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Biomedical subjects

S Weiss

Publications and source records attributed to S Weiss.

At least 199 records · Page 11Linked to original sources
PubMed1996

Orally active fibrinogen receptor antagonists. 2. Amidoximes as prodrugs of amidines.

The potent and selective GP IIb-IIIa antagonist lamifiban (1, Ro 44-9883) is currently in clinical development as an injectable antithrombotic agent for treating and preventing acute coronary syndromes. However, for secondary prevention of thrombotic occlusions, orally active inhibitors are needed. By means of a prodrug strategy, the modest oral absorption of 1 in mice was improved by a factor of 9. In addition, these studies demonstrated that an amidoxime group can serve as a prodrug functionality for an amidino group. Application of this principle to the structurally related amidino carboxylate 13 led to the amidoxime ester 18 which was absorbed approximately 20 times better, after oral administration to mice, than 13. Due to the modification of the amidino group as well as of the carboxylate group, 18 completely lost its ability to interact with purified platelet GP IIb-IIIa. After oral administration of 18 to rats, dogs, and rhesus monkeys, the bioavailability of the active derivative 13 was 26 +/- 5, 25 +/- 6, and 33 +/- 6%, respectively, and the elimination half-life was 4.1 +/- 1.7, 11.4 +/- 1.1, and 5.1 +/- 1.4 h, respectively. On the basis of these properties, the orally active 18 (Ro 48-3657), a double prodrug of the potent and selective non-peptide GP IIb-IIIa antagonist 13 (Ro 44-3888), was selected as clinical candidate for evaluation as a prophylactic agent in patients at high risk for arterial thrombosis.

Acetates↗
PubMed1996

Probing the interaction between two single molecules: fluorescence resonance energy transfer between a single donor and a single acceptor.

We extend the sensitivity of fluorescence resonance energy transfer (FRET) to the single molecule level by measuring energy transfer between a single donor fluorophore and a single acceptor fluorophore. Near-field scanning optical microscopy (NSOM) is used to obtain simultaneous dual color images and emission spectra from donor and acceptor fluorophores linked by a short DNA molecule. Photodestruction dynamics of the donor or acceptor are used to determine the presence and efficiency of energy transfer. The classical equations used to measure energy transfer on ensembles of fluorophores are modified for single-molecule measurements. In contrast to ensemble measurements, dynamic events on a molecular scale are observable in single pair FRET measurements because they are not canceled out by random averaging. Monitoring conformational changes, such as rotations and distance changes on a nanometer scale, within single biological macromolecules, may be possible with single pair FRET.

Base Sequence↗
PubMed1996

EEG coherence within the 13-18 Hz band as a correlate of a distinct lexical organisation of concrete and abstract nouns in humans.

Coherence analysis was applied to the EEG of 19 female participants who had to memorize auditorily presented abstract and concrete nouns. The EEG was recorded from 19 scalp electrodes (10/20 system). Significant differences between both word classes were found only in the beta 1-band (13-18 Hz) whereas the alpha 1-band (8-10 Hz) revealed coherence patterns which were identical for both word classes. These results indicate that the alpha 1-band reflects cognitive processes that were common to both word classes, whereas the beta 1-band seems to be closely related to associative processes and more complex cognitive functions.

Brain↗
PubMed1996

A longitudinal study of low-level lead exposure and impairment of renal function. The Normative Aging Study.

OBJECTIVE: To determine whether low-level lead exposure is associated with impaired renal function. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Subjects were 459 men randomly selected from the participants of the Normative Aging Study who were originally recruited from healthy veterans in the greater Boston area in 1961 and were periodically examined at the Department of Veterans Affairs Outpatient Clinic every 3 to 5 years. We reconstructed blood lead concentrations for the period between 1979 and 1994 using samples of either archived red blood cells or fresh whole blood. MAIN OUTCOME MEASURES: Serum creatinine concentration. RESULTS: After adjustment for age, body mass index, smoking, alcohol consumption, educational level, and hypertension, blood lead concentration was positively and significantly associated with concurrent concentration of serum creatinine (P=.005). A 10-fold increase in blood lead level predicted an increase of 7 micromol/L (0.08 micrograms/dL) in serum creatinine concentration, which is roughly equivalent to the increase predicted by 20 years of aging. The association was also significant among subjects whose blood lead concentrations had never exceeded 0.48 micromol/L (10 micrograms/L) throughout the study period. The age-related increase in serum creatinine level was earlier and faster in the group with the highest-quartile levels of long-term lead exposure than in the group with the lowest-quartile levels. CONCLUSIONS: Low-level exposure to lead may impair renal function in middle-aged and older men. Longitudinal data suggest an acceleration of age-related impairment of renal function in association with long-term low-level lead exposure.

