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Benign Prostatic Hyperplasia

Reversal of Benign Prostate Hyperplasia by Super-selective Intraprostatic Androgen Deprivation Therapy

Y i g a l G a t 1,2 a n d M i c h a e l G o r n i s h 2

1. Sub-micron Research, Condensed Matter Physics, Weizmann Institute of Science, Rehovot; 2. Andrology and Interventional Radiology, Maynei Hayeshua Medical Centre, Bnei Brak

Abstract

The prostate ­ an exocrine gland regulated by testosterone that is produced by the testes ­ is an essential and integral part of the male reproductive system. By producing approximately 30% of the non-cellular components of semen, it has a crucial and essential function in the creation of an optimal environment for the survival and motility of sperm in the long, hostile route to meet and fertilise the egg in the fallopian tube. Benign prostate hyperplasia (BPH) is the most common benign neoplasm in men. Although testosterone has been known to be the promoter of prostate cell proliferation since 1941, when Huggins and Hodges published their landmark work on prostate cancer, in the 60 years that have passed no causal relationship between serum testosterone and BPH has yet been established. The aetiology of BPH is unknown, and researchers have been puzzled by the following paradox: relatively low levels of serum testosterone are found in patients with BPH. Thus, it has remained unclear whether BPH is related to serum testosterone or attributable to other factors. Recent studies have proposed a novel and tested explanation of a pathophysiological mechanism for the evolution of BPH and suggest a tested and effective treatment. It was found that in all BPH patients the one-way valves (OWVs) in the vertically orientated internal spermatic veins (ISVs) are destroyed (clinically manifested as varicocele, a phenomenon that increases rapidly with age). It causes elevated hydrostatic pressure ­ some six-fold greater than normal in the venous drainage of the male reproductive system ­ which leads to a unique biological phenomenon: venous blood flows retrograde from the higher pressures in the testicular venous drainage system to the lower pressures in the prostatic drainage system. Free testosterone (FT) levels in this blood are markedly elevated, with a concentration of some 130 times serum level. Consequently, the prostate is exposed to increased venous pressure, which causes hypertrophy, and elevated concentrations of FT, causing hyperplasia. BPH patients were treated using the Gat­Goren technique, which restores normal pressure in the venous drainage of the male reproductive system, eliminating back-pressure and the back-flow of blood from the testicular to the prostate drainage system. Consequently, stable reduction in prostate volume and regression of prostate symptoms were observed in the treated patients.

Keywords

Benign prostate hyperplasia (BPH), testicular drainage systems, super-selective intraprostatic androgen deprivation therapy

Disclosure: The authors have no conflicts of interest to declare. Received: 30 May 2009 Accepted: 10 July 2009 Correspondence: Yigal Gat, Sub-micron Research, Condensed Matter Physics, Weizmann Institute of Science, Rehovot, 76100 Israel. E: [email protected]

The prostate is an integral and essential part of the male reproductive system. It is a testosterone-regulated exocrine gland producing >30% of the non-cellular components of the semen, promoting optimal conditions for survival and motility of sperm in the hostile environment in the vagina and retaining its reproductive potential for fertilisation in the fallopian tube. The testes are the production site of two products: sperm and free testosterone (FT). The testes drain their waste products and FT via the internal spermatic veins (ISVs) to the systemic circulation. Epidemiological studies in castrated males strongly support the important role of the testes in the pathogenesis of benign prostate hyperplasia (BPH). 1,2 FT diffuses into prostate cells and is known to be a promoter of prostate cell proliferation.3 It is mainly produced by the testes and, under normal conditions, reaches the systemic blood through the testicular venous drainage system (ISV; see Figure 1). It eventually reaches the prostate via the prostate artery after it has passed through the venous and arterial circulation, where it undergoes marked dilution and >98% binds to albumin and

