Biomedical subjects

D Schwartz

Publications and source records attributed to D Schwartz.

At least 91 records · Page 5Linked to original sources

PubMed1999

Pregnancy decreases immunoreactive parathyroid hormone level in rats with chronic renal failure.

Normal pregnancy is associated with an increase in serum parathyroid hormone and 1,25-dihydroxyvitamin D3 (calcitriol). The effect of pregnancy on these hormones in chronic renal failure (CRF) is unknown. The present work was undertaken to study the changes of serum immunoreactive parathyroid hormone (iPTH) and calcitriol in pregnant rats with CRF. The following experimental groups were studied: CRF1 (5/6 nephrectomized virgin female rats), CRF2 (5/6 nephrectomized pregnant rats at day 20-21 of pregnancy), CRF3 (5/6 nephrectomized rats 2 weeks after delivery) and their respective sham-operated control groups: N1, N2 and N3. The 5/6 nephrectomy (CRF1) resulted in renal failure with very high serum iPTH (100+/-18 pg/ml) and low calcitriol levels (10.6+/-4.3 pg/ml) compared with normal rats [N1: 14+/-2.5 pg/ml (P<0.001) and 18.2+/-4.2 pg/ml (P<0.01) respectively]. The pregnancy in CRF rats (CRF2) resulted in normalization of serum iPTH levels (18.2+/-5.41 pg/ml), which was associated with a parallel increase in serum calcitriol (29.4+/-8.0 pg/ml) similar to that in pregnancy of normal rats (N2). Two weeks after delivery the CRF rats (CRF3) once again had high serum iPTH (87+/-17 pg/ml) and low calcitriol levels (9.3+/-1.2 pg/ml), similar to those observed in non-pregnant uraemic rats (CRF1). It is concluded that pregnancy decreases serum iPTH in 5/6 nephrectomized CRF rats most probably by the increased level of calcitriol synthesized by the feto-placental unit.

Analysis of Variance↗

PubMed1999

Nitric oxide, sepsis, and the kidney.

Although excess nitric oxide (NO) production plays a major role in the hypotension characteristic of sepsis, concurrent constitutive NO generation in the kidney during sepsis is essential for preservation of renal perfusion and prevention of glomerular thrombosis. The authors have shown that although all nitric oxide synthase (NOS) inhibitors restore normal blood pressure in lipopolysaccharide (LPS) treated rats, only selective inducible NOS (iNOS) inhibition prevents the reductions in glomerular filtration rate (GFR), whereas nonselective inhibition of NOS further decreases GFR. Glomerular endothelial NOS (eNOS) activity was found to be inhibited by LPS. The decrease in eNOS activity was completely prevented by selective iNOS inhibition in vivo and in vitro. The adverse renal outcomes after LPS administration correlated with decreased glomerular eNOS activity rather than elevated NO production. These findings suggest that the decrease in GFR after LPS is caused by local inhibition of eNOS by iNOS possibly via NO autoinhibition. Selective inhibition of iNOS could represent a substantially superior approach for the treatment of the sepsis syndrome.

Animals↗

PubMed1999

The independence of maximal intimal thickening from severity of balloon injury in the rabbit aorta.

Endothelial injury induces intimal thickening, but whether more extensive injury increases the extent of neointimal proliferation in the rabbit aorta is not well defined. We induced graded injury in the abdominal aortas of rabbits and maximal intimal/medial (I/M) area and thickness ratios were calculated from aortic cross sections harvested 2 weeks after injury. The degree of injury was verified by blinded observers who graded the extent of disruption of the internal elastic laminae. Intimal thickening was not significantly different after severe injury (mean maximal I/M area ratio 0.32+/-0.02 [SE], n = 16) compared with moderate injury (0.23+/-0.02, n = 8, p = 0.24), but was greater than that induced by mild injury (0.08+/-0.01, n = 7, p <0.0001). The ratio of the maximal I/M thickness was similar in all groups (I/M thickness ratio 0.68+/-0.04, 0.73+/-0.04, and 0.56+/-0.04 for severe, moderate, and mild focal injury groups. respectively; p = 0.19). Thus, balloon injury of the rabbit aorta induces reproducible thickening of the intima by 2 weeks. The maximal I/M area ratio is dependent on the extent of injury, while the maximal intimal thickening is independent.

