Biomedical subjects

S Weis

Publications and source records attributed to S Weis.

At least 19 recordsLinked to original sources

PubMed2001

Coupling of cholesterol and cone-shaped lipids in bilayers augments membrane permeabilization by the cholesterol-specific toxins streptolysin O and Vibrio cholerae cytolysin.

Vibrio cholerae cytolysin (VCC) forms oligomeric pores in lipid bilayers containing cholesterol. Membrane permeabilization is inefficient if the sterol is embedded within bilayers prepared from phosphatidylcholine only but is greatly enhanced if the target membrane also contains ceramide. Although the enhancement of VCC action is stereospecific with respect to cholesterol, we show here that no such specificity applies to the two stereocenters in ceramide; all four stereoisomers of ceramide enhanced VCC activity in cholesterol-containing bilayers. A wide variety of ceramide analogs were as effective as D-erythro-ceramide, as was diacylglycerol, suggesting that the effect of ceramide exemplifies a general trend of lipids with a small headgroup to augment the activity of VCC. Incorporation of these cone-shaped lipids into cholesterol-containing bilayers also gave similar effects with streptolysin O, another cholesterol-specific but structurally unrelated cytolysin. In contrast, the activity of staphylococcal alpha-hemolysin, which does not share with the other toxins the requirement for cholesterol, was far less affected by the presence of lipids with a conical shape. The collective data indicate that sphingolipids and glycerolipids do not interact with the cytolysins specifically. Instead, lipids that have a conical molecular shape appear to effect a change in the energetic state of membrane cholesterol that in turn augments the interaction of the sterol with the cholesterol-specific cytolysins.

Bacterial Proteins↗

PubMed2001

Apoptosis in the basal ganglia of the developing human nervous system.

Programmed cell death (PCD) plays a crucial role in the development of the central nervous system through controlling neuronal numbers and adequate synaptic connections. PCD has been considered to occur in the form of apoptosis. To examine how apoptosis occurs in the developing human brain, we performed a morphometric TUNEL study, using a commercially available kit (ApopTag Kit, Oncor Inc.). We examined apoptotic cells in the basal ganglia of 47 fetuses and newborns without macroscopical and microscopical evident congenital anomalies. Gestational age ranged from 12 to 40 weeks. The numerical density as well as the labeling index of TUNEL-positively labeled nuclei were evaluated. In the caudate nucleus and putamen, TUNEL-labeled cells were observed around the 12th week of gestation. The numerical density of total cells was significantly decreased, whereas the labeling index of apoptotic cells was significantly increased with advanced gestational age. In the globus pallidus, the numerical density of total cells decreased with advancing gestational age, while the labeling index of apoptotic cells increased between the 20th and 28th week, followed by a decrease until the 40th week. The analysis of TUNEL-positive cells revealed a different reaction pattern for the various basal ganglia with regard to the timing and degree of the apoptotic process in regulating cell numbers.

Age Factors↗

PubMed2001

Etomidate and thiopental inhibit platelet function in patients undergoing infrainguinal vascular surgery.

