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Biomedical subjects

R Schwartz

Publications and source records attributed to R Schwartz.

At least 19 recordsLinked to original sources
PubMed1998

Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 7. 8-Arylethyldipyridodiazepinones as potent broad-spectrum inhibitors of wild-type and mutant enzymes.

Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is associated with resistance to most reported nonnucleoside inhibitors. Introduction of an arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers enhanced potency against Y181C RT. Several analogues of this series display good broad spectrum potency against a panel of mutant enzymes.

Amino Acid Substitution↗
PubMed1998

Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 8. 8-Aryloxymethyl- and 8-arylthiomethyldipyridodiazepinones.

Nevirapine (I) is the first human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor to reach regulatory approval. As a result of a second generation program around the tricyclic core system of nevirapine, 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido[3, 2-b:2',3'-e][1,4]diazepin-6-one (II)1a and 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-phenylethyl-6H-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one (III)1a were identified as broad spectrum HIV-1 RT inhibitors. A detailed examination of replacing either of the methylenes of the 8-ethyl linker of II or III is presented. It was found that 8-aryloxymethyl and 8-arylthiomethyl are the preferred pattern of substitution for potency against RT. The most potent compounds were further evaluated against a panel of clinically significant mutant RT enzymes (K103N, V106A, G190A, P236L) and in cytotoxicity and in vitro metabolism assays. The most potent compound was 2-chloro-8-phenylthiomethyl analogue 37 which displayed sub-100 nM activity against all HIV-1 RT enzymes tested.

Animals↗
PubMed1998

Interleukin-12 enhances the virus-specific interferon gamma response of pigs to an inactivated pseudorabies virus vaccine.

Cell-mediated immunity is a major component of the host defense system against viral infections. Since interleukin (IL)-12 has been shown to be a potent stimulus for the in vivo generation of interferon-gamma (IFN-gamma)-producing T cells (i.e. Th-1 cells) in laboratory animals, we evaluated the effect of IL-12 on the cellular immune response of pigs to vaccination against pseudorabies virus (PrV), a herpesvirus of swine. The magnitude of the cellular immune response was measured by IFN-gamma ELISPOT analysis of peripheral blood mononuclear cells (PBMC) from pigs which had been immunized twice, at 2-week intervals, with either, modified live virus (MLV) alone or with a commercial inactivated PrV vaccine with or without the coadministration of human recombinant IL-12 (HrIL-12). No significant differences in the titer of virus-neutralizing antibodies or in the intensity of the virus-specific lymphoproliferative response among the different treatment groups was observed. However, the number of virus-specific IFN-gamma-producing cells among PBMC isolated from animals receiving the MLV vaccine was on average 3.5 times more than animals immunized with the inactivated vaccine (P = 0.01). Administration of the inactivated vaccine and IL-12 induced a two-fold higher frequency of virus-specific IFN-gamma-producing cells from that induced by the inactivated vaccine alone (P < 0.05). Despite this enhancement, the level of protection from lethal PrV challenge provided by the inactivated vaccine in combination with IL-12 was the same as that induced by the inactivated vaccine alone. Both of these vaccination regimes provided significantly lower levels of protection than those afforded by the MLV vaccine. This study demonstrates that an inactivated PrV vaccine is a poor inducer of virus-specific IFN-gamma-producing cells and that this response can be enhanced by administration of exogenous IL-12. The data provides evidence of a dichotomy in the humoral and cellular immune responses of pigs to a viral antigen and implies the existence of a Th-1/Th-2 type regulation of the anti-viral immune response in pigs.

Adjuvants, Immunologic↗
PubMed1998

Protein size resolution in human eye lenses by dynamic light scattering after in vivo measurements.

Dynamic light scattering (DLS) measurements were conducted with lowest intensity levels on human eye lenses (3.2 mW/cm2) within measurement times of 3-5 s. A characterisation of the human eye under in-vivo conditions along the optical axis is given and a careful interpretation of the data is made, referring not only to in-vitro results of investigated solutions of lens chemistry and various crystallin fractions but also to measurements performed on intact human lenses under various scattering angles. The clinical study was expanded to 79 subjects with ages varying from 9 to 85 years with no serious diseases of the ocular lenses. A normalisation of Scheimpflug photography density data to the data obtained by DLS enables comparison of the two techniques and shows good agreement. The bimodal character of the viscoelastic properties of healthy eye lenses was confirmed; with an assumed viscosity of 2 cP, the mean size parameter of the smaller component is 5.13 +/- 1.6 nm and of the polymeric fraction 690 nm.