Angioplasty, Balloon↗

PubMed1999

Early puberty in Williams syndrome.

Pubertal development was evaluated in nine males and 16 females with Williams syndrome (WS). Our results indicate that puberty in WS occurred earlier than in published population controls; specifically, 90% of menstruating females reached menarche and 83% of pubertal males showed Tanner III pubic hair development prior to the age of 12 years. The sequence of pubertal development was normal, bone age was always consistent with, or in excess of, chronological age, and there was evidence of central (hypothalamic-pituitary mediated) activation as the cause of early puberty in a subset of subjects.

Age of Onset↗

PubMed1999

Cellular events and the pattern of p53 protein expression following cyclophosphamide-initiated cell death in various organs of developing embryo.

This study was aimed at characterizing the temporal patterns of cell responses and p53 protein expression in the limbs, head, and liver of embryos responding to cyclophosphamide (CP)-induced teratogenic insult. ICR murine embryos were examined 24, 48, or 72 h after injection of 40 mg/kg CP on day 12 of pregnancy. The cellular events and temporal pattern of p53 protein expression were determined by FACS analysis and by TUNEL (apoptosis) in the head, limbs, and liver of the embryos. All tested organs showed apoptosis and a significantly decreased proportion of live cells after 24 h. Subsequent events were organ-dependent. In the liver, there were no dysmorphic events at any time and excessive cell death had been almost compensated for by 48 h. Compensation was preceded by G(1) arrest and accompanied by an increased level of p53 protein in surviving cells. Excessive cell death in the head and the limbs resulted in structural anomalies. In the head, there was an increased level of p53 protein and G(1) arrest after 24 h and the number of live cells at 48 h was equal to that seen in earlier samples, despite apoptosis. In the limbs, however, only isolated viable cells were seen by 48 h, but there was no increased level of p53 protein or G(1) arrest. Results of this study suggest that the differential sensitivity of tested organ systems to CP may be associated with differences in cellular events following CP-initiated cell death. They also suggest that the input of p53 in determining the response of these organ systems to CP-induced teratogenic insult may be different. Teratogenesis Carcinog. Mutagen. 19:353-367, 1999.

Animals↗

PubMed1999

p53 controls low DNA damage-dependent premeiotic checkpoint and facilitates DNA repair during spermatogenesis.

Previously, it was implicated that p53 plays a role in spermatogenesis. Here we report that p53 knockout mice exhibit significantly less mature motile spermatozoa than their p53(+/+) counterparts. To better understand the role of p53 in spermatogenesis, we analyzed the response of spermatogenic cells to DNA insult during prophase. It was found that although low-level gamma-irradiation activated a p53-dependent premeiotic delay, higher levels of gamma-irradiation induced a p53-independent apoptosis during meiosis. Furthermore, p53 knockout mice exhibited reduced in vivo levels of unscheduled DNA synthesis, indicative of compromised DNA repair. Thus, p53 provides another level of stringency in addition to other spermatogenic "quality control" mechanisms.

Animals↗

PubMed1999

Genomics via optical mapping. III: Contiging genomic DNA.

In this paper, we describe our algorithmic approach to constructing an alignment of (contiging) a set of restriction maps created from the images of individual genomic (uncloned) DNA molecules digested by restriction enzymes. Generally, these DNA segments are sized in the range of 1-4 Mb. The goal is to devise contiging algorithms capable of producing high-quality composite maps rapidly and in a scaleable manner. The resulting software is a key component of our physical mapping automation tools and has been used to create complete maps of various microorganisms (E. coli, P. falciparum and D. radiodurans). Experimental results match known sequence data.

Algorithms↗

PubMed1999

p53 tumor suppressor gene expression in the mouse ovary during an artificially induced ovulatory cycle.

