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Biomedical subjects

B Schwartz

Publications and source records attributed to B Schwartz.

At least 145 records · Page 8Linked to original sources
PubMed1996

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

Acute Disease↗
PubMed1996

Invasive group A streptococcal infections in Ontario, Canada. Ontario Group A Streptococcal Study Group.

BACKGROUND: Several reports suggest that the incidence of invasive group A streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, is increasing. METHODS: During 1992 and 1993 we conducted prospective, population-based surveillance of invasive group A streptococcal disease in Ontario, Canada. We reviewed clinical and laboratory records, searched for secondary cases of invasive disease, and cultured specimens from household contacts. RESULTS: We identified 323 patients with invasive group A streptococcal infections, for an annual incidence of 1.5 cases per 100,000 population. The rates were highest in young children and the elderly. Fifty-six percent of the patients had underlying chronic illness. Risk factors for disease included infection with the human immunodeficiency virus, cancer, diabetes, alcohol abuse, and chickenpox. The most common clinical presentations were soft-tissue infection (48 percent), bacteremia with no septic focus (14 percent), and pneumonia (11 percent). Necrotizing fasciitis occurred in 6 percent of patients, and toxic shock in 13 percent. The mortality rate was 15 percent overall, but it was 29 percent among those over 64 years of age (P<0.001) and 81 percent among those with toxic shock (P<0.001). Fourteen percent of the cases were nosocomial, and 4 percent occurred in nursing home residents, often in association with disease outbreaks. Invasive disease occurred in 2 household contacts of patients with infection, for an estimated risk of 3.2 per 1000 household contacts (95 percent confidence interval, 0.39 to 12 per 1000). CONCLUSIONS: The elderly and those with underlying medical conditions are at greatest risk for invasive group A streptococcal disease, toxic shock, and necrotizing fasciitis. Invasive steptococcal infection is associated with a substantial risk of transmission in households and health care institutions.

Adolescent↗
PubMed1996

The ion conductances of colonic crypts from dexamethasone-treated rats.

Whole-cell patch-clamp studies were performed in isolated colonic crypts of rats pretreated with dexamethasone (6 mg/kg subcutaneously on 3 days consecutively prior to the experiment). The cells were divided into three categories according to their position along the crypt axis: surface cells (s.c.); mid-crypt cells (m.c.) and crypt base cells (b.c.). The zero-current membrane voltage (Vm) was -56 +/- 2 mV in s.c (n = 34); -76 +/- 2 mV in m.c. (n = 47); and -87 +/- 1 mV in b.c. (n = 87). The whole-cell conductance (Gm) was similar (8-12 nS) in all three types of cells. A fractional K+ conductance accounting for 29-67% of Gm was present in all cell types. A Na+ conductance was demonstrable in s.c. by the hyperpolarizing effect on Vm of a low-Na+ (5 mmol/l) solution. In m.c. and b.c. the hyperpolarizing effect was much smaller, albeit significant. Amiloride had a concentration-dependent hyperpolarizing effect on Vm in m.c. and even more so in s.c.. It reduced Gm by approximately 12%. The dissociation constant (KD) was around 0.2 micromol/l. Triamterene had a comparable but not additive effect (KD = 30 micromol/l, n = 14). Forskolin (10 micromol/l, in order to enhance cytosolic adenosine 3', 5'-cyclic monophosphate or cAMP) depolarized Vm in all three types of cells. The strongest effect was seen in b.c.. Gm was enhanced significantly in b.c. by 83% (forskolin) to 121% [8-(4-chlorophenylthio)cAMP]. The depolarization of Vm and increase in Gm was caused to large extent by an increase in Cl-conductance as shown by the effect of a reduction in bath Cl-concentration from 145 to 32 mmol/l. This manoeuvre hyperpolarized Vm under control conditions significantly by 6-9 mV in all three types of cells, whilst it depolarized Vm in the presence of forskolin in m.c. and in b.c.. These data indicate that s.c. of dexamethasone-treated rats possess mostly a K+ conductance and an amiloride- and triamterene-inhibitable Na+ conductance. m.c. and b.c. possess little or no Na+ conductance; their Vm is largely determined by a K+ conductance. Forskolin (via cAMP) augments the Cl- conductance of m.c. and b.c. but has only a slight effect on s.c.

