Harnessing genomics and biotechnology to improve global health equity.

With decisive and timely action, genome-related biotechnology can be harnessed to improve global health equity. In June 2002 in Kananaskis, Canada, leaders of the G8 industrial nations will develop an action plan to support implementation of the New African Initiative. By extending their discussion of health issues raised in the New African Initiative to include genomics, G8 leaders could signal their intention to increase global health equity by preventing a health genomics divide from developing. There are already some early and growing examples of genome-related biotechnology being applied successfully to health problems in developing countries. But how can genomics be systematically harnessed to benefit health in developing countries? We propose a five-point strategy, including research, capacity strengthening, consensus building, public engagement, and an investment fund.

Emerging science, emerging ethical issues: who should fund innate alloimmunity-suppressing drugs?

An emerging body of evidence suggests that the innate immune system plays a critical role in allograft rejection. Any injury to the donor organ, e.g. the reperfusion injury, induces an inflammatory milieu in the allograft which appears to be the initial event for activation of the innate immune system. Injury-induced intragraft damage- associated molecular patterns (DAMPs) are recognized by donor-derived and recipient-derived, TLR4/2-bearing immature dendritic cells (iDCs). After recognition, these cells mature and initiate allorecognition/alloactivation in the lymphoid system of the recipient. Indeed, the key "innate" event, leading to activation of the adaptive alloimmune response, is the injury-induced, TLR4-triggered, and NFkappaB-mediated maturation of DCs ("innate alloimmunity"). Time-restricted treatment of innate immune events would include 1) treatment of the donor during organ removal, 2) in-situ/ex-vivo treatment of the donor organs alone, and 3) treatment of the recipient during allograft reperfusion and immediately postoperatively. Treatment modalities would include 1) minimization of the oxidative allograft injury with the use of antioxidants; 2) prevention of the TLR4-triggered maturation of DCs with the use of TLR4-antagonists; 3) inhibition of complement activation with the use of complement inhibiting agents. According to data from clinical and experimental studies it can be assumed that successful suppression of innate alloimmune events results in either subsequent significant reduction in, or even complete avoidance of the currently applied adaptive alloimmunity-suppressing drugs. However, in view of the time-restricted period of treatment, and the fear to potentially destroy its own business with currently applied alloimmunity-suppressing drugs, the pharmaceutical industry is still, but quite legitimately, reluctant to invest in the high cost of clinical development of those drugs for transplant patients because there are no marketing interests. On the other hand, clinical development of innate alloimmunity-suppressing drugs is urgently warranted. But: Who should fund? In this article, three options are explored which may contribute to a solution of the problem: 1) provision of incentives to companies for drug development; 2) conduction of clinical trials in developing countries; and 3) creation of a public-private professional partnership in analogy to the "European Rare Diseases Therapeutic Initiative" (ERDITI). We suggest and recommend the creation of such a partnership which may be called: "The European Initiative for the Suppression of Innate Alloimmunity" ("EISIA"). In analogy to ERDITI, the main goals of this organization should be:--to provide a streamlined facilitated process of collaboration between Academic Teams/Transplant Centres, Study Groups, and Pharma Companies to develop innate alloimmunity-suppressing drugs;--to give Academic Teams/Transplant Centres facilitated access to a large variety of compounds, developed by companies for other indications, which can be evaluated pre-clinically and, if warranted, clinically;--to guarantee the continuity all the way from research to development and commercialisation of the drug. If preclinical studies uncover the potential of a compound for suppressing innate alloimmune events, the Pharma Partner who has rights to this compound will either develop himself the drug for organ transplantation indication or allow its development by the academic team or a third party if he has no intentions of developing himself.

The Developmental Origins of Health and Disease and Sustainable Development Goals: mapping the way forward.

In this paper, meant to stimulate debate, we argue that there is considerable benefit in approaching together the implementation of two seemingly separate recent developments. First, on the global development agenda, we have the United Nations General Assembly's 2015 finalized list of 17 Sustainable Development Goals (SDGs). Several of the SDGs are related to health. Second, the field of Developmental Origins of Health and Disease (DOHaD) has garnered enough compelling evidence demonstrating that early exposures in life affect not only future health, but that the effects of that exposure can be transmitted across generations - necessitating that we begin to focus on prevention. We argue that implementing the SDGs and DOHaD together will be beneficial in several ways; and will require attending to multiple, complex and multidisciplinary approaches as we reach the point of translating science to policy to impact. Here, we begin by providing the context for our work and making the case for a mutually reinforcing, synergistic approach to implementing SDGs and DOHaD, particularly in Africa. To do this, we initiate discussion via an early mapping of some of the overlapping considerations between SDGs and DOHaD.

