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Biomedical subjects

M Haslbeck

Publications and source records attributed to M Haslbeck.

At least 37 records · Page 2Linked to original sources

Hsp26: a temperature-regulated chaperone.

Small heat shock proteins (sHsps) are a conserved protein family, with members found in all organisms analysed so far. Several sHsps have been shown to exhibit chaperone activity and protect proteins from irreversible aggregation in vitro. Here we show that Hsp26, an sHsp from Saccharomyces cerevisiae, is a temperature-regulated molecular chaperone. Like other sHsps, Hsp26 forms large oligomeric complexes. At heat shock temperatures, however, the 24mer chaperone complex dissociates. Interestingly, chaperone assays performed at different temperatures show that the dissociation of the Hsp26 complex at heat shock temperatures is a prerequisite for efficient chaperone activity. Binding of non-native proteins to dissociated Hsp26 produces large globular assemblies with a structure that appears to be completely reorganized relative to the original Hsp26 oligomers. In this complex one monomer of substrate is bound per Hsp26 dimer. The temperature-dependent dissociation of the large storage form of Hsp26 into a smaller, active species and the subsequent re-association to a defined large chaperone-substrate complex represents a novel mechanism for the functional activation of a molecular chaperone.

Chromatography, High Pressure Liquid↗

Mapping of 41 chemotaxis, flagellar and motility genes to a single region of the Sinorhizobium meliloti chromosome.

Three previously identified gene clusters that contain chemotaxis (che), flagellar (fla) and motility (mot) genes of Sinorhizobium meliloti (formerly Rhizobium meliloti) were mapped to a contiguous 45-kb region of the S. meliloti RU11/001 genome by pulsed-field gel electrophoresis (PFGE) in combination with Southern hybridization. The entire region was cloned and sequenced. The map combines 32 che, fla (flg, flh, fli) and mot genes and nine new open reading frames that probably encode taxis-related functions as well. It is concluded that between 80 and 90% of the genes responsible for chemotaxis and motility are located in a single region of the S. meliloti chromosome near the his-39 marker.

Chemotaxis↗

Evidence for specific autoimmunity against sympathetic and parasympathetic nervous tissues in Type 1 diabetes mellitus and the relation to cardiac autonomic dysfunction.

There is growing evidence for the involvement of immunological factors in the pathogenesis of cardiac autonomic dysfunction in Type 1 diabetes mellitus (DM). To evaluate the presence of autoantibodies against autonomic nervous tissues and their relationship with tests of autonomic function, 64 newly diagnosed and 142 long duration Type 1 DM patients were investigated for sympathetic and parasympathetic ganglia (CF-SG and CF-PSG) autoantibodies with a complement-fixing indirect immunofluorescence technique. Five cardiac reflex tests were performed to assess autonomic function. Fifty-seven patients with neurological diseases other than diabetic neuropathy and 131 healthy control subjects were also tested for CF-SG and CF-PSG autoantibodies. CF-SG autoantibodies were observed in 47 (23%) and CF-PSG autoantibodies in 21 (10%) of 206 Type 1 DM patients (p < 0.001). In contrast, these autoantibodies were detected in 3 (5%) and 1 (2%) of patients with non-diabetic neurological diseases and 3 (2%) and 4 (3%) of control subjects (p < 0.01, p < 0.05, p < 0.0001, p < 0.05 vs Type 1 DM patients). All except two Type 1 DM patients with CF-PSG autoantibodies also presented with CF-SG autoantibodies. In diabetic patients with long duration, CF-SG autoantibodies were more frequent in patients with ECG-based cardiac autonomic neuropathy (CAN; > or =2 of 5 cardiac reflex tests abnormal) compared to patients without CAN although this did not reach statistical significance (29% vs 17%, p = 0.06). However, 4 (80%) of 5 newly diagnosed and 23 (32%) of 73 established Type 1 DM patients with abnormalities in heart rate variation during deep breathing and/or standing from lying presented with CF-SG autoantibodies compared to 12 (25%) of 58 newly diagnosed (p < 0.05) and 7 (11%) of 63 established Type 1 DM patients (p < 0.01), in whom both tests were normal. The results suggest that autoimmune factors contribute to the pathogenesis of cardiac autonomic dysfunction in Type 1 DM and that autoantibodies against sympathetic and parasympathetic nervous tissues are relatively specific for Type 1 DM.