Amiloride↗
PubMed1996

Risk factors for carriage of drug-resistant Streptococcus pneumoniae among children in Memphis, Tennessee.

OBJECTIVES: To determine risk factors for carriage of drug-resistant Streptococcus pneumoniae to understand better the factors promoting spread of these isolates. STUDY DESIGN: We obtained medical and demographic information and nasopharyngeal swab specimens from 216 children less than 6 years old with upper respiratory tract infections, seeking medical care at five Memphis, Tenn, study sites. We evaluated risk factors for carriage of penicillin-nonsusceptible S. pneumoniae (NSSP) among 100 children with S. pneumoniae isolates. Patterns of antimicrobial prescription were recorded for enrolled children. RESULTS: Independent risk factors for carriage of NSSP included an increased number of antimicrobial treatment courses during the previous 3 months and white race. Day care attendance approached statistical significance (p = 0.07). Most children with upper respiratory tract infection received a prescription for antimicrobial drugs. These prescriptions were more common for white children than for black children. CONCLUSIONS: Increased use of antimicrobial drugs enhances the risk of carriage of NSSP. This may contribute to the higher risk among white children of NSSP infection; however, after control for antimicrobial use, white children were still at an increased risk of infection with NSSP, possibly through greater exposure to resistant strains.

Anti-Bacterial Agents↗
PubMed1996

Cerebral aneurysm thrombosis, shrinkage, then disappearance after subarachnoid hemorrhage.

The case is presented of a 37-year-old man with spontaneous thrombosis of a 10-mm left posterior communicating artery aneurysm, following presumed subarachnoid hemorrhage with negative angiography. Sequential magnetic resonance angiography and magnetic resonance source imaging (at 2 weeks, 3 months, 2 years, and 2 years, 5 months) showed progressive shrinkage and disappearance of the aneurysm.

Adult↗
PubMed1996

Gene transfer by naked DNA into adult mouse brain.

Nonviral gene transfer into the central nervous system could provide a basis for therapeutic uses and fundamental research. We show that naked DNA injected intracerebrally into the mouse brain can provide expression of a reporter protein. Expression is dose dependent, being maximal for 150 mu g DNA injected. We observed less than 5 days expression of the luciferase transgene, which is not improved with plasmid preparations virtually free of lipopolysaccharide. Thus, the adult brain behaves as striated muscle for naked DNA uptake and transcription, albeit at a much lower efficiency. In neither adult brain nor muscle did complexation of DNA with cationic lipid improve transgene expression. Double immunolabeling using cell-specific markers shows that both neurons and glia are transfected by naked DNA gene transfer methodology.

Animals↗
PubMed1995

alpha-Fluoro acid and alpha-fluoro amide analogs of acetyl-CoA as inhibitors of citrate synthase: effect of pKa matching on binding affinity and hydrogen bond length.

An alpha-fluoro acid analog and an alpha-fluoro amide analog of acetyl-CoA have been synthesized. The ternary complexes of these inhibitors with oxaloacetate and citrate synthase have been crystallized and their structures analyzed at 1.7 A resolution. The structures are similar to those reported for the corresponding non-fluorinated analogs (Usher et al., 1994), with all forming unusually short hydrogen bonds to Asp 375. The alpha-fluoro amide analog binds with an affinity 1.5-fold lower than that of a previously described amide analog lacking the alpha-fluoro group. The alpha-fluoro acid analog binds with a 50-fold decreased affinity relative to the corresponding unfluorinated analog. The binding affinities are consistent with increased strengths of hydrogen bonds to Asp 375 with closer matching of pKa values between hydrogen bond donors and acceptors. The results do not support any direct correlation between hydrogen bond strength and hydrogen bond length in enzyme-inhibitor complexes.

Acetyl Coenzyme A↗
PubMed1995

A new model for disruption of the ornithine decarboxylase gene, SPE1, in Saccharomyces cerevisiae exhibits growth arrest and genetic instability at the MAT locus.