sex-hormone-binding globulin (SHBG), in which form it is not able to diffuse into the prostatic cells. Upon entering the prostatic cell cytoplasm, 90% of FT is converted irreversibly by the 5-reductase enzymes to dihydrotestosterone (DHT) ­ a more potent androgenic hormone that has an obligatory role in the development of BPH. DHT has a five- to 10-fold higher affinity for the androgen receptor (AR) than FT. 2­4 FT and DHT control and regulate a diverse range of target genes to produce various proteins that are involved in prostate cell proliferation, survival, maintenance, homeostasis, angiogenesis, differentiation and apoptosis. 2,3 The one-way valves (OWVs) in the ISVs facilitate venous blood flow upwards against gravity since there is no `active pump' in the vertically orientated testicular venous drainage system found in the erect male. Recent studies have demonstrated that the destruction of OWVs, recognised clinically as varicocele, is a bilateral vascular disease.5,6 Its incidence is high in the ageing male,7 with a prevalence that increases rapidly with age, reaching >75% at 70 years of age7 and >86% above 80 years of age.8

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Reversal of BPH by Super-selective Intraprostatic Androgen Deprivation Therapy

Figure 1: Anatomy (Left Side) of the Testicular and Prostatic Venous Drainage Systems Under Normal Conditions

Figure 2: Anatomy of Testicular and Prostatic Venous Drainage Systems After Destruction of One-way Valves in Internal Spermatic Veins

Renal vein RV ISV (to right testis) IVC Right ISV K 0mmHg (-5/+5)

K

Left ISV

ISV (left) Inferior vena cava V ISV 35cm CI CI Int. I 6mmHg VP VV DV PP P PVP T Left testis

The testes and the prostate share a common drainage venous flow: vesicular vein (VV), internal iliac vein (IIV), common iliac vein (CIV) and inferior vena cava (IVC). Since no one-way valves exist between the testicular and prostatic drainage systems, and the hydrostatic pressure is equal, venous blood from both arrives at a common vessel ­ VV ­ at approximately 6mmHg, and blood arriving from both sides flows jointly towards IIV, CIV and IVC. CI = common iliac; CV = cremasteric vein; DV = deferential vein; Int.I = internal iliac; ISV = internal spermatic; IVC = inferior vena cava; K = kidney; P = prostate; PP = pampiniform plexus; PVP = prostatic venous plexus (Santorini); RV = renal vein; SV = scrotal vein; T = testis; V = one-way valve; VP = vesicular plexus.

CI

Int. I +27mmHg CV CV PP DV SV VP TA T Right P PVP Left VV 6mmHg

Int. I +32mmHg 6mmHg VV PP DV SV CV

SV

T

TA

Fluid Mechanics Analysis of the Testicular Venous Drainage System

Without competent OWVs the ISVs cease to function as drainage systems and become passive vessels. Each ISV then contains a vertical blood column that produces elevated hydrostatic pressure in the testicular venous drainage system, found to be approximately six to eight times normal. Note that the pressure in this system depends only on the height of the vertical blood column and not on the diameter of the blood vessel (see Equation 1).9,10 This pathologically elevated hydrostatic pressure causes persistent hypoxia in the testicular microcirculation, leading to deterioration in spermatogenesis11 followed by a reduction in testosterone production.12,13 Each ISV is associated with a network of small bypasses and retroperitoneal collaterals produced in the course of the disease, and each of these, when vertically orientated, results in similar pathological hydrostatic pressure in the pampiniform plexus (PP).14,15 Hence, effective treatment of varicocele must include the occlusion of the ISVs on both sides and of all the associated vertical venous bypasses and the retroperitoneal collaterals by microsurgery or by super-selective retrograde venographic techniques.11 The technique for percutaneous transvenous

Loss of one-way valves in the internal spermatic vein (ISV) causes increased hydrostatic pressures in the testicular drainage system nearly six times above the pressures in the prostate venous drainage system and loss of mechanism directing venous blood upwards in ISVs. Deferential veins (DVs) become an alternative route for testicular venous drainage, carrying high concentrations of free testosterone (FT) under elevated hydrostatic pressure (about six times normal). According to the principle of communicating vessels (Bernoulli), since pressure at the testicular side is higher than at the prostate side, testicular venous blood will flow into the prostate venous drainage (from high to low pressure) via the vesicular plexus (VP) and prostatic venous plexus (PVP) to the prostate gland. Consequently, FT arrives at the prostate not only physiologically via the prostate artery but mainly via the prostate venous drainage system (the `back door'), carrying undiluted and yet unbound to sex-hormone-binding globulin (SHBG) and high concentrations of FT, which bypasses the systemic circulation and is not detected in the peripheral blood.

varicocele treatment was originally developed by Comhaire and Kunnen16 for the treatment of varicocele in male infertility and has been modified and further perfected specifically as the Gat­Goren technique17 for treatment of impaired venous drainage apparatus in the male reproductive system, including all vertical venous bypasses and collaterals, bilaterally.11,17 The mechanisms leading to BPH are explained below in some detail.