Adult↗

On the prognosis of IDDM patients with large kidneys.

BACKGROUND: Approximately 10-30% of IDDM patients develop diabetic nephropathy depending on the metabolic control. Previous examinations on the significance of the kidney size prior to the manifestation of nephropathy produced varying results. METHODS: The present study, therefore, was designed to assess the correlation between sonographically determined kidney size and kidney function over 8 years in a follow-up examination, and to evaluate a potential risk pattern. Data could be collected from 73 (66%) of 110 IDDM patients with initially normal serum creatinine whose sonographically determined kidney volume (cm3 = L cm x W cm x D cm x pi/6) and kidney function (creatinine, albuminuria, beta2-microglobulin in serum) had been examined in 1986, and who had a diabetes duration of 1 month to 25 years at that time. RESULTS: 30% (11 of 37) patients with large kidneys (>170 cm3) reached at least one serious renal end-point (increase of serum creatinine by more than 50%, requirement of dialysis or kidney transplantation, or death in end-stage renal disease) versus one of 36 patients with normal kidney size (P<0.002). As many as 42% of patients with large kidneys developed abnormal creatinine values (>106 micromol/l) in contrast to only 20% of the patients with normal kidney volume (P<0.05). Six of seven patients with a more than 50% increase of serum creatinine from baseline showed large kidneys in 1986, but had a normal serum creatinine, and four also a normal urine albumin excretion. Furthermore all five patients with more severe end-points (two deaths in end-stage renal disease and three patients presently requiring dialysis) exhibited either an increased serum creatinine or large kidneys at baseline; four of these, however, were still in the normoalbuminuric state in 1986. CONCLUSIONS: These results indicate that large kidneys might be a morphological marker for subsequent diabetic nephropathy, and as a consequence, renal insufficiency.

Adult↗

Partial restoration of scintigraphically assessed cardiac sympathetic denervation in newly diagnosed patients with insulin-dependent (type 1) diabetes mellitus at one-year follow-up.

Diabetic neuropathy is thought to comprise a reversible metabolic and an irreversible structural component of neuronal abnormality. To investigate whether the cardiac sympathetic denervation recently described in newly diagnosed, but metabolically stabilized, diabetic patients without myocardial perfusion abnormalities reflects transient or permanent sympathetic abnormalities, 123-I-metaiodobenzylguanidine (123-I-MIBG) scintigraphy was performed in 16 patients with insulin-dependent (Type 1) diabetes mellitus (IDDM) 1 year after initial assessment and diagnosis. All patients had been treated with an intensified insulin therapy for 1 year. HbA1c had fallen from 11.5 +/- 2.0% to 6.3 +/- 0.9% (p < 0.001). The global myocardial 123-I-MIBG uptake (score 1-6) had improved in 7 patients at 1 year, remained unchanged in 7, and deteriorated in 2 patients. Regionally, the myocardial uptake score of the posterior and septal regions had improved significantly (p < 0.01, p = 0.02) with a mean uptake score in the groups of 3.8 +/- 1.1 and 3.4 +/- 1.2 at diagnosis versus 2.6 +/- 0.5 and 2.5 +/- 0.9 at 1 year. Myocardial uptake scores of the anterior, lateral, and apical regions had also improved in 7, 6, and 9 patients, but the mean changes of these scores did not reach significance. The study demonstrates that scintigraphically assessed cardiac sympathetic denervation in newly diagnosed, but metabolically stabilized, IDDM patients is partially reversed with improved metabolic control after 1 year of intensified insulin therapy. We suggest that even in the early stage of IDDM, cardiac sympathetic dysfunction is composed of reversible and irreversible neuronal abnormalities.

