Search PubMed⌕ Search

Biomedical subjects

M Huber

Publications and source records attributed to M Huber.

At least 91 records · Page 5Linked to original sources
PubMed1999

An asparagine to threonine substitution in the 1A domain of keratin 1: a novel mutation that causes epidermolytic hyperkeratosis.

Epidermolytic hyperkeratosis (EHK) is a congenital, autosomal dominant disorder of cornification characterized by hyperkeratosis and blister formation. The clinical manifestations are heterogeneous, with respect to the extent of body surface involvement, palmar and plantar hyperkeratosis and the presence of erythroderma. Point mutations in the genes encoding the suprabasal-specific keratins, keratins 1 and 10 have been identified in EHK patients. The inappropriate amino acid substitutions cause a collapse of the keratin filament network, resulting in cytolysis of the involved keratinocytes. We report a severe case of EHK with a single base pair mutation that causes a threonine for asparagine substitution in residue 8 (N8T) of the 1A region of the keratin 1 protein. This is the region involved in molecular overlaps between neighboring keratin heterodimers. These findings suggest that even conservative amino acid substitutions in overlap regions can cause tonofilament clumping.

Amino Acid Sequence↗
PubMed1999

Cleavage of RasGAP and phosphorylation of mitogen-activated protein kinase in the course of coxsackievirus B3 replication.

Recently, we reported on tyrosine phosphorylation of distinct cellular proteins in the course of enterovirus infections (M. Huber, H.-C. Selinka, and R. Kandolf, J. Virol. 71:595-600, 1997). These phosphorylation events were mediated by Src-like kinases and were shown to be necessary for effective virus replication. That study is now extended by examination of the interaction of the adapter protein Sam68, a cellular target of Src-like kinases which has been shown to interact with the poliovirus 3D polypeptide, with cellular signaling proteins as well as the function of the latter during infection. Here, we report that the RNA-binding and protein-binding protein Sam68 associates with the p21(ras) GTPase-activating protein RasGAP. Remarkably, RasGAP is cleaved during infections with different strains of coxsackievirus B3 as well as with echovirus 11 and echovirus 12, yielding a 104-kDa protein fragment. This cleavage event, which cannot be prevented by the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, may promote the activation of the Ras pathway, as shown by the activating dual phosphorylation of the mitogen-activated protein kinases Erk-1 and Erk-2 in the late phase of infection. Moreover, downstream targets of the mitogen-activated protein kinases, i.e., the p21(ras) exchange factor Sos-1 and cytoplasmic phospholipase A2, are phosphorylated with parallel time courses during infection. Activation or inhibition of cellular signaling pathways may play a general role in regulating effective enterovirus replication and pathogenesis, and the results of this study begin to unravel the molecular cross talk between enterovirus infection and key cellular signaling networks.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Correlation of duplex sonography findings and portal pressure in 375 patients with portal hypertension.

OBJECTIVE: The purpose of this study was to determine the potential usefulness of duplex sonography in the grading of portal hypertension. SUBJECTS AND METHODS: Duplex sonography of the portal vein system and measurement of the portal pressure and portosystemic pressure gradient were performed in 375 patients before placement of transjugular intrahepatic portosystemic shunts. Subgroups included patients with recent variceal bleeding (n = 296) and patients with refractory ascites without previous variceal bleeding (n = 79). A matched cohort of 100 patients without portal hypertension was also examined. Differences between the groups in portal and splenic vein diameter, flow velocity, congestion index, and hepatic arterial resistive index were assessed using the Wilcoxon rank sum test. RESULTS: Compared with healthy individuals, our patients had an increased portal vein diameter (+30%, p < .001), decreased portal vein flow velocity (-44%, p < .001), and increased congestion index (+185%, p < .001). A portal vein diameter greater than 1.25 cm or a portal vein flow velocity less than 21 cm/sec indicated portal hypertension with a sensitivity and specificity of 80%. If the congestion index exceeded 0.1, portal hypertension was diagnosed with a 95% sensitivity and specificity. The portal pressure and gradient correlated only weakly (r < .2, p < .05) with sonographic variables. Using multivariate analysis, subgroups with variceal bleeding or refractory ascites did not show differences in hemodynamics, including pressures. CONCLUSION: Duplex sonography contributes to the diagnosis of portal hypertension but does not allow its grading. Similarity of portal hemodynamics between patients with variceal bleeding and patients with refractory ascites suggests that additional factors determine the respective clinical presentation.