Ornithine decarboxylase (ODC) is a rate-determining enzyme of the polyamine-biosynthetic pathway. We sought to produce cells with impaired ODC function in order to study the biological functions of polyamines. Saccharomyces cerevisiae strains were obtained by one-step gene replacement of a 900 bp fragment of the yeast ODC gene (SPE1) with the yeast URA3 gene. Spores derived from SPE1/spe1 cells germinated at reduced efficiency relative to SPE1/SPE1. Sustained growth of spe1 haploid mutants in polyamine-free medium led to intracellular polyamine depletion, reduction in budding index, G1 arrest and cessation of growth, and cells that were large and misshapen. All of these effects were completely reversed by adding polyamines to the medium, even after 5 days of polyamine starvation. A diploid yeast strain bearing two copies of disrupted spe1 lost heterozygosity at the mating-type locus more often when grown in the absence of polyamines than when grown in their presence, indicating that polyamine deficiency leads to either chromosome loss or to mitotic recombination.

Blotting, Southern↗
PubMed1995

Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure.

BACKGROUND: Clinical trials have shown that beta-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated. METHODS AND RESULTS: We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16 +/- 0.01 and a mean maximal oxygen consumption of 13.6 +/- 0.6 mL.kg-1.min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n = 33) or matching placebo (n = 16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P = .005) and stroke volume index (P = .010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P = .003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P = .002), functional class (P = .013), and submaximal exercise tolerance (P = .006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P = .028), but carvedilol-treated patients had more dizziness and advanced heart block. CONCLUSIONS: Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.

Adrenergic beta-Antagonists↗
PubMed1995

Spermine induces haemoglobin synthesis in murine erythroleukaemia cells.

The naturally occurring polyamine spermine induces haemoglobin synthesis in murine erythroleukaemia (MEL) cells. Haemoglobin production was accompanied by accumulation of cytoplasmic beta-globin mRNA and growth inhibition, but not by cell-cycle block or changes in cell volume. Hexamethylene-bisacetamide (HMBA), a well known differentiating agent, also induces haemoglobin production, but causes a G1 block and decreases cell volume. These findings indicate that HMBA and spermine affect MEL cells differently, even though both induce haemoglobin production.

Acetamides↗
PubMed1995

The laminin alpha 1 chain Ile-Lys-Val-Ala-Val (IKVAV)-containing peptide promotes liver colonization by human colon cancer cells.

Laminin, a major basement membrane-specific glycoprotein, promotes the attachment, migration, and invasion of a variety of tumor cells. Since laminin is present in the perisinusoidal matrix of the liver, we studied its effects on liver colonization by human colon cancer cells (HM7, LiM6) previously shown to have liver-metastasizing ability in athymic mice. These malignant cells expressed high levels of a 32-kDa laminin-binding protein on Western blot analysis when compared to the low metastatic parental cell line. Coinjection of laminin alpha chain-derived peptides which contain the amino acid sequence Ile-Lys-Val-Ala-Val (IKVAV) significantly stimulated liver colonization as determined by liver weight (P < 0.005) and number of tumor nodules (P < 0.02) 3 weeks after splenic-portal inoculation into nude mice. No stimulation was seen with a control peptide containing the same amino acids but in a scrambled sequence. In contrast, the Tyr-Ile-Gly-Ser-Arg peptide from the laminin beta 1 chain significantly inhibited HM7 liver colonization. These differences were not due to alterations in the number of cells initially reaching the liver as determined by injection of [125I]iododeoxyuridine-labeled tumor cells, but retention in the liver was stimulated by the IKVAV-containing peptides. Flow analysis indicated that the IKVAV peptide may act, in part, by stimulating homotypic adhesion of tumor cells. These data suggest that interactions of colon cancer cells with the IKVAV site on laminin may play a role in the formation of metastatic foci in the liver through cell-cell or cell-substratum interactions which promote metastasis.

Adenocarcinoma↗
PubMed1995

Induction of blood-brain barrier differentiation in a rat brain-derived endothelial cell line.

