Search PubMed⌕ Search

Biomedical subjects

J Cohen

Publications and source records attributed to J Cohen.

At least 685 records · Page 38Linked to original sources
PubMed1994

Nonpeptide renin inhibitors with good intraduodenal bioavailability and efficacy in dog.

The aim of this study was the discovery of nonpeptide renin inhibitors with much improved oral absorption, bioavailability, and efficacy, for use as antihypertensive agents. Our prior efforts led to the identification of A-74273 [1,R = 3-(4-morpholino)propyl], with a bioavailability of 26 +/- 10% [10 mg/kg intraduodenally (id), dog]. In vivo metabolism studies of A-74273 showed that the morpholino moiety underwent metabolic degradation. Computer modeling of A-74273 bound to renin indicated that the C-terminus was involved in a hydrogen-bonding network. New C-terminal groups were examined in two series of nonpeptides for effects on renin binding potency, lipophilicity (log P), and aqueous solubility. Those groups which possessed multiple hydrogen-bonding ability (3,5-diaminotriazole, cyanoguanidines, morpholino) provided particularly potent renin binding. Intraduodenal bioavailabilities of selected compounds, evaluated in rats, ferrets, and dogs, were higher for inhibitors with moderate solubility as well as moderate lipophilicity, in general. Although the absolute values varied substantially among species, the relative ordering of the inhibitors in terms of absorption and bioavailability was reasonably consistent. Such well absorbed inhibitors (e.g. 41, 44, and 51) were demonstrated as highly efficacious hypotensive agents in the salt-depleted dog. We report here the discovery of a series of efficacious nonpeptide renin inhibitors based on the 3-azaglutaramide P2-P4 replacement, the best of which showed id bioavailabilities > 50% in dog.

Amides↗
PubMed1994

Bumps on the vaccine road.

Explore the source record for details and available documents.

Centers for Disease Control and Prevention, U.S.↗
PubMed1994

Four nucleotides are the minimal requirement for RNA recognition by rotavirus non-structural protein NSP3.

The interaction of the group A rotavirus non-structural protein NSP3 (NSP3A) with RNA has been studied in vitro. Using semi-purified NSP3A protein expressed by a recombinant baculovirus and in vitro synthesized RNA, we determined by UV cross-linking and gel retardation assays that NSP3A binds, in a sequence-specific manner, the consensus sequence (AUGUGACC) present on the 3' ends of all group A rotavirus mRNAs. Using short oligoribonucleotides, we established that the minimal RNA sequence required for binding of NSP3A is GACC. Modifications of the UGACC oligonucleotide sequence impaired binding of the protein to the RNA. Furthermore, the recombinant NSP3 protein from rotavirus group C showed specificity for the 3' end consensus sequence (AUGUGGCU) of only group C mRNAs. Sequence analysis of the NSP3 proteins did not reveal significant homologies with other RNA binding proteins, thus the NSP3 proteins of rotaviruses are the prototypes of a new kind of sequence-specific RNA binding protein.

Baculoviridae↗
PubMed1994

Decline in sperm counts: an artefact of changed reference range of "normal"?

OBJECTIVE: To investigate a reported fall in sperm counts during 1940-90 in relation to the reduced lower reference value of "normal" during the same period by assuming the null hypothesis that no change had occurred in the probability distribution of the sperm concentration. DESIGN: Analysis by using various mathematical models of the probability distribution of sperm concentration together with experimental data which supported a model employing a logarithmic distribution. SUBJECTS: 235 men presenting for stimulated in vitro fertilisation at Midland Fertility Services, Aldridge, in 1992 together with samples of 20 ejaculates from each of five men attending the same centre during 1992-3. RESULTS: The effect of the change in lower reference value for the "normal" sperm concentration (from 60 x 10(9) to 20 x 10(9)/l) depended on the probability distribution of the concentration in the population. If that distribution was normal or uniform, then very little of the reported decline was a consequence of the change in lower reference value. If it was heavily skewed, then most or all of the reported decline may have been a consequence of that change. The limited experimental data available indicate that the distribution was heavily skewed. CONCLUSIONS: Depending on the actual distribution of sperm concentration in the population, the reported decline in concentration may have been accounted for entirely or in part by the change in lower reference value. The original evidence does not support the hypothesis that the sperm count declined significantly between 1940 and 1990.