3-Iodobenzylguanidine↗

Autoantibodies to sympathetic ganglia, GAD, or tyrosine phosphatase in long-term IDDM with and without ECG-based cardiac autonomic neuropathy.

OBJECTIVE: To evaluate the association of autoantibodies to complement-fixing sympathetic ganglia (CF-SG), and tyrosine phosphatase (IA-2) with electrocardiogram (ECG)-based cardiac autonomic neuropathy (CAN) in long-term IDDM. RESEARCH DESIGN AND METHODS: We examined the prevalence of autoantibodies to CF-SG (by complement-fixing indirect immunoflourescence), GAD, and IA-2 (by radioligand assay) and islet cells (by indirect immunofluorescence) in 96 long-term IDDM patients (41 with ECG-based CAN, > or = 2 of 5 cardiac reflex tests abnormal; 55 without ECG-based CAN). As a control group, 89 healthy nondiabetic subjects were investigated. RESULTS: CF-SG autoantibodies were observed more frequently in long-term IDDM patients than in the control group (25 vs. 4%, P = 0.0001). Of the IDDM patients, 14 (34%) with CAN and 10 (18%) without CAN presented with CF-SG autoantibodies (P = 0.06). GAD or IA-2 autoantibodies were detected in 14 (34%) and 17 (41%) IDDM patients with CAN, compared with 24 (44%) and 29 (53%) IDDM patients without CAN (P = 0.2, P = 0.2). Islet cell antibodies were observed in 6 (15%) IDDM patients with and in 9 (16%) IDDM patients without CAN (P = 0.5). CONCLUSIONS: In long-term IDDM, the role of CF-SG autoantibodies, which tend to be more frequent in patients with ECG-based CAN, requires further investigations. The persistence of GAD and IA-2 autoantibodies is not related to ECG-based CAN.

Adult↗

[The diagnostic value of the rate-corrected QT interval in long-term type-1 diabetes mellitus].

OBJECTIVE: To assess the relationship between rate-corrected QT interval (QTc interval) and cardiac reflex tests in order to determine the value of QTc interval measurements in the diagnosis of diabetic cardiac autonomic neuropathy. INVESTIGATIONS: The QTc interval was measured in the resting ECG of 97 type 1 diabetics (58 women, 39 men; mean age 35 +/- 12 years; duration of diabetes 18 +/- 10 years; HbA1c 7.8 +/- 1.8%). Age-related results were compared with five cardiac function tests (heart rate variation at rest and on forced breathing; 30/15 ratio of heart rate; Valsalva manoeuvre; orthostasis). RESULTS: The QTc interval was not prolonged ( < or = 440 ms) in 68 patients (70%), while in 29 (30%) it was prolonged ( > 440 ms). No significant differences regarding QTc interval were found between patients with autonomic cardiac neuropathy ( > or = 2 abnormal function tests) and those without ( < 2 abnormal function tests) (QTc interval 436 +/- 25 vs 426 +/- 19 ms). QTc intervals correlated with the coefficients of variation for heart rate variation at rest and on forced breathing and the 30/15 ratio of heart rate (p = 0.001; p = 0.001; p = 0.03), but not with the results of the Valsalva manoeuvre and the orthostasis test. CONCLUSION: Prolongation of the QTc interval in longstanding type 1 diabetes does not provide a reliable indication of cardiac autonomic neuropathy and this measure cannot replace conventional reflex tests for its diagnosis.

Adult↗

Autoantibodies against sympathetic ganglia and evidence of cardiac sympathetic dysinnervation in newly diagnosed and long-term IDDM patients.

