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Biomedical subjects

Thomas Weber

Publications and source records attributed to Thomas Weber.

At least 73 records · Page 4Linked to original sources
PubMed2003

Mutations in human parainfluenza virus type 3 hemagglutinin-neuraminidase causing increased receptor binding activity and resistance to the transition state sialic acid analog 4-GU-DANA (Zanamivir).

Entry and fusion of human parainfluenza virus type 3 (HPF3) require the interaction of the viral hemagglutinin-neuraminidase (HN) glycoprotein with its sialic acid receptor. 4-GU-DANA, a potent inhibitor of influenza virus neuraminidase, inhibits not only HPF3 neuraminidase but also the receptor binding activity of HPF3 HN and thus its ability to promote attachment and fusion. We previously generated a 4-GU-DANA-resistant HPF3 virus variant (ZM1) with a markedly fusogenic plaque morphology that harbored two HN gene mutations resulting in amino acid alterations. The present study using cells that express the individual mutations of ZM1 HN shows that one of these mutations is responsible for the increases in receptor binding and neuraminidase activities as well as the diminished sensitivity of both activities to the inhibitory effect of 4-GU-DANA. To examine the hypothesis that increased receptor binding avidity underlies 4-GU-DANA resistance, parallel studies were carried out on the high-affinity HN variant virus C22 and cells expressing the C22 variant HN. This variant also exhibited reduced sensitivity to 4-GU-DANA in terms of receptor binding and infectivity but without concomitant changes in the neuraminidase activity of HN. Another high-affinity HN variant, C0, was not resistant in terms of infectivity; however, a small increase in the receptor binding activity of C0 HN and a partial resistance of this activity to 4-GU-DANA were revealed by sensitive methods that we developed. In each virus variant, one mutation in HN accounted for both increased receptor binding avidity and 4-GU-DANA resistance; the higher affinity for the receptor overcomes the inhibitory effect of 4-GU-DANA. Thus, in contrast to influenza viruses for which 4-GU-DANA escape variants include hemagglutinin mutants with decreased receptor binding avidity that promotes virion release, for HPF3, HN mutants with increased receptor binding avidity are those that can escape the growth inhibitory effect of 4-GU-DANA.

Animals↗
PubMed2003

D-dimer in acute aortic dissection.

STUDY OBJECTIVE: Laboratory testing plays a minor role in the assessment of aortic dissection. Its main value is in the exclusion of other diseases. Following an incidental observation, we systematically investigated the relationship between elevated d-dimer levels and acute aortic dissection. DESIGN: We prospectively tested d-dimer levels in patients with suspected acute aortic dissection (10 patients). In addition, we investigated 14 patients who had received a confirmed diagnosis of thoracic aortic dissection during the previous 5 years, in whom d-dimer testing had been performed for differential diagnosis. Thirty-five patients with acute chest pain of other origin served as a control group. SETTING: Tertiary referral hospital. PATIENTS: Twelve patients had type A dissection (Stanford classification), and 12 patients had type B. MEASUREMENTS AND RESULTS: A d-dimer analysis was performed (Tina-quant assay; Roche Diagnostics; Mannheim, Germany) [normal limit of the assay, 0.5 micro g/mL]. The result of the d-dimer test was positive (ie, > 0.5 micro g/mL) in all patients (sensitivity of the test, 100%) with a mean value of 9.4 micro g/mL and a range of 0.63 to 54.7 micro g/mL. The degree of the elevation was correlated to the delay from the onset of symptoms to laboratory testing (mean, 12.6 h; range, 1 to 120 h) and showed a trend to the extent of the dissection, but not to the outcome (14 patients could be discharged; 10 patients died). CONCLUSIONS: Based on our observation, we suggest that testing for d-dimer should be part of the initial assessment of patients with chest pain, especially if aortic dissection is suspected. A negative test result makes the presence of the disease unlikely.

Acute Disease↗
PubMed2003

Genetic polymorphisms in cytokine and adhesion molecule genes in coronary artery disease.