OBJECTIVE: To evaluate the expression of p53 in the mouse ovary during an artificially induced ovulatory cycle. STUDY DESIGN: Ovulation induction was performed using pregnant mares' serum gonadotropin/human chorionic gonadotropin (PMSG/hCG). First, a p53 promoter-chloramphenicol acetyl transferase (CAT) transgenic mouse model was used. Protein samples from ovaries of transgenic mice were assayed for CAT activity as evidence of p53 promoter activation. Next, RNA extracted from CD-1 mouse ovaries was used for reverse transcription/polymerase chain reaction (PCR) and northern blot analysis using a p53-specific probe. RESULTS: Increased CAT activity was noted in transgenic mice treated with PMSG/hCG as compared with controls. PCR studies on transgenic mice using primers for CAT and on CD-1 mice using primers for wild type p53 substantiated this observation. Furthermore, CAT assay and northern analysis, performed on samples obtained at serial time intervals from induction, indicated that maximal p53 expression occurs around the time of ovulation, beginning 48 hours after PMSG and peaking 6-12 hours after hCG administration. CONCLUSION: The temporal expression of p53 in the ovary during a PMSG/hCG artificially induced ovulatory cycle may indicate a role for p53 in processes of differentiation of granulosa cells into luteal cells.

Animals↗

PubMed1998

Mutant p53 protein expression interferes with p53-independent apoptotic pathways.

Loss of normal p53 function was found frequently to interfere with response of cancer cells to conventional anticancer therapies. Since more than half of all human cancers possess p53 mutations, we decided to explore the involvement of mutant p53 in drug induced apoptosis. To further evaluate the relationship between the p53-dependent and p53-independent apoptotic pathways, and to elucidate the function of mutant p53 in modulating these processes, we investigated the role of a p53 temperature-sensitive (ts) mutant in a number of apoptotic pathways induced by chemotherapeutic drugs that are currently used in cancer therapy. To that end, we studied the M1/2, myeloid p53 non-producer cells, and M1/2-derived temperature-sensitive mutant p53 expressing clones. Apoptosis caused by DNA damage induced with gamma-irradiation, doxorubicin or cisplatin, was enhanced in cells expressing wild type p53 as compared to that seen in parental p53 non-producer cells; mutant p53 expressing clones were found to be more resistant to apoptosis induced by these factors. Actinomycin D, a potent inhibitor of transcription, as well as a DNA damaging agent, abrogated the restraint apoptosis mediated by mutant p53. These observations suggest that while loss of wild type p53 function clearly reduces the rate of apoptosis, p53 mutations may result in a gain of function which significantly interferes with chemotherapy induced apoptosis. Therefore, to achieve a successful cancer therapy, it is critical to consider the specific relationship between a given mutation in p53 and the chemotherapy selected.

Animals↗

PubMed1998

Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels.

Polyamines are required for entry and progression of the cell cycle. As such, augmentation of polyamine levels is essential for cellular transformation. Polyamines are autoregulated through induction of antizyme, which represses both the rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase and cellular polyamine transport. In the present study we demonstrate that agmatine, a metabolite of arginine via arginine decarboxylase (an arginine pathway distinct from that of the classical polyamines), also serves the dual regulatory functions of suppressing polyamine biosynthesis and cellular polyamine uptake through induction of antizyme. The capacity of agmatine to induce antizyme is demonstrated by: (a) an agmatine-dependent translational frameshift of antizyme mRNA to produce a full-length protein and (b) suppression of agmatine-dependent inhibitory activity by either anti-antizyme IgG or antizyme inhibitor. Furthermore, agmatine administration depletes intracellular polyamine levels to suppress cellular proliferation in a transformed cell line. This suppression is reversible with polyamine supplementation. We propose a novel regulatory pathway in which agmatine acts as an antiproliferative molecule and potential tumor suppressor by restricting the cellular polyamine supply required to support growth.

3T3 Cells↗

PubMed1998

Isolation and characterization of the PEP-phosphomutase and the phosphonopyruvate decarboxylase genes from the phosphinothricin tripeptide producer Streptomyces viridochromogenes Tü494.

The previously isolated non-phosphinothricin tripeptide producing Streptomyces viridochromogenes gene disruption mutant SP62/2 was used to identify and analyze genes encoding early steps of the phosphinothricin tripeptide biosynthesis. Cross-feeding and bioconversion experiments between SP62/2 and known non-phosphinothricin tripeptide producing mutants or presumptive phosphinothricin tripeptide precursors revealed that SP62/2 was blocked in step one or two of the phosphinothricin tripeptide biosynthesis. It was shown that the block in the biosynthesis is due to the integration of a temperature-sensitive plasmid by illegitimate recombination into the phosphinothricin tripeptide biosynthetic gene cluster. The corresponding region was isolated from the wild-type. A 2.7-kb DNA fragment was analyzed comprising three ORFs (ppm, ppd, orfX) which are probably translationally coupled. The ppm gene encodes a protein which is similar to PEP-phosphomutases and the deduced Ppd product shows similarity to the phosphonopyruvate decarboxylase from Streptomyces wedmorensis.