Female↗
PubMed1999

[Neonatal hearing screening--consequences for public health policy].

In Germany 1-2 of every thousand newborns suffer from severe hearing impairment. The fatal consequences of this irreversible condition are avoidable only if therapy is started as early as possible--according to current US-American recommendations before the age of 6 months. In Germany children even with severe hearing loss are identified only when they are 21 months old (average figure). Universal hearing screening before the age of 3 months could be a useful measure to reduce the mean age of children at the time of diagnosis and so to give them a chance of an early and promising therapy. In the USA this has been recommended by the National Institute of Health since 1993.

Germany↗
PubMed1999

The importance of a nitrogen atom in modulators of multidrug resistance.

The presence of a nitrogen atom, charged at physiological pH, has frequently been considered to be a hallmark of P-glycoprotein (PGP) inhibitors, although certain steroids, such as progesterone, lack a nitrogen atom and still are active modulators of PGP. The present study was aimed at investigating the role the nitrogen atom plays in the activity of PGP inhibitors. Propafenone-related amines, anilines, and amides that cover a broad range of pK(a) values, as well as an ester, were synthesized and tested for multidrug resistance-reverting activity. The sum of the hydrogen bond acceptor strengths was calculated and correlated with EC(50) values for PGP inhibition. For the complete set of 12 compounds, an excellent correlation between these two parameters was found; this included the ester GP570, which lacks a nitrogen atom but contains the strong hydrogen bond-accepting ester unit. The interaction of the nitrogen atom with PGP therefore is nonional and is determined by the sum of the hydrogen acceptor strengths of the region. The high predictivity of the obtained model is demonstrated in a leave-one-out cross-validation procedure.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Health expenditure trends in OECD countries, 1970-1997.

This article provides an overview of current trends in health expenditures in 29 OECD countries and recent revisions of OECD health accounts. U.S. health expenditures are compared with those of other OECD countries. The interactions of cost-containment measures with changes in the public-private mix of financing and in the composition of health care spending are discussed.

Accounting↗
PubMed1998

Targeted disruption of SHIP leads to Steel factor-induced degranulation of mast cells.

To investigate the role of the src homology 2 (SH2)-containing inositol 5' phosphatase (SHIP) in growth factor-mediated signalling, we compared Steel factor (SF)-induced events in bone marrow-derived mast cells (BMMCs) from SHIP-/- and SHIP+/+ littermates. We found SF alone stimulated massive degranulation from SHIP-/- but none from SHIP+/+ BMMCs. This SF-induced degranulation, which was not due to higher c-kit levels in SHIP-/- cells, correlated with higher intracellular calcium than that in SHIP+/+ cells and was dependent on the influx of extracellular calcium. Both this influx and subsequent degranulation were completely inhibited by PI-3-kinase inhibitors, indicating that SF-induced activation of PI-3-kinase was upstream of extracellular calcium entry. A comparison of phosphatidylinositol-3,4,5-trisphosphate (PIP3) levels following SF stimulation of SHIP+/+ and SHIP-/- BMMCs suggested that SHIP restricted this entry by hydrolyzing PIP3. Although PI-3-kinase inhibitors blocked the release of intracellular calcium, implicating PIP3, and PLCgamma-2 was slightly more tyrosine phosphorylated in SHIP-/- cells, the increase in inositol-1,4,5-trisphosphate (IP3) and intracellular calcium levels were identical in SHIP-/- and SHIP+/+ BMMCs. These results suggest that SHIP prevents SF from triggering degranulation of normal BMMCs, and does so by hydrolyzing PIP3, which in turn limits extracellular calcium entry at a step after the release of intracellular calcium.

