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Biomedical subjects

M Silverman

Publications and source records attributed to M Silverman.

At least 19 recordsLinked to original sources
PubMed1992

The MDR1 gene product, P-glycoprotein, mediates the transport of the cardiac glycoside, digoxin.

Digoxin, a widely used cardiac glycoside with a low therapeutic index, is known to interact with a large and diverse group of co-administered drugs, frequently leading to toxic accumulation of the glycoside. Establishing the mechanism(s) of these interactions, therefore, has potential clinical significance. The present studies implicate P-glycoprotein, the MDR1 gene product overexpressed in multidrug resistant cells, as the apical membrane protein responsible for the renal secretion of digoxin and provide an explanation for the occurrence of digoxin toxicity in the presence of certain co-administered medications. Since digoxin is considered a prototype for endogenous digitalis-like glycosides, the results also allow for speculation that endogenous digitalis-like glycosides may be the natural substrates for P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Delivery of micronized budesonide suspension by metered dose inhaler and jet nebulizer into a neonatal ventilator circuit.

We compared the delivery of a micronized suspension of budesonide by a metered dose inhaler (MDI) with two different spacers (Aerochamber and Aerovent) and by two jet nebulizers (MAD2 and Ultravent) to a ventilated neonatal test-lung using a standard neonatal ventilator circuit. The combination of MDI and Aerochamber was significantly better at delivering budesonide to a filter in front of the test lung (14.2% of aerosolized dose) than were either the MDI and Aerovent (3.6%) or the Ultravent or MAD2 jet nebulizers (0.02% and 0.68% of initial reservoir dose). Of the droplets emerging from the MDI, Aerochamber, and ET tube, 18% of the initial dose was in droplets less than 4.7 microns. Assuming that the test-lung model accurately reflects in vivo deposition, the combination of MDI and Aerochamber appears to be an extremely effective way of delivering budesonide aerosol to ventilated newborn infants.

Aerosols↗
PubMed1992

A new regime in the management of gastroschisis.

In this review of 24 patients with gastroschisis, we illustrate a regime of management with a low morbidity and no mortality. The essence of the technique relies on antenatal diagnosis, intrauterine transfer, and a planned cesarean section with immediate repair performed at 37 to 38 weeks' gestation. Although the operation may be technically easier at lower gestational ages, we believe the concomitant increase in complications such as respiratory distress syndrome outweigh the advantage of easier surgery. The results of this series compare favorably with other published results.

Abdominal Muscles↗
PubMed1992

Evaluation of new anti-infective drugs for the treatment of syphilis. Infectious Diseases Society of America and the Food and Drug Administration.

Syphilis is caused by Treponema pallidum, a spirochetal bacterium pathogenic only for humans. The clinical course of disease is divided into three stages interspersed by periods of latency. Penicillin remains the treatment of choice for all stages of infection; tetracycline or erythromycin may be used as therapeutic alternatives in defined circumstances. Patients enrolled in clinical trials should be evaluated clinically, microscopically, and serologically for the presence of the spirochete. All participants, after undergoing counseling and giving informed consent, should be tested for infection with human immunodeficiency virus. Specific criteria exist for diagnosis of syphilis and response to therapy. It may be desirable to perform a small, uncontrolled, open trial of a new anti-infective drug for the collection of preliminary evidence of efficacy. A larger-scale, randomized, active-control comparative clinical trial is necessary to prove efficacy.

Animals↗
PubMed1992

The luxR gene product of Vibrio harveyi is a transcriptional activator of the lux promoter.

Expression of the lux operon from the marine bacterium Vibrio harveyi is dependent on cell density and requires an unlinked regulatory gene, luxR, and other cofactors for autoregulation. Escherichia coli transformed with the lux operon emits very low levels of light, and this deficiency can be partially alleviated by coexpression of luxR in trans. The V. harveyi lux promoter was analyzed in vivo by primer extension mapping to examine the function of luxR. RNA isolated from E. coli transformed with the Vibrio harveyi lux operon was shown to have a start site at 123 bp upstream of the first ATG codon of luxC. This is in sharp contrast to the start site found for lux RNA isolated from V. harveyi, at 26 bp upstream of the luxC initiation codon. However, when E. coli was cotransformed with both the lux operon and luxR, the start site of the lux mRNA shifted from -123 to -26. Furthermore, expression of the luxR gene caused a 350-fold increase in lux mRNA levels. The results suggest that LuxR of V. harveyi is a transcriptional activator stimulating initiation at the -26 lux promoter.

