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H Rau

Publications and source records attributed to H Rau.

At least 37 records · Page 2Linked to original sources
PubMed1999

Intraocular pressure changes: the influence of psychological stress and the Valsalva maneuver.

The effects of psychological stress and the Valsalva maneuver on short-term variations of intraocular pressure (IOP) were studied in 49 healthy adults. Psychological stress consisted of mental arithmetic tasks presented in counterbalanced order by computer and by the experimenter. Additionally, a standardized Valsalva maneuver was performed (in counterbalanced order with the psychological stressors). IOP was measured with a Goldmann tonometer before and after performance of each stressor. All three stressors transiently and highly significantly increased IOP, although the Valsalva maneuver produced changes of a greater magnitude (10.2 mmHg) than the psychological stressors (1.3 mmHg). Subjective stress ratings and heart rate increased in response to all stressors. There were no effects of task sequence, eye muscle tension, sex, smoking status (some smokers misreported their smoking status), or regular marijuana use, but regular physical exercise was associated with less IOP increase during psychological stress.

Adult↗
PubMed1999

Genetic susceptibility to type 1 diabetes: clinical and molecular heterogeneity of IDDM1 and IDDM12 in a german population.

Type 1 Diabetes mellitus (IDDM) results from an immune-mediated destruction of the pancreatic b-cells. The genetic predisposition is mainly confered by variations within MHC class II region on chromosome 6p as well as the CTLA4 gene located on chromosome 2q33. We analysed the transmission of HLA DQA1, DQB1, DRB1*04 alleles as well as an endogenous retroviral element (DQLTR3) in 130 families with a type 1 diabetic offspring in order to evaluate their role in genetic susceptibility to IDDM. Also the combined transmission of HLA and CTLA4 haplotypes was investigated. MHC class II alleles were typed using sequence-specific primer analysis. The presence or absence of DQLTR3 was defined by a nested PCR approach and CTLA4 microsatellite polymorphisms were detected with fluorescence-labeled primer on an automated sequencing system. By transmission distortion test we confirm the linkage of HLA DQA1*0501 DQB1*0201 (DR3 DQ2) as well as DQA1*0301 DQB1*0302 (DR4 DQ8) with IDDM. Whereas the combination with CTLA4 risk markers leads to the highest transmission rate on DR3 positive haplotypes, the predisposing CTLA4 variant does not modulate the risk on DR4 haplotypes. However, the absence of DQLTR3 on DR3, but its presence on DR4 haplotypes significantly increases the genetic risk for type 1 diabetes. Therefore predisposing MHC class II haplotypes are defined by distinct loci which differentially control genetic susceptibility. The combined transmission of protective CTLA4 and HLA DR3 as well as DR4 haplotypes confirms the dominant role of HLA class II polymorphisms in defining disease susceptibility to type 1 diabetes mellitus.

Abatacept↗
PubMed1999

Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport.

We recently described a homozygous frameshift mutation in the human leptin (ob) gene associated with undetectable serum leptin and extreme obesity in two individuals. This represented the first identified genetic cause of morbid obesity in humans. Preliminary data suggested a defect in the secretion of this truncated (delta133) mutant leptin. In the present investigation, we have examined the mechanisms underlying the defective secretion of the delta133 leptin in transient transfection studies in Chinese hamster ovary and monkey kidney epithelium cells. Consistent with our previous observations, only immunoreactive wild-type (wt) leptin was secreted. In pulse chase experiments, intracellular wt leptin levels decreased, concomitant with secretion into the medium. In contrast, though immunoreactive delta133 leptin disappeared from cell lysates with kinetics similar to those of wt leptin (half-life, 45 min), it was not detected in the medium. Inhibition of the proteasome, using the inhibitor clastolactacystin beta-lactone, led to a significant increase in the intracellular levels of delta133 leptin, indicating a role for the proteasome in the degradation pathway. Although intracellular immunoprecipitated wt and delta133 leptin levels were comparable, analysis of total cell lysates revealed a 7-fold increase in total intracellular delta133 leptin, compared with wt leptin. Size-exclusion membrane filtration demonstrated that intracellular delta133 leptin accumulated in an aggregated form, presumably as a result of misfolding in the endoplasmic reticulum. Consistent with this, an endoplasmic reticulum-like localization for delta133 leptin was detected by immunofluorescence microscopy. In conclusion, the delta133 mutant leptin is not secreted but accumulates intracellularly, as a consequence of misfolding/aggregation, and is subsequently degraded by the proteasome. These studies further define the genotype/phenotype correlation in this paradigmatic case of human leptin deficiency.