BACKGROUND: Postoperative platelet hyperaggregability following general anesthesia has been reported in patients undergoing major vascular surgery. In contrast, since anesthetic agents inhibited platelet function both in vitro and in vivo, an increased risk for postoperative bleedings due to prolonged platelet dysfunction has been discussed. Nevertheless, data describing platelet-affecting properties of induction agents such as etomidate and thiopental in patients undergoing major vascular surgery are lacking. METHODS: Platelet function was determined at 0, 2, 20, and 200 microg/ml thiopental and at 0, 0.2, 2, 20 microg/ml etomidate in vitro in blood samples drawn from 16 patients suffering from severe occlusive arterial disease. In addition, 30 patients undergoing vascular surgery were investigated before (PRE) and after anesthesia induction (T0) either with etomidate (ETO group, n=16) or thiopental (THIO group, n=14), and 2 h after the beginning of surgery (T2). Platelet function was determined according to platelet aggregation, in vitro bleeding time, and flow cytometric measurements. RESULTS: In vitro, P-selectin expression was inhibited by etomidate at 2 and 20 microg/ml (-28% and -38%, respectively) and also by thiopental at 200 microg/ml (-27%). In patients undergoing vascular surgery, anesthesia induction in the ETO group resulted in a 31% prolongation of the in vitro bleeding time and an inhibition of ADP- and collagen-induced platelet aggregation (-30% and -17%, respectively) and of P-selectin expression (-25%) at T0. In the THIO group, only ADP-induced platelet aggregation was affected (-16%). At T2, all parameters had reached PRE level again in both groups. Furthermore, in comparison with the THIO group, operation time was significantly prolonged and transfusion volume was significantly increased in the ETO group. In addition, platelet count and hematocrit significantly decreased at T2, whereas levels of tPA, PAI-1, fibrinogen and antithrombin III and partial thromboplastin time remained unchanged in both groups during the study period. CONCLUSIONS: In the present study, etomidate and, to a minor extent, thiopental offered significant platelet inhibitory properties. Anesthetic-induced platelet inhibition may lead to higher transfusion rates and prolonged operation times. Therefore, anesthetic-related platelet inhibitory properties should be considered when searching for the anesthetic agent of choice, especially in patients with compromised hemostasis and co-existing bleeding disorders.

Aged↗

PubMed2001

Sonography and neuropathology of a congenital brain tumor: report of a rare incident.

A rare case of a congenital brain tumor was diagnosed by sonography in a fetus at 33 weeks' gestation. The ultrasound examination showed a large area of both increased echogenicity and echolucency in one hemisphere suggestive of brain tumor or hemorrhage. The neuropathological examination revealed an undifferentiated glial tumor with large areas of necrosis.

Adult↗

PubMed2000

Effect of lovastatin on cardiovascular resource utilization and costs in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). AFCAPS/TexCAPS Research Group.

This cost-consequences analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study compares the costs of lovastatin treatment with the costs of cardiovascular hospitalizations and procedures. The cost of lovastatin treatment was defined as the average retail price and the cost of drug safety monitoring and adverse experiences. Costs were determined by actual rates of hospitalizations and procedures. Within a trial, lovastatin treatment cost approximately $4,654/patient. Lovastatin treatment significantly reduced the cumulative rate of cardiovascular hospitalizations and procedures (p = 0.002). Over the duration of the study, the cumulative number of cardiovascular hospitalizations and related therapeutic procedures was significantly reduced by 29%. The time to first cardiovascular-related hospitalization or procedure was significantly extended by lovastatin (p = 0.002). Lovastatin reduced the frequency of cardiovascular hospitalization (28%), and cardiovascular therapeutic (32%) and diagnostic procedures (23%). Among therapeutic procedures, treatment reduced coronary artery bypass graft surgery by 19% and percutaneous transluminal coronary angioplasty by 37%. Total cardiovascular-related hospital days were reduced by 26% (p = 0.025). The between-group offset in direct medical costs was $524, which resulted in a 11% cost offset of lovastatin therapy over the mean study duration of 5.2 years. Lovastatin provides meaningful reductions in cardiovascular-related resource utilization and reductions in direct cardiovascular-related costs associated with the onset of coronary disease.

Aged↗

PubMed2000

The neuropathology of heroin abuse.

