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Biomedical subjects

B Schwartz

Publications and source records attributed to B Schwartz.

At least 91 records · Page 5Linked to original sources
PubMed1999

Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa.

Menopause and estrogen deficiency are associated with apparent intestinal resistance to vitamin D, which can be reversed by estrogen replacement. The in vivo influence of estrogens on duodenal vitamin D receptor (VDR) was studied in three groups of rats: ovariectomized (OVX), sham-operated, and ovariectomized rats treated daily with estrogen (40 microg/kg BW) for 2 weeks (OVX + E). Estrogen administration to OVX rats resulted in a 2-fold increase in VDR messenger RNA transcripts. 1,25(OH)2D3 was shown to bind specifically to one class of receptors in duodenal mucosal extracts, with a dissociation constant of 0.03 nM. Binding was significantly increased in duodenal extracts from OVX + E rats, compared with OVX rats (735 +/- 81 vs. 295 +/- 26 fmol/mg protein; P < 0.001); a comparable, 1.5- to 2-fold increase in VDR protein expression was observed in Western blot analyzes of the duodenal mucosa. Markers of VDR activity were increased in estrogen-exposed rats: calbindin-9k messenger RNA transcript content was 1.4- to 1.6-fold higher, and alkaline phosphatase activity was 1.4- to 3-fold higher in sham-operated and OVX + E, respectively, compared with OVX. 25(OH)D, 1,25(OH)2D, or PTH levels were not altered by estrogen treatment. Cumulatively, these findings suggest that estrogen up-regulates VDR expression in the duodenal mucosa and concurrently increases the responsiveness to endogenous 1,25(OH)2D. Modulation of intestinal VDR activity by estrogen, and subsequent influence on intestinal calcium absorption, could be one of the major protective mechanisms of estrogen against osteoporosis.

Alkaline Phosphatase↗
PubMed1999

Risk factors for invasive pneumococcal disease in children: a population-based case-control study in North America.

OBJECTIVE: To identify risk factors for invasive pneumococcal disease, including penicillin-resistant infections, among children 2 to 59 months of age. DESIGN: Case-control study. PARTICIPANTS: Patients with invasive pneumococcal infections identified by population-based surveillance (n = 187) and controls identified through random-digit telephone dialing (n = 280). OUTCOME MEASURES: Invasive pneumococcal disease was defined as isolation of Streptococcus pneumoniae from a normally sterile site. Patients 2 to 59 months of age who were residents of one of four active surveillance areas were included. S pneumoniae isolates were tested by broth microdilution. Isolates with a minimum inhibitory concentration to penicillin >/=2 microg/mL were considered resistant. RESULTS: Invasive pneumococcal disease was strongly associated with underlying disease and with day care attendance in the previous 3 months. Among 2- to 11-month-olds, current breastfeeding was associated with a decreased likelihood of invasive pneumococcal disease (odds ratio, 0.27; 95% confidence interval: 0.08, 0.90). Penicillin-resistant infections were independently associated with day care attendance, at least one course of antibiotics, and at least one ear infection in the previous 3 months. CONCLUSIONS: This study shows the association of underlying illnesses, day care attendance, and lack of breastfeeding with risk of invasive pneumococcal disease in children. The association of recent antibiotic use and infection with penicillin-resistant S pneumoniae highlights the need to avoid unnecessary antibiotic use in children.

Anti-Bacterial Agents↗
PubMed1999

Antimicrobial use for pediatric upper respiratory infections: reported practice, actual practice, and parent beliefs.