Animals↗
PubMed1998

Alteration of digital representations in somatosensory cortex in focal hand dystonia.

Focal hand dystonia involves a loss of motor control of one or more digits; it is associated with the repetitive, synchronous movements of the digits made by musicians over periods of many years. Magnetic source imaging revealed that there is a smaller distance (fusion) between the representations of the digits in somatosensory cortex for the affected hand of dystonic musicians than for the hands of non-musician control subjects. The data suggest that use-dependent susceptibility to digital representation fusion in cortex may be involved in the etiology of focal dystonia. A successful therapy for the condition has been developed based on this consideration.

Adult↗
PubMed1998

Cardiovascular autonomic dysregulation in users of MDMA ("Ecstasy").

The present study examined resting heart rate variability (HRV; an index of parasympathetic tone) and heart rate response to the Valsalva maneuver (Valsalva ratio; an index of overall autonomic responsiveness) in 12 repeat users of 3.4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), and a matched comparison group of presumed nonusers. HRV and Valsalva ratio were smaller in users than in controls. Three out of 12 MDMA users but no controls had Valsalva ratios below 1.50, the cut-off for autonomic dysfunction. In several users, there was a total absence of post-Valsalva release bradycardia. All MDMA users were polydrug users. Parasympathetic cardiovascular tone appears impaired in repeat MDMA users, although the ubiquitous problems in such epidemiologic designs (including lack of testing before the first use of the drug and confounding with use of other drugs) preclude definitive causal interpretations.

Adolescent↗
PubMed1998

[Effect of mental and physical stress on intraocular pressure--a pilot study].

BACKGROUND: The aim of the present study was to examine the influence of phasic stressors on intraocular pressure (IOP). SUBJECTS AND METHODS: We exposed 15 ophthalmologically and systemically healthy non-smoking subjects (m:f = 8:7; mean age 25.4 years) to both bicycle ergometry physical stress and a computer-game psychological stress. IOP, blood pressure, and subjective stress were measured. To adjust for between-subject variance, we calculated intra-subject z-scores based on IOP values. Because of the habituation occurring during repeated tonometric measurements, we tested the significance of the difference between the observed and expected IOP z-values for each of the stressors. The expected IOP value was the mean of the pre- and post-stress relaxation-period values. Student's t-tests were used to assess the impact of the stressors on blood pressure. RESULTS: Both stressors increased the systolic blood pressure, but only under mental stress was the intraocular-pressure increase statistically significant (p = 0.048). DISCUSSION: The selective increase in intraocular pressure during mental stress by similar reaction of blood pressure to both stressors is a hint for possible different regulation circuits in the autonomic nerve system for intraocular- and blood pressure, respectively. Additionally, it was possible to demonstrate that mental stress could lead to a rise in intraocular pressure.

Adult↗
PubMed1997

Congenital leptin deficiency is associated with severe early-onset obesity in humans.

The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.

Adult↗
PubMed1997

Differential beta- and alpha-adrenergic activation during psychological stress.

The responsivity of several cardiovascular indices to a computerized mental arithmetic stress and a cold pressor stress were investigated in 22 healthy adult subjects. The major findings were that the largely beta-adrenergically driven T-wave amplitude, pre-ejection period, R-wave to pulse interval, and left ventricular ejection time values responded only to mental arithmetic; a significant decrease in cardiac output and increase in peripheral resistance were elicited during the cold pressor test; inter-beat-interval and subjective stress ratings responded significantly to both stresses compared to baseline levels, but more intensely to mental arithmetic than the cold pressor test; blood pressure, stroke volume and the maximum of the first derivative of the raw impedance signal responded unspecifically to both stresses. These findings support the idea that cardiovascular responses to psychological challenge depend on the level of cognitive processing required for the task. In addition, the superfluity of multiple variable measurements to study cardiovascular reactivity in such situations is discussed.

Adult↗
PubMed1997

The influence of low blood pressure and baroreceptor activity on pain responses.