A broad spectrum of neuropathologic changes are encountered in the brains of heroin abusers. The main findings are due to infections, either due to bacterial spread from bacterial endocarditis, mycoses, or from HIV-1 infection. Other complications include hypoxic-ischemic changes with cerebral edema, ischemic neuronal damage and neuronal loss, which are assumed to occur under conditions of prolonged heroin-induced respiratory depression, stroke due to, for example, thromboembolism, vasculitis, septic emboli, hypotension, and positional vascular compression. Myelopathy is believed to be the result of an isolated vascular accident within the spinal cord due to an as yet unknown mechanism. A distinct entity, spongiform leukoencephalopathy, has been described mainly after inhalation of pre-heated heroin. A lipophilic toxin-induced process was considered to be due to contaminants and to be induced or enhanced by cerebral hypoxia, but a definite toxin could not be identified. At the cellular level, abnormalities in signal transduction systems and changes of various receptor densities have been reported. The exact etiology of the different neuropathological alterations associated with heroin abuse is still unclear, but may also be related to additional substances used as adulterants.

Autopsy↗

PubMed2000

Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

BACKGROUND: The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25% reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk for first acute major coronary event (AMCE), defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. This article describes the relation between baseline and on-treatment lipid and apolipoprotein (apo) parameters and subsequent risk for AMCEs. METHODS AND RESULTS: With all available data from the entire 6605-patient cohort, a prespecified Cox backward stepwise regression model identified outcome predictors, and logistic regression models examined the relation between lipid variables and AMCE risk. Baseline LDL-C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment LDL-C was not. When event rates were examined across tertiles of baseline lipids, a consistent benefit of treatment with lovastatin was observed. CONCLUSIONS: Persons with average TC and LDL-C levels and below-average HDL-C may obtain significant clinical benefit from primary-prevention lipid modification. On-treatment apoB, especially when combined with apoAI to form the apoB/AI ratio, may be a more accurate predictor than LDL-C of risk for first AMCE.

Acute Disease↗

PubMed2000

Neuronal damage of the substantia nigra in HIV-1 infected brains.

Extrapyramidal motor disorders are frequently noted in HIV-1-infected patients. In the present study, the substantia nigra was analyzed morphometrically to detect neuronal changes which might contribute to the pathogenetic mechanisms causing extrapyramidal motor dysfunction in HIV-1-infected patients. The numerical density and the size of pigmented, non-pigmented small, and non-pigmented large neurons in four nuclei of the substantia nigra pars compacta (antero-medial, antero-intermediolateral, postero-lateral, and postero-medial nuclei) in HIV-1-infected patients and in age-matched normal controls were determined. In HIV-1-infected brains, the numerical density of total neurons (i.e., pigmented and non-pigmented) as well as of pigmented neurons was significantly decreased, whereas that of non-pigmented neurons was not significantly changed in all investigated nuclei of the substantia nigra as compared to normal controls. A specific pattern of increase and decrease of nonpigmented large and non-pigmented small neurons was observed. The size of total neurons (pigmented and nonpigmented neurons) and of pigmented neurons was significantly reduced in all investigated nuclei of HIV-1-infected brains. The results suggest that neuronal degeneration in the substantia nigra commonly occurs and may be related to extrapyramidal symptoms in HIV-1-infected patients.

AIDS Dementia Complex↗

PubMed2000

Amplification of a long terminal repeat-like element on the Y chromosome of the platyfish, Xiphophorus maculatus.

The platyfish (Xiphophorus maculatus), in which sex chromosomes are evident from stable and predictable inheritance of sex, is one of the best-studied lower vertebrates with respect to sex determination. In order to identify the structural equivalent for this in the karyotype, which does not contain heteromorphic pairs of chromosomes, two sex-linked molecular probes were used for fluorescent in situ hybridization analysis. One probe, derived from the melanoma oncogene locus ONC-Xmrk, stained both the X and the Y chromosome. This cytogenetic analysis mapped the sex-determining locus to the subtelomeric region of a medium-sized telocentric chromosome. Another probe, a repetitive element (XIR), specifically labeled the Y chromosome in metaphase spreads and in interphase nuclei. The sex chromosomes of X. maculatus can be considered to be at an early stage of evolution of gonosomes. Expansion of the XIR repeat is obviously one of the earliest of the molecular events that lead to divergence of the Y chromosome and recombinational isolation of the sex-determining locus.