Applying genomics-related technologies for Africa's health needs.

While the past century has seen significant improvement in life expectancies in the developed world, it has also witnessed diseases like HIV/AIDS, malaria and tuberculosis ravage populations in the developing world. In some Sub-Saharan African countries, life expectancies have plummeted to less than 40 years--nearly half of those in developed countries. Unequal access to the benefits of science and technology, including medical advances, exacerbate this disparity. In order to address the challenge of global health inequities and strengthen the role of science and technology innovation in contributing to real solutions, the Canadian Program on Genomics and Global health (CPGGH), based at the University of Toronto, has identified three guiding questions: Which genomics-related technologies are most likely to improve the health of people in developing countries?; How can developing countries harness these technologies for health development?; and What can industrialized countries do to assist developing countries?

Prostate cancer risk: the significance of differences in age related changes in serum conjugated and unconjugated steroid hormone concentrations between Arab and Caucasian men.

INTRODUCTION: Factors responsible for the low incidence of clinical prostate cancer (3-8/100,000 men/year) in the Arab population remain unclear, but may be related to changes in steroid hormone metabolism. We compared the levels of serum conjugated and unconjugated steroids between Arab and Caucasian populations, to determine if these can provide a rational explanation for differences in incidence of prostate cancer between the two populations. PATIENTS/METHOD: Venous blood samples were obtained from 329 unselected apparently healthy indigenous Arab men (Kuwaitis and Omanis) aged 15-80 years. Samples were also obtained from similar Arab men with newly diagnosed prostate cancer or benign prostatic hyperplasia (BPH). The samples were taken between 8:00 am and 12:00 noon. Serum levels of total testosterone, (TT), sex hormone binding globulin (SHBG), free androgen index (FAI); adrenal C19-steroids, dehydroepiandrosterone sulphate (DHEAS) and androstenedione (ADT) were determined using Immulite kits (Diagnostic Systems Laboratories Inc, Webster Texas, USA). The results obtained in Arab men were compared with those reported for similarly aged Chinese, German and White USA men. RESULTS: In all four ethnic groups, median TT and FAI declined with age, while SHBG increased with age. However, the mean TT and SHBG was significantly lower (p < 0.01) and the FAI significantly higher in Arab men (p < 0.01) compared to German men only in 21-30 years age group. In the other age groups the levels of TT and SHBG were higher in the Germans but the differences were not statistically significant. In all the racial groups serum levels of DHEAS and ADT reached a peak by about 20 years of life, and then declined progressively. The mean DHEAS in American Caucasians aged 20-29 years was 11.4 micromol/l compared to 6.22 micromol/l in the Arabs (p < 0.001). The mean DHEAS in USA Caucasians aged 70-79 years was 2.5 micromol/l compared to 1.8 micromol/l (p < 0.03) in the Arabs. There was no significant difference in mean serum levels of DHEAS between German and USA men. Similarly, there was no significant difference in the level of the hormones between Arab and Chinese men. Arab men with newly diagnosed prostate cancer had high serum TT, SHBG and DHEAS compared to those without the disease. CONCLUSIONS: The mean TT and SHBG was significantly lower in Arab men compared to Caucasian men especially in early adulthood. Caucasians have significantly higher serum levels of the precursor androgens DHEAS and ADT especially in early adulthood compared to Arab men. These observations of low circulating androgens and their adrenal precursors in Arab men may partially account for the decreased risk for prostate cancer among Arab men.

Identification of a novel 4 kDa immunoglobulin-A-binding peptide obtained by the limited proteolysis of jacalin.

