, Sikic BI. Drug resistance in clinical oncology and hematology. Introduction. Hematol Oncol Clin North Am 1995 Apr;9(2):xi-xii. 12. Type of article indicated as needed Enzensberger W, Fischer PA. Metronome in Parkinson's disease [letter]. Lancet 1996; 347: 1337. Clement J, De Bock R. Hematological complications of hantavirus nephropathy (HVN) [abstract]. Kidney Int 1992; 42: 1285. 13. Article containing retraction Garey CE, Schwarzman AL, Rise ML, Seyfried TN. Ceruloplasmin gene defect associated with epilepsy in EL mice [retraction of Garey CE, Schwarzman AL, Rise ML, Seyfried TN. In: Nat Genet 1994; 6: 426-31]. Nat Genet 1995; 11: 104. 14. Article retracted Liou GI, Wang M, Matragoon S. Precocious IRBP gene expression during mouse development [retracted in Invest Ophthalmol Vis Sci 1994; 35: 3127]. Invest Ophthalmol Vis Sci 1994; 35: 1083-8. 15. Article with published erratum Hamlin JA, Kahn AM. Herniography in symptomatic patients following inguinal hernia repair [published erratum appears in West J Med 1995; 162: 278]. West J Med 1995; 162: 28-31. Books and other monographs (Note: Previous Vancouver style incorrectly had a comma rather than a semicolon between the publisher and the date.) 16. Personal author(s) Ringsven MK, Bond D. Gerontology and leadership skills for nurses. 2nd ed. Albany (NY): Delmar Publishers; 1996.

17. Editor(s), compiler(s) as author Norman IJ, Redfern SJ, editors. Mental health care for elderly people. New York: Churchill Livingstone; 1996. 18. Organization as author and publisher Institute of Medicine (US). Looking at the future of the Medicaid program. Washington: The Institute; 1992. 19. Chapter in a book (Note: Previous Vancouver style had a colon rather than a p before pagination.) Phillips SJ, Whisnant JP. Hypertension and stroke. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis, and management. 2nd ed. New York: Raven Press; 1995. p. 465-78. 20. Conference proceedings Kimura J, Shibasaki H, editors. Recent advances in clinical neurophysiology. Proceedings of the 10th International Congress of EMG and Clinical Neurophysiology; 1995 Oct 15-19; Kyoto, Japan. Amsterdam: Elsevier; 1996. 21. Conference paper Bengtsson S, Solheim BG. Enforcement of data protection, privacy and security in medical informatics. In: Lun KC, Degoulet P, Piemme TE, Rienhoff O, editors. MEDINFO 92. Proceedings of the 7th World Congress on Medical Informatics; 1992 Sep 6-10; Geneva, Switzerland. Amsterdam: North-Holland; 1992. p. 15615. 22. Scientific or technical report Issued by funding/sponsoring agency: Smith P, Golladay K. Payment for durable medical equipment billed during skilled nursing facility stays. Final report. Dallas (TX): Dept. of Health and Human Services (US), Office of Evaluation and Inspections; 1994 Oct. Report No.: HHSIGOEI69200860. Issued by performing agency: Field MJ,

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Tranquada RE, Feasley JC, editors. Health services research: work force and educational issues. Washington: National Academy Press; 1995. Contract No.: AHCPR282942008. Sponsored by the Agency for Health Care Policy and Research. 23. Dissertation Kaplan SJ. Post-hospital home health care: the elderly's access and utilization [dissertation]. St. Louis (MO): Washington Univ.; 1995. 24. Patent Larsen CE, Trip R, Johnson CR, inventors; Novoste Corporation, assignee. Methods for procedures related to the electrophysiology of the heart. US patent 5,529,067. 1995 Jun 25. Other published material 25. Newspaper artic le Lee G. Hospitalizations tied to ozone pollution: study estimates 50,000 admissions annually. The Washington Post 1996 Jun 21;Sect. A:3 (col. 5). 26. Audiovisual material HIV+/AIDS: the facts and the future [videocassette]. St. Louis (MO): MosbyYear Book; 1995. 27. Legal material Public law: Preventive Health Amendments of 1993, Pub. L. No. 103-183, 107 Stat. 2226 (Dec. 14, 1993). Unenacted bill: Medical Records Confidentiality Act of 1995, S. 1360, 104th Cong., 1st Sess. (1995). Code of Federal Regula tions: Informed Consent, 42 C.F.R. Sect. 441.257 (1995). Hearing: Increased Drug Abuse: the Impact on the Nation's Emergency Rooms: Hearings Before the Subcomm. on Human Resources and Intergovernmental Relations