Bacterial Proteins↗
PubMed1992

Bronchial responsiveness and lung function in infants with lower respiratory tract illness over the first six months of life.

The aim of this study was to determine whether increased bronchial responsiveness to histamine is associated with lower respiratory tract illness (one or more episodes of wheeze or cough, or both) in infancy. Fifty four normal newborn infants who had at least one atopic parent were recruited. At a median age of 6.5 months, 45 infants, 23 with a history of lower respiratory tract illness, and 22 without, underwent pulmonary function testing during a symptom free period. The maximum flow at functional residual capacity (VmaxFRC) was calculated from partial forced expiratory flow volume curves using the squeeze technique. Bronchial responsiveness to increasing doses of histamine was assessed by determining the provoking concentration which caused a 30% decrease in VmaxFRC (PC30). The length adjusted VmaxFRC was lower for symptomatic infants before the challenge (median 125 ml/s; 95% confidence intervals (CI) 85 to 164 ml/s) compared with control infants (median 215 ml/s; 95% CI 159 to 298 ml/s). There was no significant difference in PC30 between symptomatic infants (median 10.3 g/l; 95% CI 2.8 to 23.8 g/l) and control infants (median 16.5 g/l; 95% CI 2.4 to 27.9 g/l). Bronchial responsiveness to histamine can be shown in most infants early in life and is independent of lower respiratory tract symptoms including wheezing.

Bronchi↗
PubMed1992

Delivery of therapeutic aerosols to intubated babies.

Delivery of drug aerosols to the lungs of ventilated neonates by metered dose inhaler and spacer (Aerochamber) and ultrasonic nebuliser (Pentasonic) was assessed using sodium cromoglycate. The mean proportion of a known intratracheal dose of sodium cromoglycate excreted in the urine of four intubated infants was 37.5%. After assuming that 38% of the sodium cromoglycate aerosol reaching the neonatal lung will be excreted in the urine, three puffs (15 mg) delivered by metered dose inhaler and spacer resulted in a pulmonary dose of 258 micrograms (1.7%, n = 7). A dose of 20 mg (4 ml) sodium cromoglycate ultrasonically nebulised over five minutes into the inspiratory limb of a standard ventilator circuit produced a pulmonary dose of 257 micrograms (1.3%, n = 7). Of two in vitro lung models assessed, a combination of filter and neonatal test lung was superior to a multistage impactor in estimating the in vivo pulmonary sodium cromoglycate dose delivered by metered dose inhaler and spacer (243 micrograms v 1740 micrograms).

Aerosols↗
PubMed1992

Atopy, bronchial responsiveness, and symptoms in wheezy 3 year olds.

Fifty children with at least one hospital admission for acute lower airway obstruction in the first 2.5 years of life were assessed at 3 years of age to determine the relationship between atopy, bronchial responsiveness, and the pattern of their symptoms. Bronchial responsiveness was measured by assessing the effect of inhaled metacholine, using the change in transcutaneous oxygen tension (PtCO2) as an indirect measure of response. Symptom patterns were defined by the number of wheezing episodes associated with colds and the presence or absence of cough or wheeze unrelated to viral infections. Forty per cent of the children were found to be atopic by skin prick test or history. In contrast to the situation found in older children and adults, the non-atopic children had significantly greater bronchial responsiveness (lower mean concentration of methacholine causing a 20% fall in PtCO2, the PC20) than the atopic children and significantly more of them had an onset of respiratory symptoms in the first year of life. Cough and wheeze in the absence of colds was more frequently found in the atopic children as was the use of continuous medication. However, the number of reported acute episodes of wheeze associated with colds was the same in the two groups. The findings of the study suggest that in this hospital based group of children, acute wheeze associated with colds in the first three years of life is independent of the finding of atopy and that bronchial responsiveness in this age group may have a different pathogenesis from that in older subjects.