Alleles↗

PubMed2000

Histologically repeatedly confirmed gliosarcoma with long survival: review of the literature and report of a case.

OBJECTIVE AND IMPORTANCE: A rare case of gliosarcoma in a 61-year-old woman is presented with a stable situation over 22 years with an excellent quality of life. CLINICAL PRESENTATION: The patient was initially symptomatic and was operated on in 1975 for a deep-seated left parietal gliosarcoma. During the following 20 years, she was clinically asymptomatic until she complained of increasing headache in 1995. Neuroradiological imaging showed a sharply demarcated lesion on MRI at the former operative site, which was operated on again. Four months later, the residual tumour did grow again. INTERVENTION: As radiation therapy could not stop tumour progression and the neurological status worsened, the patient was operated on again for a massive tumour mass in the left parieto-occipital region, filling out nearly all of the previous resection cavity. Despite radio-immunotherapy, the patient finally died 22 years after the first discovery of the tumour. CONCLUSION: The present case shows that, in rare instances, gliosarcomas may show prolonged survival, although the underlying pathogenetic mechanisms for this clinical behaviour are not understood.

Brain Neoplasms↗

PubMed2000

Application of the National Cholesterol Education Program and joint European treatment criteria and clinical benefit in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

AIMS: The Air Force/Texas Coronary Atherosclerosis Prevention Study reported that diet with lovastatin, 20-40 mg daily, reduced the risk for a first coronary event by 37%. Because only 17% of this cohort would have qualified for drug therapy according to current U.S. guidelines, we assessed clinical benefit by risk categories. METHODS AND RESULTS: The main outcome measures were event rates of first acute major coronary events stratified by National Cholesterol Education Program and European criteria and target goal. Both those who would and would not be eligible for drug therapy, according to National Cholesterol Education Program guidelines, benefited from intervention. As expected, drug-eligible participants (event rate: lovastatin 1%/year, placebo 1.87%/year [relative risk 0.53, 95% confidence interval: 0.33, 0.84]) were at greater absolute risk for acute major coronary events than non-eligible participants (lovastatin 0.62%/year, placebo 0.93%/year [relative risk 0.67, 95% confidence interval: 0.51, 0.88]). Similar results were found using European guidelines for coronary risk management. Treatment to a target goal suggested a non-significant trend to greater benefit. CONCLUSIONS: The consistent relative benefit across risk categories suggests that it may be possible to improve identification of at-risk persons who would benefit from primary prevention, and to recommend appropriate goals of such treatment.

Aged↗

PubMed2000

Reduction of benzodiazepine receptor binding is related to the seizure onset zone in extratemporal focal cortical dysplasia.

PURPOSE: Comparison of regional reduction of GABA receptor binding and seizure onset zone in patients with extratemporal epilepsy due to focal cortical dysplasia. METHODS: Two patients with frontal lobe epilepsy who remained seizure free after partial frontal lobe resection were investigated with magnetic resonance imaging, positron emission tomography (PET) with 18F-fluoro-deoxy-glucose (FDG) and 11C-flumazenil, subdural EEG-video recordings, and postoperative benzodiazepine (BDZ)-receptor autoradiography. RESULTS: The area of reduced BDZ-receptor binding as documented by preoperative flumazenil-PET and postoperative BDZ-receptor autoradiography corresponded to the seizure onset zone and was smaller than the interictal hypometabolism documented by FDG-PET. CONCLUSION: Flumazenil-PET is a useful tool for localization of the epileptogenic zone in patients with extratemporal epilepsy caused by focal cortical dysplasia. Neuronal distribution of BDZ-receptor density confirms in vivo flumazenil-PET findings. The regional reduction of BDZ-receptor binding in focal cortical dysplasia seems to be confined to the seizure onset zone and not to the extent of dysplastic cortex.