BACKGROUND: In response to the dramatic emergence of resistant pneumococci, more judicious use of antibiotics has been advocated. Physician beliefs, their prescribing practices, and the attitudes of patients have been evaluated previously in separate studies. METHODS: This 3-part study included a statewide mailed survey, office chart reviews, and parent telephone interviews. We compared survey responses of 366 licensed pediatricians and family physicians in Georgia to recently published recommendations on diagnosis and treatment of upper respiratory infections (URIs). We further evaluated 25 randomly selected pediatricians from 119 surveyed in the Atlanta metropolitan area. For each, charts from the first 30 patients between the ages of 12 and 72 months seen on a randomly selected date were reviewed for encounters during the preceding year. A sample of parents from each practice were interviewed by telephone. RESULTS: In the survey, physicians agreed that overuse of antibiotics is a major factor contributing to the development of antibiotic resistance (97%), and that they should consider selective pressure for resistance in their decisions on providing antibiotic treatment for URIs in children in their practices (83%). However, many reported practices do not conform to the recently published principles for judicious antibiotic use. For example, 69% of physicians considered purulent rhinitis a diagnostic finding for sinusitis; 86% prescribed antibiotics for bronchitis regardless of the duration of cough; and 42% prescribed antibiotics for the common cold. Reported practices by family physicians were more often at odds with the published principles: they were significantly more likely than pediatricians to omit pneumatic otoscopy (46% vs 25%); to omit the requirement for prolonged symptoms to diagnose sinusitis (median 4 vs 10 days); and to omit laboratory testing for pharyngitis (27% vs 14%). Of the 7531 encounters analyzed in the chart review, 43% resulted in an antibiotic prescription, including 11% of checkups, 18% of telephone calls, and 72% of visits for URIs. There was wide variability in the overall antibiotic use rates among the 25 physicians (1-10 courses per child per year). There was an even wider variability in some diagnosis-specific rates; bronchitis and sinusitis in particular. Those with the highest antibiotic prescribing rates had up to 30% more return office visits. Physicians who prescribed antibiotics for purulent rhinitis were more likely to see parents who believed that their children should be evaluated for cold symptoms. CONCLUSIONS: Physicians recognize the problem of antibiotic resistance but their reported practices are not in line with recently published recommendations for most pediatric URIs. The actual prescribing practices of pediatricians are often considerably different from their close colleagues. Patient beliefs are correlated with their own physician's practices.

Anti-Bacterial Agents↗
PubMed1999

Invasive group A streptococcal infections in children.

Invasive group A streptococcal infections and STSS have increased as causes of morbidity and mortality among children and adults. In children, respiratory foci appear to be the most common, but skin and soft tissue infection, particularly associated with varicella, also are common. Early diagnosis requires awareness of the presenting features and a high index of suspicion. Antimicrobial therapy that includes clindamycin, therapy with IVIG for those with STSS, and surgical intervention for patients with necrotizing fasciitis may improve outcome. Chemoprophylaxis should be considered among household contacts of patients with severe group A streptococcal disease in high-risk settings. Further studies are ongoing to evaluate the hypothesized link of invasive group A streptococcal infection in children with varicella and NSAID use, to better clarify the pathogenesis of STSS and necrotizing fasciitis, and to better document the risk of secondary spread among close contacts of case patients.

Adolescent↗
PubMed1999

Diversity of response of optic nerve head circulation to timolol maleate in gel-forming solution.

PURPOSE: This randomized, double-masked, placebo-controlled, two-period crossover study was conducted to investigate the effects of 0.5% timolol maleate in gel-forming solution on intraocular pressure (IOP) and blood circulation in the optic nerve head in patients with untreated ocular hypertension. METHODS: The effects of 0.5% timolol in gel-forming solution on IOP and optic nerve head capillary blood speed were studied in 12 patients with untreated ocular hypertension. Optic nerve capillary blood speed was measured using the laser Doppler technique before and at the end of each treatment period. RESULTS: In each patient, IOP decreased after treatment with timolol (mean decrease 16.8% versus placebo). Systemic blood pressure and pulse rate did not differ significantly after treatment with topical timolol from values after placebo. The mean change from baseline in Doppler broadening was 10.6% greater after treatment with timolol than after placebo. There was no significant change in mean Doppler broadening from baseline after treatment with either timolol or placebo. However, optic nerve head capillary blood speed increased in six patients, and was within the range of placebo response in six patients after treatment with timolol. Spearman correlation analysis of the baseline with Doppler broadening measurements after treatment showed a correlation for placebo but not for timolol. The percent change in Doppler broadening after timolol treatment was correlated with iris color. CONCLUSION: These results indicate that administration of timolol for 4 weeks reduces IOP in patients with ocular hypertension and generally does not change the blood circulation in the optic nerve head. Individual patients, however, showed variable changes in optic nerve head circulation after topical administration of timolol. Although the sample size was small, these changes in optic nerve head circulation were correlated with iris color.

Adrenergic beta-Antagonists↗
PubMed1999

The protective effect of estrogen against chemically induced murine colon carcinogenesis is associated with decreased CpG island methylation and increased mRNA and protein expression of the colonic vitamin D receptor.

