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Biomedical subjects

H Schatz

Publications and source records attributed to H Schatz.

At least 109 records · Page 6Linked to original sources
PubMed1997

Insulinoma cells contain an isoform of Ca2+/calmodulin-dependent protein kinase II delta associated with insulin secretion vesicles.

The Ca2+/calmodulin dependent protein kinase II (CaM kinase II) is thought to play an important part in glucose-stimulated insulin secretion. To determine which of the known subtypes (alpha, beta, gamma, delta) occur in insulin-secreting cells, we amplified all types of CaM kinase II by RT-PCR and found the beta3-, gamma-, delta2- and delta6-subtypes in RINm5F insulinoma cells. None of the other 8 delta-subtypes was present. Antibodies generated against the bacterially expressed association domain of the delta2-subtype recognized the recombinant gamma and delta-subtypes. In INS-1 and RINm5F cells, as well as freshly isolated rat islets, only a 55-kDa protein corresponding in size to the delta2-subtype expressed in NIH3T3 fibroblasts was detected. The delta2-subtype therefore appears to represent the predominant subtype of CaM kinase II present in insulin secreting cells. The enzyme was primarily associated with cytoskeletal structures, and very little was present in the soluble compartment or detergent soluble fraction in INS-1- or RINm5F-cells. An analysis of its subcellular distribution was performed by sucrose and Nycodenz density gradient fractionation of INS-1 cells and detection of CaM kinase II delta by immune blots. The enzyme codistributed with insulin used as a marker for secretory granules but not with the lighter synaptic-like microvesicles detected with an antibody against synaptophysin, plasma membranes (syntaxin 1), lysosomes (arylsulfatase), or mitochondria (cytochrome c oxidase). CaM kinase II delta2 thus is identified as the subtype associated with insulin secretory granules and is likely to be involved in insulin secretion.

Animals↗
PubMed1997

Growth factor alterations in advanced diabetic retinopathy: a possible role of blood retina barrier breakdown.

Chronic hyperglycemia may cause growth factor alterations that are likely to participate in tissue remodeling typical for diabetic late complications. However, few details of such events are known. The ocular vitreous fluid allows studies of growth factor levels in human eyes (after vitrectomy). The vitreous is highly inert and protected by the blood-retina barrier and thus probably reflects growth factor production by the normal retina. Vitreous from patients with proliferative diabetic retinopathy (PDR) was compared with vitreous obtained from patients with nonproliferative eye disease and with vitreous from patients without diabetes but with marked neovascular proliferations due to ischemia. This design permits us to distinguish diabetes-related from non-diabetes-related alterations. Insulin-like growth factor I (IGF-I), IGF-II, IGF binding protein 2 (IGFBP-2), and IGFBP-3 were elevated 3- to 13-fold in nondiabetic retinal ischemia and 1.5- to 3-fold in PDR, indicating that the changes were not restricted to diabetes. These changes may partially be explained by leakage of serum into the vitreous, since IGFs and IGFBPs are 20- to 50-fold higher in serum than in vitreous, and vitreous protein content was 1.5-fold elevated in PDR subjects and 5-fold in ischemia patients compared with control subjects. TGF-beta is a proposed antiangiogenic factor in the eye. TGF-beta2 was the predominant subtype in vitreous, and its total amount was not altered in PDR patients. More importantly, the active fraction of TGF-beta was decreased by 30 and 70% in PDR and nondiabetic retinal ischemia patients, respectively. Since plasmin may control TGF-beta activation, the serum protein alpha2-antiplasmin was measured and found to be significantly elevated to 150 and 250% of control values in PDR and ischemia patients, respectively. Thus, influx of serum proteins due to microvascular disturbances and hypoxia is proposed as a possible cause for vitreous alterations of IGF-I and of active TGF-beta. These changes seem to occur late in the sequence of events leading to PDR and are not specific for diabetes, but they were also observed in other diseases characterized by retinal hypoxia.

Blood-Retinal Barrier↗
PubMed1997

Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie.