of the House Comm. on Government Operations, 103rd Cong., 1st Sess. (May 26, 1993). 28. Map North Carolina. Tuberculosis rates per 100,000 population, 1990 [demographic map]. Raleigh: North Carolina Dept. of Environment, Health, and Natural Resources, Div. of Epidemiology; 1991. 29. Book of the Bible The Holy Bible. King James version. Grand Rapids (MI): Zondervan Publishing House; 1995. Ruth 3:1-18. 30. Dictionary and similar references Stedman's medical dictionary. 26th ed. Baltimore: Williams & Wilkins; 1995. Apraxia; p. 119-20. 31. Classical material The Winter's Tale: act 5, scene 1, lines 1316. The complete works of William Shakespeare. London: Rex; 1973. Unpublished Material 32. In press (Note: NLM prefers "forthcoming" because not all items will be printed.) Leshner AI. Molecular mechanisms of cocaine addiction. N Engl J Med. In press 1996. Electronic Material 33. Journal article in electronic format Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis [serial online] 1995 Jan-Mar [cited 1996 Jun 5];1(1):[24 screens]. Available from: URL: http://www.cdc.gov/ncidod/EID/eid.htm 34. Monograph in electronic format CDI, clinical dermatology illustrated [monograph on CD-ROM]. Reeves JRT, Maibach H. CMEA Multimedia Group, producers. 2nd ed. Version 2.0. San Diego: CMEA; 1995.

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35. Computer file Hemodynamics III: the ups and downs of hemodynamics [computer program]. Version 2.2. Orlando (FL): Computerized Educational Systems; 1993. Tables Type or print out each table with double spacing on a separate sheet of paper. Do not submit tables as photographs. Number tables consecutively in the order of their first citation in the text and supply a brief title for each. Give each column a short or abbreviated heading. Place explanatory matter in footnotes, not in the heading. Explain in footnotes all nonstandard abbreviations that are used in each table. For footnotes use the following symbols, in this sequence: Identify statistical measures of variations, such as standard deviation and standard error of the mean. Do not use internal horizontal and vertical rules. Be sure that each table is cited in the text. If you use data from another published or unpublished source, obtain permission and acknowledge them fully. The use of too many tables in relation to the length of the text may produce difficulties in the layout of pages. Examine issues of the journal to which you plan to submit your paper to estimate how many tables can be used per 1000 words of text. The editor, on accepting a paper, may recommend that additional tables containing important backup data too extensive to publish be deposited with an archival service, such as the National Auxiliary Publication Service in the United States, or

made available by the authors. In that event an appropriate statement will be added to the text. Submit such tables for consideration with the paper. Illustrations (figures) Submit the required number of complete sets of figures. Figures should be professionally drawn and photographed; freehand or typewritten lettering is unacceptable. Instead of original drawings, x-ray films, and other material, send sharp, glossy, black-andwhite photographic prints, usually 127 × 173 mm (5 × 7 inches) but no larger than 203 × 254 mm (8 × 10 inches). Letters, numbers, and symbols should be clear and even throughout and of sufficient size that when reduced for publication each item will still be legible. Titles and detailed explanations belong in the legends for illustrations not on the illustrations themselves. Each figure should have a label pasted on its back indicating the number of the figure, author's name, and top of the figure. Do not write on the back of figures or scratch or mar them by using paper clips. Do not bend figures or mount them on cardboard. Photomicrographs should have internal scale markers. Symbols, arrows, or letters used in photomicrographs should contrast with the background. If photographs of people are used, either the subjects must not be identifiable or their pictures must be accompanied by written permission to use the photograph (see Protection of Patients' Rights to Privacy). Figures should be numbered consecutively according to the order in which they have been first cited in the text. If a figure has

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been published, acknowledge the original source and submit written permission from the copyright holder to reproduce the material. Permission is required irrespective of authorship or publisher except for documents in the public domain. For illustrations in color, ascertain whether the journal requires color negatives, positive transparencies, or color prints. Accompanying drawings marked to indicate the region to be reproduced may be useful to the editor. Some journals publish illustrations in color only if the author pays for the extra cost. Legends for Illustrations Type or print out legends for illustrations using double spacing, starting on a separate page, with Arabic numerals corresponding to the illustrations. When symbols, arrows, numbers, or letters are used to identify parts of the illustrations, identify and explain each one clearly in the legend. Explain the internal scale and identify the method of staining in photomicrographs. Units of Measurement Measurements of length, height, weight, and volume should be reported in metric units (meter, kilogram, or liter) or their decimal multiples. Temperatures should be given in degrees Celsius. Blood pressures should be given in millimeters of mercury. All hematologic and clinical chemistry measurements should be reported in the metric system in terms of the International System of Units (SI). Editors may request that alternative or non-SI units be added by the authors before publication.