Epidemiological studies suggest that estrogen prevents neoplastic transformation in the intestinal mucosa. Estrogen was shown to increase the expression of vitamin D receptors (VDR) in a variety of tissues. 1,25-Dihydroxyvitamin D [1,25-(OH)2D] and several of its analogues are known as potent antineoplastic and prodifferentiative in many cell types, including colon-derived cells. The present study was designed to examine the effect of estradiol (E2) on dimethylhydrazine (DMH)-induced colon cancer in rats, and the possibility that E2 may exert its protective effect on the colon through modulation of the vitamin D-endocrine system. The in vivo effect of E2 on DMH-induced colorectal cancer was studied in four groups of ovariectomized female rats: (I) untreated control, (II) E2 treated, (III) DMH treated, and (IV) combined E2 and DMH treated. Significantly higher uterine weights and higher colonic estrogen receptor content confirmed the effectiveness of ovariectomy and E2 replacement. The number of malignant tumors in group IV was 2.3+/-1.1 (mean +/- SE) per rat, compared with 8.1+/-1.9 in group III (P < 0.001). Exposure to estrogen was associated with a marked increase in VDR mRNA content and VDR protein expression in the normal colonic mucosa. In tumor extracts VDR protein expression was considerably lower compared with normal mucosa. Estrogen treatment did not affect serum levels of 25(OH)D, 1,25(OH)2D, and PTH. Significant CpG island methylation in the VDR gene was observed in colonic tissue DNA harvested from rats treated with DMH, but not in colonic mucosae from rats treated with DMH + E2. The highest frequency of CpG methylation in the VDR gene was detected in DNA extracted from cancer tissue rims. In summary, the protective effect of estrogen against chemically induced colonic carcinogenesis is associated with reduced methylation of the VDR gene and with upregulation of both VDR gene transcription and protein expression. We suggest that estrogen may interfere with the process of CpG DNA methylation in the colonic mucosa to prevent silencing of the VDR gene. Increased VDR activity could be one of the mechanisms by which estrogen protects against neoplastic transformation in the colon.

Animals↗
PubMed1999

Acute otitis media: management and surveillance in an era of pneumococcal resistance--a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group.

OBJECTIVE: To provide recommendations [corrected] for the management of acute otitis media (AOM) and the surveillance of drug-resistant Streptococcus pneumoniae (DRSP). Five questions were addressed: (1) Can amoxicillin remain the best initial antimicrobial agent for treating AOM in the current period of increasing prevalence of DRSP? (2) What are suitable alternative agents for use if amoxicillin fails? (3) Should empiric treatment of AOM vary by geographic region? (4) Where can clinicians learn about resistance patterns in their patient populations? (5) What modifications to laboratory surveillance would improve the utility of the information for clinicians treating AOM? PARTICIPANTS: Experts in the management of otitis media and the DRSP Therapeutic Working Group. This group was convened by the CDC to respond to changes in antimicrobial susceptibility among pneumococci and includes clinicians, academicians and public health practitioners. EVIDENCE: Published and unpublished data summarized from the scientific literature and experience from the experts present. PROCESS: [corrected] After group presentations and review of background materials, subgroup chairs prepared draft responses to the five questions, discussed the responses as a group and edited those responses [corrected]. CONCLUSIONS: Oral amoxicillin should remain the first line antimicrobial agent for treating AOM. In view of the increasing prevalence of DRSP, the safety of amoxicillin at higher than standard dosages and evidence that higher dosages of amoxicillin can achieve effective middle ear fluid concentrations, an increase in the dosage used for empiric treatment from 40 to 45 mg/kg/day to 80 to 90 mg/kg/day is recommended. For patients with clinically defined treatment failure after 3 days of therapy, useful alternative agents include oral amoxicillin-clavulanate, cefuroxime axetil and intramuscular ceftriaxone. Many of the 13 other Food and Drug Administration-approved otitis media drugs lack good evidence for efficacy against DRSP. Currently local surveillance data for pneumococcal resistance that are relevant for the clinical management of AOM are not available from most areas in the United States. Recommendations to improve surveillance include establishing criteria for setting susceptibility breakpoints for clinically appropriate antimicrobials to ensure relevance for treating AOM, testing middle ear fluid or nasal swab isolates in addition to sterile site isolates and testing of drugs that are useful in treating AOM. The management of otitis media has entered a new era with the development of DRSP. These recommendations are intended to provide a framework for appropriate clinical and public health responses to this problem.

Acute Disease↗
PubMed1998

Relationship between conserved consensus site residues and the productive conformation for the TPQ cofactor in a copper-containing amine oxidase from yeast.