OBJECTIVE: To evaluate the efficacy and safety of oral treatment with the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic neuropathy (CAN), assessed by heart rate variability (HRV). RESEARCH DESIGN AND METHODS: In a randomized, double-blind placebo-controlled multicenter trial (Deutsche Kardiale Autonome Neuropathie [DEKAN] Study), NIDDM patients with reduced HRV were randomly assigned to treatment with daily oral dose of 800 mg ALA (n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at rest included the coefficient of variation (CV), root mean square successive difference (RMSSD), and spectral power in the low-frequency (LF; 0.05-0.15 Hz) and high-frequency (HF; 0.15-0.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed. RESULTS: Seventeen patients dropped out of the study (ALA n = 10; placebo n = 7). Mean blood pressure and HbA1 levels did not differ between the groups at baseline and during the study, but heart rate at baseline was higher in the group treated with ALA (P < 0.05). RMSSD increased from baseline to 4 months by 1.5 ms (-37.6 to 77.1) [median (minimum-maximum)] in the group given ALA and decreased by -0.1 ms (-19.2 to 32.8) in the placebo group (P < 0.05 for ALA vs. placebo). Power spectrum in the LF band increased by 0.06 bpm2 (-0. 09 to 0.62) in ALA, whereas it declined by -0.01 bpm2 (-0.48 to 1.86) in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a trend toward a favorable effect of ALA versus placebo for the CV and HF band power spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo). The changes in cardiovascular autonomic symptoms did not differ significantly between the groups during the period studied. No differences between the groups were noted regarding the rates of adverse events. CONCLUSIONS: These findings suggest that treatment with ALA using a well-tolerated oral dose of 800 mg/day for 4 months may slightly improve CAN in NIDDM patients.

Autonomic Nervous System Diseases↗
PubMed1996

Upregulation of PKC delta- and downregulation of PKC alpha-mRNA and protein by phorbol ester in human T84 cells.

Protein kinase C (PKC) family members are downregulated by chronic activation at the protein level in most cell types. In T84 human epithelia] cells 12-O-tetradecanoyl phorbol 13-acetate (TPA) caused persistent translocation of PKC delta to the membrane compartment and a 400% increase of PKC delta-mRNA after 24 h. In contrast, PKC alpha protein was completely downregulated and its mRNA was decreased to 60% of control levels after 24 h. This is the first report of PKC delta-mRNA upregulation by TPA which was previously only shown for PKCbeta. In view of the antimitogenic actions of PKC delta this pattern of regulation may serve to preserve growth control even in the presence of chronic cell activation.

Animals↗
PubMed1996

Fibrovascular tissue in bilateral juxtafoveal telangiectasis.

OBJECTIVE: To study the natural history and retinal findings associated with the intraretinal and subretinal fibrovascular tissues that develop in the late phases of bilateral juxtafoveal telangiectasis. METHODS: The records of 10 patients (11 eyes) with bilateral juxtafoveal telangiectasis who developed these fibrovascular tissues were examined. RESULTS: Throughout the follow-up period (average 44 months), only 2 eyes (18%) lost 2 or more lines of vision; the final visual acuities were similar for the eyes both with and without fibrovascular tissues. Sixty-four percent of fibrovascular tissues showed little to no growth. Eyes with fibrovascular tissue commonly had retinal pigment epithelial hyperplasia (72%), draining retinal venules (82%), and retinal vascular distortion (64%). CONCLUSIONS: Fibrovascular tissues of bilateral juxtafoveal telangiectasis have little proliferative potential and minimal effects on visual acuity. Nevertheless, these fibrovascular tissues do remodel over time, leading to retinal vascular distortion. Given these benign findings, the role of laser photocoagulation treatment of these tissues is questionable.

Aged↗
PubMed1996

Restricted geographical extension of the association of a glucagon receptor gene mutation (Gly40Ser) with non-insulin-dependent diabetes mellitus.

A mutation within the glucagon receptor gene (GRG) at codon 40 (Gly40Ser) was reported to be associated with non-insulin-dependent diabetes mellitus (NIDDM) in France and Sardinia. Since the frequency of the mutation, about 5% in the French and 8% in the Sardinian group was higher than that of any of the candidate gene mutations described so far, it appeared to be relevant to determine the prevalence within different populations. While a single mutation has not been found recently either in a Japanese, a Finnish or a Dutch cohort, but only in a British study in 2.2% of NIDDM patients, in this study we investigated the association of this mutation with NIDDM in 104 German patients by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). None of the German NIDDM patients had a Gly40Ser mutation. The results indicate that the mutation plays little role in susceptibility to NIDDM in this German region, and also indicate the genetic heterogeneity in NIDDM, and further emphasize the importance of studies in different ethnic groups.

Aged↗
PubMed1996

Vitrectomy in eyes with peripheral retinal angioma associated with traction macular detachment.