To investigate the presence of autoantibodies against sympathetic nervous tissue and their correlation with cardiac sympathetic dysinnervation in insulin-dependent diabetes mellitus (IDDM), 20 newly diagnosed (age 26 +/- 6 years) and 48 long-term IDDM patients (age 40 +/- 13 years, duration of diabetes 22 +/- 12 years) without myocardial perfusion abnormalities (normal 99mTC-methoxyisobutylisonitrile uptake) were assessed for myocardial 123I-metaiodo benzylguanidine (123I-MIBG) uptake and complement-fixing sympathetic ganglia (CF-SG) autoantibodies. Both groups of patients were also studied for islet cell antibodies (ICA) and ECG-based cardiac autonomic neuropathy. Eighty control subjects (age 18-49 years) were investigated for CF-SG autoantibodies. Eight newly diagnosed (40%) and 12 long-term (25%) IDDM patients exhibited CF-SG autoantibodies, compared to 4 control subjects (5%; p < 0.01, p < 0.05). In long-term diabetic patients, the reduction of global but not of regional myocardial 123I-MIBG uptake correlated with CF-SG autoantibodies (r = 0.34, p = 0.02). Newly diagnosed diabetic patients did not show an association between CF-SG autoantibodies and global or regional myocardial 123I-MIBG uptake. ECG-based cardiac autonomic neuropathy (> or = two of five cardiac reflex tests abnormal) was present in 22 and absent in 26 long-term IDDM patients, of whom 9 (41%) and 3 (12%), respectively were positive for CF-SG autoantibodies (p = 0.02). Only 1 newly diagnosed IDDM patient demonstrated ECG-based cardiac autonomic neuropathy and was also positive for CF-SG autoantibodies. Although they are somewhat suggestive, results concerning autoantibodies against sympathetic nervous tissue and cardiac sympathetic dysinnervation do not strongly support the view that autoimmune mechanisms play a major role in the pathogenesis of cardiac sympathetic neuropathy in IDDM.

3-Iodobenzylguanidine↗

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↗

Reduced myocardial 123I-metaiodobenzylguanidine uptake in newly diagnosed IDDM patients.

123I-labeled metaiodobenzylguanidine (123I-MIBG) scintigraphy is a novel technique for the assessment of cardiac sympathetic dysinnervation. To evaluate defects of the cardiac autonomic nervous system at the onset of IDDM, this technique together with conventional electrocardiogram (ECG)-based cardiac reflex tests and measurement of the QT interval was applied to 22 newly diagnosed metabolically stabilized IDDM patients without myocardial perfusion abnormalities (99mTc-labeled methoxyisobutylisonitrile scintigraphy) and 9 matched control subjects. Seventeen diabetic patients (77%), but none of the control subjects, were observed to have a reduced global myocardial uptake of 123I-MIBG. In contrast, only two diabetic patients (9%) demonstrated an ECG-based cardiac autonomic neuropathy (two or more of five age-related cardiac reflex tests abnormal) (P < 0.001). In newly diagnosed IDDM patients, the uptake of 123I-MIBG was reduced more in the posterior myocardial region compared with the lateral and apical region (P < 0.01, P = 0.03). The septal myocardial region exhibited a smaller uptake than the lateral myocardial region (P = 0.02). The maximum/minimum 30:15 ratio correlated with the global, anterior, lateral, and septal myocardial uptake of 123I-MIBG (P < 0.05, P < 0.05, P < 0.01, P < 0.05). A correlation between global and regional myocardial 123I-MIBG uptake and HbA1c or QT interval was not observed. Newly diagnosed metabolically stabilized IDDM patients without myocardial perfusion defects show evidence of cardiac sympathetic dysinnervation, as indicated by a reduction of 123I-MIBG uptake, at a significant higher proportion than ECG-based cardiac autonomic neuropathy. Furthermore, they present with regional differences of myocardial 123I-MIBG uptake.

3-Iodobenzylguanidine↗

Scintigraphic evidence for cardiac sympathetic dysinnervation in long-term IDDM patients with and without ECG-based autonomic neuropathy.