Abbreviations and Symbols Use only standard abbreviations. Avoid abbreviations in the title and abstract. The full term for which an abbreviation stands should precede its first use in the text unless it is a standard unit of measurement. Sending the Manuscript to the Journal Send the required number of copies of the manuscript in a heavy-paper envelope, enclosing the copies and figures in cardboard, if necessary, to prevent the photographs from being bent. Place photographs and transparencies in a separate heavy-paper envelope. Manuscripts must be accompanied by a covering letter signed by all coauthors. This must include 1) information on prior or duplicate publication or submission elsewhere of any part of the work as defined earlier in this document; 2) a statement of financial or other relationships that might lead to a conflict of interest (see below); 3) a statement that the manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work; and 4) the name, address, and telephone number of the corresponding author, who is responsible for communicating with the other authors about revisions and final approval of the proofs. The letter should give any additional information that may be helpful to the editor, such as the type of article in the particular journal that the manuscript represents and whether the author(s) would be willing to meet the cost of reproducing color illustrations.

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News.

The manuscript must be accompanied by copies of any permission to reproduce

published material, to use illustrations or report information about identifiable people, or to name people for their contributions.

News

National events

2004

December 9-12, 2004 Silver Jubilee Conference of Pakistan Association of Dermatologists, Karachi. Organizing Chairman: Dr. Khurshid H. Alvi, Suite No. 11, 3rd Floor, Taj Medical Complex, M.A. Jinnah Road, Karachi, 74400 Pakistan Tel: +92 21 7789666 Fax: +92 21 7789677 E-mail: [email protected] [email protected] Website: www.pad.org.pk

International events

2005

February 3 -6 4th South Asian Regional Conference of Dermatology, Venereology & Leprology DERMACON 2005 New Delhi, India Contact: Dr. Vijay K. Garg Tel: 020 7383 0266 E-mail: [email protected] www.dermacon2005.com October 12-15 European Academy of Dermatology and Venereology Congress (EADV) London, UK Contact: Marilyn Benham Tel: 020 7383 0266 E-mail: [email protected] www.eadv.org

Inauguration of www.jpad.org.pk

JPAD

web

site

JPAD has launched its Web site www.jpad.org.pk. The site will be regualy updated. Viewers are welcome to give constructive uggestions.

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Journal of Pakistan Association of Dermatologists 2004; 14: 277-279.

