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Biomedical subjects

R G Bretzel

Publications and source records attributed to R G Bretzel.

At least 91 records · Page 5Linked to original sources
PubMed1998

Evaluation of serum and urinary estrogen levels in male patients with HIV-infection.

Several endocrine functions are described which are altered in patients with human immunodeficiency virus infection. However, there is limited information available on estrogens and their function in these patients. The aim of this study was to relate the stage of the disease with urinary and serum estrogens and the influence of heroin consumption on gonadal steroids. Forty human immunodeficiency virus infected outpatients without AIDS or the clinical picture of AIDS were involved in this cross-sectional study. The subjects were divided in two groups: heroin addicts and non heroin addicts. Blood samples were taken and 24 h urines collected. Serum follicle stimulating hormone, luteinizing hormone, prolactin, estrone, estradiol, testosterone and urinary total estrogens were measured by commercially available radioimmunoassays. Prolactin levels were not affected in the patients. However, compared with controls, follicle stimulating hormone and luteinizing hormone were significantly higher for both groups tested. In contrast, the elevated serum estrone levels were significantly lower expressed in the patients with heroin abuse compared to those of the other group. Urinary estrogens in human immunodeficiency virus infected patients of both groups were found to be higher than those compared to healthy controls. Since these drugs are known to enhance estrogen levels, we conclude that other factors are modulating estrogen formation and degradation in these patients.

Adult↗
PubMed1998

Successful islet auto- and allotransplantation in diabetic pigs.

BACKGROUND: Because of its anatomical and physiological similarities to humans, the pig appears to be a suitable large animal model for preclinical studies of islet transplantation. The aim of this study was to investigate islet auto- and allotransplantation in a pig model with diabetes induced by total pancreatectomy. METHODS: Porcine islets were isolated by a continuous digestion-filtration device at 32 degrees C and purified by a discontinuous iso-osmolar Ficoll-sodium-diatrizoate gradient on a Cobe 2991. The purified islets were autografted into the liver or the renal subcapsular space. The liver appears to be a more suitable site for the islet grafts than the renal subcapsular space, and the minimal amount of islets for reversal of diabetes is >5 microl/kg of body weight. RESULTS: Persistent normoglycemia (fasting blood glucose level: 72.4+/-44.38 mg/dl) with a normal insulin secretion response to glucose stimulation was successfully achieved in five of six diabetic pigs by implanting a sufficient islet mass into the liver. Triple-drug immunosuppressive therapy with cyclosporine, azathioprine, and prednisolone did not prevent porcine islet allografts from experiencing early failure. However, the addition of 15-deoxyspergualin to the triple-drug immunosuppressive regimen significantly prolonged the function of the islet allografts. When antithymocyte globulin was added to the above-mentioned immunosuppressive drug regimen, the normoglycemic period was prolonged to more than 1 month (fasting blood glucose level: 75.4+/-17 mg/dl). CONCLUSION: We conclude that autotransplantation with a sufficient islet mass can induce normoglycemia with a normal insulin secretion response to glucose stimulation in pancreatectomized diabetic pigs and that allotransplantation can be successfully achieved when 15-deoxyspergualin and antithymocyte globulin are combined with the triple-drug immunosuppression described above. However, this immunosuppressive protocol results in a high rate of infectious complications.

Animals↗
PubMed1998

Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with long-standing type I diabetes mellitus.