Flow in the Testicular and Prostate Venous Drainage Systems in Normal Conditions and After Destruction of One-way Valves

Normally, as seen in Figure 1, the prostatic venous drainage flows in part through the prostatic venous plexus (PVP), the vesicular vein (VV), the internal iliac vein (II), the common iliac vein (CI) and, ultimately, to the inferior vena cava (IVC). The testes are drained mainly via the ISVs, with some participation by three other vessels:

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40cm

40cm

35cm

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Benign Prostatic Hyperplasia

the deferential vein system (DV), the scrotal vein system (SV) and the cremasteric vein (CV). The blood in the DV flows to the VV, the CI and, ultimately, the IVC. Note that both the testicular and the prostatic drainage systems share a common space, the VV, which, from a hydraulic point of view, is a connecting vessel between these two drainage systems. So, the intra-vascular pressures in these vessels are subject to the principle of communicating vessels, a direct derivative of Bernoulli's 1738 law of energy conservation in fluids dynamics. Under normal conditions, the OWVs have two main functions: to facilitate the flow of venous blood upwards against gravity and to divide the vertical ISV into between six and eight separate compartments, limiting the hydrostatic pressure on each valve to 6mmHg. However, when the OWVs are destroyed, two adverse hydraulic phenomena take place in the testicular venous drainage system, creating abnormal conditions in the testicular­ prostate drainage systems. The first of these is loss of the mechanism that propels the venous blood upwards against gravity ­ that is, the ISVs cease to function as drainage systems in erect or sitting positions. With the loss of the valves, the entire ISV becomes a single filled compartment that exerts an elevated hydrostatic pressure in the testicular drainage system. The pressure exerted on the testicular venous system can be calculated using equation 1. It has been found to be six to eight times the normal venous pressure. Consequently, testicular venous drainage is shunted to existing alternative venous routes, all of which then experience elevated pressure according to the law of communicating vessels. 10 Subsequently, the increased pressure propagates along all interconnected vessels. Testicular blood now flows along the pressure gradient, from the testicular drainage system to the prostate drainage system (which is at a lower pressure), carrying undiluted and unbound high concentrations of FT, bypassing the systemic blood circulation and flowing directly to the prostate gland. Consequently, FT arrives in the prostate not only pathologically via the prostate artery, but also (some 130-fold) physiologically via the prostate venous drainage system (the `back door'). This blood carries undiluted FT and is unbound to SHBG with extremely high concentrations, which bypasses the systemic circulation. Importantly, by bypassing the systemic circulation this concentration of FT is not detected in the peripheral blood; therefore, the information on testosterone levels we receive from blood tests are entirely dissociated from intraprostatic testosterone. Consequently, serum testosterone is not relevant as a source of information in terms of the intraprostatic androgen microenvironment. hydrostatic pressure in the testicular drainage systems is transmitted to the prostate via the impaired testicular­prostate drainage systems. Hyperplasia of the prostate is a biological process of accelerated prostate cell proliferation resulting from the extremely high concentration of FT reaching directly from the testes to the prostate (via the `back door' in contrast to the normal pathway via the systemic circulation and the prostatic artery).

Treatment Technique for Super-selective Intraprostatic Androgen Deprivation Therapy

Derived from the above explanation, it is clear that effective treatment for BPH would need to eliminate the pathological hydrostatic pressure in the testicular venous drainage system. This can be achieved by microsurgery or super-selective venography and sclerotherapy of the impaired internal spermatic veins bilaterally, including the network of venous bypasses and retroperitoneal collaterals associated the impaired ISVs. This treatment prevents the pressure gradient between the two drainage systems and eliminates the back-pressure and the back-flow from the testes directly to the prostate. The normal physiological environment of the prostate gland would be restored with normal venous pressures and normal physiological concentration of FT that reaches the prostate gland only via the prostatic artery.