Index Volume 14

Author index

Ahad SMMMA see Choudhary AG Ahmad I, Wahid Z, Anari M. Melasma: a comparative trial of azelaic acid (20%) cream alone and in combination with tretinoin (0.1%) cream 10 Ahmad I, Wahid Z, Nasreen S, Anari M. Fluconazole pulse therapy: effect on inflammatory tinea capitis (kerion and agminate folliculitis) 70 Ahmad ML see Shaheen JA. Ahmad ML, Khan MS, Hussain I, Kazmi AH. Deformity and disability index in leprosy 64 Ahmed SI see Shamim SM. Akhtar MS see Zaman T. Also see Cutaneous leishmaniasis in Sadda, Kurram Agency, Pakistan 114 Aman S, Akbar TM, Hussain I, Jahangir M, Haroon TS. The effect of itraconazole pulse Ansai M see Ahmad I. Ansari A see Moizuddin. Ansari M see Ahmad I. Anwer J, Iqbal P, Jesrani AK, Baloch R. Leprosy in Hyderabad 23 Anwer J, Iqbal P, Ursani NM. Urticaria: a threat to betel consumers 229 Asad F, Haider M, Pal SS. Leukemia cutis: an Asad F, Pal SS. Annular erythematous plaque on the dorsum of hand 45 Baloch R see Anwer J Bari A.U, Rahman S.B. Zosteriform lichen planus: a new variant of a common disorder 5 Bari AU, Rashid M, Rahman SB. Acquired hemangioma: an uncommon vascular cutaneous tumour in elderly persons 42 Bari AU, Rashid M, Rahman SB. Diagnostic modalities in cutaneous leishmaniasis 81 Bari AU, Rashid M, Rahman SB. Porokeratosis: a review of unique group of keratinizing disorders 130 Bari AU, Rashid M, Rahman SB. Porokeratosis of Mibelli: an uncommon genodermatosis 93 Bari AU, Rahman SB. Nevoid psoriasis: an uncommon blaschkolinear dermatosis 157 Bari AU. Military dermatology in Pakistan 184 Bari AU, Rahman SB. Hematological changes in adults with chicken pox 193 Bari AU, Rahman SB. Papular mucinosis: an overview 245 Bari AU, Rashid M, Rahman SB. Acral Choudhary AG, Islam AZMM, Ahad SMMMA. Topical calcipotriol in the treatment of chronic plaque psoriasis in Bangladeshi patients 214 Dammas AS see Saadeldin IY. Dar NR see Dilnawaz M. Dilnawaz M, Dar NR. Mastocytoses 31 Ejaz A, Raza N. Management of atopic dermatitis: a review 140 Haider M see Asad F Handjani F see Namazi MR Haroon TS. Dermatology in Pakistan: past, present and future 165 see Kamal T, Noor SM. see Zaman T. see Aman S. Hussain D see Noor SM. Hussain I. History of dermatology in Pakistan 172 see Ahmad ML. see Kamal T. Iqbal P see Anwer J, indicator of relapse in a patient with myeloid leukemia ­ a case 260 Islam AZMM see Choudhary AG, Islam F see Shamim SM Jahangir M, Zaman T, Rashid T. Dermatological literacy among medical graduates 189 see Zaman T see Zaman T Janjua S.A. Mastocytosis: from Nettleship and Darier to Metcalfe and Valent (editorial) 1 Janjua S.A. Papillon-Lefèvre syndrome. All about palms, soles and gums: a brief review 27 Janjua S.A. Tuberous sclerosis complex: Bourneville's disease 75 Janjua S.A. The guardian of the genome: p53 107 see Kachemoune A. Jesrani AK see Anwer J Jowkar F see Namazi MR. Kachemoune A, Janjua SA. What caused this plaque? 263 Kamal T, Rani Z, Haroon TS, Hussain I. Comparative efficacy of topical calcipotriol ointment with betamethasone valerate ointment in chronic plaque psoriasis 16

277

Index

Kazmi AH see Ahmad ML. Khan MS see Ahmad ML. Khurshid K see Noor SM. Mahmood T see Noor SM. Mashhood AA. Diagnostic yield of various traditional laboratory investigations in the diagnosis of cutaneous leishmaniasis in Pakistan 59 Mashhood AA.Generalized pustular rash of acute onset 161 Mashood AA, Khan I, Nazir S.Histopathological spectrum in cutaneous leishmaniasis 209 Mashood AA. Ehlers-Danlos syndrome: not so rare entity 249 McColl I. Genetic mosaicism 168 melanoma of index finger 257 Moizuddin, Valimohd A, Ansari A. Malignant Muzaffar F. Cutaneous manifestations of Muzaffar F. Quality of life in skin disease (editorial) 52 Nabi H, Rani Z, Shahzad A. Netherton's Namazi MR, SalmanpourR, Handjani F, Jowkar F. Nitric oxide may directly induce the psoriatic disease process via suppression of keratinocyte apoptosis and induction of keratinocyte hyperproliferation 233 Naqqash S, Tameez-ud-deen, Naqqash S, Butt AQ. Family history of psoriasis and recent infectious disease are risk factors for the first episode of acute guttate psoriasis 124 Nasreen S see Ahmad I Noor SM, Khurshid K, Mahmood T, Haroon TS. Quality of life in vitiligo patients 55 of cutaneous mucinosis 253 onychomycosis198 Pakistani children 110 Pal SS see Asad F Pal SS see Asad F. patients of disto-lateral subungual persistent papular mucinosis: a rare variant

