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AbstractBackground/Objective:Recently, several studies have reported that DNA methylation changes in tissue are reflected in blood, sparking interest in the potential use of global DNA methylation as a biomarker for gestational diabetes mellitus (GDM). This study investigated whether global DNA methylation is associated with GDM in South African women.Methods:Global DNA methylation was quantified in peripheral blood cells of women with (n = 63) or without (n = 138) GDM using the MDQ1 Imprint® DNA Quantification Kit.Results: Global DNA methylation levels were not different between women with or without GDM and were not associated with fasting glucose or insulin concentrations. However, levels were 18% (p = 0.012) higher in obese compared to non-obese pregnant women and inversely correlated with serum adiponectin concentrations (p = 0.005).Discussion: Contrary to our hypothesis, global DNA methylation was not associated with GDM in our population. These preliminary findings suggest that despite being a robust marker of overall genomic methylation that offers opportunities as a biomarker, global DNA methylation profiling may not offer the resolution required to detect methylation differences in the peripheral blood cells of women with GDM. Moreover, global DNA methylation in peripheral blood cells may not reflect changes in placental tissue. Further studies in a larger sample are required to explore the candidacy of a more targeted approach using gene-specific methylation as a biomarker for GDM in our population.

Yellow fever virus (YFV) is a reemerging global health threat, driven by several factors, including increased spread of the mosquito vector and rapid urbanization. Although a prophylactic vaccine exists, vaccine hesitancy, supply deficits, and distribution difficulties leave specific populations at risk of severe YFV disease, as evidenced by recent outbreaks in South America. To establish a treatment for patients with severe YFV infection, we tested 37 YFV-specific monoclonal antibodies isolated from vaccinated humans and identified two capable of potently neutralizing multiple pathogenic primary YFV isolates. Using both hamster and nonhuman primate models of lethal YFV infection, we demonstrate that a single administration of either of these two potently neutralizing antibodies during acute infection fully controlled viremia and prevented severe disease and death in treated animals. Given the potential severity of YFV-induced disease, our results show that these antibodies could be effective in saving lives and fill a much-needed void in managing YFV cases during outbreaks.

The incidence of type 2 diabetes (T2D) increases dramatically worldwide and has created an enormous health care burden. Obesity, dyslipidemia and insulin resistance are major risk factors for the development of T2D, but the major factor leading to the disease is failure of the insulin-producing beta cell mass to compensate for increasing insulin demands of the body. Progression of the disease further diminishes the beta cell mass as a result of lipotoxicity and glucotoxicity for which beta cells are particularly sensitive. Hence, treatment aiming to prevent beta cell loss or increase the number of beta cells could inhibit diabetes progression or lead to restoration of normal metabolism. Whereas current and new antidiabetic drugs are mainly targeting insulin secretion and action or glucose uptake, newer interventions must be found that prevent beta cell loss or increase beta cell number. The targets for this are beta cell proliferation, neogenesis and survival. This review examines major evidence from animal experiments suggesting that it is feasible to regulate the beta cell mass by bioactive compounds like growth factors, cytokines, hormones, phytochemicals and small molecules. Often the mode of action remains unclear due to inadequate methods to assess the effects of the compounds on the beta cell dynamics. Furthermore, a major challenge is to identify compounds with sufficient specificity in order to avoid unwanted effects on other cell types. Provided such safety issues can be solved, this may provide a curative approach for diabetes treatment.

Reported here are the effects of a high-fat diet (HFD) fed to dams during pregnancy on the weight, - and -cell development, and -cell function of their weanling offspring.

Provided engraftment can be ensured, vascularization promoted, and ischaemic damage due to storage prevented, foetal pancreatic transplantation (FPT) has the potential to ameliorate the endocrine and metabolic disturbances in diabetic animal models including hyperglycaemia. In a syngeneic Wistar rat substrain (WAG) model (WAG → WAG), FPT was capable of restoring normoglycaemia in diabetic rats rendered diabetic by streptozotocin (STZ). Post‐transplantation growth and development of the foetal tissue was characterised by acinar atrophy, preservation of islet tissue, and development and proliferation of fat accumulations at the site of engraftment. B‐ and A‐cell staining and distribution on ICC appeared normal after 12 months. Mycophenolate mofetil (MMF) together with cyclosporine (CSA) was selected to suppress rejection of foetal rat pancreatic allografts in a strong responder allogeneic model (WAG → Sprague‐Dawley). MMF, a novel immunosuppressive agent that selectively inhibits de novo purine synthesis, was administered in combination with subtherapeutic doses of CSA (2 mg/kg/day) to prevent rejection after allogeneic foetal rat pancreatic transplantation. Although CSA monotherapy in this model can partially suppress rejection, the combination of CSA and MMF results in significant inhibition of acute allograft rejection and mononuclear cellular (MNC) infiltration as assessed by sequential histology post‐operatively. Although the follow‐up period of allografts was restricted to 30 days of treatment, histology showed low graft infiltrate scores (1.2+) and preservation of islets and immunocytochemical staining. The results in this animal transplantation model confirm that sub‐therapeutic doses of MMF and CSA therapy are effective in preventing acute rejection of foetal rat pancreatic allografts in the short‐term, thus allowing preservation of vital endocrine components of the foetal pancreas such as islets. Microsc. Res. Tech. 43:343–355, 1998. © 1998 Wiley‐Liss, Inc.