Adolescent↗

PubMed2000

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): baseline characteristics and comparison with USA population.

BACKGROUND: Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that treatment with lovastatin, in addition to modifications of diet and lifestyle, reduced the rate of first acute major coronary events compared with placebo in a cohort that included participants with average to mildly elevated total levels of cholesterol, and below average levels of high-density lipoprotein cholesterol, women, and elderly subjects. OBJECTIVE: To describe the baseline characteristics of the study's cohort. DESIGN: This was a double-blind, placebo-controlled, primary-prevention trial in which Americans with average to mildly elevated total levels of cholesterol [4.65-6.83 mmol/l (180-264 mg/dl)] and no clinical evidence of atherosclerotic cardiovascular disease were randomly allocated either 20-40 mg/day lovastatin or placebo in addition to a low-saturated fat, low-cholesterol diet. Baseline characteristics of the study cohort are described, and the characteristics of a USA reference population based upon NHANES III data are provided for comparison. RESULTS: The study includes 5608 men (85%) and 997 women (15%) with mean total cholesterol level 5.71 +/- 0.54 mmol/l (221 +/- 21 mg/dl), low-density lipoprotein cholesterol level 3.88 +/- 0.44 mmol/l (150 +/- 17 mg/dl), high-density lipoprotein cholesterol 0.96 +/- 0.15 mmol/l (37 +/- 6 mg/dl), and median triglyceride level 1.78 +/- 0.86 mmol/l (158 +/- 76 mg/dl). The mean age is 58 years (ranges 45-73 years for men and 55- 73 years for women). The participants are 89% white, 7% Hispanic, and 3% black. CONCLUSION: Results from AFCAPS/TexCAPS will be applicable to large segments of populations; in the USA alone, eight million share the demographic and baseline-lipid-level characteristics of the study cohort.

Aged↗

PubMed1999

Expression of metabotropic glutamate receptor subtype mRNA (mGluR1-8) in human cerebellum.

The expression of metabotropic glutamate receptor (mGluR) mRNAs in the human cerebellar neocortex was investigated using in situ hybridization. mGluR1, 3 and 4 mRNAs were most abundant and widely distributed, whereas mGluR2, 5 and 7 mRNA expression was circumscript. mRNAs coding for mGluR1, 3, 4 and 7 were expressed in Purkinje cells. mGluR1 and 4 mRNAs detectable in granule cells and mGluR1, 2, 3, 4 and 7 mRNAs in Golgi cells. mGluR5 mRNA was detectable in putative Bergmann glia as well as mGluR3 mRNA, which was widely expressed in glial cells. mGluR8 mRNA expression was very low in a subset of stellate/basket cells of the molecular layer whereas mGluR6 mRNA was not detectable in the cerebellar cortex.

Aged↗

PubMed1999

Streptolysin O: inhibition of the conformational change during membrane binding of the monomer prevents oligomerization and pore formation.

Streptolysin O is a four-domain protein toxin that permeabilizes animal cell membranes. The toxin first binds as a monomer to membrane cholesterol and subsequently assembles into oligomeric transmembrane pores. Binding is mediated by a C-terminally located tryptophan-rich motif. In a previous study, conformational effects of membrane binding were characterized by introducing single mutant cysteine residues that were then thiol-specifically derivatized with the environmentally sensitive fluorophoracrylodan. Membrane binding of the labeled proteins was accompanied by spectral shifts of the probe fluorescence, suggesting that the toxin molecule had undergone a conformational change. Here we provide evidence that this change corresponds to an allosteric transition of the toxin monomer that is required for the subsequent oligomerization and pore formation. The conformational change is reversible with reversal of binding, and it is related to temperature in a fashion that closely parallels the temperature-dependency of oligomerization. Furthermore, we describe a point mutation (N402E) that, while compatible with membrane binding, abrogates the accompanying conformational change. At the same time, the N402E mutation also abolishes oligomerization. These findings corroborate the contention that the target membrane acts as an allosteric effector to activate the oligomerizing and pore-forming capability of streptolysin O.