Jacalin, an IgA-binding lectin from jackfruit (Artocarpus heterophyllus) seeds, was isolated by the passage of PBS extracts of seeds over an affinity matrix containing IgA-Sepharose-4B. It was further purified by HPLC. When analyzed by SDS-PAGE under both reducing and nonreducing conditions, the native jacalin was dissociated into two subunits of 12 and 15.4 kDa. Both the subunits could bind IgA. Peptide mapping performed with radioiodinated jacalin indicated that both the subunits were susceptible to proteolysis by Staphylococcus aureus V8 proteinase. One degradation product was a small peptide of 4 kDa. This small proteolytic fragment also bound IgA. The amino-termini of the two major IgA binding subunits, 12 and 15.4 kDa, were identical. The 4 kDa IgA-binding proteolytic fragment of jacalin had a different amino-terminal sequence, suggesting that the region of jacalin which binds IgA does not remain close to the amino-terminus of the peptide.

Putative role of serum insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels in the development of prostate cancer in Arab men.

INTRODUCTION: The incidence of clinical prostate cancer in the Arab population is among the lowest in the world. High serum IGF-1 level has been implicated as a possible risk factor for the development of prostate cancer in Caucasians. The purpose of this study was to determine serum IGF-1 and IGFBP-3 levels in healthy Arab men and in Arab men with newly diagnosed benign prostatic hyperplasia (BPH) and prostate cancer, and to compare these values with values reported in Caucasians. PATIENTS AND METHODS: Subjects were recruited in two groups: (a) indigenous, healthy Arab men aged 15-90 y (n = 383); (b) Arab men with newly diagnosed prostate cancer (n = 30) or BPH (n = 40). Blood was obtained from fasting patients and volunteers, between 8:00 a.m. and 12:00 noon. The serum concentrations of IGF-1 and IGFBP-3 were determined using Immunoradiometric assay (IRMA) kits. RESULTS: As in Caucasians, serum IGF-1 and IGFBP-3 levels declined with age in Arab men. The mean +/- s.d. of serum IGF-1 levels in healthy Arab men in the age group 15-20, 51-60, 61-70 y were lower (376.2 +/- 153.2, 134.9 +/- 105.7 and 89.6 +/- 48.4 ng/ml, respectively), compared to values reported for similarly aged Caucasians. Arab men with newly diagnosed prostate cancer had significantly higher serum IGF-1 level (P < 0.01) and lower IGFBP-3 levels (P < 0.01) compared to age-matched Arabs without the disease. CONCLUSIONS: Arab men have lower serum IGF-1 levels compared to Caucasians and this may be an important factor in the explanation of the low incidence of prostate cancer in the Arab population.

Complete regression of visceral Kaposi's sarcoma after conversion to sirolimus.

The prevalence of Kaposi's sarcoma (KS) is much greater in organ transplant recipients than it is in the general population. Its etiology appears to be related to geographic, genetic, and viral factors. Treatment of transplant-related KS has, until now, consisted mainly of reduction of, or withholding of, immunosuppression, often with deleterious effects on both graft and patient survival. In recent years, the immunosuppressive drug, sirolimus, has been demonstrated as possessing anti-neoplastic properties in both in vitro and animal models. In view of these properties and some preliminary clinical experience, we postulated that sirolimus would be beneficial in our patients who developed transplant-related KS. Here, we report the first case of a patient with both cutaneous and visceral KS who was successfully treated in the Middle East by conversion from a cyclosporine-based to a sirolimus-based immunosuppression regimen. The KS regressed completely within a few months after the conversion. The chronologic events and the extensive documentation, which included repeat computed tomography scans, are very suggestive of a selective anti-neoplastic effect of sirolimus.

Localization of major histocompatibility complex (HLA-ABC and DR) antigens in 46 kidneys. Differences in HLA-DR staining of tubules among kidneys.

Biopsies from 46 kidneys that were subsequently transplanted were examined with monoclonal antibodies and the peroxidase-antiperoxidase technique to localize HLA-ABC and DR antigens. There was no variation in the expression of HLA-ABC which was present on all cells of the renal parenchyma. HLA-DR was found consistently on the endothelium of glomeruli and of intertubular capillaries but was only weakly expressed, or not expressed at all, on the endothelium of large vessels. The mesangium of glomeruli also stained for HLA-DR. But there was a striking variation in the expression of HLA-DR by proximal renal tubular cells in the 46 kidneys. HLA-DR was absent from tubules in 11 of 46 kidneys (23%) and probably absent or very weakly expressed in a further 8 kidneys (17%). The expression of HLA-DR in tubular epithelium was not related to the donor's age, sex, blood group, or ischemia times. However, the frequency of HLA-DR3 increased (55%) in donors of kidneys with tubular DR-negative kidneys, as compared with a frequency of 15% in donors of tubular DR-positive kidneys. Although this difference was not significant after a correction for the number of comparisons made, it suggests a genetic influence on the expression of tubular DR. The survival of tubular DR-negative kidneys was better at 1 year than that of tubular DR-positive kidneys (70% vs. 57%--not significant), and tubular DR-positive grafts may have had a higher rate of delayed function when transplanted in cases with a donor-specific positive B cell crossmatch. There was no obvious variation in the number of dendritic cells stained with antibodies to HLA-DR and the leukocyte common antigen despite prior administration of high doses of steroids to some donors before nephrectomy.

