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Biomedical subjects

D Schwartz

Publications and source records attributed to D Schwartz.

At least 145 records · Page 8Linked to original sources
PubMed1995

Accumulation of wild-type p53 protein upon gamma-irradiation induces a G2 arrest-dependent immunoglobulin kappa light chain gene expression.

The exposure of cells to DNA-damaging agents leads to the accumulation of wild-type p53 protein. Furthermore, overexpression of the wild-type p53, mediated by transfection of p53-coding cDNA, induced cells to undergo apoptosis or cell differentiation. In this study we found that the gamma-irradiation that caused the accumulation of wild-type p53 in 70Z/3 pre-B cells induced, in addition to apoptosis, cell differentiation. This was manifested by the expression of the kappa light chain immunoglobulin gene that coincided with the accumulation of cells at the G2 phase. Overexpression of mutant p53 in 70Z/3 cells interferes with both differentiation and accumulation of cells at the G2 phase, as well as with apoptosis, which were induced by gamma-irradiation. Furthermore, the increment in the wild-type p53 protein level following gamma-irradiation was disrupted in the mutant p53 overproducer-derived cell lines. This suggests that mutant p53 may exert a dominant negative effect in all of these activities. Data presented here show that while p53-induced apoptosis is associated with the G1 checkpoint, p53-mediated differentiation, which may be an additional pathway to escape the fixation of genetic errors, may be associated with the G2 growth arrest phase.

Amino Acid Sequence↗
PubMed1995

Intensive home-care surveillance prevents hospitalization and improves morbidity rates among elderly patients with severe congestive heart failure.

The purpose of this study was to examine the impact of intensive home-care surveillance on morbidity rates of elderly patients with severe congestive heart failure. Forty-two patients aged 78 +/- 8 years who had severe congestive heart failure (New York Heart Association functional classes III through IV, mean ejection fraction 27% +/- 6%), were examined at least once a week at home by internists from the district hospital and by a trained paramedical team. The year before entry to the home-care program was compared to the first year of home surveillance. The mean total hospitalization (hosp) rate was reduced from 3.2 +/- 1.5 hosp/yr to 1.2 +/- 1.6 hosp/yr and duration from 26 +/- 14 days/yr to 6 +/- 7 days/yr (p < 0.001 for both). Cardiovascular admissions decreased from 2.9 +/- 1.5 hosp/yr to 0.8 +/- 1.1 hosp/yr and duration from 23 +/- 13 days/yr to 4 +/- 4 days/yr (p < 0.001). The vital status (ability to perform daily activities, expressed in a 1 to 4 scale) was improved from 1.4 +/- 0.9 to 2.3 +/- 0.7 (p < 0.001). In conclusion, an intensive home-care program was associated with a marked decrease in the need for hospitalization and improved the functional status of elderly patients with severe congestive heart failure. Such a service might also have a cost-effective advantage and a major impact on health expenditure.

Activities of Daily Living↗
PubMed1995

Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production.

The effect of oral supplementation of L-arginine, the substrate of nitric oxide, (1.25 g/liter water) and captopril (15 mg/liter water) was studied in 5/6 nephrectomized rats for a period of three months. N-omega-nitro L-arginine, a nitric oxide synthase inhibitor, was given orally (70 mg/liter water) with or without L-arginine or captopril. The urinary excretion of nitrite (NO2) + nitrate (NO3), the known metabolites of nitric oxide, was taken as an index of nitric oxide production. Chronic renal failure rats were characterized by a low creatinine clearance, high FENa%, proteinuria, hypertension and a low urinary excretion of NO2 + NO3; 0.152 +/- 0.06 (P < 0.001) nmol/micrograms creatinine compared with 0.481 +/- 0.004 (P < 0.001) in normal rats and 0.479 +/- 0.11 (P < 0.001) in untreated sham-operated rats. Both L-arginine and captopril were effective in the normalization of all these parameters. The combination of L-arginine and captopril had no additive effects. The nitric oxide synthase inhibitor significantly diminished the captopril beneficial effect. It is concluded that chronic renal failure in rats is a low nitric oxide production state. The supplementation of L-arginine is shown to overcome this condition. It is suggested that the beneficial effect of captopril on chronic renal failure is through a specific L-arginine--nitric oxide synthase--nitric oxide pathway.