Blood Gas Monitoring, Transcutaneous↗
PubMed1992

Repeatability of methacholine challenge in asthmatic children measured by change in transcutaneous oxygen tension.

BACKGROUND: The airway response to bronchial provocation may be evaluated by monitoring the fall in transcutaneous oxygen tension (PtcO2) but the repeatability of this method has not been rigorously assessed. METHODS: To determine the repeatability of this indirect method of assessment, bronchial challenge was performed with methacholine in nine children with stable asthma (age range 6-12 years) and was repeated 24 hours later. The response was determined by the fall both in forced expiratory volume in one second (FEV1) and in PtcO2. A modified tidal inhalation protocol was used in which quadrupling concentrations of methacholine were given, thereby reducing the time taken for the full challenge by almost half. The concentrations of methacholine that provoked a 20% decrease in FEV1 (PC20FEV1) and 15% and 10% falls in PtcO2 (PC15PtcO2, PC10PtcO2) were calculated. RESULTS: Repeatability measures, assessed as the 95% range for a single determination, were +/- 0.96 and +/- 1.12 doubling concentration differences respectively for PC15PtcO2 and PC10PtcO2 and +/- 0.80 for PC20FEV1. CONCLUSION: This challenge method using quadrupling concentrations and an indirect assessment of the response by PtcO2 was sufficiently repeatable for clinical use and compared favourably with repeated challenge assessed by FEV1. The PtcO2 method is simple and effort independent, and should prove particularly useful for measuring bronchial reactivity in young children.

Asthma↗
PubMed1992

Cyclosporin and quinidine inhibition of renal digoxin excretion: evidence for luminal secretion of digoxin.

We studied the in vivo luminal and contraluminal uptake of [3H]digoxin in dog kidney using the single-pass multiple indicator dilution method. A bolus tracer of 125I-albumin (plasma reference), creatinine, or L-[14C]glucose [extracellular reference (ecf)] and [3H]digoxin (or [3H]ouabain) was injected into the left renal artery, and timed serial samples were collected from the left renal vein (basolateral uptake) and left and right ureters (luminal uptake). [3H]ouabain was excreted solely by filtration and exhibited saturable and irreversible binding at the basolateral surface. Uptake of [3H]digoxin across the basolateral membrane was large and nonsaturable. Despite urine flow-dependent reabsorption and approximately 20% protein binding, the urine recovery ratio for [3H]-digoxin/glomerular (ecf) marker was 0.97 +/- 0.04 (n = 29), indicating net digoxin secretion. After intravenous infusions of cyclosporin in Cremophor EL (0.5-3.5 microM), the urine recovery ratio decreased in a dose-dependent manner from control values of 1.13 +/- 0.06 (n = 12) to 0.62 +/- 0.03 (n = 14). There was no change in the relative renal vein recovery. Left renal artery infusion of quinidine (37.5 micrograms.min-1.kg-1) decreased the relative urine recovery of [3H]digoxin by 46% (n = 6) but had no effect on postglomerular extraction. Cyclosporin and quinidine are known inhibitors of P-glycoprotein. But digoxin did not compete with [3H]azidopine for binding in rat brush-border membranes or membranes prepared from the multidrug-resistant cell line CHRC5. The exact mechanism for renal digoxin secretion remains to be determined, but our results point to a luminal localization of this secretory system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Increased levels of bronchoalveolar lavage fluid interleukin-6 in preterm ventilated infants after prolonged rupture of membranes.

This study investigated the effect of prolonged rupture of the amniotic membranes (PROM) and probable maternal or fetal sepsis without PROM on the newborn preterm airway. Bronchoalveolar lavage fluid (BALF) was obtained from 38 infants in the first day of life and analyzed for number of white cells and concentration of interleukin-6 (IL-6). The volume of lung epithelial lining fluid (ELF) was estimated using the urea dilution technique. Infants with PROM (n = 13) and those with sepsis (n = 8) had higher total numbers of white cells in BALF compared with infants without PROM or sepsis (n = 17) (55 and 44 versus 7 x 10(4) white cells, p less than 0.01). Uncorrected and urea-corrected IL-6 concentrations were also higher in the two groups (18.5 and 30.8 versus 5.0 fmol/ml BALF, p less than 0.01; 157.7 and 444 versus 88.5 fmol/ml ELF, p less than 0.05). There was a significant correlation between BALF white cells and uncorrected IL-6 concentrations (rs = 0.78, p less than 0.0001). Detectable serum C-reactive protein in newborn infants was associated with increased levels of IL-6 in BALF (42.2 versus 11.8 fmol/ml BALF, p less than 0.05). We conclude that PROM is associated with airway inflammation and raised levels of IL-6 in neonatal lung fluid within the first 24 h of life and that this may initiate a systemic stress response.