Age Factors↗
PubMed1996

In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain.

The lateral ventricle subependyma in the adult mammalian forebrain contains both neural stem and progenitor cells. This study describes the in situ modulation of these subependymal neural precursor populations after intraventricular administration of exogenous growth factors. In vivo infusion of epidermal growth factor (EGF) into adult mouse forebrain for 6 consecutive days resulted in a dramatic increase in the proliferation and total number of subependymal cells and induced their migration away from the lateral ventricle walls into adjacent parenchyma. Immediately after EGF infusion, immunohistochemical characterization of the EGF-expanded cell population demonstrated that >95% of these cells were EGF receptor- and nestin-positive, whereas only 0.9% and 0.2% labeled for astrocytic and neuronal markers, respectively. Seven weeks after EGF withdrawal, 25% of the cells induced to proliferate after 6d of EGF were still detectable; 28% of these cells had differentiated into new astrocytes and 3% into new neurons in the cortex, striatum, and septum. Newly generated oligodendrocytes were also observed. These in vivo results (1) confirm the existence of EGF-responsive subependymal neural precursor cells in the adult mouse forebrain and (2) suggest that EGF acts directly as a proliferation, survival, and migration factor for subependymal precursor cells to expand these populations and promote the movement of these cells into normal brain parenchyma. Thus, in situ modulation of endogenous forebrain precursor cells represents a novel model for studying neural development in the adult mammalian brain and may provide insights that will achieve adult replacement of neurons and glia lost to disease or trauma.

Animals↗
PubMed1996

Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell.

In cultures of embryonic striatum, we previously reported that EGF induces the proliferation of single precursor cells, which give rise to spheres of undifferentiated cells that can generate neurons and glia. We report here that, in vitro, these embryonic precursor cells exhibit properties and satisfy criteria representative of stem cells. The EGF-responsive cell was able to generate the three major phenotypes of the mammalian CNS--neurons, astrocytes, and oligodendrocytes. Approximately 90% of both primary spheres and secondary expanded clones, derived from the primary spheres, contained all three cell types. The increase in frequency of EGF-generated spheres, from 1% in primary culture to close to 20% in secondary culture, and the large number of clonally derived secondary spheres that could be generated from a single primary sphere indicate that EGF induces both renewal and expansion of the precursor cell itself. In population studies, the EGF-responsive cells were carried through 10 passages, resulting in a 10(7)-fold increase in cell number, without losing their proliferative and multilineage potential. Thus, this study describes the first demonstration, through clonal and population analyses in vitro, of a mammalian CNS stem cell that proliferates in response to an identified growth factor (EGF) and produces the three principal cell types of the CNS.

Animals↗
PubMed1996

Recombinant prion protein rPrP27-30 from Syrian golden hamster reveals proteinase K sensitivity.

PrP27-30 represents the protease-resistant core of the prion protein and was found to be the main component in Scrapie prion preparations. Recombinant (r) PrP27-30 corresponding to aa 90-231 from the Syrian golden hamster prion protein was expressed as a fusion with GST in E. coli and secreted from insect cells infected with recombinant baculoviruses, GST::rPrP27-30 isolated from either system was purified to homogenity by glutathione-Sepharose chromatography. rPrP27-30 from both systems was generated by direct cleavage of GST::rPrP27-30 in the presence of thrombin revealing a molecular weight of 17 kDa. GST::rPrP27-30 as well as the authentic protein rPrP27-30 were identified by immunoblotting employing a polyclonal antibody directed against a peptide corresponding to aa 95-110 of the Syrian golden hamster prion protein. In contrast to scrapie prior PrP27-30, the recombinant proteins GST::rPrP27-30 and rPrP27-30 were both sensitive towards proteinase K, suggesting that the molecules lack infectivity.

Animals↗
PubMed1996

Angiotensin converting enzyme inhibitor-associated angioedema: higher risk in blacks than whites.