Administration, Oral↗
PubMed1995

In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency.

Although it is presumed that the integration of HIV-1 into the genome of infected CD4+ T lymphocytes allows viral persistence, there has been little direct evidence that CD4+ T cells with integrated provirus function as a latent reservoir for HIV-1 in infected individuals. Using resting CD4+ T-cell populations of extremely high purity and a novel assay that selectively and unambiguously detects integrated HIV-1, we show that resting CD4+ T cells harbouring integrated provirus are present in some infected individuals. However, these cells do not accumulate within the circulating pool of resting CD4+ T cells in the early stages of HIV-1 infection and do not accumulate even after prolonged periods in long-term survivors of HIV-1 infection. These results suggest that because of viral cytopathic effects and/or host effector mechanisms, productively infected CD4+ T cells do not generally survive for long enough to revert to a resting memory state in vivo.

Base Sequence↗
PubMed1995

Lower survival in AIDS patients receiving dapsone compared with aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia. Study Group.

A randomized, unblinded study compared aerosolized pentamidine, 300 mg every month, and dapsone, 50 mg/day, for secondary prophylaxis of pneumocystosis in 196 AIDS patients. The study was prematurely discontinued due to excess mortality in the dapsone group. After a mean follow-up of 13 +/- 6.4 months, 22 (21%) of 103 patients in the pentamidine group were dead compared with 39 (42%) of 93 receiving dapsone; the estimated mortality rates at 18 months were 24.6% and 53.1%, respectively (P < .003, log-rank test). A negative interaction was observed between zidovudine and dapsone (P < .049, interaction test of Cox model), and the mean CD4 cell count during the study was lower in the dapsone (49 +/- 61/mm3) than in the pentamidine group (83 +/- 88/mm3; P < .002, t test). The lower survival might also be related to the oxidative effect of dapsone or to the addition of iron protoxalate to dapsone in this study. These results suggest caution in using dapsone as long-term therapy in advanced human immunodeficiency virus infection, especially in those receiving zidovudine.

AIDS-Related Opportunistic Infections↗
PubMed1995

HIV-1 p17 synthetic peptide vaccine HGP-30: induction of immune response in human subjects and preliminary evidence of protection against HIV challenge in SCID mice.

An HIV-1 p17 subunit vaccine, HGP-30, was evaluated in 38 HIV-1 seronegative individuals in phase I clinical trials in U.K. and U.S.A. The vaccine preparation induced cytotoxic T-cell (CTL) (11/25) and lymphocyte proliferation responses to KLH (19/20) and HGP-30/p17 (24/29) as well as antibody responses to HGP-30 (29/38) and KLH (38/38). The CTL activity was observed in a higher number of vaccine recipients (9/18) in the lower dose groups (10 and 25 micrograms/kg) than the vaccine recipients (2/7) in the 50 and 100 micrograms/kg dose group. These observations suggest that the 10-25 micrograms/kg vaccine dose may preferentially induce TH1 cell responses. TH1 cell responses have been suggested as important in inducing protective cell mediated immunity. The CTL response has been shown to be CD8+. In a pilot study in SCID mice, HIV-1 virus challenge studies in mice reconstituted with cells from an HGP-30 immunized individual showed protection against virus challenge as compared to SCID mice reconstituted with cells from a non-immunized subject. These studies suggest that HGP-30 is capable of inducing protective cellular immunity.

AIDS Vaccines↗
PubMed1994

Selective chemical modification of Cys264 with diiodofluorescein iodacetamide as a tool to study the membrane topology of cytochrome P450scc (CYP11A1).