Animals↗
PubMed1998

The src homology 2-containing inositol phosphatase (SHIP) is the gatekeeper of mast cell degranulation.

To clarify the role that the src homology 2-containing inositol phosphatase (SHIP) plays in mast cell degranulation, the gene for SHIP was disrupted by homologous recombination in embryonic stem cells. Bone-marrow-derived mast cells from SHIP+/+, +/-, and -/- F2 littermates were compared. SHIP-/- mast cells were found to be far more prone to degranulation, after the crosslinking of IgE preloaded cells, than SHIP+/- or +/+ cells. Intriguingly, IgE alone also stimulated massive degranulation in SHIP-/- but not in +/+ mast cells. This degranulation with IgE alone, which may be due to low levels of IgE aggregates, correlated with a higher and more sustained intracellular calcium level than that observed with SHIP+/+ cells and was dependent upon the entry of extracellular calcium. Immunoprecipitation studies revealed that the addition of IgE alone to normal mast cells stimulates multiple cascades, which are prevented from progressing to degranulation by SHIP. PI 3-kinase inhibitor studies suggested that IgE-induced activation of PI 3-kinase is upstream of the entry of extracellular calcium and that SHIP restricts this entry by hydrolyzing phosphatidylinositol 3,4, 5-trisphosphate. These results show the critical role that SHIP plays in setting the threshold for degranulation and that SHIP directly modulates a "positive-acting" receptor.

Androstadienes↗
PubMed1998

Regulation of mouse PECAM-1 tyrosine phosphorylation by the Src and Csk families of protein-tyrosine kinases.

PECAM-1 is an adhesion molecule expressed on hemopoietic and endothelial cells. Recently, it was observed that PECAM-1 becomes tyrosine-phosphorylated in response to a variety of physiological stimuli. Furthermore, tyrosine-phosphorylated PECAM-1 was shown to associate with SHP-2, a Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase expressed ubiquitously. In light of the significance of tyrosine protein phosphorylation as a regulatory mechanism, we wished to understand better the nature and impact of the protein-tyrosine kinases (PTKs) mediating PECAM-1 tyrosine phosphorylation. Through reconstitution experiments in COS-1 cells, we determined that mouse PECAM-1 could be tyrosine-phosphorylated by Src-related PTKs and Csk-related PTKs, but not by other kinases such as Syk, Itk, and Pyk2. Using site-directed mutagenesis and peptide phosphorylation studies, we found that these PTKs were efficient at phosphorylating Tyr-686, but not Tyr-663, of PECAM-1. Src-related enzymes also phosphorylated mouse PECAM-1 at one or more yet to be identified sites. In other studies, we demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances.

Amino Acid Sequence↗
PubMed1998

Costimulation via TCR and IL-1 receptor reveals a novel IL-1alpha-mediated autocrine pathway of Th2 cell proliferation.

Previous studies have shown that triggering of Th2 cells via the TCR is sufficient for production of IL-4 but not for proliferation of these cells. Proliferation of Th2 cells occurs only in the additional presence of a costimulatory signal delivered by IL-1. For the majority of Th2 cell clones, this type of proliferation was found to be independent of IL-4. Here, we further investigated the mechanism of IL-4-independent proliferation. We demonstrate that, after costimulation via TCR and IL-1R, but not via either receptor alone, Th2 cells are triggered to produce cell-associated IL-1alpha, as detected at the level of function, protein, and mRNA expression. In the presence of the TCR signal, autocrine IL-1alpha is then able to costimulate IL-4-independent proliferation of Th2 cells and to further enhance its own production. Thus, our results point to a novel, IL-4-independent, self-amplifying autocrine pathway of Th2 cell proliferation that requires a signal via the TCR and a costimulatory signal via IL-1R. This pathway may explain frustrating results in experimental models that attempted to treat established Th2-mediated diseases in vivo with IL-4-neutralizing agents alone.