PURPOSE: Peripheral angiomas have been associated with epiretinal membranes and traction retinal detachment. The authors investigated the timing, results, and complications of vitreous surgery to remove the retinal traction and treat the peripheral vascular tumor. METHODS: The authors reviewed the results of ten eyes that had undergone vitrectomy for macular pucker and/or traction retinal detachment. These eyes had either preoperative or intraoperative treatment of the peripheral tumor. RESULTS: Patients were followed 4 to 95 months. Six eyes had nonfamilial peripheral acquired retinal hemangioma, three had von Hippel angiomas, and one had multiple large peripheral retinal angiomas associated with extensive retinal telangiectasis. Four eyes received cryotherapy and/or laser photocoagulation 2 to 3 months before surgery. In the remaining six eyes, initial treatment to the peripheral angioma was performed at the time of vitreous surgery. At final follow-up, all eyes were attached without retinal traction. Vision improved in all eyes; six (60%) achieved 20/50 or better visual acuity. Complications included recurrent epiretinal membrane (n=3); nonregressed angiomas (n=3); increased nuclear sclerosis (n=2); and retinal detachment (n=1). CONCLUSION: Vitreous surgery, when applied to epiretinal membranes or traction retinal detachments associated with peripheral vascular tumors, has a good chance of improving vision. Treatment of the hemangioma, before or during vitrectomy, usually results in tumor regression.

Adult↗
PubMed1996

Thalidomide prolonged graft survival in a rat cardiac transplant model but had no inhibitory effect on lymphocyte function in vitro.

The effects of thalidomide on in vitro interleukin 2 (IL-2) production and thymidine uptake by human peripheral blood lymphocytes or rat splenocytes were investigated. Phytohaemagglutinin-stimulated human lymphocytes were incubated in the presence of thalidomide added at culture initiation. No immunosuppressive effect of thalidomide was observed in these experiments. Primary human mixed lymphocyte cultures treated with thalidomide for 6 days were also unaffected. A microsomal rabbit liver homogenate was prepared for metabolizing thalidomide. Stimulated lymphocytes secreted significantly more IL-2 in the presence of microsomal-treated thalidomide than did controls. The effect of thalidomide was then studied either as single therapy or in combination with cyclosporin A (CyA) in a rat allograft cardiac transplantation model. In addition, T cell subsets were analysed by flow cytometry in untransplanted rats treated with thalidomide. Treatment was given as induction therapy from the day of transplantation until day 9. Graft survival in rats treated with thalidomide was significantly prolonged compared to the untreated group. No difference in graft survival was detected between rats treated with thalidomide or CyA only. Graft survival was found to be slightly prolonged in rats given thalidomide and CyA in combination compared to rats treated with CyA alone. In untransplanted rats given thalidomide a decrease of CD4 positive T cells was detected on days 3 and 5. The T helper/cytotoxic-suppressor cell ratio was significantly diminished but, after 1 week of treatment, values for T cell subsets had almost returned to baseline levels. No inhibitory effect was obtained when phytohaemagglutinin-stimulated rat splenocytes were cultured with metabolized thalidomide. In summary, the ability of thalidomide to improve allograft survival in a solid organ transplant model was verified. The occurrence of thalidomide-induced changes in T cell subset ratios was demonstrated. In in vitro studies, however, there was no decrease but an increase in IL-2 production, and no change in thymidine uptake. The mechanism responsible for the immunosuppressive effect of thalidomide remains to be elucidated.

Animals↗
PubMed1996

Intensive insulin therapy with insulin lispro in patients with type 1 diabetes reduces the frequency of hypoglycemic episodes.

In a randomized, open-label, controlled cross-over trial, 107 patients with type 1 diabetes were treated with either regular human insulin or insulin lispro, a rapid-acting insulin analogue. After a lead-in period of 2 to 4 weeks, the patients were randomized to receive intensified insulin treatment with one of the insulins. NPH-human insulin was used for basal substitution in both groups. The crossover took place after 3 months of treatment. Efficacy and safety of the drugs were established by the assessment of hemoglobin A1c, pretest blood glucose, 1 and 2-hour postprandial glucose excursions, number of hypoglycemic episodes, daily insulin doses, body weight, insulin antibodies, and the number and severity of adverse events. A questionnaire comprised of four primary domains was used to measure some quality of life aspects of the patients. Both treatment regimens were well tolerated. While no differences were seen in the hemoglobin A1c values, there was a trend for a decrease in the pretest blood glucose levels and significant decreases of the 1 and 2-hour postprandial glucose excursions in the patients treated with insulin lispro. The number of hypoglycemic episodes was also significantly lower in the insulin lispro treatment period. The evaluation of the quality of life questionnaire revealed an improvement in the patients treatment satisfaction for the insulin lispro group. During treatment with insulin lispro, the basal insulin doses increased slightly. However, the total daily insulin doses decreased to a greater extent with insulin lispro as compared to regular human insulin. Human insulin-specific antibody binding values at endpoint were not different for the two treatments. In conclusion, intensive insulin treatment with insulin lispro therapy results in improved postprandial glycemic control and HbA1c levels at least equal to the treatment with regular human insulin but with less hypoglycemia and more treatment satisfaction for the patient.

Adult↗
PubMed1996

Activation of human platelet protein kinase C-beta 2 in vivo in response to acute hyperglycemia.