The influence of baroreceptor modulation on pain perception has been extensively studied in normal and hypertensive subjects, but not in hypotensive subjects. The present experiment was performed to verify the following hypotheses: 1. Hypotensive subjects exhibit an increased pain response following baroreceptor activation compared to normals; 2. unlike the hypotensives, normal subjects, with normal baroreceptor reflexes, would learn to choose more often the baroreceptor activation condition compared to the opposite condition, during painful stimulation; 3. sensory and pain thresholds are correlated with blood pressure. The subjects (39 men), divided according to low and normal blood-pressure groups, participated in an experiment in which electrically-induced pain ratings and pain-evoked potentials were measured. Baroreceptor manipulation was performed by means of the PRES procedure. Whereas hypotensive subjects did not perceive any pain difference between the two baroreceptor conditions, activation and inhibition, normotensive men were able to perceive the baroreceptor activation condition as less painful. Similarly to subjective ratings, pain-evoked potentials of the low blood-pressure group showed a reversed trend compared to normals: larger somatosensory evoked potentials (N150-P260) to the baroreceptor activation condition and the opposite to the baroreceptor deactivation condition. Furthermore, results showed a negative correlation between diastolic blood pressure and sensory perception threshold, and a positive correlation between systolic pressure and pain threshold. Contrary to expectations, the rate of choice of baroreceptor conditions during painful stimulation did not show, in either group, any preference for baroreceptor activation.

Adolescent↗
PubMed1997

Somatotosensory evoked potentials during baroreceptor stimulation in chronic low back pain patients and normal controls.

Nineteen chronic low back pain patients (aged 19-63) and 17 controls (aged 20-41) received electrical pain stimuli during manipulation of their carotid baroreceptors. The non-invasive mechanical manipulation of baroreceptors, using the PRES technique (Phase Related External Suction), simulates the end-effects of phasic blood pressure changes. This technique was developed to assess pain responses induced by changes in blood pressure without the typical shortcomings of pharmacological manipulation or lack of a control condition. During maximum baroreceptor activity, there was an unexpected increase in the amplitude of the somatosensory evoked potentials (SEPs) elicited by the electrical pain stimuli condition (N150-P260 peak-to-peak). In most other studies the opposite effect was found, with decreased pain responses during maximum baroreceptor activity. The chronic pain group reported greater pain during highest baroreceptor activation than did the controls. In addition, the chronic pain group showed lower diastolic blood pressure. To determine whether pain and baroreceptor responses observed in the chronic pain group depended on lower blood pressure levels, a second experiment with a non-clinical sample was performed. Results showed that lower tonic blood pressures are associated with greater baroreceptor activity amplifying pain, while higher blood pressure is associated with pain dampening during high baroreceptor activity. Data suggested that the differences in pain responses found in low back pain patients were associated with their lower tonic blood pressure levels. It is proposed that in general, lower blood pressures may be associated with greater pain during baroreceptor activation.

Adolescent↗
PubMed1997

Four-year stability of cardiovascular reactivity to psychological stress.

The 4-year stability of cardiovascular responses to laboratory psychological stress (mental arithmetic) was examined in 75 adults. The stability coefficients were .76 for heart rate (HR) change and .81 for absolute HR, .66 for systolic blood pressure (SBP) change and .52 for absolute SBP, .16 for diastolic blood pressure (DBP) change and .27 for absolute DBP. Males had greater SBP and DBP reactivity than females in the first session, but this reactivity decreased by the 4-year follow-up session (which was not the case for women).

Adult↗
PubMed1997

Polymorphisms of TAP1 and TAP2 genes in German patients with type 1 diabetes mellitus.

Type 1 diabetes mellitus (IDDM) is an autoimmune disorder in which the alleles HLA DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 confer strong susceptibility. The genes for transporters associated with antigen processing (TAP1 and TAP2) are located near HLA DQ and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to IDDM possibly by selection of different antigen peptides, we investigated sequence variants of TAP1 and TAP2 genes in 120 German patients with IDDM and 218 random healthy German controls by polymerase chain reaction (PCR) followed by sequence-specific oligonucleotide analysis (SSO), single-strand conformation polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*02011 (16% vs. 4% in controls, P = 0.001, RR = 5.0) and TAP2*0101 (96% vs. 69% in controls, P < 0.0001, RR = 10.6) showed a positive association with IDDM. However, these associations disappeared when patients and controls were matched for predisposing HLA DQA1 or DQB1 alleles as well as for DRB1*0401. In conclusion, our findings indicate that the observed association of TAP variants with IDDM in German patients is due to linkage disequilibrium with HLA DQ alleles/DRB1*04 subtypes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Polymorphisms of TAP1 and TAP2 genes in Graves' disease.