Adolescent↗
PubMed1998

Local rules simulation of the kinetics of virus capsid self-assembly.

A computer model is described for studying the kinetics of the self-assembly of icosahedral viral capsids. Solution of this problem is crucial to an understanding of the viral life cycle, which currently cannot be adequately addressed through laboratory techniques. The abstract simulation model employed to address this is based on the local rules theory of. Proc. Natl. Acad. Sci. USA. 91:7732-7736). It is shown that the principle of local rules, generalized with a model of kinetics and other extensions, can be used to simulate complicated problems in self-assembly. This approach allows for a computationally tractable molecular dynamics-like simulation of coat protein interactions while retaining many relevant features of capsid self-assembly. Three simple simulation experiments are presented to illustrate the use of this model. These show the dependence of growth and malformation rates on the energetics of binding interactions, the tolerance of errors in binding positions, and the concentration of subunits in the examples. These experiments demonstrate a tradeoff within the model between growth rate and fidelity of assembly for the three parameters. A detailed discussion of the computational model is also provided.

Biophysical Phenomena↗
PubMed1998

Rapidly progressive herpetic retinal necrosis: a blinding disease characteristic of advanced AIDS.

Eleven patients with rapidly progressive herpetic retinal necrosis (RPHRN) complicating AIDS were investigated retrospectively to study the disease spectrum, systemic involvement, and therapy. The mean CD4 cell count was 24/microL. There was a characteristic disease pattern with rapid progression, 82% bilaterality, relative resistance to intravenous antiviral therapy, and 70% retinal detachment. Varicella-zoster virus was the probable cause in 10 patients (detected by polymerase chain reaction in two eyes investigated), and herpes simplex virus was the probable cause in one. Cutaneous zoster occurred previously in 73% but was not concurrent. Seventy-three percent had central nervous system disease, possibly virus-related. RPHRN may be a local herpetic recrudescence in an immune-privileged site with transneural spread. Only four of 20 affected eyes retained useful vision. Poor ocular bioavailability, retinal ischemia, acquired drug resistance, and strain pathogenicity may underlie treatment failure. Acyclovir therapy appears relatively ineffective. Combined intravenous and intravitreal therapy with foscarnet and ganciclovir may be the best current management. Research advances are needed urgently.

AIDS-Related Opportunistic Infections↗
PubMed1998

Anthropometric and hormone effects of an eight-week exercise-diet intervention in breast cancer patients: results of a pilot study.

To assess the feasibility of an exercise-diet intervention in sedentary, overweight breast cancer patients, we conducted a pilot 8-week intervention. Recruitment letters and interest surveys were sent to 99 stage 1 or 2 breast cancer patients, ages 25-75 years, who were identified through two Seattle breast surgery practices and the University of Washington Breast Clinic. Ten patients were eligible and interested and were enrolled in the intervention, which consisted of thrice-weekly monitored aerobic exercise sessions and a low-fat (20% of calories from fat) diet. Nine patients completed the program; all adhered well to the intervention and data collection protocol. The patients, ages 40-74 years, lost, on average, 2.6 pounds of body weight, 3.4 cm in waist circumference, 4.6 cm in hip circumference, 2.3% body fat, 3.3 systolic blood pressure points, 0.67 diastolic blood pressure points, and 4.0 pulse beats/min, and they gained an average of 2.3% lean mass. Slight, nonsignificant decreases were observed in serum concentration of total and free estradiol, estrone sulfate, total testosterone, androstenedione, and dehydroepiandrosterone. These pilot data indicate that breast cancer patients are highly motivated to join and adhere to an intense exercise-diet intervention and can experience significant measurable changes in anthropometric and fat mass measures.