Cys264 of cytochrome P450scc (CYP11A1) was selectively labelled with diiodofluorescein iodacetamide in solution and in proteoliposomes. The labelling affected the interaction of P450scc with adrenodoxin and significantly inhibited the side-chain cleavage activity of the soluble and membrane-bound hemeprotein in the reconstituted system. In proteoliposomes both the labelled and unlabelled hemeproteins were susceptible to trypsin and split into F1 and F2, two fragments corresponding to the two main domains of P450scc. These results suggest that the hinge connecting the two domains in the region Arg250-Asn257 is exposed to the surface of the membrane and involved in the interaction of P450scc with adrenodoxin.

Adrenodoxin↗
PubMed1994

Karyotype analysis of the monogenetic trypanosomatid Leptomonas collosoma.

In order to develop a genetic system for the monogenetic trypanosomatids, we have analyzed the molecular karyotype of Leptomonas collosoma based on chromosome separation by clamped homogeneous electric field (CHEF) gel electrophoresis. The chromosome location of 5 RNA coding genes (SL, U6, 5S, 7SL and rRNA) and 2 protein coding genes (for HSP83 and alpha-tubulin) was determined. All of the L. collosoma genes examined were found on at least 2 chromosomes, which differ in size in the range of 100-500 kb, suggesting that the organism is diploid. The weighted sum of L. collosoma chromosomes separated by CHEF analysis was approximately 62 +/- 3 Mb, whereas the genome size determined by FACS was estimated at approx. 80 Mb. This suggests that some of the homologous chromosomes differ in their size. The analysis presented here may facilitate studies on the function of individual genes, and on the genetic stability of this organism.

Animals↗
PubMed1994

Polymicrobial and monomicrobial bacteraemic urinary tract infection.

Polymicrobial blood or urine cultures in bacteraemic urinary tract infection (UTI) are relatively common. There is, however, very little information available on the clinical and bacteriological features that distinguishes between monomicrobial and polymicrobial urosepsis. During 1980-84, 68 of 198 episodes (34%) of urosepsis with at least one identical organism in blood and urine, had multiple growth in either one or the other. Comparison between monomicrobial and polymicrobial infectious episodes showed that the latter were more often hospital-acquired and more frequently associated with urinary catheters. Pseudomonas aeruginosa was more often associated with polymicrobial than with monomicrobial infections, whereas Escherichia coli was more common in monomicrobial infections. Mortality was higher in polymicrobial infections, and was further increased if multiple organisms grew from blood rather than from urine. Thus, there are clinical, microbiological and prognostic characteristics that distinguish polymicrobial from monomicrobial bacteraemic UTIs.

Adult↗
PubMed1994

Iron-regulated proteins in outer membranes of Campylobacter jejuni diarrhoea isolates and immune response to the proteins in patients.

The outer membrane protein (OMP) profiles from 8 Campylobacter jejuni and 5 Campylobacter coli fecal isolates grown under various conditions were compared by SDS-PAGE. The bacteria were grown under usual conditions, in iron-deficient medium (Dip) and on iron-supplemented medium (Fe). The OMP profiles of most bacterial strains grown under usual conditions, or in the Fe-supplemented medium, contained four major bands of approximately 31, 45, 63-66 and 97 kDa, and in addition, a number of minor bands. It was found that OMP from 10 of 13 strains tested and grown on iron deficient medium contained an intensive band of a protein in the molecular weight region of 76 kDa which was lacking in the OMP of bacteria grown in the presence of iron (iron-regulated protein). Sera from 11 children with C. jejuni infection analyzed by Western blot recognized the 76 kDa bands, in contrast to only one out of 10 control sera from healthy children. The Western-blot experiments demonstrated also various bands of other OMP components, both in OMP-Dip and OMP-Fe. The 45 kDa (porin protein) was recognized by all 11 serum samples from C. jejuni-infected patients and in 8 out of 10 control sera. The data suggested that the 76 kDa iron-regulated protein was expressed by bacteria during infection and it stimulated the immune response in children infected with C. jejuni.