The detailed distribution of HLA-A, B, C antigens in normal human organs.

We have used a monoclonal antibody, PA2.6, directed against the heavy chain of HLA-ABC antigens to study the detailed tissue distribution of MHC class I antigens. Normal tissues from throughout the human body were obtained fresh from organ donors or operative specimens and were snap-frozen in liquid nitrogen within 1-2 hr of removal. Frozen sections were then studied using a sensitive peroxidase-antiperoxidase immunohistological technique. The results of our study show that class I antigens could be detected on most, but not all, the nucleated cells in the body. They were only weakly detectable in several tissues including endocrine cells in the thyroid, parathyroid, pituitary and islets of Langerhans in the pancreas and on gastric mucosa, the myocardium, skeletal muscle, and hepatocytes in some of the specimens. Spermatozoa were positively stained in the testis, but as they moved up into the epididymis class I antigens were no longer detectable. We found that class I antigens were not detectable on corneal endothelium, some Brunner's glands in the duodenum, villous trophoblast, central nervous system neurones, the exocrine portion of the pancreas, and acinar cells in the parotid. We conclude, therefore, that class I antigens are not ubiquitous, as previously thought.

The detailed distribution of MHC Class II antigens in normal human organs.

In a previous article we described the detailed tissue distribution of MHC class I antigens. In this study, we have used a monoclonal antibody, NFK1, to study the tissue distribution of MHC class II antigens. This antibody, which detects a monomorphic determinant common to the DR, SB, and DC molecules, was used to stain frozen sections of normal tissues from throughout the human body by a sensitive peroxidase-antiperoxidase immunohistological technique. Although previous studies, both in animal models and in human beings, have shown that class II antigens are expressed on a limited number of nonlymphoid tissues, our study has extended the spectrum of tissues on which this class of antigens is detectable. Epithelial cells in a number of organs were positively stained--these include the tongue, tonsils, epiglottis, trachea, small intestine, urethra, epididymis, and proximal renal tubules. Lymphatics throughout the body appeared to express class II antigens. Capillaries in brain, testis, and placenta appeared not to express class II antigens, but in the rest of the body they showed strong and uniform staining. These and other observations, and their implications, are discussed in relation to previously published studies.

The new chimaera: the industrialization of organ transplantation. International Forum for Transplant Ethics.

Clinical organ transplantation has evolved through advances in patient care in parallel with investigations in associated biologies. It has developed from a cottage industry to an important medical specialty driven increasingly by the availability of newer and more effective immunosuppressive drugs, and dependent on consistently close collaborations between university-based clinical scientists and the pharmaceutical industry. Particularly during the past decade, however, this industry has undergone striking changes, consolidating into huge multi-national corporations, each competing for patients, their doctors, and for support of the allied hospitals. Because of the growth of "Big Pharma," the relationship between academia and industry has changed. There have been many advantages to such mutually dependent interactions. A combination of university-based expertise and the specialized knowledge and resources of industry have produced important scientific gains in drug development. Commercial sponsorship of applied research has been crucial. The orchestration of multicenter controlled clinical drug trials has provided invaluable information about the effectiveness of newer agents. But there are also disadvantages of increasing concern. Indeed, the power of "Big Pharma" in many medical fields including transplantation is such that presentation of data can be delayed, adverse results withheld, and individual investigations hampered. Clinical trials may be protracted to stifle competition. Monetary considerations may transcend common sense. Several measures to enhance the clinical relationship between the pharmaceutical industry and those involved with organ transplantation are suggested, particularly the use of third party advisors in the production of clinical trials, support for more basic research and in the dissemination of results. In this way, the increasingly problematic phenomenon of commercialization of the field of transplantation can be tempered and controlled.