To analyse the presence and extent of global and regional distributions of cardiac sympathetic dysinnervation in long-term insulin-dependent diabetes mellitus (IDDM) without myocardial perfusion abnormalities (99mTc-methoxy isobutyl isonitrile study), 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy was performed in two clinically-comparable groups (20 diabetic patients with and 22 diabetic patients without ECG-based cardiac autonomic neuropathy). For comparison nine control subjects without heart disease were investigated. Only six diabetic patients (27%) without and one diabetic patient (5%) with ECG-based autonomic neuropathy were found to have a uniform homogeneous uptake of 123I-MIBG, in contrast to a uniform homogeneous uptake in all control subjects. The uptake of 123I-MIBG in the posterior myocardium of diabetic patients was smaller than in the anterior, lateral and septal myocardium (p < 0.001, p < 0.001, p = 0.001). In addition, diabetic patients with cardiac autonomic neuropathy (> or = two of five age-related cardiac reflex tests abnormal) demonstrated a more reduced uptake in the global, lateral and posterior myocardium than diabetic patients without (p < 0.01, p < 0.01, p < 0.001). A correlation between global or regional myocardial 123I-MIBG uptake, however, and duration of diabetes, HbA1c, body mass index or QT interval length was not observed. Our study demonstrates that cardiac sympathetic dysinnervation is common in long-term IDDM even in patients without ECG-based cardiac autonomic neuropathy and that the posterior myocardium is predominantly affected. We conclude that 123I-MIBG scintigraphy is a promising approach to further elucidate the pattern and natural history of myocardial dysinnervation in IDDM.

3-Iodobenzylguanidine↗

[Autonomic neuropathies in diabetes mellitus: diagnosis--therapy--risks].

Autonomic neuropathy is a complication of diabetes which is observed in about 20% of all patients. This complication is often not adequately diagnosed. Neuropathy is a syndrome of various diseases that is classified according to the organs involved in the clinical picture. For the diagnosis of autonomic neuropathy besides the careful examination of the patient (metabolic and neurologic status, diabetic complications) a number of specific tests are available i.e. cardiovascular reflex tests and some other organ-specific tests. The review attempts to give an update of the presently used diagnostic approaches. As far as the therapy of all forms of neuropathy is concerned the careful control of blood glucose of the diabetic patient is still the only therapy which counteracts specifically the pathogenesis of autonomic neuropathy. There is however a number of drugs available which are useful for symptomatic therapy. Their effectiveness is discussed in this review. There is no doubt that diabetic autonomic neuropathies will have consequences for long-term prognosis and quality of life.

Autonomic Nervous System↗

[The periodontal findings and microflora in insulin-dependent (type 1) diabetics].

In 42 insulin-dependent type-I diabetics (age: 25.1 +/- 6 years; history of diabetes: 6.7 +/- 6.6 years) and in 118 control patients (age: 26.1 +/- 5.7 years) the oral health status including a periodontal examination was assessed. In addition, diabetic patients served to study the microflora in gingival pockets and on the mucosa of the cheek. The dental examination comprised the assessment of oral hygiene (Approximal Plaque Index, API), gingival inflammation (Sulcus Bleeding Index, SBI, and Gingival Index, GI) and of loss of attachment. Special medical history forms were used to gather information about the quality of metabolic equilibration and about laboratory values pertinent to diabetes. A significant positive correlation was found between poor metabolic adjustment (high glykosylized HbA1) and loss of attachment (r = 0.527). A significant relation was also detected between the administered insulin dose and gingival conditions (r = 0.404). The plasma leukocyte level was positively correlated to the SBI value (r = 0.546) as well as to the GI value (r = 0.496). Bacteriological investigation of subgingival samples revealed an increased amount of gram-positive, anaerobic rods (27.5%), especially corynebacteria (7.4%). Their numbers showed a narrow correlation to SBI (mean value: 48.1%) and GI (mean value: 1.9).

Adolescent↗