Materials, Methods and Results

In order to substantiate these assertions, the following studies were conducted.18 In 245 cases, while performing venographies on patients with varicocele, the height of the vertical blood columns in the ISVs was measured in order to estimate the venous hydrostatic pressure. The average vertical height of the blood column in the right ISV was ~35cm and in the left ISV was ~40cm. The hydrostatic pressure in the vein was calculated from the equation10 P=xh, leading to 27mmHg on the right and 31mmHg in the left drainage system. These pressures are elevated six- to eight-fold above normal. Twenty-one blood samples were taken from the lower part of the left and the right ISV along with peripheral blood testosterone and FT levels. The average concentration of the total testosterone in the lower part of each ISV (adjacent to the DV) was 2,084nmol/l compared with 21.33nmol/l in the serum. The unbound FT was found to be 3,632pmol/l compared with 27.33pmol/l in the serum. Hence, the concentration of total testosterone was nearly 100-fold higher 19,20 and the FT level was nearly 133 times normal values in the serum. 18 The treatment was performed on a series of 28 men between 41 and 77 years of age. Initial mean prostate volume was 56ml (ranging from 28 to 122); initial mean PSA was 3.5ng/ml (ranging from 0.4 to 13). The mean frequency of nocturia in these patients was 3.57 (ranging from one to seven). Six months after the treatment, the prostate volume decreased to a mean of 36.9ml (ranging from 22 to 93), PSA decreased to 3.2ng/ml (ranging from 0.3 to 8.9), and nocturia decreased to an average of 0.96 (range zero to two) (see Table 1). In two cases (7%) there was some regression in the improvement of the urinary symptoms, possibly due to the development of new vertical bypasses (recurrent), which can be treated again.

Pathophysiological Mechanism

A recent study based on the above fluid mechanics analysis of the impaired testicular and prostate drainage systems has proposed a novel pathophysiogical mechanism and, consequently, a new treatment.18 The study showed that the mechanism that causes BPH does not depend on causes originating in the prostate; rather, it results as a secondary phenomenon to the destruction of the OWVs in the ISVs. The phenomenon of progressive destruction/dysfunction of the OWVs (varicocele) increases with age and at an increasing rate, reaching a prevalence of 80% of the male population in the eighth decade of life.7,8 This study18 suggested the following pathophysiological mechanism for the evolution of BPH. Hypertrophy of the prostate is a mechanical effect of congestion and enlargement of the prostate that occurs because the pathological

Discussion

For the benefit of the reader, we will briefly review the main points in our discussion.

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Reversal of BPH by Super-selective Intraprostatic Androgen Deprivation Therapy

Physical Deterioration of the One-way Valves in the Internal Spermatic Vein

Normally, lacking an active pump in the testicular venous drainage system, the OWVs function as a unique hydraulic system that raises the venous blood upwards, stepwise, against gravity while preventing downward flow. The valves do not open and close in a synchronous way (as they do in the lower limbs), but are activated by intermittent pressure fluctuations produced by the action of nearby muscles and abdominal structures. Under these conditions, some of the valves are closed while others above them are open. Hence, there is a high probability that the average hydrostatic pressure exerted on lower valves is higher than the average calculated physiological hydrostatic pressure exerted on each valve, which is ~4­6mmHg (see above and Figures 1 and 2). This is also the approximate hydrostatic pressure at the testicular and the prostate venous drainage systems under normal conditions. This pressure can be calculated via the equation for calculation the hydrostatic pressure (a derivative of Pascal and Newton's principles): P = xh (1)

Table 1: Prostate Volume, Prostate-specific Antigen and Nocturia Before and After Treatment of 28 Patients with Benign Prostate Hyperplasia

Parameters Prostate volume (cc) PSA (ng/ml) Nocturia 3.5 3.5 3.2 1 Before Treatment 56 After Treatment 37 Change 55% (compared with normal prostate volume) None 70% 0.1117 <0.0001 p-value <0.0001

PSA = prostate-specific antigen.