Bacterial Outer Membrane Proteins↗
PubMed1994

Absence of recoverable infectious virus and unique immune responses in an asymptomatic HIV+ long-term survivor.

We have studied a woman with transfusion-acquired HIV who appears to have contained infectious virus to consistently undetectable levels over a 13-year period without antiviral treatment. She received the infected transfusion for intra- and postpartum blood loss immediately after delivery of her second child in 1981. She had no acute febrile syndrome and has never had HIV-associated clinical signs or symptoms in the 13 years since infection. She was first tested and found positive for HIV antibodies in 1985, and the infected blood donor was diagnosed with AIDS in 1986 and died of AIDS-related complications in 1989. Two other recipients of packed erythrocytes from this donor (in 1980 and 1982) also became infected and were subsequently diagnosed with AIDS. Between January 1986 and April 1994, in the setting of continuous and unambiguous Western blot HIV-specific antibodies and intermittently positive low-level HIV DNA signal after polymerase chain reaction (PCR) amplification, more than 30 separate cell cocultures performed in several independent laboratories failed to yield evidence of infectious virus, despite special efforts to induce and detect HIV replication. Immunologically, a strong in vitro proliferative response to HIV envelope proteins also distinguished this subject from other asymptomatic HIV+ individuals.

Adult↗
PubMed1994

Studies of high doses of a human immunodeficiency virus type 1 recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. The AIDS Vaccine Clinical Trials Network.

We examined the safety and immunogenicity of a baculovirus-derived recombinant HIV-1 envelope glycoprotein vaccine candidate, rgp160 (VaxSyn; MicroGeneSys, Meriden, CT), administered at doses of 160 or 640 micrograms to 56 healthy, HIV-1-seronegative adults, in a randomized, double-blind, placebo-controlled study. Immunizations were given intramuscularly at 0, 1, 6, and 12 months. Both doses were generally well tolerated, although self-limited local reactions were frequent. No other clinical or laboratory toxicities were noted, and no effects on CD4 or CD8 lymphocyte counts or percentages were noted. Serum antibody responses to HIV proteins were detected by Western blot (WB) in 19 of 20 and in 19 of 19 recipients of four doses of 160 and 640 micrograms, respectively. Western blot responses developed more rapidly in the 640-micrograms group. High rates of EIA antibody responses to HIV-1 lysate were also present in both groups, and developed more rapidly in the 640-micrograms group. Enzyme immunoassay antibody responses to the immunogen (rgp160) were also frequent, but were infrequent to V3 to gp41 peptides. Neutralizing antibodies against the homologous HIV-1 LAI isolate were seen in 3 of 20 subjects (GMT = 11) who received four doses of 160 micrograms, and in 10 of 19 subjects who received four doses of 640 micrograms (GMT = 32). Fusion inhibiting antibody was not detected. CD4 blocking activity was seen in 3 of 19 subjects who received four doses of 640 micrograms. Complement-mediated antibody-dependent enhancement was found in sera from 11 of 19 volunteers in the 640-micrograms group. Lymphocyte proliferative responses to the immunogen were detected in 4 of 4 subjects tested, but no cytotoxic T cell activity was noted in 11 subjects. Administration of the 640-micrograms dose of this rgp160 vaccine candidate relative to the lower doses was associated with increased immunogenicity, including higher rates of homologous neutralizing antibody responses, although at low titer.

AIDS Vaccines↗
PubMed1994

Comparison of the immune response to recombinant gp120 in humans and chimpanzees.