Adult↗
PubMed1998

New Jersey Caucasian, African American, and Hispanic population data on the PCR-based loci HLA-DQA1, LDLR, GYPA, HBGG, D7S8, and Gc.

New Jersey Caucasian, African American, and Hispanic genotype and allele frequencies were determined for the six PCR-based loci, HLA-DQA1, LDLR, GYPA, HBGG, D7S8, and Gc. All but one locus (HLA-DQA1 for African Americans) meet Hardy-Weinberg expectations. However, observing one departure in 18 loci over the three New Jersey sample populations is not unexpected. There is little evidence for departures from independence between pairs of loci in the three populations studied. Thus, multiple locus profile frequencies can be determined using the product rule.

Alleles↗
PubMed1997

Relation of coronary artery disease to atherosclerotic disease in the aorta, carotid, and femoral arteries evaluated by ultrasound.

This prospective study was conducted to correlate the presence of angiographically significant coronary artery disease (CAD) and atherosclerotic disease in the aorta, carotid, and femoral arteries as measured by ultrasound. One hundred two consecutive patients admitted for coronary angiography for suspected CAD participated in the study. All patients underwent transesophageal echocardiography for the evaluation of thoracic aortic atherosclerosis and B-mode ultrasound for evaluation of carotid and femoral atherosclerosis. Intimal-medial thickness > 1 mm in the thoracic aorta or peripheral vessels was considered as evidence of atherosclerosis. Patients with CAD (n = 64) had a significantly higher incidence of atherosclerotic plaques in the thoracic aorta, carotid, and femoral arteries than subjects with normal coronary arteries: 91%, 72%, 77% vs 31%, 47% and 42%, respectively. Extracoronary plaque was a stronger predictor of CAD than conventional risk factors. Evidence of plaque in patients younger than median age (64 years) had a higher specificity than in patients above median age (77% vs 40%, respectively, p <0.0001). Plaque score of the extracardiac vessels was significantly higher in patients with multivessel CAD than in patients with 1-vessel CAD disease and in subjects with normal coronary arteries (p <0.001). Thus, atherosclerotic plaques in the aortic and femoral arteries and, to a lesser extent, in the carotid arteries are strong predictors of CAD.

Adult↗
PubMed1997

Overexpression of hIGF-1 exclusively in skeletal muscle increases the number of dihydropyridine receptors in adult transgenic mice.

The number of dihydropyridine receptors (DHPR) and sarcoplasmic reticulum (SR) Ca2+ release channels (RyR1) and their interaction determine the efficacy of the sarcolemmal excitation-SR Ca2+ release-contraction coupling (ECC). Both receptors play a central role in ECC as demonstrated in various animal species and muscle subtypes. In the present work we studied the effect of transgenic overexpression of human insulin-like growth factor 1 (hIGF-1) on the levels of these two Ca2+ channels in extensor digitorum longus (EDL) (fast-twitch), soleus (slow-twitch) and pool of fast- and slow-twitch muscles from adult C57BL/6 mice. Muscles from hIGF-1 transgenic mice showed a significant increase in IGF-1 concentration (20-30-fold) and in the number of DHPR (52% increase) whereas no significant change in RyR1 binding sites was detected. The differential effect on DHPR and RyR1 resulted in a 30% increase in DHPR/RyR1 ratio. Fast- and slow-twitch muscles showed 50 and 70% increase in the number of DHPR and 30 and 80% increase in DHPR/RyR1, respectively. These results support the concept that the increased autocrine/paracrine secretion of hIGF-1 exerts potent stimulatory effects on DHPR alpha1 subunit expression in adult skeletal muscle.

Animals↗
PubMed1997

Analyses of frameshifting at UUU-pyrimidine sites.