Rahman S.B. see Bari AU. Rani Z see Nabi H. Rani Z. see Kamal T. Rashid T see Jahangir M. Raza A see Zaman T. Raza N see Ejaz A. Saadeldin IY, Satti SA, Dammas AS. Dyskeratosis congenita in a Saudi boy: an uncommon genodermatosis 153. Salmanpour R see Namazi MR Satti SA see Saadeldin IY. see Jahangir M Shaheen JA, Ahmad ML. Generalized pruritus in an adult male 101 Shahzad A see Nabi H. Shamim SM, Sultana K, Fareeda Islam F, Ahmed SI. Olive oil: an effective emollient for lichen simplex chronicus 118 Sikder S, Rahman MH, Maidul AZM, Khan MSU, Rahman MM. Study on the histopathology of chronic arsenicosis 204 Sultana K see Shamim SM syndrome: a case report 96 systemic lupus erythematosus in therapy on quality of life in Pakistani Thomas J. Herpes zoster: complications and management 238 Thomas J. Urticaria and the role of antihistamines in pruritus 87 Ursani NM see Anwer J Valimohd A see Moizuddin Wahid Z see Ahmad I. Zaman T, Jahangir M, Akhtar MS. VogtKoyanagi-Harada Syndrome: a case report and review of literature 36 Zaman T, Raza .A Biostatistics ­ I: Introduction, role and application in medicine 148 Zaman T, Jahangir M, Raza A, Haroon TS. Spectrum of cutaneous infections in patients of leukemia 218

Subject index

acquired hemangioma 42 acral persistent papular mucinosis 253 acute necrotizing ulcerative gingivitis 153 agminate folliculitis (and fluconazole) 70 antihistamines in urticaria 87 apoptosis 232 arsenicosis 205 ASO titer (in guttate psoriasis) 124 atopic dermatitis 140 azelaic acid in melasma 10 betamethasone valerate in psoriasis 16 betel (and chronic urticaria) 228 biostatistics 148 Blaschko lines (and lichen planus) 5 Bourneville's disease 75 calcipotriol 215 calcipotriol in psoriasis 16 calcitonin gene-related peptide 232 cathepsin C 27 chicken pox 193

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Journal of Pakistan Association of Dermatologists 2004; 14: 277-279.

chronic urticaria 228 connective tissue disorders 244 cornoid lamella 130 cutaneous infections (in leukemia) 220 cutaneous leishmaniasis 59, 81, 114, 210 cutaneous manifestations (in SLE) 110 cutaneous mucinosis 244 dermal mucinoses 244 dermatological literacy 189 dermatology in Pakistan 165 diffuse cutaneous mastocytosis 31 disability in leprosy 64 disseminated superficial actinic porokeratosis 130 DLQI 55 dyskeratosis congenita 153 Ehlers-Danlos syndrome 248 emollient (olive oil)118 fluconazole (in tinea capitis) 70 generalized pruritus 101 generalized pustular rah 161 genetic mosaicism 168 granuloma annulare (quiz) 45 guttate psoriasis 124 herpes zoster (and lichen planus) 5, herpes zoster 237 histopathology (arsenicosis) 205 in cutaneous leishmaniasis 210 history of dermatology (in Pakistan) 172 Hyderabad (leprosy) 23 ichthyosis linearis circumflexa 96 immunodiagnosis (in leishmaniasis) 81 inflammatory linear verrucous epidermal naevi 157 itraconazole 198 keratinocyte 232 kerion (and fluconazole) 70 leishmania culture (in leishmaniasis) 59 leishmanin test (in leishmaniasis) 59 leprosy in Hyderabad 23 and disability 64 leukemia 220 leukemia cutis 259 lichen myxedematosus 253 lichen planus 5 lichen simplex chronicus 118 linear porokeratosis 130 linear psoriasis 157 lines of Blaschko 157 LT bodies 210 malignant melanoma 256 management (atopic dermatitis) 140 mast cell leukemia 31 mastocytoses 31

mastocytosis 1 medical graduates 189 melasma 10 mucin 244 neonatal LE 110 neopterin 232 nerve growth factor 232 Netherton's syndrome 96 nevoid psoriasis 157 nevus anemicus 262 nevus depigmentosus 262 nitric oxide 232 olive oil 118 onychomycosis 198 p53 gene 107 pancytopenia (in dyskeratosis congenita) 153 Papillon-Lefèvre syndrome 27 papular mucinosis 253 parasitological diagnosis (in leishmaniasis) 81 PASI 215 porokeratosis 93, 130 porokeratosis of Mibelli 93, 130 porokeratosis palmaris et plantaris disseminate 130 psoriasis 16 psoriasis 232 psoriasis treatment 215 punctate porokeratosis 130 quality of life in skin disease 52 in vitiligo patients 55 in onychomycosis 198 Sadda (leishmaniasis) 114 scleromyxedema 253 serological tests (in leishmaniasis) 81 SLE 110 solitary mastocytoma 31 streptococcal pharyngitis (in guttate psoriasis) 124 systemic mastocytosis 31 telangiectasia macularis eruptiva perstans 31 thrombocytopenia (in chicken pox)193 tinea capitis 70 tretinoin in melasma 10 trichorrhexis invaginata 96 tuberous sclerosus 75 Urticaria 87 urticaria pigmentosa 31 varicella 193 varicella-zoster virus 193 vitiligo 55 Vogt-Koyanagi-Harada syndrome 36