Humans↗
PubMed1994

The Rochester practice-based experience. An experiment in medical education.

BACKGROUND: Recent changes in the organization and financing of medical practice have resulted in a shift of patient care from the hospital to ambulatory locations and dramatically changed the mix and severity of the inpatient population. Medical educators are concerned that hospitalized patients are not truly representative of the practice of internal medicine and may be unsuitable for the education of third-year medical students. The University of Rochester (NY) Department of Medicine recently established a "practice-based" component to complement the inpatient segment of the third-year medicine clerkship. METHODS: Participating students work with a practicing internist for the second half of the 12-week clerkship. Students evaluate office and hospital patients in the internist's practice and attend didactic conferences. We used a multi-measurement curriculum evaluation system to assess the new program and compare it with the established hospital experience. Evaluation components included the following: logs in which students profiled their clinical activities; questionnaires that assessed opinions and satisfaction about the clerkship; group interviews with students; and visits to practice-based sites to interview both preceptor and student. RESULTS: Practice-based students saw many more patients with a broader range of illnesses and had more observation and supervision from faculty than hospital-based students. Practice-based students discussed all of their patients with their preceptors, who were perceived as being excellent teachers. Hospital-based students, although generally positive, were also generally less enthusiastic about the amount and quality of teaching, observation, and supervision. Practice-based and hospital-based students achieved similar grades on the final examination and received a similar number of honors grades. Preceptors were enthusiastic in their endorsement of the practice-based experience and patient acceptance of students was high. CONCLUSION: The practice-based experience is feasible and of equal academic rigor to the hospital experience. This realistic immersion into the daily activities of an internist provides an enriching balance to the traditional hospital-based clerkship.

Ambulatory Care↗
PubMed1994

Characterization of rotavirus VP2 particles.

Rotavirus particles consist of three concentric proteinaceous capsid layers. The innermost capsid (core) is made of VP2. The genomic RNA and the two minor proteins VP1 and VP3 are encapsidated within this layer. Empty rVP2 particles are produced when insect cells are infected with a recombinant baculovirus which contains the bovine Rf rotavirus gene 2 (Labbé et al., 1991, J. Virol. 65, 2946-2952). Analysis of expressed rVP2 particles by SDS-PAGE showed these particles were composed of three major VP2-related proteins, called bands A, B, and C, with apparent molecular weights of 94K, 85K, and 77K, respectively. N-Terminal amino acid sequence analysis of each band showed that band A and band B were blocked, and band C lacked 92 amino acids from the N terminus. Bands B and C were predicted to also lack an approximately 10K peptide fragment from the C terminus. Electron microscopy (EM) showed negatively stained rVP2 particles to be spherical with icosahedral symmetry, 520 +/- 20 A in diameter. Highly concentrated rVP2 particles were converted to unusual forms, including elongated bristly structures, helix-like structures, and sheet-like helix structures. These unusual forms apparently resulted from a structural conversion of individual rVP2 particles. This conversion was reversible both in solution or on a collodion-carbon-coated grid support. The reconstituted rVP2 particles possessed normal morphology and reacted with purified VP6 to form rVP2/6 empty double-layered (previously called single-shelled) virus-like particles with an association constant Ka approximately 10(11) M-1. Native viral core particles lacking RNA were obtained by dialysis of full cores prepared from purified SA11-4F rotavirus double-layered particles against a hypotonic buffer in the presence of EDTA. EM showed both the full and empty native viral cores to be spherical with icosahedral symmetry. Highly concentrated SA11-4F full and empty cores also were converted into elongated and bead-like structures. However, in contrast to rVP2 particles, the conversion of SA11-4F cores was not reversible. These results provide some helpful clues to understanding VP2 functions, the assembly of VP2 particles, the assembly of VP2/6 double-layered particles, and the transport of metabolites inside and outside of the core particle.

Amino Acid Sequence↗