Protein kinase C (PKC) is known to be activated in experimental model systems by elevated glucose and may play an important role in the pathogenesis of diabetic complications. Since there is no information about its role in humans in vivo we investigated the activation of PKC in human thrombocytes during infusion of glucose and insulin in normal controls and in 19 NIDDM patients by determining membrane and cytosol levels of PKC beta 2 using immune blots. In the 27 subjects investigated (8 controls, 19 NIDDM) membrane-associated levels of PKC beta 2 increased significantly after 60 and 150 min (p < 0.005). In controls an increase of membrane and of cytosolic PKC beta 2 occurred upon elevation of glucose by 5.5 mmol/L or more and the membrane association persisted for at least 60 min. In NIDDM glucose was elevated by 7.5-10 mmol/L during infusions. Increases of both membrane and cytosolic PKC beta 2 (< 20%-300%) occurred in 10 NIDDM patients suggesting that both, translocation and increased synthesis of PKC beta 2 were stimulated by glucose. Nine other patients showed no alteration (i.e. < 20%) of PKC beta 2. The 2 groups were similar regarding parameters of diabetes control, baseline glucose and glucose elevation during the test. However, the PKC beta 2 responsive group had lower levels of serum triglycerides (1.39 +/- 0.19 vs. 2.32 +/- 0.34 g/L; p = 0.038). To assess whether absolute levels of PKC were altered in human diabetes, platelet levels of PKC alpha, beta 1 and beta 2 were determined in 22 controls and 25 NIDDM subjects with poorly controlled diabetes (HbA1c = 9.8 +/- 0.36%). Cytosolic levels of PKC alpha were significantly decreased by 27% compared to controls in NIDDM but there was no change of PKC beta 1 or PKC beta 2. We conclude that 1. acute elevation of glucose by 5.5 mmol/L or more can activate PKC beta 2 translocation in controls and NIDDM patients in vivo irrespective of parameters of metabolic control. 2. NIDDM patients differ in their PKC beta 2-responses to glucose and 3. poor metabolic control leads to moderate downregulation of PKC alpha suggesting continued activation.

Adult↗
PubMed1996

Expression of apoptosis-related proteins in thyroid tumors and thyroid carcinoma cell lines.

Whereas in normal human thyroid tissue total cell mass is maintained by a balance between cell proliferation and apoptosis, the programmed cell death, in thyroid tumors this equilibrium is disrupted. In tumor cells, an augmented proliferation rate is no longer counterbalanced by an equally enhanced apoptosis resulting in an increased netto growth rate. To investigate regulation of apoptosis in thyroid tumors, we analyzed the expression of apoptosis-related proteins of the bcl-2 family in human thyroid tissues and in the human thyroid carcinoma cell lines FTC 133, HTC, HTC-TSHr and HTh74. In comparison to normal tissue, we detected an increased expression of the anti-apoptotic protein bcl-2 in adenomas, whereas follicular carcinomas showed various expression of bcl-2 with decreased levels in 32% of cases. BclxL expression was comparable in all tissues examined. The pro-apoptotic protein bax was expressed at lower levels in carcinomas than in adenomas, whereas bak and bclx were expressed in the same order of magnitude in all tissues examined. In contrast, thyroid carcinoma cell lines exhibited a relatively strong expression of bclxL, but a weak expression of bcl-2. In all four cell lines, the amounts of the pro-apoptotic proteins bax, bak and bclx were higher than in most tumor tissues. Our data show that in thyroid tumors expression of members of the bcl-2 protein family is not uniform. Rather, the expression pattern of pro- and anti-apoptotic proteins in thyroid tumors is heterogeneous. This may, at least in part, reflect the futile attempt of tumor cells to counterbalance the action of growth-promoting factors in thyroid tumor-igenesis.

Adenoma↗
PubMed1996

Widespread expression of a new putative hormone extrusion pump: NG-TRA transporter protein in human and rat tissue.

In 1991 Becker and co-workers isolated a new ATP-dependent transporter from a neuroblastomaXglioma-hybrid-cell line, called NG-TRA. This protein was proposed to represent a hormone extrusion pump. To gain further insight into its significance we studied the expression of NG-TRA in human and rat tissues and compared the nucleotide sequences derived from both species using reverse transcription PCR, subcloning and nucleotide sequencing. A 97% sequence homology was found between the original and the human subcloned fragments, derived from thyroid and colon carcinoma tissue, while the rat subcloned fragments, derived from brain cortex and heart muscle, showed a 25 amino acid deletion at the 3'end compared with both the original and human subclones. Expression of NG-TRA at the mRNA level was found in all tissues studied except blood and fat tissue, and additionally rat lung tissue. We conclude that NG-TRA is a widely expressed protein consistent with a general function in diverse species.

ATP-Binding Cassette Transporters↗