where is the density of the liquid and h the vertical height of the blood column (cm). Moreover, P is independent of the shape or size of the liquid column and of any motion in the liquid. For a normal compartment size of 6­8mm (see Figures 1 and 2), the physiological average pressure on a valve is ~4­6 mmHg. This pressure is also the approximate hydrostatic pressure at the testicular and the prostate venous drainage systems under normal conditions. Since each valve opens and closes at least 100,000 times a year (~2­3% of the number of heart beats), the valves are exposed repeatedly to an excessive load exerted on their elastic collagen tissue, leading to their progressive physical deterioration culminating eventually in their complete destruction. The vertical height of the blood column in the right ISV is ~35cm and in the left ISV ~40cm. When all of the valves in each of the ISVs are incompetent, the hydrostatic pressure at the drainage system relative to the corresponding insertion of the ISV is more than 30mmHg on the left side and 27mmHg on the right side. Recent studies have shown that the incidence of this phenomenon increases with age,7 reaching >75% in those 70 years of age.8

It is clear that under these conditions the supply of FT to the prostate that arrives physiologically via the prostate artery is negligible compared with the FT flow via the prostate venous drainage system (back door). This blood is carries undiluted FT and is unbound to SHBG with extremely high concentrations, which bypasses the systemic circulation. These levels of FT are not detected in the peripheral blood; therefore, the information on testosterone levels we receive from blood tests are entirely dissociated from intraprostatic testosterone levels. Hence, serum testosterone is not relevant as a source of information about the intraprostatic androgen microenvironment. It should be noted that in contrast to the erect posture of humans, the horizontal posture of quadruped animals does not exert a downward gravitational force on the venous drainage of the reproductive system and, therefore, OWVs are not necessary (and do not exist). Two parallel effects then occur in the prostate: a rapid mechanical effect ­ hypertrophy ­ and a slower, biological process ­ hyperplasia. Hypertrophy occurs due to the elevated venous back-pressure causing congestion and enlargement of the gland. It can be appreciated by studying its effect on the lower segment of the ISVs and the PP, which dilate until they can be easily palpated (variocele). The volume of the ISVs and, in particular, that of the PP can increase by three- to nine-fold under the elevated pressure.21 The prostate, exposed to that elevated pressure and composed of elastic tissue, enlarges in response to the increasing pressure in a similar manner, leading to hypertrophy of the prostate. Hyperplasia, the biological process, can be explained as follows: under normal conditions FT reaches the prostate gland via the prostatic artery after travelling through the general circulation system. Over this long route the testosterone dilutes by 70­100-fold19,20 and binds to SHBG. Only a small fraction of the testosterone (less than 2%) remains free.3 However, when the valves are destroyed, the blood that arrives directly from the testes to the prostate via the back door travels only 10­15cm, in which FT, undiluted and not yet bound to SHBG, is in concentrations approximately 130 times above physiological levels, arrives from its production site within the testes directly to the prostate, promoting accelerated prostatic cell proliferation. The result is a change in the normal proliferation/ apoptosis balance of prostatic cells,2 leading to hyperplasia of the prostate. Of course, this process of accelerated proliferation of prostate cells would not be expected to stop with hyperplasia and could, we suggest, progress with time to neoplasia.18

Effect of Elevated Pressure in the Testicular Venous Drainage System on the Entire Reproductive System

When the valves are destroyed, venous blood in the ISVs cannot flow upward against gravity; ISVs on both sides cease to function as normal physiological testicular venous drainage systems. The venous drainage from the testes is thus diverted into three other alternative channels (shunts) with elevated pressure. One of these, the DV, which drains the testes, creates a hydraulic connection with the PVP (Santorini's plexus), which partially drains the prostate via the VV. The VV, being the connecting vessel between the two systems, is a common space shared by the testicular and prostate drainage systems. However, on the side of the prostatic drainage system there is physiological pressure; on the side of the testicular drainage systems the pressure is substantially higher. Venous blood from the testicular side will flow retrograde into the prostate venous drainage (via the VV and the PVP), reaching the prostate at elevated hydrostatic pressure with an elevated concentration of FT (approximately 130-fold above physiologicallevels ) (see Figure 2).