Analysis of the distribution of HLA-B alleles in populations from five continents.

A two stage PCR-SSOP typing procedure, that permitted HLA-B allele assignment, was applied to DNA samples obtained from six diverse populations -Brazilian, Mexican (Series and Mestizos), Cuban (Caucasoid and Mulatto), South African Zulu, Omani, and Singapore Chinese. HLA-B allele frequencies and HLA-A/B two locus haplotype frequencies were compiled for each population.

Analysis of the distribution of HLA-A alleles in populations from five continents.

The variation and frequency of HLA-A genotypes were established by PCR-SSOP typing in diverse geographically distributed populations: Brazilian, Colombian Kogui, Cuban, Mexican, Omani, Singapore Chinese, and South African Zulu. HLA-A allelic families with only one allele were identified for HLA-A*01, -A*23, -A*25, -A*31, -A*32, -A*36, -A*43, -A*69, -A*80; and with two alleles for HLA-A*03, -A*11, -A*26, -A*29, -A*33, -A*34, and -A*66. Greater variation was detected for HLA-A*02, -A*24, and -A*68 allele families. Colombian Kogui and Mexican Seris showed the least diversity with respect to HLA-A alleles, albeit with small numbers tested, with only four and five HLA-A alleles identified, respectively. It would appear by their presence in all populations studied, either rural or indigenous, that certain alleles are very important in pathogen peptide presentation.

A controlled trial of surgery for trachomatous trichiasis of the upper lid.

The effectiveness of commonly used procedures to correct trachomatous trichiasis of the upper lid was examined in a clinical trial in Oman. Lids were graded as having minor trichiasis (five or fewer lashes), major trichiasis (more than five lashes), and defective lid closure. Randomly allocated surgery specific for lid grade was completed in 384 lids, of which 369 (96%) were followed up once or twice approximately 9 and 21 months after surgery. The definition of operative success included no evidence of trichiasis and complete lid closure. Tarsal rotation was the most effective operation and was successful in 80% of cases of minor trichiasis, compared with success rates of 29% for electrolysis and 18% for cryoablation. Tarsal rotation was successful in 77% of cases of major trichiasis, compared with a 41% success rate for tarsal advance and rotation. Surgery for major trichiasis produced a significant improvement in visual acuity in operated vs nonoperated fellow eyes in a regression model incorporating the between-eyes correlation of visual acuity.

Analysis of factors for the prediction of the response to xenotransplantation.

Predicting the response to xenotransplantation is difficult, but can be based upon (i) past clinical experience, (ii) opinion surveys and focus groups, (iii) predictable variables, and (iv) the allotransplant experience. Baby Fae, the Pittsburgh baboon liver transplants, and the Jeff Getty baboon marrow transplant have taught us (a) not to underestimate hurdles, (b) to communicate professionally, (c) not to promise too much, (d) that lobbying can be effective, (e) that "being the first" is important, and (f) that the media can be fickle. The Swedish islet cell and the U.S. neural tissue transplants suggest that patients without immediately life-threatening illnesses will accept xenogeneic tissue and that the public/media will not respond negatively when there is little fanfare. Limited opinion surveys/focus groups suggest a degree of reluctance/revulsion that is more common in women, minorities, and the less-educated, and when the likely donor is a subhuman primate. Predictable positive public-response variables include perceptions of (a) adequacy of the scientific base, (b) adherence to globally agreed upon guidelines, (c) legitimacy/competence of regulatory bodies, and (d) adequate infectious risk assessment and management. A likely negative predictor is the role of animal rights activists (more in Europe, less in the U.S. and the developing world). Less predictable is the response of the media and what other societal concerns dominate the news at the time. Cultural concerns will need careful study. Allotransplant experience suggests that informed religious opinion can be accommodating a new technology. Psychological factors will be important and will need professional management.

HLA antigens in Omanis with blinding trachoma: markers for disease susceptibility and resistance.

