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.

Deceased donor renal transplantation and the disruptive effect of commercial transplants: the experience of Oman.

The Oman Renal Transplantation Program was established in 1988 as a joint venture between Sultan Qaboos University and the Ministry of Health. It began with both living related donor (LRD) and deceased donor (DD) transplants. Over the next nine years, while the LRD programme progressed relatively well, there were only thirteen DD transplants. Two of the DD kidneys were obtained from overseas via an active collaboration with the Euro-transplant organisation, and one DD kidney was obtained from Saudi Arabia within the Gulf Cooperative Council exchange programme. The rest of the DD kidneys were obtained in Oman. The Omani DD programme, although it was a pioneering effort in the Gulf region at the time, was not entirely sustainable. In this paper we focus on the challenges we encountered. Among the major challenges was the absence of resources to establish a dedicated DD programme and particularly the failure to develop a cadre of dedicated transplant coordinators.

The future of replacement and restorative therapies: from organ transplantation to regenerative medicine.

As we continue to have severe shortages of organs for transplantation, we need to consider alternatives for the future. The most likely to make a real difference in the long term is regenerative medicine (RM), a field that has emerged from the conjunction of stem cell biology and cell therapies; gene therapy; biomaterials and tissue engineering; and organ transplantation. Transplantation and RM share the same essential goal: to replace or restore organ function. Herein I briefly review some major breakthroughs of RM that are relevant to the future of organ transplantation, with a focus on the needs of people in the developing world. A definition of RM is provided and the ethical, legal, and social issues are briefly highlighted. In conclusion, I provide a projection of what the future may be for RM.

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.

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?

Donor gender balance in a living-related kidney transplantation program in Oman.

It has been observed in several Eastern and Western countries that there is a gender imbalance among kidney donors. In the international experience, approximately 65% of live kidney donors have been women. We retrospectively studied the distribution of female and male donors or recipients among living kidney transplantations performed from 1980 to 2005, namely 198 Omani recipients of living-related kidney transplantations. To examine cultural influences, transplantations performed or expatriates were excluded from the study. For the whole period, 98 out of 198 donors (49.5%) were women. The number of female recipients 75 of 198 (38%) versus males were 123 (62%) recipients. We then subdivided the period into three intervals: 1980 to 1990, 1991 to 2000, and 2001 to 2005. The numbers of female donors for these three periods were 29 of 64 (45%), 42 of 89 (47%), and 27 of 45 (60%), respectively. There was a persistent preponderance of male recipients ranging from 58% to 66% during these periods. We concluded that there was no gender imbalance for kidney donors. Nevertheless, there was a male preponderance in the recipient group.

Complete regression of cutaneous B-cell lymphoma in a renal transplant patient after conversion from cyclosporin to sirolimus.

Posttransplant lymphoproliferative disease remains a serious morbidity. Herein we have reported a case of complete regression of a biopsy-proven B-cell lymphoma that occurred in the posttransplant period. A 48-year-old man received a living donor renal transplant for end-stage renal disease due to undetermined etiology. His initial immunosuppression consisted of corticosteroid, mycophenolate mofetil, and cyclosporin. The patient developed severe pneumonia within the first 2 months after transplantation due to Acineotobacter, fungus, and cytomegalovirus infections. He experienced a complete recovery and was discharged for regional follow-up. Four months after discharge, he was referred again because of presence of two nodules on his trunk. A biopsy of the nodules revealed B-cell lymphoma. Cyclosporin was stopped and he was converted to sirolimus. The lesions regressed progressively and completely within 7 weeks. The patient remains well without clinical relapses at 19 months after conversion. Renal functions remained stable. We postulated that the antincoplastic properties of sirolimus may have played an active part in the positive outcome.

Retinal injury as an early manifestation of posttransplant thrombotic microangiopathy: recovery with plasma exchanges and conversion to sirolimus--case report and review of the literature.

Thrombotic microangiopathy (TMA) remains a serious event. We report a case of occurrence of TMA in the immediate postoperative period after a living-related renal transplantation. A distinguished feature of the case was major, early involvement of the retina with marked by decreased visual acuity along with thrombocytopenia and renal functional impairment. The syndrome was reversible with plasma exchange and conversion from tacrolimus to sirolimus. The patient's renal function is excellent at 11 months after transplantation. Decreased visual acuity and cotton wool exudates may be the first manifestation of posttransplant TMA.

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.

Low tacrolimus dose requirements in renal transplant recipients in the omani population: implications for pharmacogenetics?