Both inflammation and genetics play an important role in the pathogenesis of atherosclerosis and coronary artery disease. Epidemiological studies have investigated the association between coronary artery disease (CAD) and gene polymorphisms of the inflammatory molecules tumor necrosis factors (TNF) alpha and beta, transforming growth factors (TGF) beta-1 and beta-2, interleukin (IL)-1 and its receptor antagonist (IL-1ra), CD14 (the receptor for lipopolysaccharide), P- and E-selectins, and platelet endothelial cell adhesion molecule (PECAM)-1. Current evidence suggests that the TNF polymorphisms explored so far are not linked to CAD. The majority of studies conducted showed no significant association between TGFbeta-1 and coronary atherosclerosis, but the data currently available are somewhat controversial. Some polymorphisms may increase the risk of myocardial infarction (MI) within specific ethnic groups or in certain populations. The association between the IL-1 system and atherosclerosis is complex and may vary as a result of a number of factors, such as stage of disease, clinical phenotype, and possibly population characteristics. The E-selectin gene (SELE) Arg128, 98T, and Phe554 alleles may increase the risk of atherosclerosis, but not necessarily the risk of MI. This association seems to be more pronounced in younger patients. The PECAM1 Leu125Val and Ser563Asn polymorphisms may increase the risk of atherosclerosis but not necessarily of MI. This association may be especially important in patients with a low risk for developing atherosclerosis. Current data indicate that screening for CD14-260C/T genotypes is unlikely to be a useful tool for risk assessment and it remains unclear whether CD14 polymorphisms significantly increase the risk of MI. The associations between candidate gene polymorphisms and CAD are complex as a consequence of pleiotropy, variations with age, selection due to the high lethality of the disease, and interactions with other genes and environmental factors. Nonetheless, although the current data is preliminary and partly conflicting, it does provide some evidence that alterations in the genetics of the inflammatory system may modify the risk of CAD.

Animals↗
PubMed2003

Arterial stiffness and cardiovascular drugs.

Arterial stiffness is the most important cause of increasing systolic and pulse pressure, and for decreasing diastolic pressure with ageing. Many measures can be applied to quantify arterial stiffness, but all are approximations only, on account of the nonhomogenous structure of the arterial wall, its variability in different locations, at different levels of distending pressure, and with changes in smooth muscle tone. This article summarizes those indices with a focus on newer non-invasive methods and provides an overview of physiological, pathological and pharmacological influences on arterial hemodynamics. In the near future, the ability to detect and monitor subclinical arterial damage will improve cardiovascular risk stratification and act as a better guide in assessing the efficacy of therapeutic interventions than monitoring blood pressure alone. However, large-scale clinical trials are needed to prove the hypothesis that treatment of these new therapeutic targets will translate into clinical benefit, expressed in cardiovascular events or even mortality.

Age Factors↗
PubMed2002

Determination and refinement of disordered crystal structures using evolutionary algorithms in combination with Monte Carlo methods.

An evolutionary algorithm called 'differential evolution' is combined with Monte Carlo simulation to determine and optimize models of disordered crystal structures. Requirements for successfully finding the parameters describing disorder from diffuse scattering data are discussed and the algorithm is applied to resolving the racemic and associated displacive disorder of the host substructure in a perhydrotriphenylene inclusion compound. Refinement resulted in a very good visual agreement between observed and calculated intensities and in a relatively low value of R(diffuse) = 0.148 (3). The computations for determining and refining the structure took 29 d with five to ten workstations running in parallel. Analysis of the progress of the structure determination shows that the essential information can be obtained within a few hours. Limits of the technique and strategies to optimize the procedure are discussed.

Journal Article↗
PubMed2002

Regulation of membrane fusion by the membrane-proximal coil of the t-SNARE during zippering of SNAREpins.

We utilize structurally targeted peptides to identify a "tC fusion switch" inherent to the coil domains of the neuronal t-SNARE that pairs with the cognate v-SNARE. The tC fusion switch is located in the membrane-proximal portion of the t-SNARE and controls the rate at which the helical bundle that forms the SNAREpin can zip up to drive bilayer fusion. When the fusion switch is "off" (the intrinsic state of the t-SNARE), zippering of the helices from their membrane-distal ends is impeded and fusion is slow. When the tC fusion switch is "on," fusion is much faster. The tC fusion switch can be thrown by a peptide that corresponds to the membrane-proximal half of the cognate v-SNARE, and binds reversibly to the cognate region of the t-SNARE. This structures the coil in the membrane-proximal domain of the t-SNARE and accelerates fusion, implying that the intrinsically unstable coil in that region is a natural impediment to the completion of zippering, and thus, fusion. Proteins that stabilize or destabilize one or the other state of the tC fusion switch would exert fine temporal control over the rate of fusion after SNAREs have already partly zippered up.

Amino Acid Sequence↗
PubMed2002

Coagulation profiles and intraoperative substitution requirements during elective piggyback liver transplantation with prophylactic antifibrinolytic therapy.