Animals↗
PubMed1998

Modification of glassy carbon surfaces with synthetic laminin-derived peptides for nerve cell attachment and neurite growth.

Interactions between cultured nerve cells and surfaces are of importance for the implantation of biocompatible electrode materials such as glassy carbon (GC). Since implants serve as recording sensors in prosthetic neuroscience, we investigated whether coating electrodes with certain laminin derivatives containing the peptide sequences SIKVAV, CDPGYIGSR, PDSGR, YFQRYLI, and RNIAEIIKDA influences neuronal adhesion and neurite outgrowth in vitro. The coating of GC was performed by electrochemical polymerization and, for comparison, by adsorption or covalent coupling. Electrochemical polymerization is suitable for the coupling of peptides to GC, as shown by amino acid analysis and sequencing. Embryonic chicken retinal ganglion cells and brain cells (days E7 or E17) were used for both attachment and growth studies. Surfaces made by electrochemical polymerization of peptides were more efficient than those made by adsorption or covalent coupling of peptides. Synthetic cyclic peptide derivatives of CDPGYIGSR and 18-mer SIKVAV were found to be more efficient than the linear peptides. Competitive effects that resulted in a decreased cell attachment could be found upon application of soluble peptides. Nevertheless, irrespective of the method of coating, peptides were less efficient compared with the whole laminin molecule, as expected from its multiple adhesion sites. When small GC pins were implanted into the brain of E17 chicken after coating with the 18-mer SIKVAV peptide, nerve cell attachment was observed in vivo. The results suggest that chronically implantable materials may exert a higher neurocompatibility when coated with synthetic peptides.

Amino Acid Sequence↗
PubMed1998

Coxsackie B virus and its interaction with permissive host cells.

BACKGROUND: Observations in humans and the results of experiments on laboratory animals have provided evidence that coxsackieviruses of group B (CVB) are major etiologic agents of acute and chronic enterovirus myocarditis and various other virus-induced diseases. OBJECTIVE: This minireview briefly summarizes the investigations to elucidate various molecular mechanisms for the induction and maintenance of persistent CVB infections. With regard to the recent findings that CVB may use several different receptor proteins, this article focuses on virus-host cell interactions and the potential impact of these interactions for enteroviral replication. STUDY DESIGN: The interaction of CVB with specific cell surface proteins was analyzed in cultured cell lines and murine tissues at the level of virus attachment and virus internalization. As example for the interaction of CVB with intracellular proteins, the state of p21rasGTPase-activating protein (RasGAP) was investigated in mock-infected and CVB3-infected HeLa cells. RESULTS AND CONCLUSIONS: The experiments to elucidate the virus receptor interactions revealed the necessity to differentiate between CVB attachment proteins and proteins involved in virus internalization. Since more than one protein may be required to initiate the uptake of CVB into permissive host cells, a model of the putative interaction of these proteins within a multimeric receptor complex is proposed. It is further tempting to speculate that the presence of multiple attachment proteins may influence the tissue tropism of CVB as well as pathogenicity.

Animals↗
PubMed1998

In vitro and rapid in situ transglutaminase assays for congenital ichthyoses--a comparative study.