Alanine↗

PubMed1999

Unexpected death in persons with symptomatic epilepsy due to glial brain tumors: a report of two cases and review of the literature.

Two cases of unexpected death in persons with epileptic seizures due to a brain tumor are presented which encompassed an astrocytoma WHO grade II and an anaplastic astrocytoma WHO grade III. A 35-year-old man was found somnolent and disoriented at home. A computed tomography (CT) scan revealed a tumor of the right frontal lobe suggestive for an oligodendroglioma. During an angiographic examination the patient experienced an epileptic seizure. Some weeks later, the man was found dead in front of his house with a fresh bite mark of the tongue. Neuropathological examination revealed an astrocytoma WHO grade II of the right frontal lobe. A 47-year-old man plunged into a swimming-pool and was found submerged some minutes later. After resuscitation he survived comatose for 8 days but finally died due to severe hypoxic brain damage. He had been operated on a brain tumor of the temporal lobe 1 year before the accident. Neuropathological examination revealed residual tumor tissue at the operation site corresponding to an anaplastic astrocytoma WHO grade III. Although rare, death in persons with epileptic seizures due to brain tumors is an important mechanism of death encountered by the forensic pathologist.

Adult↗

PubMed1999

[Noninvasive protocol for surgical treatment of focal epilepsies].

We present a non-invasive epilepsy surgery protocol, which includes EEG-video-monitoring, magnetic resonance imaging (MRI), interictal positron emission tomography (PET) and ictal single photon emission computerized tomography (SPECT). According to this non-invasive protocol 50 of 173 patients with medically intractable focal epilepsy underwent resective surgery. The localization of the epileptogenic zone was based on the congruence of the localizing results of EEG-video-monitoring, MRI, interictal PET and ictal SPECT. 46 (92%) of the patients had temporal and 4 (8%) had extratemporal epilepsies. 78% (n = 39) of all patients operated according to our non-invasive protocol were postoperatively completely or almost seizure free. Extramesiotemporal resections could be carried out without invasive EEG-recording if the epileptogenic zone was not adjacent to the eloquent cortex. We conclude from our results that in a considerable number of patients with medically intractable particularly temporal focal epilepsies, resective epilepsy surgery can be based on non-invasive EEG-evaluations and the risk of invasive recordings can be avoided.

Adolescent↗

PubMed1999

Properties of a model of Ca++-dependent vesicle pool dynamics and short term synaptic depression.

We explore the properties of models of synaptic vesicle dynamics, in which synaptic depression is attributed to depletion of a pool of release-ready vesicles. Two alternative formulations of the model allow for either recruitment of vesicles from an unlimited reserve pool (vesicle state model) or for recovery of a fixed number of release sites to a release-ready state (release-site model). It is assumed that, following transmitter release, the recovery of the release-ready pool of vesicles is regulated by the intracellular free Ca(++) concentration, [Ca(++)](i). Considering the kinetics of [Ca(++)](i) after single presynaptic action potentials, we show that pool recovery can be described by two distinct kinetic components. With such a model, complex kinetic and steady-state properties of synaptic depression as found in several types of synapses can be accurately described. However, the specific assumption that enhanced recovery is proportional to [Ca(++)](i), as measured with Ca(++) indicator dyes, is not confirmed by experiments at the calyx of Held, in which [Ca(++)](i)-homeostasis was altered by adding low concentrations of the exogenous Ca(++) buffer, fura-2, to the presynaptic terminal. We conclude that synaptic depression at the calyx of Held is governed by localized, near membrane [Ca(++)](i) signals not visible to the indicator dye, or else by an altogether different mechanism. We demonstrate that, in models in which a Ca(++)-dependent process is linearly related to [Ca(++)](i), the addition of buffers has only transient but not steady-state consequences.

Action Potentials↗