Clinical observations suggested that the dose requirements for some immunosuppressive drugs might be lower in some Eastern populations. We performed a study of 50 among 162 patients who were converted from a cyclosporine-based immunosuppression regimen to one based on tacrolimus. The reasons for conversion were as follows: acute rejection (n = 23), hirsutism and gingival hypertrophy (n = 12), chronic allograft nephropathy (n = 4), hypertension (n = 3), and other reasons (n = 8). Target levels were 10-15 ng/mL for patients with acute rejection and 5-8 ng/mL for patients after the first year of transplantation. We measured 180 tacrolimus blood levels in 44 patients using the IMx Abbott system of mean weight 64.5 kg and mean daily dose of 4.89 +/- 2.56 mg with mean blood levels of 11.31 +/- 5.22 ng/mL. Thus, to achieve the above-mentioned levels the average dose was 0.076 mg/kg, which is lower than that generally recommended to achieve 5-8 ng/mL levels, namely, 0.15 mg/kg. In this study, we did not address the reasons for these findings. The possibilities include dietary factors influencing the absorption of tacrolimus, and genetic polymorphisms in the Omani population that affect drug levels through several possible pharmacogenetic/genomic mechanisms. We intend to perform such studies in the future.

High incidence of early posttransplantation diabetes mellitus in an eastern population.

The prevalence of diabetes mellitus (DM) in the Gulf region is among the highest in the world. In the general population of Oman, the rate is approximately 11.7% with an additional 6.1% of the population having an abnormal glucose tolerance. This study reviewed the data for 162 adults who received kidney transplants between 2001 and 2004. The immunosuppression regimen was cyclosporine, mycophenolate mofetil (MMF), and steroids. The mean age of the group was 40.2 years. Twenty-two patients (13.6%) had DM prior to transplantation. Within the first 2 months after transplantation, 45 (32%) of the remaining 140 patients required insulin, and 10 (7.1%) required oral agents. A further 16 patients (11.4%) displayed blood glucose levels >11 mmol/L, but required only a special diet for control. The data indicate that 50% of recent adult kidney recipients in Oman receiving cyclosporine develop posttransplantation DM. This major problem in our transplant population requires special attention. Protocols with minimal steroid use and/or steroid withdrawal may be beneficial for the Oman kidney recipient population.

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.

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.

Non-heart-beating donation: ten evidence-based ethical recommendations.

The renewed interest in non-heart-beating donation (NHBD) in the past decade has resulted in renewed examination of the concept and meaning of death; of the nature of consent; of the propriety of interventions for the benefit of the recipient and not the donor; of potential conflicts of interest; and of defining futility. There is recognition of the need to maintain public trust. Recent experience indicates that NHBD could make a significant contribution to total renal transplant numbers. While there is graft dysfunction in the short term, the long-term results are comparable to those of transplants from heart-beating kidney donors, and in one series, even to living donors. The University of Zurich's experience indicates that waiting 10 minutes after asystole and not using in situ cooling do not adversely affect long-term outcomes. NHBD under ideal conditions could be extended to other organs such as the liver and pancreas. Ethical concerns are not insurmountable and can be minimized if cooling procedures and the use of drugs, such as heparin and phentolamine, is minimized, and if a period of 10 minutes is allowed to elapse after asystole before death is declared. We make a series of evidence-based recommendations for protocol development.

Stem cell research and transplantation: science leading ethics.

One of the most exciting developments in the biological sciences in the past decade has been the discovery and characterization of human embryonic stem cells (ESCs). The interest to transplanters is the potential applications of stem cells in regenerative medicine (RM), which may involve tissue engineering, genetic engineering, and other techniques to repair, replace, or regenerate failing tissues and organs. There is little controversy surrounding human adult stem cells. However, human ESCs are surrounded by a number of ethical controversies, the extent of which is partly dependent on their source. Those derived from currently existing embryonic stem cell lines are less controversial than those derived from "excess" embryos from in vitro fertilization (IVF) clinics, while ESCs derived from IVF embryos specifically created for the purpose are not acceptable to many people arguing from religious and other moral perspectives. Somatic cell nuclear transfer, or therapeutic cloning, must be distinguished from reproductive cloning. It holds the most promise for regenerative medicine. ESCs can also be derived from gonadal ridges of aborted fetuses. The transplant community must strive to uphold societal values in its effort to find remedies for their ailing patients and address the perennial problem of organ shortage. Transplanters also have a responsibility to engage the public in their efforts to gain public understanding and support, and policy makers must take into account public opinion. Only in this way can we realize the great potential of stem cell research for organ transplantation.