BACKGROUND: Defective glucose counterregulation and hypoglycemia unawareness are both well-recognized risk factors for recurrent episodes of severe hypoglycemia in patients with type I diabetes. At present, no conventional therapy is available to routinely overcome these acquired impairments in long-standing diabetes. METHODS: To test the hypothesis that successful intraportal islet transplantation could improve this syndrome, hormonal counterregulatory responses and symptoms were studied during stepped hypoglycemic clamp tests before and after intraportal islet transplantation in three patients with type I diabetes who were prone to severe hypoglycemia. RESULTS: As compared with matched nondiabetic control subjects, before islet transplantation, glucagon responses were absent while epinephrine and cortisol responses were either markedly decreased or absent in all diabetic subjects. One patient also had decreased norepinephrine and growth hormone responses. Autonomic warning symptoms were absent in all patients during hypoglycemia. One month after successful islet transplantation, there was no improvement in the glucagon response. However, glycemic thresholds and/or peak incremental responses of epinephrine, norepinephrine, and cortisol improved in all patients. Moreover, all patients had developed autonomic warning symptoms so that glycemic thresholds were detectable within the examined range. CONCLUSION: We conclude that intraportal islet transplantation does not restore hypoglycemia-induced glucagon secretion, but it improves the responses of most counterregulatory hormones and hypoglycemic warning symptoms even in long-standing type I diabetes.

Adult↗
PubMed1998

The relationship of glycaemic level to advanced glycation end-product (AGE) accumulation and retinal pathology in the spontaneous diabetic hamster.

To assess the relationship between glucose and advanced glycation end products (AGE) and the relationship between AGE and retinal changes in vivo, we studied the time course of retinopathy over 12 months in trypsin digest preparations and measured glycaemia and retinal AGE in spontaneous diabetic hamsters of mild (MD) and severe (SD) phenotypes. Blood glucose levels were elevated in MD (9.44+/-0.76 mmol/l) and in SD (3 months: 24.3+/-1.4 mmol/l; 12 months: 31.7+/-0.8 mmol/l) over non-diabetic controls (NC: 7.15+/-0.25 mmol/l; p < 0.05 or less vs MD; p < 0.001 vs SD). Similar relations were found for HbA1. Retinal AGE in mild diabetes was 405+/-11.3 arbitrary units (AU) (NC 245+/-7.7; p < 0.01) after 3 months and remained unchanged. A non-linear increase of AGE over time was found in severe hyperglycaemic hamsters (466+/-21 AU after 3 months and 758+/-21 AU after 12 months; p < 0.001 vs MD). Pericyte loss in mild diabetes progressed from -26% after 3 months to 41% after 12 months (p < 0.001 vs NC). Whereas the initial pericyte loss in severely diabetic hamsters was identical to the mildly diabetic group, a higher degree of pericyte loss occurred after 12 months (-57%; p < 0.05 vs MD). Endothelial cell numbers remained unaffected by mild hyperglycaemia, but significantly increased over time in severe diabetes reaching 31.7% above controls after 12 months (p < 0.001 vs NC and MD). Microaneurysms were absent in all retinae examined. Acellular capillary segments were increased in mild diabetes (3.83+/-0.31 per mm2 of retinal area) and severe diabetes (7.83+/-0.73) over controls (1.0+/-0.23). These data suggest that a threshold of glycaemia might exist above which AGE removal systems become saturated. Pericyte loss and acellular capillary formation are associated with mild increases in blood glucose and AGE levels while endothelial cell proliferation requires higher glucose and AGE levels.

Animals↗
PubMed1998

Transduction of non-dividing adult human pancreatic beta cells by an integrating lentiviral vector.

Pancreatic islet cells are terminally differentiated endocrine cells and are refractory to stable infection by retroviral vectors, which require the breakdown of the nuclear membrane during cell division in order to insert the transgene into the host cell genome. Thus, attempts to render beta-cell allografts less immunogenic have had to rely on stable transfection of surrogate cells. Similarly, this problem has precluded the development of conditionally immortalized human beta cells for clinical allotransplantation. In this report, we demonstrate that adult human islet beta cells can be transduced by a new three-plasmid integrating lentiviral vector with an efficiency of 62 +/- 1.8 % at a multiplicity of infection (MOI) of 2.5 in vitro. This work makes genetic engineering of adult human pancreatic beta cells possible for the first time, allowing strategies to render beta-cell allografts non-immunogenic to be optimized and to creating conditionally immortalized human beta cells for clinical transplantation.