During recent years, piggyback liver transplantation (pOLT) with preservation of the retrohepatic vena cava has been introduced in adults. The objective of this study was to evaluate hemostatic changes associated with this transplantation technique. Fifty-seven patients undergoing elective pOLT for endstage liver disease were studied. Most significant changes were observed after graft reperfusion, when PT showed a 49% decrease and activated partial thromboplastin time (aPTT) as well as TT a 2- to 3-fold prolongation. At the same time, factors of the extrinsic coagulation pathway (II, V, VII) revealed an overall 50% decline. Similar changes were observed for antithrombin III (ATIII) and fibrinogen plasma levels. However, only 42% of all patients required intraoperative substitution with coagulation components. There was an association between preoperative fibrinogen (<1.7 g/dl) and ATIII (<50%) plasma levels and the substitution requirement. Multiple linear regression showed a significant correlation between preoperative ATIII activity and intraoperative blood loss. Despite a marked impairment of hemostasis, pOLT can frequently be performed with minimized substitution therapy.

Adolescent↗
PubMed2002

Thyroid hormone is a critical determinant for the regulation of the cochlear motor protein prestin.

The most impressive property of outer hair cells (OHCs) is their ability to change their length at high acoustic frequencies, thus providing the exquisite sensitivity and frequency-resolving capacity of the mammalian hearing organ. Prestin, a protein related to a sulfate/anion transport protein, recently has been identified and proposed as the OHC motor molecule. Homology searches of 1.5 kb of genomic DNA 5' of the coding region of the prestin gene allowed the identification of a thyroid hormone (TH) response element (TRE) in the first intron upstream of the prestin ATG codon. Prestin(TRE) bound TH receptors as a monomer or presumptive heterodimer and mediated a triiodothyronine-dependent transactivation of a heterologous promotor in response to triiodothyronine receptors alpha and beta. Retinoid X receptor-alpha had an additive effect. Expression of prestin mRNA and prestin protein was reduced strongly in the absence of TH. Although prestin protein typically was redistributed to the lateral membrane before the onset of hearing, an immature pattern of prestin protein distribution across the entire OHC membrane was noted in hypothyroid rats. The data suggest TH as a first transcriptional regulator of the motor protein prestin and as a direct or indirect modulator of subcellular prestin distribution.

5' Flanking Region↗
PubMed2002

[Angiographic results of "atypical" chest pain].

BACKGROUND AND AIMS: Coronary angiography permits evaluation of coronary artery morphology and coronary pathology. It represents an accurate method of defining stenotic coronary lesions. Chest pain may be caused by coronary artery disease as well as by other cardiac and noncardiac disorders. However, sensitivity of clinical evaluation and noninvasive diagnostic assessment in detection of coronary artery disease is limited. Noninvasive diagnostic strategies give inconsistent results in about 10-30%. Here coronary angiography is regarded as an accurate method for appropriate diagnosis. Ist sophisticated apparatus, cost, and invasiveness necessitate well-considered application of this procedure. Therefore, it appears important to analyze coronary angiograms in patients with the referral diagnosis of "atypical" chest pain with inconsistent noninvasive testing or impossibility to perform noninvasive assessment. PATIENTS AND METHODS: We analyzed records of 1,000 consecutive patients (625 men, 375 women, mean age 63.1 years), who underwent coronary angiography at our institution from January 5, 1998 to May 5, 1998. RESULTS: 49 patients (17 women, 32 men; mean age 59 years) were referred due to "atypical" chest pain. 21 (42.9%, nine women, twelve men) of these 49 patients had normal coronary arteries at angiography. 21 (42.9%) patients showed coronary artery disease with a diameter stenosis > 50%. In seven (14.2%) patients, coronary sclerosis with a diameter stenosis < 50% could be observed. Only five (29.4%) of the 17 women but 16 of the 32 men (50%) had coronary artery disease with a diameter stenosis > 50% (p < 0.01). CONCLUSIONS: In unselected patients referred for coronary angiography due to "atypical" chest pain and inconsistent noninvasive testing or impossibility to perform noninvasive assessment. 42.9% had coronary artery disease with a diameter stenosis > 50%. Angiographic evaluation of symptomatic patients with "atypical" signs and symptoms and inconsistent noninvasive testing seems to be appropriate.

Aged↗
PubMed2002

Multiple complex coronary plaques in a patient with acute myocardial infarction.

This report describes the case of a patient who developed acute myocardial infarction with ST segment elevation in anterior and inferior leads, simultaneously. After treatment with systemic thrombolysis, and after an initial short-lasting symptomatic improvement, chest pain and ST segment elevation recurred. Coronary angiography revealed severe complex stenotic lesions at both the right coronary artery and the left anterior descending (LAD) coronary artery. Percutaneous coronary angioplasty and stent implantation were successfully performed at both lesions. This case supports the concept that, at least in some patients, acute coronary artery disease reflects a diffuse pathophysiologic process that may lead to multifocal plaque instability associated with clinical instability at multiple sites.

Angioplasty↗