Graves' disease is an autoimmune disorder in which HLA DQA1*0501 and DQB1*0201 confer predisposition. The genes for transporters associated with antigen processing (TAP1 and TAP2) locate near to HLA DQ coding regions and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to Graves' disease by a possibly different selection of antigenic peptides, we investigated sequence variants of TAP1 and TAP2 genes in 235 patients with Graves' disease and 218 random healthy controls by polymerase chain reaction (PCR) followed by sequence specific oligonucleotide analysis (SSO), single strand conformational polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*0301 (Val-333/Asp-637: 71% vs. 55% in controls, p < 0.008, RR = 2.05) and TAP2*0101 (Val-379/Ala-565/Thr-665/stop-687: 83% vs. 69% in controls, p < 0.03, RR = 2.20) showed a positive association with Graves' disease whereas TAP1*0401 a negative (Ile-333/Gly-637: 4% vs. 13% in controls, p < 0.01, RR = 0.25). After selection of patients and controls for HLA DQA1*0501 a similar association was found for TAP1*0301 (72% vs. 50% in controls, p < 0.02, RR = 2.63) and TAP1*0401 (4% vs. 16% in controls, p < 0.04, RR = 0.22), when matching for HLA DQB1*0201 as well as for TAP1*0401 (3% vs. 16% in controls, p < 0.05, RR = 0.18). Our findings indicate that the positive association of TAP1*0301 and the negative of TAP1*0401 with Graves' disease cannot only be explained by linkage disequilibrium between TAP alleles and HLA DQ. Therefore, these TAP alleles contribute to genetic susceptibility in Graves' disease as additional permissive and protective factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Polymorphisms of tumor necrosis factor receptor 2 are not associated with insulin-dependent diabetes mellitus or Graves' disease.

Insulin-dependent diabetes mellitus (IDDM) and Graves' disease (GD) are autoimmune endocrinopathies and associated with distinct HLA-DR and -DQ alleles as well as several tumor necrosis factor alpha (TNF-alpha) and beta (TNF-beta) alleles. TNF-alpha and TNF-beta interact with TNF receptor (TNF-R), of which two subtypes have been described: TNF-R1 and TNF-R2. We investigated TNF-R2 alleles in 90 patients with IDDM, 101 with GD and 70 healthy controls. Genomic DNA was amplified with specific flanking primers for the untranslated 3' region of TNF-R2. SSCP analysis revealed two alleles by different fragment patterns: TNF-R2*1 and TNF-R2*2. Patients with IDDM or Graves' disease and controls did not differ significantly: TNF-R2*1/*1:IDDM(8%)/GD(2%)/KO(4%); TNF-R2*2/*2:IDDM(34%)/GD(48%)/KO(42%), heterozygosity TNF-R2*1/*2:IDDM(58%)/GD(50%)/KO(54%) (IDDM vs KO: P=0.46, chi2=1.57; GD vs KO: P=0.59, chi2=1.05). In conclusion, the studied polymorphism of TNF-R2 was associated with neither IDDM nor GD in a German population.

Alleles↗
PubMed1997

Highly polymorphic promoter regions of HLA DQA1 and DQB1 genes do not help to further define disease susceptibility in insulin-dependent diabetes mellitus.

HLA DQA1, HLA DQB1 genes confer susceptibility to insulin-dependent (type 1) diabetes mellitus (IDDM). Since variants of their upstream regulatory regions are linked to the exons, we investigated their promoter polymorphisms (QAP and QBP) by a combination of PCR-based typing protocols in 136 IDDM patients, 167 controls and 6 families with an IDDM proband to identify possible additional susceptibility markers. Of major interest for IDDM susceptibility are the promoter "splits" of HLA DQA1*0301 (QAP3.1 and QAP3.2) and HLA DQB1*0302 (QBP3.2 and QBP3.3). QAP 3.1 (96% in patients vs 98% in controls) and QBP3.2 (100% vs 99%) were found to be the most frequent promoter variants for HLA DQA1*0301 and DQB1*0302, respectively, whereas QAP3.2 and QBP3.3 were very rare. Furthermore the promoter "splits" were equally distributed on the respective exon alleles in all groups and cosegregated in families as expected. In conclusion, HLA DQ-mediated susceptibility and protection in IDDM is not restricted to the exon but extends to the promoter region without further defining the genetic risk.

Diabetes Mellitus, Type 1↗
PubMed1997

CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus.

The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.

Abatacept↗