An immortalized brain capillary endothelial cell line displaying blood-brain barrier characteristics may represent a useful tool for studying blood-brain barrier endothelial cell differentiation and for the in vitro prediction of drug brain penetration. In the present study, we have established a rat cerebral capillary endothelial cell line (CR3) by genomic introduction of the immortalizing SV40 large T gene under the control of the human vimentin promoter. The CR3 cell line displayed endothelial morphological and biochemical characteristics for up to 30 passages. However, the CR3 cell line did not spontaneously express the specific blood-brain barrier markers gamma-glutamyl transpeptidase and mdr P-glycoprotein. However, when the cells were treated with the cell differentiating agent all-trans-retinoic acid, the blood-brain barrier markers were induced. Retinoic acid-treated CR3 cells may thus represent a useful tool for biological and pharmacological research related to the blood-brain barrier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Lipospermine-based gene transfer into the newborn mouse brain is optimized by a low lipospermine/DNA charge ratio.

Nonviral, plasmid-based gene transfer into somatic tissues offers the prospect of various simple and safe therapeutic possibilities as well as applications in fundamental research. Although cationic lipids display efficient transfection activities in many in vitro systems, only low success rates using these vectors in vivo have been reported. We succeeded in defining conditions providing high levels of in vivo transfection in the brains of newborn mice. Our hypothesis was that conditions favorable for in vitro transfection (highly positively charged particles) were unlikely to be appropriate for in vivo conditions. When using the cationic lipid dioctadecylamido glycylspermine (Transfectam, DOGS) with a cytomegalovirus (CMV)-luciferase reporter gene, the best levels of transfection were obtained when using a low ratio of positive charges (supplied by the DOGS) to negative charges (carried by the DNA). Moreover, addition of the neutral lipid dioleoylphosphatidyl ethanolamine (DOPE) significantly enhanced transfection. Expression of the transgene diminished over time, independently of lipopolysaccharide content of the plasmid preparation used. This suggests that either a mitotic population of cells was preferentially transfected, or that promoter silencing was occurring. Histological examination of the spatial distribution of a beta-galactosidase-expressing transgene showed numerous groups of transfected cells both within the striatal parenchyma and in the paraventricular area. Thus, DNA-lipid complexes bearing overall charges close to neutrality open promising possibilities for modulating gene expression in the developing central nervous system and for therapy in the brain.

Animals↗
PubMed1995

Evaluation of short-course therapy with cefixime or rifampin for eradication of pharyngeally carried group A streptococci. The Ontario GAS Study Group.

Therapy to eradicate pharyngeally carried group A streptococci (GAS) has increasingly been used in the management of institutional outbreaks and is now recommended for household contacts of patients with streptococcal toxic shock syndrome. In this randomized, controlled trial, contacts of patients with GAS infections were screened for pharyngeal GAS colonization. Those whose cultures were positive were randomized to receive either cefixime (8 mg/[kg.d]; maximum 400 mg) or rifampin (20 mg/kg; maximum, 600 mg) once a day for 4 days. Two to five days following completion of therapy, repeated cultures were negative for 13 (38%) of 34 rifampin recipients and 71 (77%; 95% CI, 69%-85%) of 97 cefixime recipients. At 10-14 days after treatment, only 53% of cefixime recipients remained culture-negative. Rates of successful clearance improved with increasing age (P < .01); among 17 adults who received cefixime, the success rate was 94%. Four days of therapy with rifampin is not effective for eradication of pharyngeally carried GAS. Four days of therapy with cefixime may be effective for adults, but further studies are needed.

Adolescent↗
PubMed1995

Selective depletion of V beta-bearing T cells in patients with severe invasive group A streptococcal infections and streptococcal toxic shock syndrome. Ontario Streptococcal Study Project.

The V beta repertoire of T cells of patients with gram-positive group A streptococcal (GAS) and non-GAS infections was analyzed to seek evidence for the role of superantigens in streptococcal toxic shock syndrome. No evidence of V beta overexpression but a consistent pattern of depletion of V beta 1, V beta 5.1, and V beta 12 was observed in patients with severe GAS infections. This pattern of V beta depletion was not observed in patients with nonsevere GAS infections or with severe non-GAS gram-positive infections. T cells from patients with severe GAS infections showed evidence of apoptosis; no apoptosis was found when there was no evidence of V beta depletion. There was no correlation with streptococcal M or T serotype or known spe genes. The depletion of specific V beta-bearing T cells in patients with severe GAS infections supports the role of a superantigen in these infections. The in vivo pattern of V beta specificity implicates a novel superantigen(s) in this disease.

Adolescent↗