A highly conserved asparagine residue is contained in the consensus site sequences of all known copper-containing amine oxidases (CAOs). On the basis of published crystallographic structures, the asparagine is found to reside proximal to the active site redox cofactor, 2,4,5-trihydroxyphenylalanine quinone (TPQ). In this study, the conserved asparagine was changed to an alanine in a CAO from Hansenula polymorpha expressed in Saccharomyces cerevisiae, and the mutant's catalytic properties were characterized using steady-state kinetics and resonance Raman spectroscopy. Several lines of evidence point to TPQ exisiting in an nonproductive orientation in the mutant, including reductions in several steady-state parameters and an accumulation of an inactive product Schiff base complex when the enzyme is incubated with methylamine as the substrate. This product Schiff base complex was previously found to form following mutation of another conserved consensus site residue, a glutamate (or aspartate) at the C + 1 position from TPQ [Cai, D., Dove, J., Nakamura, N., Sanders-Loehr, J., and Klinman, J. P. (1997) Biochemistry 36, 11472-11478]. The results suggest that these two residues are crucial in maintaining the balance of cofactor mobility versus rigidity expected to be necessary during the dual processes of biogenesis and catalysis, respectively, that all CAOs must accomplish. In addition, a previously unidentified structural linkage between these two highly conserved residues is proposed which spans both subunits of the dimeric CAOs, and may have implications for intersubunit communication.

Alanine↗
PubMed1998

Appropriate use of antibiotics for URIs in children: Part II. Cough, pharyngitis and the common cold. The Pediatric URI Consensus Team.

This article summarizes the principles of judicious antimicrobial therapy for three of the five conditions--cough, pharyngitis, the common cold--that account for most of the outpatient use of these drugs in the United States. The principles governing the other two conditions, otitis media and acute sinusitis, were presented in the previous issue. This article summarizes evidence against the use of antibiotic treatment for illness with cough or bronchitis in children, unless the cough is prolonged. Although empiric treatment may be started in patients with pharyngitis when streptococcal infection is suspected, the authors recommend withholding antibiotic treatment until antigen testing or culture is positive. There is never any indication for antibiotic treatment of the common cold; it is important to understand the natural history of colds, because symptoms such as mucopurulent rhinitis or cough, even when they persist for up to two weeks, do not necessarily indicate bacterial infection.

Anti-Bacterial Agents↗
PubMed1998

Appropriate use of antibiotics for URIs in children: Part I. Otitis media and acute sinusitis. The Pediatric URI Consensus Team.

Five conditions--otitis media, acute sinusitis, cough, pharyngitis and the common cold--account for most of the outpatient use of antibiotics in the United States. The first part of this two-part article presents guidelines that encourage physicians to make an appropriate distinction between acute otitis media and otitis media with effusion, to use shorter courses of antibiotic therapy in uncomplicated cases of otitis media and to limit prophylaxis to recurrence as defined strictly by number of episodes. Sinusitis in younger children is difficult to distinguish from the common cold, and the criterion for use of antibiotics should be duration of symptoms.

Acute Disease↗
PubMed1998

Antimicrobial resistance and clinical effectiveness of co-trimoxazole versus amoxycillin for pneumonia among children in Pakistan: randomised controlled trial. Pakistan Co-trimoxazole Study Group.

BACKGROUND: Co-trimoxazole is widely used in treatment of paediatric pneumonia in developing countries, but drug resistance may decrease its effectiveness. We studied the effectiveness of co-trimoxazole compared with that of amoxycillin in pneumonia therapy, and assessed the clinical impact of co-trimoxazole resistance. METHODS: We recruited 595 children, aged 2-59 months, with non-severe or severe pneumonia (WHO criteria) diagnosed in the outpatient wards of two urban Pakistan hospitals. Patients were randomly assigned on a 2:1 basis co-trimoxazole (n=398) or amoxycillin (n=197) in standard WHO doses and dosing schedules, and were monitored in study wards. The primary outcome was inpatient therapy failure (clinical criteria) or clinical evidence of pneumonia at outpatient follow-up examination. FINDINGS: There were 92 (23%) therapy failures in the co-trimoxazole group and 30 (15%) in the amoxycillin group (p=0.03)-26 (13%) versus 12 (12%) among children with non-severe pneumonia (p=0.856) and 66 (33%) versus 18 (18%) among those with severe pneumonia (p=0.009). For patients with severe pneumonia, age under 1 year (p=0.056) and positive chest radiographs (p=0.005) also predicted therapy failure. There was no significant association between antimicrobial minimum inhibitory concentration and outcome among bacteraemic children treated with co-trimoxazole. INTERPRETATION: Co-trimoxazole provided effective therapy in non-severe pneumonia. For severe, life-threatening pneumonia, however, co-trimoxazole is less likely than amoxycillin to be effective.

Amoxicillin↗
PubMed1998

Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. Acute Renal Failure Investigation Team.