Amino Acid Sequence↗

PubMed1998

Glial cells production of inflammatory mediators induced by Streptococcus pneumoniae: inhibition by pentoxifylline, low-molecular-weight heparin and dexamethasone.

Exposure of primary rat glial cells to heat inactivated Streptococcus pneumoniae, induced dose-dependent production of tumor necrosis factor alpha (TNF alpha), nitric oxide (NO) and prostaglandin E2 (PGE2). Concomitant addition of the bacterium and the synthetic glucocorticoid dexamethasone resulted in complete suppression of TNF alpha, NO and PGE2 production. Pentoxifylline, a phosphodiesterase inhibitor completely blocked TNF alpha secretion, whereas NO and PGE2 were not affected. Low-molecular-weight heparin enoxaparin caused 25-64% inhibition in TNF alpha production, up to 30% inhibition of NO secretion and a 10% reduction in PGE2. Thus, Streptococcus pneumoniae, the pathogen most commonly associated with meningitis in the Western world can be added to the list of agents causing direct stimulation of glial cells. Pentoxifylline and enoxaparin in addition to dexamethasone may limit the central nervous system local inflammatory responses and could improve the effort towards reducing the dismal outcome of patients with pneumococcal meningitis.

Animals↗

PubMed1998

Phosphinothricin-tripeptide synthetases from Streptomyces viridochromogenes.

Phosphinothricyl-alanyl-alanine (Pt tripeptide (Ptt), bialaphos) is a metabolite produced by Streptomyces viridochromogenes and Streptomyces hygroscopicus. It contains the unique phosphinoamino acid phosphinothricin (Pt), which after cleavage from Ptt is active as an inhibitor of glutamine synthetase. We have isolated three enzymes that assemble the building block of the Ptt peptide backbone in a nonribosomal mechanism. The first enzyme, named Ptt-synthetase I (PTTS I), activates N-acetyldemethylphosphinothricin (AcDMPt) as adenylate and thioester. Pt is not activated. PTTS I can also activate N-acetylphosphinothricin (AcPt) or N-acetylglutamate as structural analogues of AcDMPT. Native PTTS I has an estimated size of 62 kDa whereas the denatured form displays a size of 76 kDa. Immunoblot analysis and determination of its N-terminal protein sequence revealed that PTTS I is identical with the gene product of phsA. The phsA gene was previously identified near the Pt-resistance gene pat in the Ptt biosynthesis gene cluster in S. viridochromogenes. Besides PTTS I, two alanine-activating enzymes (PTTS II/III) were partially purified from S. viridochromogenes with estimated native sizes of ca. 120 kDa (enzyme 1) and ca. 140 kDa (enzyme 2). Both enzymes bind alanine as a thioester via the corresponding adenylate. Level of PTTS II/III and product formation were correlated with each other in several different strains of S. viridochromogenes. These results indicate that Ptt is synthesized by three peptide synthetases, each activating one single amino acid. The data also confirm previous genetic data, which suggest that AcDMPt-Ala-Ala is the precursor of Ptt.

Alanine↗

PubMed1998

p53-dependent cell cycle control: response to genotoxic stress.

p53 protein is involved in key responses to genotoxic stress. These functions underlie the role of p53 as the 'guardian of the genome'. In a simplified manner, upon low or repairable levels of DNA damage, p53 mediates the delay or arrest at checkpoints preceding cell replication (the G1/S checkpoint), and is involved in delaying damaged cells prior premitotic chromosome condensation (the G2 and pre-meiotic check-points) and actual chromosome partition (the spindle check-point). During these delays, an opportunity is given to repair the DNA damage, before its fixation and propagation, that may lead to carcinogenesis. Upon high or irreparable DNA damage, p53 promotes the cells towards apoptosis. Here we review the known molecular pathways by which p53 controls the cell cycle, with a specific focus on the significance of p53-mediated checkpoint response for its 'tumor suppressor' function. The data reviewed is concerned with the in vivo mouse models including p53 knockout mice, transgenic mice harboring various mutant forms of p53 and mice knocked out for cell-cycle- and apoptosis-associated genes situated upstream or downstream from p53, that have been elaborated upon over the last few years.