AIM: To determine the presence of HLA antigens in people with blinding trachoma. METHODS: Fifty Omanis with blinding trachoma were serologically typed for HLA A, B, C, DR, and DQ antigens and DNA typed for class II DR beta and DQ beta alleles and compared with a population of 100 healthy controls. RESULTS: chi 2 analysis of serological reactions did not reveal any significant differences in HLA antigen frequencies after correction of probability, although DR4, DR7, and DR53 were completely absent in the patients and all of the patients were HLA DQ1 positive. In the case of DQ1 the relative risk was 22.6 (95% confidence interval of 20.7-24.7). Class II DNA low resolution DR beta typing showed a significant increase in HLA DR16 (pc = 0.036, relative risk = 3.8) and a significant decrease in HLA DR53 (pc = 0.018, relative risk = 0.05). CONCLUSION: The finding that HLA DR16 (a DR2 subtype) is associated with susceptibility to blinding trachoma, a disease that is caused by an intracellular micro-organism, is consistent with reports of an HLA DR2 association with leprosy and tuberculosis, diseases also caused by an intracellular micro-organism. Similarly, resistance to leprosy is associated with HLA DR53 as is the case with blinding trachoma described here. It is postulated that HLA DR2 or subtypes in association with HLA DQ 1 may enable an intracellular micro-organism to enter the cell or are involved in presentation of peptides derived from intracellular micro-organisms to T lymphocytes initiating a delayed hypersensitivity or autoimmune reaction. These findings are the first report that genetic factors are of major importance in the development and protection against blinding trachoma.

HLA antigens in an Omani population with dilated cardiomyopathy.

We have investigated the frequency of HLA antigens in 50 Omanis with idiopathic dilated cardiomyopathy to establish whether there are ethnic/racial differences in the reported HLA associations with this disease. There were no statistically significant HLA-A, B, C, DR or DQ antigen frequency differences between the patients and 247 healthy Omanis. THe reported association of HLA-DR4 with idiopathic dilated cardiomyopathy in the Caucasian population does not apply to the Omanis. This confirms the heterogeneity of this disease and points to ethnic/racial origins as important factors when examining the HLA association. This is particularly pertinent as HLD-DR4 has been strongly linked to autoantibody formation in idiopathic dilated cardiomyopathy in Caucasians. The lack of any HLA antigen association in Omanis would argue against the proposed HLA-linked autoimmune pathology of idiopathic dilated cardiomyopathy.

Organ donation--world experience; the Middle East.

Many countries in the Middle East began renal transplantation in the late 1970s and the 1980s. In many countries transplantation has evolved through distinct stages of development, and at present living-related donors continue to be the main source of kidneys. Islamic opinion has been strongly in favour of transplantation of organs from both living and cadaveric donors. Brain death as a criterion of death was accepted by Islamic Jurists in 1986, and in Saudi Arabia about 35% of all transplants are from cadaveric donors. Some patients continue to go to neighbouring countries to buy kidneys for transplantation; there is evidence that this practice has resulted in unacceptable morbidity and mortality, and is currently associated with a risk of at least 1:18 of acquiring HIV infection. Extrarenal solid organ transplantation is very new, with heart transplants being performed in Turkey, Jordan, and Saudi Arabia. Liver transplants have been initiated in Turkey and Kuwait. The favourable religious rulings and the resources available should enable transplantation to develop rapidly in the next few years in the Middle East and West Asia.

Paid organ procurement: pragmatic and ethical viewpoints.

None of the familiar arguments against paid organ procurement really works. Most arguments spring from revulsion that arises from the abuses of the practice rather than the act itself. This has not stopped official condemnation. However, the evidence we have at present is that such condemnation, aimed at correcting a perceived moral wrong rather than at abuses of a practice (the correction of which might actually bring some moral good), has utterly failed, and many more countries including the United States now harbor paid organ procurement. We can try to develop and articulate a truly compelling moral argument against paid organ procurement or we can try to minimize the harm that comes out of this practice. Since it is unlikely that all countries will agree on a standardized approach in such a muddled field, the best way may be to let every country decide on what is best for itself. Some may want to ban the practice using legislation. Others may want to try regulating the practice, knowing full well that they cannot stop it and that turning a blind eye to the practice, or simply condemning it, does no good whatsoever and actually increases the harm because everything is done underground, with middlemen and mafia-like organizations making a lot of money out of a lot of misery. Some countries may choose to find other, more innovative solutions. We call attention to an important resolution dealing with this subject at the December 2002 ethics and transplantation congress in Munich.