Autosomal recessive congenital ichthyoses are a heterogeneous group of disfiguring skin diseases. They are generally characterized by variable scaling and erythroderma, and patients are frequently collodion babies at birth. Autosomal recessive congenital ichthyoses are represented in 25 of our 50 families by a defective keratinocyte transglutaminase (TGK). Pathogenic classification is difficult to assess on clinical grounds for autosomal recessive congenital ichthyoses and impossible for collodion babies. Thus, we have established a rapid TGK assay in situ on frozen skin sections using incorporation of dansyl-cadaverin to assess transglutaminase (TG) activity in combination with immunohistochemistry for TGK protein. Results were compared with TG activity levels measured in cultured differentiating keratinocytes. Sixteen of 26 patients, including a collodion baby, had strongly diminished TG activity in the cell periphery of differentiating keratinocytes and membrane-bound TG activities in vitro, ranging from 2.2 to 281.3 pmol per h mg. Nine of 26 patients, including a collodion baby, showed strong TG activity in the cell periphery of differentiating keratinocytes in situ and membrane-bound TG activities in vitro ranged from 1519 to 10917 pmol per h mg. In one case, TG assay in situ was ambiguous; however, membranous TG activity in vitro was very low at 76.9 pmol/h x mg. Our results demonstrate an excellent correlation of TG assays in vitro and in situ. In addition, we present a novel test with prognostic value for the collodion baby phenotype. This assay allows rapid pathogenic classification of autosomal recessive congenital ichthyoses with only one caveat that in rare ambiguous cases it might be necessary for proper classification to assess membrane-bound TG activity in vitro.

Animals↗
PubMed1998

Selective versus non-selective antiarrhythmic approach for prevention of atrial fibrillation after coronary surgery: is there a need for pre-operative risk stratification? A prospective placebo-controlled study using low-dose sotalol.

AIM: This study evaluated the advantages of 'selective' over 'non-selective' antiarrhythmic prevention of atrial fibrillation after coronary surgery based on a new risk prediction algorithm. METHODS AND RESULTS: In a retrospective analysis of a prospective randomized trial, a model for risk prediction was determined based on clinical data of the control group (A; n = 107) and tested in a test group (B; n = 107, treated with low dose sotalol). Using this algorithm, the effect of a 'selective' antiarrhythmic approach in high-risk patients was compared to a 'non-selective' approach, where all patients were treated. In total, 75 (35%) patients developed atrial fibrillation and 14 (7%) side-effects led to discontinuation of study medication. Based on the risk prediction algorithm, 36% of group A patients were classified as high-risk patients with an incidence of atrial fibrillation of 76% compared to 26% in low-risk patients (P < 0.0001). The selective approach, i.e. treatment of high-risk patients only reduced the incidence of atrial fibrillation from 76% to 50% (P = 0.0295) compared to a reduction from 44% to 26% (P = 0.0065) when all patients were treated. More importantly, with the non-selective approach 100% of patients were exposed to the possible side-effects of sotalol and costs compared to 24% only with the selective approach (P < 0.0001). CONCLUSIONS: Thus, a selective approach based on a clinical risk prediction algorithm should improve the cost-effectiveness and safety of low-dose sotalol in the prevention of atrial fibrillation after coronary bypass surgery.

Adult↗
PubMed1998

Medication use patterns among demented, cognitively impaired and cognitively intact community-dwelling elderly people.