Cell Division↗
PubMed1998

Elderly onset rheumatoid arthritis and polymyalgia rheumatica: ultrasonographic study of the glenohumeral joints.

The glenohumeral joints of 32 patients (aged 60 or above) were examined using ultrasonography. Thirteen patients were suffering from characteristic polymyalgia rheumatica (PMR) symptoms. In contrast 19 other patients initially had similar complaints, but were diagnosed as having elderly onset rheumatoid arthritis (EORA) upon development of typical symptoms. Ultrasound examination revealed glenohumeral joint inflammation in 61% (8 out of 13) of the patients with PMR and 63.2% (12 out of 19) of the patients with EORA. These findings suggest that a subgroup of patients with PMR and EORA suffers from shoulder joint inflammation and this synovitis/bursitis/intraarticular effusion might play an important role in the understanding of their symptoms. We conclude that overlapping forms of PMR and a predominate rheumatoid factor negative subgroup of EORA might exist and should be further characterized.

Aged↗
PubMed1998

Upregulation of the vascular endothelial growth factor/vascular endothelial growth factor receptor system in experimental background diabetic retinopathy of the rat.

Vascular endothelial growth factor (VEGF) is a major contributor to retinal neovascularization. The possible participation of VEGF and its high-affinity tyrosine kinase receptors, flk-1 and flt-1, in early background diabetic retinopathy was studied in the streptozotocin-induced diabetic rat model of experimental retinopathy using in situ hybridization, blotting techniques, and immunohistochemistry. Diabetic retinopathy was assessed by quantitative morphometry of retinal digest preparations. The number of acellular capillaries increased 2.7-fold in diabetic animals with diabetes' duration of 6 months compared with nondiabetic controls. VEGF expression was not detectable by in situ hybridization in nondiabetic rats but was highly increased in the ganglion cell layer and in the inner and outer nuclear layers of retinas from diabetic animals. VEGF protein was extractable only from diabetic retinas, and a strong immunolabeling was detected in vascular and perivascular structures. Increased flk-1 and flt-1 mRNA levels were also found in the ganglion cell and both nuclear layers of diabetic samples only. Dot blot and Western blot analyses confirmed the increase in flk-1 mRNA and protein in diabetic retinas. Also, flk-1 immunoreactivity was associated with vascular and nonvascular structures of the inner retinas from diabetic animals. These data obtained from a rodent model in which retinal neovascularization does not occur support the concept that the VEGF/VEGF receptor system is upregulated in early diabetic retinopathy.

Animals↗
PubMed1998

Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients.

OBJECTIVE: The recent EURODIAB Study has identified autonomic neuropathy as an independent risk factor for severe hypoglycemia in patients with type 1 diabetes. We tested the hypothesis that counterregulatory catecholamine responses and awareness of hypoglycemia are impaired to a greater extent in type 1 diabetic patients with autonomic neuropathy (AN+) than in those without autonomic neuropathy (AN-). RESEARCH DESIGN AND METHODS: We studied 22 type 1 diabetic patients (8 AN+, 14 AN-) matched for age, duration of diabetes, glycemic control, and history of hypoglycemic episodes. We also studied 33 nondiabetic control subjects using the stepped hypoglycemic clamp technique and determined glycemic thresholds and magnitudes of counterregulatory hormone responses and of hypoglycemia symptoms. RESULTS: Both groups of diabetic patients had reduced awareness of hypoglycemia as evidenced by an elevated glycemic threshold for autonomic symptoms > or =2 SD above normal but neither the magnitude nor thresholds for symptoms differed in AN+ patients and AN-patients. Both groups also had impaired glucagon, epinephrine, norepinephrine, growth hormone and cortisol responses to hypoglycemia. However, in AN+ patients compared with AN-patients, magnitudes of epinephrine and norepinephrine responses (194+/-49 vs. 784+/-206 pmol/l, P < 0.007, and 316+/-56 vs. 610+/-87 pmol/l, P < 0.02, respectively) and epinephrine and norepinephrine glycemic thresholds (2.33+/- 0.10 vs. 2.82+/-0.10 mmol/l, P < 0.009 and 2.34+/-0.06 vs. 2.79+/-0.10 mmol/l, P < 0.008, respectively) were impaired to a greater extent. This was associated with a 50% greater requirement of exogenous glucose to prevent more severe hypoglycemia during the 2.3 mmol/l glycemic plateau (P < 0.002). No differences were observed between other counterregulatory hormone responses in AN+ and AN- patients. CONCLUSIONS: We conclude that in patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses. Since this should increase the risk for severe hypoglycemia, one might consider safer therapeutic goals in these patients.