Bacterial Infections↗
PubMed1992

'Not waving but drowning': psychiatric inpatient services in East Lambeth 1990.

This paper presents the results of the latest in a series of surveys of an inner-city public psychiatric inpatient service. Severe pressures on the service had led to the purchase of inpatient beds in the private hospital sector and intensive care facilities in a large psychiatric hospital. On a census day the nominal occupancy for the inpatient unit was 117%. Implications of the survey, trends over time and possible solutions to the difficulties of the inpatient unit are discussed.

Adolescent↗
PubMed1992

Rat glomerular epithelial cells in culture express characteristics of parietal, not visceral, epithelium.

Glomerular epithelial cells (GEC) in culture are derived from intact isolated glomeruli. Although there is general agreement about distinguishing GEC from mesangial and endothelial cells, there is still uncertainty regarding the visceral versus parietal origin of cultured GEC. If these cells are to provide a useful model system, it is necessary to establish well-defined cell populations. The purpose of this study was to evaluate this important issue by comparing the characteristics of cultured GEC with glomerular epithelium from rat kidney sections. By electron microscopy, GEC were polygonal, with cilia and desmosomes between cells, similar to parietal cells in situ. Because intermediate filaments are specifically expressed in differentiated cells in the kidney, the expression of intermediate filaments in cultured GEC were compared with those of intact glomeruli. Cultured GEC are positive for cytokeratin and negative for vimentin and desmin, identical to parietal cells in situ. In contrast, podocytes are positive for vimentin and desmin and negative for cytokeratin. In vivo, podocytes express gp330 and puromycin-aminonucleoside (PAN) susceptibility, which are used as markers for cultured GEC. Immunoperoxidase staining of rat kidney sections with monoclonal anti-gp330 demonstrated gp330 localization to the cell surface and coated pits of the parietal cells, similar to its localization in podocytes. The presence of gp330 in cultured GEC was confirmed by immunoblot. PAN administration to rats induced vacuolization and detachment from the basement membrane in the parietal cells of Bowman's capsule, similar to the cytotoxicity observed in podocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Fractional processing of sequential bronchoalveolar lavage fluid from intubated babies.

Two groups of intubated newborn babies were studied to determine the clinical effects of interrupted bronchoalveolar lavage (BAL) by suction catheter (S-BAL) and the similarities to adult fibreoptic BAL of fractional processing of sequential lavage fluid (BALF). Both groups were lavaged by two aliquots of 1 ml.kg-1, instilled via a blindly placed suction catheter, wedged on two separate insertions through the right main bronchus. In 14 infants, (sequential lavage group), BALF aliquots were analysed separately. There were no differences in the volumes recovered or total cell counts between the first and second BALF aliquots. Where cell morphology was visible (n = 11), the percentage of macrophages, but not the absolute number, increased in the second BALF aliquot (p less than 0.01). BALF urea and epithelial lining fluid volume estimated by urea dilution were similar between the two aliquots (n = 8). In a separate group (blood gas group), vital signs were recorded in 10 infants undergoing S-BAL. At 1 min after lavage there was a rise in mean arterial blood pressure (39 vs 49.5 mmHg, p less than 0.05) and a fall in transcutaneous oxygenation (10.6 vs 7.5 kPa, p less than 0.05). Recovery was present at 3 min post-S-BAL, but mean blood pressure remained elevated (39 vs 45 mmHg, p less than 0.05) and transcutaneous oxygen continued to be lower when compared to baseline values (10.6 vs 9.2 kPa, p less than 0.05). S-BAL of intubated infants appears to sample both the proximal and distal airways and results in changes in vital signs similar to routine non-selective endotracheal suctioning.

Blood Gas Analysis↗