OBJECTIVE: To determine whether medication use patterns in community-dwelling elderly people vary with level of cognitive function-dementia, cognitive impairment (but not dementia) and intact cognition. DESIGN: Cross-sectional survey. SETTING: A five-county area of central North Carolina, USA. PARTICIPANTS: 520 members of the Duke Established Populations for Epidemiologic Studies of the Elderly. MEASUREMENTS: Medication use in the previous 2 weeks was ascertained during a interview in the patient's home and was coded as to prescription and therapeutic class status. Cognitive status, the primary independent variable, was divided into: (i) dementia (n=100); (ii) cognitive impairment but not dementia (n=117); and (iii) cognitively intact (n=303). The dependent variables were any prescription or over-the-counter (OTC) medication use (vs non-use); number of prescription or OTC medications used; and prescription and OTC use combined within major therapeutic classes. Multivariate analyses controlled for socio-demographic characteristics, health status, functional status and access to health care. RESULTS: The use of any prescription medication was similar in the three groups. The demented were significantly less likely than cognitively impaired people to use any OTC medications (OR=0.65, 95% CI=0.45, 0.93), cardiovascular medications (OR=0.70, 95% CI=0.49, 0.99) and analgesics (OR=0.54, 95% CI=0.39, 0.75). As a combined group, those who were demented and cognitively impaired were less likely than the cognitively intact group to use any OTC medications (OR=0.78, 95% CI 0.65, 0.92). Compared with the cognitively impaired subjects, the demented group took fewer prescription medications (beta coefficient=-0.31, 95% CI=-0.59, -0.03) and similar numbers of OTC medications. Compared with those who were cognitively intact, the combined group of demented and cognitively impaired subjects took fewer OTC medications (beta coefficient=-0.14, 95% CI=-0.23, -0.05) and similar numbers of prescription medications. CONCLUSION: Increasing level of cognitive dysfunction is associated with decreased use of OTC, cardiovascular and analgesic medications and the use of fewer prescription medications. These results suggest important differences in medication use patterns among community-dwelling elderly people who vary in cognitive status.

Aged↗
PubMed1998

Successful treatment of gastrointestinal vasculitis due to systemic lupus erythematosus with intravenous pulse cyclophosphamide: a clinical case report and review of the literature.

Gastrointestinal vasculitis in systemic lupus erythematosus (SLE) is quite rare and almost always accompanied by evidence of active disease in other organs, although occasionally it may be the presenting feature of the disease. Gastrointestinal involvement in SLE may present as lupus peritonitis, non-necrotizing pancreatitis, gastrointestinal vasculitis or surgical abdomen. Here we report a severe case of SLE which presented initially with fever of unknown origin. Severe distress, abdominal pain, the presence of occult blood in the stool and high acute-phase proteins were explained by a lupus peritonitis and intestinal vasculitis resembling inflammatory bowel disease. Whereas high-dose prednisone treatment did not prevent a severe relapse, we observed a sustained remission following i.v. cyclophosphamide pulse therapy. In the literature, only two similar cases are reported: one died despite a change in the therapy of a bowel perforation; our case was the second that improved under pulse cyclophosphamide. We suggest the use of cyclophosphamide after failure of steroids early in the course of SLE gastrointestinal vasculitis to prevent devastating complications.

Abdominal Pain↗
PubMed1998

The first decade of the transjugular intrahepatic portosystemic shunt (TIPS): state of the art.

The transjugular intrahepatic portosystemic shunt (TIPS) is an interventional treatment resulting in decompression of the portal system by creation of a side-to-side portosystemic anastomosis. Since its introduction 10 years ago, more than 500 publications have appeared demonstrating rapid acceptance and increasing clinical use. This review summarizes the present knowledge of technical aspects and complications, follow-up of patients, and indications. With respect to the technique, the TIPS procedure is probably one of the most difficult interventions and, therefore, technical success and complications clearly depend on the skills of the operator. Thus, the number and kind of complications reported in this review do not necessarily relate to the procedural complications of an experienced center. The follow-up of the TIPS patient has to assess shunt patency, liver function and hepatic encephalopathy. Shunt patency can best be monitored by duplex-sonography. Routine radiological revision seems not to be helpful and does not improve results, i.e., rebleeding and survival. Short term patency may be improved by anticoagulation, while such a treatment does not influence long-term patency. With respect to the indications of TIPS, much is known about treatment of variceal bleeding. The nine randomized studies that are available to date show that survival is comparable between patients receiving TIPS or endoscopic treatment. The second group of patients is the group with refractory ascites and related complications, such as hepatorenal syndrome and hepatic hydrothorax. It has been demonstrated that TIPS improves these complications, but randomized studies are still lacking. In addition, TIPS has been applied successfully to patients with Budd-Chiari syndrome, portal vein thrombosis, before liver transplantation, and for the treatment of ectopic portal hypertensive bleeding.

Ascites↗