Using immunolabelling techniques, characterization of the Vervet monkey pancreas included a study of both its development and its structure and normal functioning in the adult. We found that PP and somatostatin occurred during development before glucagon. Insulin and all four pancreatic peptides occurred in one of the primordial buds prior to fusion. These finding call into question the suggested contribution of only PP cells by the ventral bud and non‐PP cells by the dorsal bud. Co‐localization of glucagon and PP was observed extensively with their relative expressions occurring in what appeared to be an organised non‐random manner. Cells expressing both glucagon and PP persisted in the adult, together with many other combinations, suggesting an interesting plasticity of endocrine cell differentiation in the adult. Cellophane wrapping of the head of the Vervet monkey pancreas was shown to result in a noticeable increase in duct cell proliferation and endocrine cell volume but no increased replication of endocrine cells. Cells, immunoreactive for pancreatic peptides, were observed to bud from the ducts, suggesting a regeneration of endocrine cell tissue by neogenesis, although it is uncertain whether the duct epithelium contains the only stem cell source of new endocrine tissue. Hopefully, further investigations will elucidate a mechanism by which endocrine cell regenerative capacity can be stimulated in diabetics to overcome their absolute or relative deficiencies of insulin production. Microsc. Res. Tech. 43:322–331, 1998. © 1998 Wiley‐Liss, Inc.

Provided engraftment can be ensured, vascularization promoted, and ischaemic damage due to storage prevented, foetal pancreatic transplantation (FPT) has the potential to ameliorate the endocrine and metabolic disturbances in diabetic animal models including hyperglycaemia. In a syngeneic Wistar rat substrain (WAG) model (WAG → WAG), FPT was capable of restoring normoglycaemia in diabetic rats rendered diabetic by streptozotocin (STZ). Post-transplantation growth and development of the foetal tissue was characterised by acinar atrophy, preservation of islet tissue, and development and proliferation of fat accumulations at the site of engraftment. B- and A-cell staining and distribution on ICC appeared normal after 12 months. Mycophenolate mofetil (MMF) together with cyclosporine (CSA) was selected to suppress rejection of foetal rat pancreatic allografts in a strong responder allogeneic model (WAG → Sprague-Dawley). MMF, a novel immunosuppressive agent that selectively inhibits de novo purine synthesis, was administered in combination with subtherapeutic doses of CSA (2 mg/kg/day) to prevent rejection after allogeneic foetal rat pancreatic transplantation. Although CSA monotherapy in this model can partially suppress rejection, the combination of CSA and MMF results in significant inhibition of acute allograft rejection and mononuclear cellular (MNC) infiltration as assessed by sequential histology post-operatively. Although the follow-up period of allografts was restricted to 30 days of treatment, histology showed low graft infiltrate scores (1.2+) and preservation of islets and immunocytochemical staining. The results in this animal transplantation model confirm that sub-therapeutic doses of MMF and CSA therapy are effective in preventing acute rejection of foetal rat pancreatic allografts in the short-term, thus allowing preservation of vital endocrine components of the foetal pancreas such as islets. Microsc. Res. Tech. 43:343–355, 1998. © 1998 Wiley-Liss, Inc.

Using immunolabelling techniques, characterization of the Vervet monkey pancreas included a study of both its development and its structure and normal functioning in the adult. We found that PP and somatostatin occurred during development before glucagon. Insulin and all four pancreatic peptides occurred in one of the primordial buds prior to fusion. These finding call into question the suggested contribution of only PP cells by the ventral bud and non-PP cells by the dorsal bud. Co-localization of glucagon and PP was observed extensively with their relative expressions occurring in what appeared to be an organised non-random manner. Cells expressing both glucagon and PP persisted in the adult, together with many other combinations, suggesting an interesting plasticity of endocrine cell differentiation in the adult. Cellophane wrapping of the head of the Vervet monkey pancreas was shown to result in a noticeable increase in duct cell proliferation and endocrine cell volume but no increased replication of endocrine cells. Cells, immunoreactive for pancreatic peptides, were observed to bud from the ducts, suggesting a regeneration of endocrine cell tissue by neogenesis, although it is uncertain whether the duct epithelium contains the only stem cell source of new endocrine tissue. Hopefully, further investigations will elucidate a mechanism by which endocrine cell regenerative capacity can be stimulated in diabetics to overcome their absolute or relative deficiencies of insulin production. Microsc. Res. Tech. 43:322–331, 1998. © 1998 Wiley-Liss, Inc.