Animals↗

PubMed1998

Cystoid macular edema associated with cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome.

PURPOSE: To describe the clinical and fluorescein angiographic appearance of cystoid macular edema associated with cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). METHODS: We retrospectively examined the clinical and photographic records of four patients with AIDS and cytomegalovirus retinitis who developed cystoid macular edema. RESULTS: Seven eyes of four patients with AIDS and cytomegalovirus retinitis experienced decreased vision associated with cystoid macular edema. Vitreous inflammation was mild in each patient. In all eyes, the retinitis involved zone 1, and in all but one eye, the cytomegalovirus retinitis was inactive. In one eye, the cystoid macular edema was worsened by formation of a dense juxtafoveal epiretinal membrane. CONCLUSIONS: Although infrequently recognized, cystoid macular edema can cause visual loss in patients with AIDS and cytomegalovirus retinitis. Fluorescein angiography should be considered in any patient with cytomegalovirus retinitis and unexplained visual loss.

AIDS-Related Opportunistic Infections↗

PubMed1998

Peer group victimization as a predictor of children's behavior problems at home and in school.

This study reports a short-term prospective investigation of the role of peer group victimization in the development of children's behavior problems, at home and in school. Sociometric interviews were utilized to assess aggression, victimization by peers, and peer rejection, for 330 children who were in either the third or fourth grade (approximate mean ages of 8-9 years old). Behavior problems were assessed using standardized behavior checklists completed by mothers and teachers. A follow-up assessment of behavior problems was completed 2 years later, when the children were in either the fifth or sixth grade (approximate mean ages of 10-11 years old). Victimization was both concurrently and prospectively associated with externalizing, attention dysregulation, and immature/dependent behavior. Victimization also predicted increases in these difficulties over time, and incremented the prediction in later behavior problems associated with peer rejection and aggression. The results of this investigation demonstrate that victimization in the peer group is an important predictor of later behavioral maladjustment.

Aggression↗

PubMed1998

Social-cognitive and behavioral correlates of aggression and victimization in boys' play groups.

A contrived play group procedure was utilized to examine the behavioral and social-cognitive correlates of reactive aggression, proactive aggression, and victimization via peers. Eleven play groups, each of which consisted of six familiar African-American 8-year-old boys, met for 45-min sessions on five consecutive days. Social-cognitive interviews were conducted following the second and fourth sessions. Play group interactions were videotaped and examined by trained observers. High rates of proactive aggression were associated with positive outcome expectancies for aggression/assertion, frequent displays of assertive social behavior, and low rates of submissive behavior. Reactive aggression was associated with hostile attributional tendencies and frequent victimization by peers. Victimization was associated with submissive behavior, hostile attributional bias, reactive aggression, and negative outcome expectations for aggression/assertion. These results demonstrate that there is a theoretically coherent and empirically distinct set of correlates associated with each of the examined aggression subtypes, and with victimization by peers.

Black or African American↗

PubMed1998

Cytotoxic T cell and neutralizing antibody responses to human immunodeficiency virus type 1 envelope with a combination vaccine regimen. AIDS Vaccine Evaluation Group.

Effective human immunodeficiency virus (HIV) vaccination may require induction of neutralizing antibodies (NAs) and CD8+ cytotoxic T lymphocytes (CTL) to prevent transmission and control early infection. Recombinant envelope proteins induce NAs but rarely CD8+ CTL responses, and vaccinia vectors containing HIV-1 envelope elicit CD8+ cytotoxicity but few NAs. To benefit from both approaches, 56 vaccinia-naive subjects were randomized to a regimen of priming with recombinant vaccinia gp160LAI and boosting with recombinant gp120SF-2, gp120LAI, gp120MN, or gp160MN. Of 51 persons for whom assays were done, 26 demonstrated envelope-specific CTL. Boosting with gp120, compared with gp160, elicited significantly more NAs and CD4-blocking antibodies. Neutralization of the homologous and heterologous HIV-1 laboratory strains occurred in all subjects receiving vac/env and gp120 and was detectable in 91% of the subjects for >6 months. Thus, vaccine regimens in which one component elicits primarily CTL and the other NAs offer promise for the development of an effective HIV-1 vaccine strategy.

AIDS Vaccines↗