CONTEXT: Contaminated pharmaceutical products can result in substantial morbidity and mortality and should be included in the differential diagnosis of deaths of unknown origin. OBJECTIVE: To investigate an outbreak of deaths among children from acute renal failure in Haiti to determine the etiology and institute control measures. DESIGN: Case-control study, cohort study, and laboratory toxicologic evaluation. SETTING: Pediatric population of Haiti. PARTICIPANTS: Cases were defined as Haitian residents younger than 18 years with idiopathic anuria or severe oliguria for 24 hours or longer. Febrile hospitalized children without renal failure were enrolled as control subjects. MAIN OUTCOME MEASURE: The odds of exposure to suspected etiologic agents among cases and controls. RESULTS: We identified 109 cases of acute renal failure among children. The clinical syndrome included renal failure, hepatitis, pancreatitis, central nervous system impairment, coma, and death. Of 87 patients with follow-up information who remained in Haiti for treatment, 85 (98%) died; 3 (27%) of 11 patients transported to the United States for intensive care unit management died before hospital discharge. A locally manufactured acetaminophen syrup was highly associated with disease (odds ratio, 52.7; 95% confidence interval, 15.2-197.2). Diethylene glycol (DEG) was found in patients' bottles in a median concentration of 14.4%. The median estimated toxic dose of DEG was 1.34 mL/kg (range, 0.22-4.42 mL/kg). Glycerin, a raw material imported to Haiti and used in the acetaminophen formulation, was contaminated with 24% DEG. CONCLUSIONS: An epidemic of severe systemic toxicity and deaths from DEG-contaminated acetaminophen syrup occurred in Haiti. Good manufacturing practice regulations should be used by all pharmaceutical manufacturers to prevent such tragedies.

Acetaminophen↗
PubMed1998

Synthesis, activity, and structure--activity relationship studies of novel cationic lipids for DNA transfer.

We have designed and synthesized original cationic lipids for gene delivery. A synthetic method on solid support allowed easy access to unsymmetrically monofunctionalized polyamine building blocks of variable geometries. These polyamine building blocks were introduced into cationic lipids. To optimize the transfection efficiency in the novel series, we have carried out structure-activity relationship studies by introduction of variable-length lipids, of variable-length linkers between lipid and cationic moiety, and of substituted linkers. We introduce the concept of using the linkers within cationic lipids molecules as carriers of side groups harboring various functionalities (side chain entity), as assessed by the introduction of a library composed of cationic entities, additional lipid chains, targeting groups, and finally the molecular probes rhodamine and biotin for cellular traffic studies. The transfection activity of the products was assayed in vitro on Hela carcinoma, on NIH3T3, and on CV1 fibroblasts and in vivo on the Lewis Lung carcinoma model. Products from the series displayed high transfection activities. Results indicated that the introduction of a targeting side chain moiety into the cationic lipid is permitted. A primary physicochemical characterization of the DNA/lipid complexes was demonstrated with this leading compound. Selected products from the series are currently being developed for preclinical studies, and the labeled lipopolyamines can be used to study the intracellular traffic of DNA/cationic lipid complexes.

3T3 Cells↗
PubMed1998

Extensive apoptotic death of rat colonic cells deprived of crypt habitat.

Apoptosis in cells of different lineages is restrained by survival signals which depend upon cell-to-cell communication. The aim of this study was to determine whether colonic cells deprived of crypt ambient are doomed to die prior to their normal chronological demise. Apoptosis was studied in rat whole colonic tissue, in isolated intact crypts, and in colonic cell populations collected from the crypt axis at different stages of proliferation and differentiation. In a number of experiments, cell harvest was performed in the presence of either a tetrapeptide (YVAD-CMK) inhibitor of interleukin-1beta-converting enzyme (ICE), or tyrphostin A25, a protein tyrosine kinase inhibitor, or sodium-orthovanadate, a phosphatase inhibitor. DNA fragmentation was assessed by electrophoretic and nonisotopic-labeling procedures. The ultrastructure of colonic tissue specimens and isolated cells was examined by transmission electron microscopy. Apoptosis in whole colonic tissue and in isolated crypts was confined predominantly to cells resident in the upper crypt regions. In contrast, extensive apoptotic death was observed in isolated colonic cells, irrespective of their developmental stage and positional hierarchy within the crypt continuum at harvest time. An apoptotic gradient, however, was evident. Exposure to YVAD-CMK resulted in a marked decrease in the number of apoptotic cells. Treatment with tyrphostin A25 caused a sharp rise in the apoptotic index; conversely, vanadate significantly impeded apoptosis. Cumulatively, these results indicate that disordered intercellular communication provokes unscheduled ICE-mediated apoptosis of colonocytes, and that local signals along the crypt continuum control both the reprieve from death and the timely demise of distinct colonic cell populations. Attenuation of tyrosine phosphorylation may be a contributory event in the acquisition of the apoptotic phenotype.

Amino Acid Chloromethyl Ketones↗