Cellophane wrapping of the adult Syrian golden hamster pancreas has been found to result in ductular cell proliferation leading to islet regeneration. Injection of cytosol from a cellophane-wrapped pancreas into normal or diabetic hamsters evoked a similar response. In view of the therapeutic potential of the active substance in this cytosol, it was decided to investigate whether a similar response could be achieved in a primate. In normal adult Vervet monkey (Cercopithecus aerhiops) pancreas, proliferation is seen only rarely in islet cells and occasionally in duct and acinar cells. Immunohistochemi-cal investigation of normal Vervet monkey pancreas (n 4) and 14 days (n 2) and 56 days (n 1) after cellophane wrapping of the Vervet monkey pancreas revealed a slight increase in proliferation of islet and acinar cells and a larger increase in proliferation of duct cells and in total endocrine cell volume. The results suggest that there is a latent developmental capability in the adult primate pancreas.

An investigation into the development of the Vervet monkey endocrine pancreas revealed a sequence of occurrence of pancreatic peptides that differed from previous reports in mice, dog and human with PP and somatostatin occurring before glucagon and insulin. All four pancreatic peptides were identified, immunohistochemically, in only one of the pancreatic primordial buds, before fusion of the two buds to form the pancreas. This questions the hypothesis that the heterogeneous endocrine cell distribution seen in the adult pancreas is due to the contribution of only PP cells by the ventral bud and non-PP cells by the dorsal bud. Co-localization of glucagon and PP was observed extensively in the developing pancreas and the predominant expression of one over the other in an apparently organized non-random manner accounted for the glucagon- and PP-rich areas seen in the developing pancreas. A small number of cells immunoreactive to glucagon and PP were also observed in the adult. Reports of plasticity of differentiation of other pancreatic cells led us to investigate regeneration potential of the adult monkey pancreas. Partial obstruction of the Vervet monkey main pancreatic duct, by cellophane wrapping, resulted in duct cell proliferation and differentiation to form new endocrine tissue in a way that mimics normal organogenesis. Focal areas of hepatocytes were found in the regenerated pancreas of one monkey, illustrating further the latent developmental capabilities of adult pancreas cells. These findings could lead to interesting new therapies for pancreas and liver disease.

Differences in body-image between live-related and cadaver renal transplant recipients were investigated. A body-image questionnaire as part of a comprehensive psychological assessment was individually administered to ten live-related and 30 cadaver renal transplant patients. A factor analysis of the questionnaire items disclosed eight factors in the ratings of body-image. Separate factor scores were then calculated for each participant in the study on each factor. Further statistical analysis of these scores revealed no significant sex-related differences in the ratings, but indicated that live-related renal recipients overall felt less positive than cadaver renal recipients concerning the body's physical attractiveness, and physical contact. The implications of these findings for a psychonephrology service are discussed.

Coenzyme Q10(CoQ10) is well known for its beneficial effects in cardiovascular disease (CVD); however, reported evidence has not been precisely synthesized to better inform on its impact in protecting against cardiovascular‐related complications in diabetic patients. The current meta‐analysis included randomized controlled trials published in the past 5 years reporting on the effect of CoQ10 on metabolic and CVD‐related risk profiles in individuals with diabetes or metabolic syndrome. We searched electronic databases such as MEDLINE, Cochrane Library, Scopus and EMBASE for eligible studies. In addition to assessing the risk of bias and quality of evidence, the random and fixed‐effect models were used to calculate the standardized mean difference and 95% confidence intervals for metabolic parameters and CVD outcomes. Overall, 12 studies met the inclusion criteria, enrolling a total of 650 patients. Although CoQ10 supplementation did not statistically affect all metabolic profiles measured, it significantly reduced CVD‐risk‐related indexes such as total cholesterol and low‐density lipoprotein (LDL) levels in diabetic patients when compared to those on placebo [SMD = 0.13, 95% CI (0.03; 0.23), Chi2= 43.62 and I2= 29%, P= .07]. The overall results demonstrated that supplementation with CoQ10 shows an enhanced potential to lower CVD risk in diabetic patients by reducing total cholesterol and LDL. Moreover, the beneficial effects of CoQ10 in lowering the CVD risk are associated with its ameliorative properties against oxidative stress and improving endothelial health. Although clinical evidence on the impact of coenzyme Q10 (CoQ10) against cardiovascular diseases (CVDs) is available, such information has not been efficiently scrutinized to better inform on its protection against the diabetes‐associated CVD risk. In addition to modulating some metabolic disease‐associated parameters, the current meta‐analysis of randomized controlled trials showed that CoQ10 can protect against diabetes‐associated CVD‐related risk by lowering total cholesterol and lipoprotein to improve endothelial health in patients with diabetes and metabolic syndrome.