We compared the incidence of angioedema during exposure to angiotensin converting enzyme inhibitors (ACEIs) in blacks with that in whites in a retrospective cohort study of Medicaid recipients from Michigan, Ohio and Tennessee during 1986- 1992. Medicaid administrative files were used to identify filled prescriptions for ACEIs and calcium channel blockers (CCBs), and to identify first episodes of angioedema that occurred during exposure to an ACEI or CCB. There were 48,776 black and 106,482 white patients with 43,989 and 114,448 person-years of exposure to an ACEI, respectively. For comparison, there were 49,004 black and 110,129 white patients with 43,064 and 117,684 person-years of exposure to a CCB, respectively. The incidence of angioedema in blacks ranged from 3.3 to 4.6 per 1000 person-years of ACEI exposure--three to four times higher than that for whites in each state. Controlling for a slightly greater incidence of angioedema in blacks and other covariates, black users of ACEIs had a 3.1-fold greater incidence than white users. First exposure to ACEIs was associated with a higher risk of angioedema than chronic exposure in blacks, but not whites. Among blacks, the rate of angioedema during the first 30 days of exposure was 11.4 times greater (95% confidence interval [CI], 3.5 to 37.0) among ACEI users than CCB users; for those with at least 1 year of exposure, the rate was 4.5 times higher (95% CI, 2.6 to 8.0). Among whites, the increased risk of angioedema was more modest (rate ratio 1.7, 95% CI, 1.3 to 2.4 compared to CCB users) and did not differ by duration of ACEI use. In an analysis of angioedema cases and randomly selected controls in a subset of the full cohort, the greater risk of ACEI-associated angioedema in blacks was not explained by concurrent exposure to diuretics or antibiotics. Blacks may be at greater risk of angioedema when taking ACEIs than whites. Further study is necessary to confirm these findings, to examine effects of underlying disease on angioedema incidence, and to describe any racial differences in the severity of angioedema occurring with ACEIs.

Journal Article↗
PubMed1996

Anatomical studies of DNA fragmentation in rat brain after systemic kainate administration.

Rats treated systemically with kainate develop stereotyped epileptic seizures involving mainly limbic structures that may last for hours. This model of limbic status epilepticus has been widely studied using classical neuropathological techniques. We used in situ nick translation histochemistry to examine patterns of DNA fragmentation in this model. We found a stereotyped and reproducible pattern of neuronal populations that demonstrate evidence of DNA fragmentation from 24 h to one week after kainate treatment. Neither blockade of new protein synthesis nor blockade of the N-methyl-D-aspartate-type glutamate receptors significantly altered this response. Moreover, we saw no evidence of the regular internucleosomal cleavage of DNA that produces a characteristic laddered appearance of 180-200 bp DNA fragments after gel electrophoresis in samples obtained from microdissected affected regions. These studies suggest that DNA fragmentation after systemic kainate-induced seizures is not the result of programmed cell death. This assay may be useful for quantitative testing of both neuroprotective agents and mechanistic hypotheses.

Animals↗
PubMed1996

Soluble CD44 molecules in serum of patients with prostate cancer and benign prostatic hyperplasia.

Recent studies suggest that expression of CD44 splice variants are of prognostic significance for a variety of neoplasias. It was the aim of this study to investigate whether any correlation exists between the concentration of soluble CD44 molecules in serum (CD44 standard form and CD44 splice variants v5 and v6) and the prostate cancer stage. Serum levels of these soluble CD44 isoforms were measured by ELISA tests specific for these proteins in controls (n = 30), patients with benign prostatic hyperplasia (BPH; n = 30), with prostate cancer without metastasis (T1,2,3pN0M0; n = 30) and with locally advanced prostate cancer and/or metastatic disease (T3,4pN1,2M1; n = 19). sCD44std and sCD44v6 concentrations were not significantly different among the four groups studied, with few patients' levels outside the central 95% reference intervals. The mean sCD44v5 concentrations of both prostate cancer and BPH patients were significantly lower than those of the controls. There was no significant difference between the soluble CD44 concentrations of the two groups of prostate cancer patients studied. In contrast to results observed in other carcinomas, the determination of soluble CD44 proteins in serum is not suitable for providing additional prognostic information on patients with prostate cancer.

Adult↗
PubMed1996

What do Israeli Jewish and Arab adolescents know about drinking and driving?

This article describes a study, which is the first in Israel to investigate knowledge concerning drinking and driving among a large group of 2408 adolescents of four religions in the north of Israel, in the winter of 1995. The article analyses the results by referring to general scores and to five areas in the "drinking and driving" domain: legal blood alcohol concentration (BAC) limit, minimal number of drinks prohibited by the law before driving, common myths, main effects of alcohol on driving ability and youth vulnerability. The article emphasizes differences between the Jewish group and the non-Jewish (Arab) group. The average score of the sample was 2.06 (out of 5). Jews received the highest score (2.30) and Moslems got the lowest score (1.45). No differences were found among those who had a driving license and those who had not, and between the group of respondents from the north of Israel and a sample of participants from the center of the country. Lack of knowledge was revealed especially concerning knowledge about the BAC limit and youth vulnerability. Arabs tended to exaggerate the amount of drinks allowed to be consumed before driving according to the law, to hold common myths more than Jews and to get lower scores concerning alcohol main effects on driving skills. However, they tended to be more aware than Jews to youth vulnerability.