OBJECTIVE: To assess similarities and differences in antibody responses to recombinant (r) HIV-1IIIB gp120 in chimpanzees, previously protected from HIV-1 infection, and human volunteers immunized in connection with a Phase I clinical trial. METHODS: Frozen sera from humans immunized with rgp120 from HIV-1IIIB and chimpanzees immunized with the same antigen or recombinant soluble gp160 were compared in a variety of serologic assays. RESULTS: The magnitude of the antibody response to gp120 was similar in both species; however, the half-life of the antibody response to rgp120 was approximately 4.5 times longer in humans (9 weeks) than in chimpanzees (2 weeks). Antibodies to gp120 in both species were broadly cross-reactive with gp120 from diverse isolates of HIV-1 and were effective in blocking the binding of gp120 to CD4. Antibody binding to native gp120 was greater than to denatured gp120 in both species. Antibody responses to the principal neutralizing determinant (V3 domain) and virus neutralization titers were approximately 10-fold lower in humans than chimpanzees. The relative avidity of antibody binding to gp120 was higher in the sera from the immunized chimpanzees than in the immunized humans. CONCLUSIONS: While the antibody responses to rgp120 elicited in man and chimpanzees were in many ways similar, significant differences did occur. Predictions made on the basis of chimpanzee immunogenicity studies over-estimated the potency of the virus neutralizing titers and under-estimated the duration of the antibody response achieved in humans.

AIDS Vaccines↗
PubMed1994

Role of nitric oxide (EDRF) in radiocontrast acute renal failure in rats.

This study was undertaken to examine the possible role of endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), in the pathogenesis of radiocontrast-induced acute renal failure in rats. Normal and salt-depleted rats were monitored for 60 min or 24 h after radiocontrast administration. The administration of L-arginine to normal rats abolished the immediate decrease in p-aminohippurate clearance (CPAH) and attenuated the decrease in inulin clearance (CIn). The administration of NO synthase inhibitor to the salt-depleted animals resulted in a significantly more pronounced decrease in CPAH compared with both the control and the L-arginine-treated animals. The recovery of CIn 24 h after radiocontrast administration to the salt-depleted rats was significantly better in the L-arginine-treated rats than in either the control or inhibitor-treated groups. The administration of radiocontrast material resulted in a significant decrease in urinary guanosine 3',5'-cyclic monophosphate as well as NO2 + NO3 excretion. This decrease was significantly attenuated by L-arginine. Our results 1) suggest that NO plays a major role in the pathogenesis of radiocontrast-induced acute renal failure and 2) suggest a novel therapeutic approach, i.e., the use of L-arginine in this form of acute renal failure.

Acute Kidney Injury↗
PubMed1994

Outcome of the treatment for sarcoidosis.

The clinical characteristics and pathology of sarcoidosis are well defined; however, the optimal therapy for this disorder remains unclear. Although patients respond, acutely, to corticosteroid therapy, it is not clear that these agents ultimately alter the natural history of this disease. These observations and that corticosteroids have significant side effects suggest that only patients who will clearly benefit from corticosteroid therapy should be treated. In a prospective study of patients' with sarcoidosis (n = 98), we limited our use of corticosteroids to those patients who had objective evidence of recent deterioration in lung function or serious extrapulmonary disease. All patients with sarcoidosis fulfilling these criteria were treated with corticosteroids. Patients were tapered off corticosteroids after they were treated for 1 yr. Of the 98 study subjects, 91 had not received therapy for the disease and 7 were on therapy before entry into the study. Of the 91 previously untreated patients, 55 were observed without therapy and 36 were treated with corticosteroids. Of those who were observed off therapy, only eight deteriorated. Of these latter patients, six responded and stabilized with the administration of corticosteroids for treatment of the underlying disease, to antibiotics for an associated bronchiectasis, or to diuretics for treatment for congestive heart failure; two were lost to follow-up. None of these six patients deteriorated while receiving corticosteroids. Of the 36 patients who deteriorated and were treated with corticosteroids, 20 remained stable and 16 improved clinically. Of the 37 patients who were eventually tapered off corticosteroids, five deteriorated and required reinitiation of corticosteroid therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