Adult↗
PubMed1998

[Isolation of islands of Langerhans from human and porcine pancreas for transplantation to humans].

The enormous variability of donor factors and organ procurement related variables prevent a constant isolation success, thus reducing the potential number of clinical islet transplants. Since the availability of intact and viable pancreatic donor tissue intended for islet transplantation is limited, the porcine pancreas was selected as a potential source of xenogeneic islets for human recipients. The differences of islet histomorphology between porcine and human pancreas result in a higher intrinsic fragility of porcine islets during collagenase digestion. Nevertheless, if the isolation method is modified to inhibit factors potentially toxic to pig islets, reproducibility of isolation success is higher in the pig as in the human due to a lower variability in donor characteristics and the opportunity of preselection in regard to age and race. If xenograft rejection can be overcome and the risk of xenosis can be minimized, the logistic prerequisites for xenotransplantation of large amounts of viable pig islets into human recipients with insulin dependent diabetes are fulfilled.

Adult↗
PubMed1998

[Graft rejection in experimental xenogenic transplantation of isolated islands of Langerhans of the pig].

Prevention of the occurrence of diabetes-specific vascular complications is the final aim of clinical islet transplantation. Pancreatic islets isolated from adult pigs may be a suitable tissue source to transplant a large number of type 1 diabetic patients. Acute cellular rejection may be finally overcome by clinically applicable protocols for tolerance induction. However, primary nonfunction of the graft, as regularly observed in the porcine islet-to-rat xenotransplantation model, may be an additional problem. In this paper, species-specific inflammatory and immunological mechanisms are discussed which prevent early porcine islet graft function in rats but not in mice.

Adult↗
PubMed1997

Alginate-based microcapsules for immunoprotected islet transplantation.

Islet transplantation is a promising therapeutic approach for the treatment of insulin-dependent diabetes mellitus. Nevertheless, its broader clinical use is hampered by the shortage of human organ donors as well as the need for a permanent immunosuppressive drug therapy in order to avoid rejection. Microencapsulation shall help to overcome this problem by creating an immunoprotected transplantation site. Biocompatibility of the encapsulation material and the possible immuno-interaction of the grafted tissue and the host immune system need to be examined very carefully. In transplantation experiments, we could show that the long-term function of the graft is dependent on the species of the islet donor, indicating that there has to be a recognition of the encapsulated islet despite the encapsulation membrane. This could be confirmed by in vitro data in the mixed lymphocyte islet culture (MLIC). Moreover, morphological studies of the tissue reaction toward encapsulated syngeneic vs. allogeneic vs. xenogeneic encapsulated islets reveal that the greater the difference between donor and recipient species the greater the amount of fibrous tissue formation. Thus, for the outcome of transplantation experiments, not only the material-related biocompatibility but as well the reaction towards the whole device (consisting of the capsule plus the encapsulated tissue) are crucial. Therefore, immunoprotection does not only comprise the protection of the grafted tissue from the host immune effector mechanisms but as well the inhibition of the recognition of the graft by the host immune system.

Alginates↗