Reversal of Benign Prostate Hyperplasia After Treatment (Gat­Goren Technique)

We can consider this treatment as super-selective intra-prostatic androgen deprivation (SPAD) therapy. When restoration of normal

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hydrostatic pressure in the testicular venous drainage system is achieved, back-pressure and back-flow to the prostate are eliminated. Blood from both drainage systems, meeting at the VV, now jointly flows towards the II, the CI and, ultimately, the IVC. Then the effects of back-pressure and back-flow do not exist anymore. The intra-prostatic pressure returns to normal and the volume of the gland decreases rapidly, at least partially, within weeks. Androgen now arrives only via the prostatic artery and the concentration of FT arriving at the prostate is physiological: <1% of the level before treatment. The proliferation/apoptosis ratio2 returns to normal and on the one hand, prostatic cells are no longer under the influence of excessive pathological proliferative stimuli, and on the other hand, there is a drastic reduction in the maintenance capacity of (hyperplasic) prostate cells as the supplied androgen level returns to <1% compared with the level before treatment. The prostate returns gradually towards the normal `steady state', with the degree of improvement also depending on the gland's elastic properties, which also depends on the age of the patient and the duration of the disease. volume homogeneously in all dimensions; however, it leaves the gland intact while reducing the pressure exerted on the urethra.

Conclusions

BPH develops due to an impairment of the testicular venous drainage system in the erect posture of the human. Based on a fluid mechanics analysis of an impaired testicular venous drainage system and the results of the developed treatment, the following statements can be made. BPH is caused by increased hydrostatic pressure in the prostate drainage system, while BPH is caused by an excessively high concentration of FT, both arriving at the prostate by pathological backpressure and back-flow from the testicular to the prostate drainage systems. Eliminating the pathological hydrostatic pressure in the testicular venous drainage system by occlusion of the impaired ISVs, including all the associated venous bypasses and retroperitoneal collaterals by super-selective transvenous sclerotherapy or by microsurgery eliminates the venous back-pressure and back-flow of blood to the prostate. This reduces its exposure to elevated FT. This initially reduces benign prostate hypertrophy and, subsequently (at least partially), reverses BPH. We recommend that patients with BPH be examined for bilateral varicocele and be treated according to the suggested treatment that, at least partially, reverses BPH.

Hydraulics, Benign Prostate Hyperplasia and Lower Urinary Tract Symptoms

An enlarged prostate has two adverse mechanical effects on the urinary system: it reduces the bladder volume reservoir, leading to frequency of urination, and, by exerting pressure on the urethra, it narrows the urethral diameter, causing weak stream and limiting bladder emptying, as complete emptying in a narrowing urethra requires increasing intra-vesicular pressure. According to the principle in fluid mechanics developed by Hagen-Poiseuille15 in 1838 (Q2/Q1 = [D2/D1]),4 which describes the rate of flow in relation to the changing diameter of the vessels (Q is rate of urine flow, Q1 = normal conditions, Q2 = BPH; D is the uretheral diameter, D1 = in normal conditions, D2 = in BP), it can be calculated by approximation that when the urethral diameter is reduced by only 30% due to the pressure exerted by the enlarged prostate gland, the urine flow is drastically reduced to about 24% of its normal stream capacity,15 i.e. if D2 = 0.7 D1, Q2 = 0.24 Q1 in the same manner; if the urethral diameter decreases to 50%, the urine flow will deteriorate to about 7% of the normal flow. The above-proposed treatment reduces intra-prostatic pressure, resulting in a general decrease in prostate

Yigal Gat is Head of Andrology­Interventional Radiology at the Maayanei Hayeshua Medical Centre and a Research Consultant at the Weizmann Institute of Science in Rehovot in Israel. He has worked as a senior andrologist at the Rabin Medical Centrer since 1985. His research on fluid mechanics of venous drainage in the male reproductive system led him to develop the GatGoren technique, which improves sperm production and testosterone production and reverses benign prostate hyperplasia. Professor Gat received his PhD from Ghent University Hospital and his MD from Tel-Aviv University. Michael Gornish is an Interventional Radiologist specialising in the male pelvis at the Maynei Hayeshua Medical Center in Bnei Brak in Israel. He was a Senior Radiologist and the Neuroradiology Section Chief at Rabin Medical Centre, where he gained experience in the venous anatomy of the male pelvis under Professor Mark Kunnen at the University of Ghent in Belgium. Dr Gornish received his BA cum laude in biology from Harvard University and his MD from Temple University.

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