Accidents, Traffic↗
PubMed1996

Is there a neural stem cell in the mammalian forebrain?

Neural precursor cells have been of interest historically as the building blocks of the embryonic CNS and, most recently, as substrates for restorative neurological approaches. The majority of previous in vitro studies of the regulation of neural-cell proliferation by polypeptide growth factors, and in vivo studies of neural lineage, argue for the presence of precursors with limited proliferative or lineage potential in the mammalian CNS. This is in contrast to renewable tissues, such as the blood or immune system, skin epithelium and epithelium of the small intestinal crypts, which contain specialized, self-renewing cells known as stem cells. However, recent in vitro and in vivo studies from our and other laboratories lead us to conclude that neural stem cells, with self-renewal and multilineage potential, are present in the embryonic through to adult mammalian forebrain.

Animals↗
PubMed1996

Apoptosis of mouse dendritic cells is triggered by listeriolysin, the major virulence determinant of Listeria monocytogenes.

Infection of a murine-spleen dendritic cell line by Listeria monocytogenes was found to induce cell death through apoptosis. To characterize the bacterial product(s) involved in induction of apoptosis, dendritic cells were infected with the L. monocytogenes EGD strain and several isogenic mutants deficient in the production of individual listerial virulence factors. The ability to induce cellular apoptosis was retained by all mutants tested, except the prfA and delta hly mutants, both of which are unable to produce listeriolysin. Apoptosis was also induced by purified listeriolysin suggesting that this protein directly induces apoptosis. Purified recombinant listeriolysins rendered either weakly haemolytic by a C-484 to S mutation, or nonhaemolytic by a W-491 to A mutation exhibited little or no capacity to induce apoptosis, indicating that both activities are associated within the same protein region. Treatment with purified listeriolysin or L. monocytogenes infection also triggers apoptosis in explanted bone-marrow dendritic cells. Thus invasion of dendritic cells by L. monocytogenes, which results in cell death, may play an important role in the pathogenesis of listerial infections by impairing immune responses, hindering bacterial clearance and promoting spread of the infection.

Animals↗
PubMed1996

Listeriolysin is a potent inducer of the phosphatidylinositol response and lipid mediator generation in human endothelial cells.

The impact of Listeria monocytogenes listeriolysin O (LLO) secretion on phosphoinositide metabolism and mediator (platelet-activating factor and prostaglandin I2) generation was investigated in human umbilical vein endothelial cells. Wild-type L. monocytogenes, purified LLO, and an L. innocua strain engineered to secrete LLO all elicited a strong response, whereas mutant strains defective in LLO production were ineffective. Thus, human umbilical vein endothelial cell stimulation by listeriae is linked to production of LLO.

Bacterial Toxins↗
PubMed1996

Neutralizing monoclonal antibodies against listeriolysin: mapping of epitopes involved in pore formation.

Six different mouse monoclonal antibodies (MAbs) and a specific rabbit polygonal antibody were raised against listeriolysin. Four of the MAbs also recognized seeligeriolysin, and five cross-reacted with ivanolysin. The hemolytic activity could be neutralized by the polygonal antibody as well as by five of the MAbs. None of the neutralizing antibodies interfered with the binding of listeriolysin to the cellular membrane. The epitopes recognized by the MAbs were localized by using overlapping synthetic peptides between positions 59 and 279, a region hitherto not implicated in mediating hemolytic activity.

Amino Acid Sequence↗
PubMed1996

Prion protein PrPc interacts with molecular chaperones of the Hsp60 family.

Prions mediate the pathogenesis of certain neurodegenerative diseases, including bovine spongiform encephalopathy in cattle and Creutzfeldt-Jakob disease in humans. The prion particle consists mainly, if not entirely, of PrPSc, a posttranslationally modified isoform of the cellular host-encoded prion protein (PrPc). It has been suggested that additional cellular factors might be involved in the physiological function of PrPc and in the propagation of PrPSc. Here we employ a Saccharomyces cerevisiae two-hybrid screen to search for proteins which interact specifically with the Syrian golden hamster prion protein. Screening of a HeLa cDNA library identified heat shock protein 60 (Hsp60), a cellular chaperone as a major interactor for PrPc. The specificity of the interaction was confirmed in vitro for the recombinant proteins PrPc23-231 and rPrP27-30 fused to glutathione S-transferase with recombinant human Hsp60 as well as the bacterial GroEL. The interaction site for recombinant Hsp60 and GroEL proteins was mapped between amino acids 180 and 210 of the prion protein by screening with a set of recombinant PrPc fragments. The binding of Hsp60 and GroEL occurs within a region which contains parts of the putative alpha-helical domains H3 and H4 of the prion protein.

Animals↗