Others have recently shown that the UUU phenylalanine codon is highly frameshift-prone in the 3'(rightward) direction at pyrimidine 3'contexts. Here, several approaches are used to analyze frameshifting at such sites. The four permutations of the UUU/C (phenylalanine) and CGG/U (arginine) codon pairs were examined because they vary greatly in their expected frameshifting tendencies. Furthermore, these synonymous sites allow direct tests of the idea that codon usage can control frameshifting. Frameshifting was measured for these dicodons embedded within each of two broader contexts: the Escherichia coli prfB (RF2 gene) programmed frameshift site and a 'normal' message site. The principal difference between these contexts is that the programmed frameshift contains a purine-rich sequence upstream of the slippery site that can base pair with the 3'end of 16 S rRNA (the anti-Shine-Dalgarno) to enhance frameshifting. In both contexts frameshift frequencies are highest if the slippery tRNAPhe is capable of stable base pairing in the shifted reading frame. This requirement is less stringent in the RF2 context, as if the Shine-Dalgarno interaction can help stabilize a quasi-stable rephased tRNA:message complex. It was previously shown that frameshifting in RF2 occurs more frequently if the codon 3'to the slippery site is read by a rare tRNA. Consistent with that earlier work, in the RF2 context frameshifting occurs substantially more frequently if the arginine codon is CGG, which is read by a rare tRNA. In contrast, in the 'normal' context frameshifting is only slightly greater at CGG than at CGU. It is suggested that the Shine-Dalgarno-like interaction elevates frameshifting specifically during the pause prior to translation of the second codon, which makes frameshifting exquisitely sensitive to the rate of translation of that codon. In both contexts frameshifting increases in a mutant strain that fails to modify tRNA base A37, which is 3'of the anticodon. Thus, those base modifications may limit frameshifting at UUU codons. Finally, statistical analyses show that UUU Ynn dicodons are extremely rare in E.coli genes that have highly biased codon usage.

Arginine↗
PubMed1997

Evaluation of matrix scaffolds for tissue engineering of articular cartilage grafts.

Injury to articular cartilage predisposes that joint to further degeneration and eventually osteoarthritis. Recent studies have demonstrated the feasibility of using chondrocytes together with different biomaterial carriers as grafts for the repair of cartilage defects. The following study was undertaken to determine the effect of a variety of these materials on chondrocyte growth and extracellular matrix synthesis. We cultured chondrocytes on several commonly used materials and compared their rates of synthesis of proteoglycan and collagen. Additionally, we evaluated them in a closed culture recirculating system on these materials and compared them with standard culture techniques. This was done to see whether such a bioreactor-type system can be used to enhance the quality of in vitro reconstructed tissues. Our results demonstrated marked variability with respect to how chondrocytes responded to culture on the various materials. Bioabsorbable polymers such as polyglycolic acid (PGA)--enhanced proteoglycan synthesis, whereas collagen matrices stimulated synthesis of collagen. The use of the closed culture system, in general, improved the rates of synthesis of collagen and proteoglycan on the different material scaffolds. Exceptions were collagen synthesis on collagen matrices: use of the closed culture system did not enhance the rate of synthesis. Rates of proteoglycan synthesis on PGA scaffold initially was higher in the closed culture system but did not sustain a difference over the entire course of the 3-week culture period. This study demonstrates the importance of carrier material for the purpose of cartilage tissue reconstruction in vitro.

Biocompatible Materials↗
PubMed1997

Development of the St. George Hospital Memory Disorders Clinic Occupational Therapy Assessment Scale.

The St. George Hospital Memory Disorders Clinic Occupational Therapy Assessment Scale (OTAS) is a performance-based assessment of activities of daily living (ADL) administered in the home environment to monitor function among patients with early cognitive decline. Of the 30 items investigated, 19 items that measured "higher" functional domains were found to be useful in discriminating between subjects. Psychometrically, these 19 items had high internal consistency (coefficient alpha = .89) and high interrater reliability (kappa coefficient range: .71-1.0), and correlated well with other measures of higher function (Lawton's instrumental activities of daily living scale: r = .75; Nottingham extended ADL scale: r = .67). However, unlike these latter measures, the OTAS also correlated well with the Mini-Mental State Examination (r = .73), indicating that OTAS is a valid instrument that should be sensitive to functional problems among patients in the early stages of cognitive impairment.

Activities of Daily Living↗
PubMed1997

Folie à deux: three cases in the elderly.

Folie à deux is a rare, interesting disorder involving delusional beliefs shared by two persons. We report three cases of elderly couples referred to our service during an 18-month period with this disorder, and discuss the salient clinical features and the possible risk factors for folie à deux in the elderly.

Aged↗