Biomedical subjects

M Silverman

Publications and source records attributed to M Silverman.

At least 145 records · Page 8Linked to original sources

PubMed1994

Chronic lung disease of prematurity: are we too cautious with steroids?

Encompassed by the term chronic lung disease (CLD) of prematurity is a sequence of pathophysiological processes ranging from acute inflammation and its resolution to remodelling and growth. There is good evidence for clinical and biological effects of parenteral corticosteroid therapy at each stage in the disease process. A number of questions remain to be resolved: can risk prediction be refined to permit trials of prevention; what is the minimum effective dosage regime; are topical corticosteroids effective; what are the long-term effects on lung growth and development and indeed, is the long-term prognosis of CLD affected by corticosteroid therapy? It is prudent to be cautious with steroids until these questions are answered.

Adrenal Cortex Hormones↗

PubMed1994

Tumour necrosis factor-alpha and leukotriene E4 production in wheezy infants.

It is not clear why certain infants wheeze during viral upper respiratory tract infections (URTIs) but it is possible that they have a tendency to mount an exaggerated inflammatory response leading to production of mediators that induce airway narrowing. We studied nasal tumour necrosis factor-alpha (TNF alpha) and urinary leukotriene E4 (LTE4) production during infection and after recovery in 31 wheezy infants (median age 6.2 months). Urinary LTE4 production was not altered during wheezy episodes or URTIs. However, the concentration of TNF alpha in nasal lining fluid (NLF) was significantly increased during acute episodes of wheeze compared to recovery (median [interquartile range] of 293 [42-1753] vs 0 [0-203] pg/ml NLF). TNF alpha was detectable more often and in higher concentration when wheezing was due to respiratory syncytial virus. TNF alpha was also present in 7/30 asymptomatic wheezy infants who had recovered from infection (> 100 pg/ml NLF) and in 4/7 non-wheezy siblings during URTIs (> 200 pg/ml NLF). This suggests that upregulation of TNF alpha production is not the only factor that makes some infants wheeze.

Child, Preschool↗

PubMed1994

Identification and intervention for urinary incontinence by community physicians and geriatric assessment teams.

OBJECTIVE: To determine the difference in the recognition and intervention/referral rates for urinary incontinence (UI) by out-patient Geriatric Assessment Units (GAUs) and private physicians in community-based practices (CMDs). DESIGN: A multi-site, randomized, controlled study where block randomization was utilized to assign subjects 65 years of age and older to either a GAU or a CMD for assessment. SETTING: One academic and three hospital-based GAUs and CMDs in private practice in a large metropolitan area. PARTICIPANTS: Three hundred sixty-four community-dwelling frail men (14%) and women (86%) with a mean age of 75 years. MEASUREMENTS: The independent variable was the type of out patient care, either CMD or GAU, to which the subjects were randomized. The dependent variables were recognition of UI by the health care providers and intervention or referral for the problem of UI once it was identified. Instruments included a structured in-home interview performed before randomization designed to uncover health problems such as urinary incontinence, as well as a medical record review form used post-assessment to ascertain recognition rates and intervention for UI by CMDS and GAUs. Both of the instruments were developed and piloted by the investigators in a preliminary study. MAIN RESULTS: Of the 364 subjects, 151 (41.5%) reported UI during the in-home interviews. Recognition rates for UI were significantly better for GAUs (48 of 81, 59.3%) than CMDs (11 of 70, 15.7%) (P < 0.001). This was true for mild (< 3 times/week) 44.2% vs 2.1% (P < 0.000005) as well as severe UI (> 3 times/week) 86.2% vs 43.5% (P = 0.00111) for GAUs and CMDs, respectively. There were no significant differences in the rate of referral/intervention for recognized cases of UI by GAUs or CMDs. GAUs referred/treated five (21.7%) cases of mild UI and 10 (40%) cases of severe UI while CMDs referred/treated three (30%) cases of severe UI but did not offer intervention for the one recognized case of mild UI. GAUs were more likely to refer to Continence Programs (12, 25%) compared with CMDs who were more likely to refer (3, 100%) to a urologist. A majority of the subjects with UI did not receive treatment or referral for their problem (8, 72.7% CMDs and 33, 68.6% of GAUs). CONCLUSIONS: GAUs out performed CMDs in the identification of subjects with both mild and severe UI. However, the intervention/referral rates were low for both GAUs and CMDs. The outcome of this study points to the need for increased emphasis on UI in curriculum preparing physicians and other health providers as well as the need for continuing education for those already in practice.

Aged↗

PubMed1994

Bronchodilator aerosol administered by metered dose inhaler and spacer in subacute neonatal respiratory distress syndrome.

There is increasing evidence that bronchodilators are effective in ventilator dependent preterm infants. The effects of single doses of salbutamol (400 micrograms), ipratropium bromide (72 micrograms), and placebo (four puffs) given by metered dose inhaler and spacer (MDIS) were examined in 10 ventilated preterm infants, with a mean birth weight of 800 g at a postnatal age of 1 week, who were suffering from respiratory distress syndrome. The agents were each given in an open, random design. Blood gases were measured and ventilatory efficiency index (VEI) and arterial/alveolar oxygen tension ratio (PaO2/PAO2) were calculated five minutes before and 30 minutes after administration. Heart rate and mean arterial blood pressure were noted. The mean PaO2 improved by 0.61 kPa and 0.69 kPa after salbutamol and ipratropium bromide, respectively and these changes were significantly greater than the 0.5 kPa fall seen with placebo. The mean arterial carbon dioxide tension fell by 0.98 kPa after salbutamol and 0.59 kPa after ipratropium bromide. After both salbutamol and ipratropium bromide, VEI improved significantly (by 23% and 20% respectively) but there was no significant change in the PaO2/PAO2, suggesting that respiratory mechanics and not ventilation/perfusion balance had improved after a single dose of bronchodilator. We conclude that both salbutamol and ipratropium bromide given by MDIS have useful short term effects in ventilator dependent neonates with respiratory distress syndrome. Precise dose regimens and long term effects remain to be worked out.