279

Information for Authors

Manuscripts The JPAD agrees to accept manuscripts prepared in accordance with the "Uniform Requirements for Manuscript Submission to the Biomedical Journals" approved by the International Committee of Medical Journals Editors. Three copies of all material for publication should be sent to Dr. Ijaz Hussain, Editor, JPAD, Department of Dermatology, Mayo Hospital, Lahore, e- mail: [email protected] [email protected] Manuscripts should be printed on one side of paper only, with a 2.5 cm margin on either side, be double spaced, and bear the title of the paper, name and address of each author, together with the name of the hospital, laboratory or institution where the work has been carried out. The name and full address of corresponding author should be given on the first page. Pages should be numbered. Authors should keep a copy of the manuscript. In addition to the hard copy, an exact copy of the manuscript, containing all parts of the paper, must be submitted on high-density disk. The editor reserves the right to make corrections, both literary and technical, to the papers. Papers received are supposed to have been submitted exclusively to the Journal of Pakistan Association of Dermatologists and all authors must give a signed consent to publication in a letter sent with the manuscript. Authorship implies a significant contribution. In case of clinical trials, the names of pharmaceutical sponsors should be mentioned. Types of articles JPAD welcomes original and review articles, case reports, quizzes, items of correspondence etc. addressing any aspect of dermatology. The original article should be of about 2000 words, with no more than 6 tables or illustrations. Letters should not normally exceed 400 words and have more than 10 references. Parts of the paper The manuscript should be prepared as below. Title: In addition to the full title of the paper, a short version not more than 50 characters, for a running head, be provided. Author(s) details: Name(s) of the author(s) should be given as initial(s) followed by surnames, and should be clearly linked to the respective addresses by the use of symbols e.g. , , etc. Abstract: All articles other than correspondence should have an abstract. The original articles should have a structured abstract comprising of 4 subheadings: background, methods, results and conclusions. Keywords 5 should be provided to aid indexing. Main text: The main text should appear in the following sequence: introduction, methods, results, discussion, acknowledgments, references, tables and legends for illustrations. Each section should begin on a new page. Generic names of the drugs should be used. Full names with abbreviations must be used given with the first mention, thereafter the abbreviation will be used. Abbreviations should be used for unwieldy names or where the names occur frequently. For all quantitative measurements the International System of Units (SI) should be used. References Only papers closely relevant to the author's work should be referred to. References should be in the Vancouver style i.e. references should be written as unbracketed superscript numbers in the order in which they appear in the text e.g. `our previous reports1 and that of Cohen et al.2.....'. At the end of the article, references should give the name(s) and initials of author(s). If there are more than four authors, include the first three authors followed by et al., title of paper, title of the journal abbreviated in the standard manner (as published in the Index Medicus), year of publication, volume number, and first and final numbers of the article, e.g. Grattan C, Powell S, Humphreys F. Management and diagnostic guidelines for urticaria and angiooedema. Br J Dermatol 2001; 144: 708-14. References to books should give the name(s) followed by initials of author(s) or editor(s), chapter (if relevant), book title, edition, place, publisher, year, and pages referred to e.g. Friedman WF, Child JS. Congenital heart disease in the adult. In: Fauci AS, Braunwald E, Isselbacher KJ et al., editors. Harrison's principles of internal medicine. 14th edn. New York: McGraw-Hill; 1998. p. 1300-9. Tables There should be as few tables as possible and these should include only essential dat a. These should be printed on separate sheets and should be given Arabic numbers. No horizontal or vertical rules should be used. Avoid wordy, over-full tables. Legends should be provided. Illustrations Three sets of illustrations should be sent with each manuscript. Illustrations should be referred to in the text as `Figures' and be given Arabic numbers. Each figure should be marked on the back with the name of the author(s), the title of the paper and the reference number used in the text. Orientation of the illustration should be indicated by marking the top with arrow. Photographs should be unmarked glossy prints. Diagrams should be on separate sheets and a legend should be provided for each illustration. Proofs Page proofs will be sent, without the original manuscript, to the corresponding author for proof correction and should be returned to the editor within three days. Major alterations from the text cannot be accepted. Any alterations should be marked, preferably in red.

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