Aerosols↗

PubMed1994

Activation of procollagenase IV by cytochalasin D and concanavalin A in cultured rat mesangial cells: linkage to cytoskeletal reorganization.

The secretion and activation of procollagenase IV were studied in cultured rat mesangial cells. Under resting conditions, mesangial cells secrete predominantly a protein that, by gel zymography, exhibits gelatinase activity and also reacts with an anti-72-kd procollagenase IV antibody raised against a conserved region of the activation site of the enzyme. Cytochalasin D or concanavalin A treatment of mesangial cells causes disruption of actin stress fibers and results in the activation of procollagenase IV, yielding two lower molecular mass forms with gelatinase activity. Concanavalin A-induced actin filament disruption and procollagenase IV activation can be blocked by alpha-methyl-D-mannopyranoside but not by D(+)-galactose. Procollagenase IV as well as the activated forms all exhibit Ca2+ and Zn2+ dependency, characteristic of metalloproteinases. Mesangial cells in culture also secrete a specific tissue inhibitor of metalloproteinase, TIMP-2. Cytochalasin D treatment of mesangial cells reduces TIMP-2 expression. Cytochalasin D and concanavalin A both inhibited the serum-induced contraction of collagen gels embedded with mesangial cells. It was concluded that cytochalasin D-induced cytoskeletal disruption in mesangial cells may activate procollagenase IV by inhibiting TIMP-2 expression and that there is a concanavalin A-binding site on mesangial cells that is part of a transmembrane signaling system altering mesangial cell cytoskeletal organization and metalloproteinase secretion and activation.

Animals↗

PubMed1994

Characterization of cimetidine transport in LLCPK1 cells.

In this study, cimetidine uptake and its regulation by LLCPK1 monolayers were investigated. Uptake was temperature dependent with kinetic and specificity characteristics typical of a carrier-mediated mechanism. With cimetidine uptake in the presence of an excess concentration of the potent inhibitor quinidine as a measure of nonspecific transport, the estimated kinetic parameters for cimetidine uptake at 37 degrees C under steady-state conditions are Km = 32.3 +/- 6.4 microM and Vmax = 20.2 +/- 2.1 pmol/mg per minute. Amiloride, quinidine, and quinine inhibited cimetidine uptake, whereas N1-methylnicotinamide, tetraethylammonium, and guanidine did not. The uptake of cimetidine was increased in the presence of a cell-->lumen H+ gradient, consistent with the behavior of a cimetidine-H+ antiport system. Furthermore, the activity of both the Na(+)-H+ exchanger and H(+)-ATPase acted to dissipate the cell-->lumen H+ gradient, thereby decreasing net cimetidine transport. These results suggest that there is a cimetidine-H+ exchange system in LLCPK1 cells and that the net secretion of organic base in vivo may be regulated by luminal acidification mechanisms.

Amiloride↗

PubMed1994

Renal secretion of vinblastine, vincristine and colchicine in vivo.

The MDR1 gene product, P-glycoprotein, has been localized to the apical surface of the renal proximal tubule, but its functional role in the kidney is unknown. We studied renal luminal and antiluminal uptake of three known substrates of P-glycoprotein: vinblastine, vincristine and colchicine, by using the single pass multiple indicator dilution method under control conditions and in the presence of increasing concentrations of cyclosporin A, a potent inhibitor of P-glycoprotein. A bolus of [125I]albumin (plasma reference), L-[14C]glucose (extracellular and glomerular reference) and tracer 3H-substrate was injected into the left renal artery of anesthetized dogs and timed serial samples were collected from the left renal vein and left and right ureters. In a single pass, approximately 38, 13 and 8% of [3H]vinblastine, [3H] vincristine and [3H]colchicine, respectively, was extracted from the postglomerular circulation. Drug binding to plasma proteins was determined to be 81% for [3H]vinblastine, 71% for [3H] vincristine and 23% for [3H]colchicine. Despite the high degree of drug protein binding, the urine recoveries of [3H]vinblastine, [3H]vincristine and [3H]colchicine relative to L-[14C]glucose were 0.75 +/- 0.06, 0.69 +/- 0.06 and 0.94 +/- 0.02, confirming net secretion of each of these substrates. Infusion of cyclosporin A (0.1-5 microM) significantly decreased the urine recovery of [3H] vinblastine and [3H]vincristine relative to L-[14C]glucose in a dose-dependent manner. The renal excretion of [3H]colchicine was not affected by cyclosporin A at the concentrations tested (1-2 microM). The evidence suggests that net secretion of [3H]vinblastine and [3H]vincristine occurs across the luminal membrane of the renal cell.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Diabetes mellitus: a frequent factor in liability claims.

Inappropriate treatment of diabetes mellitus is the cause of an increasing number of malpractice claims. The authors present pertinent trends elicited by an analysis of diabetes claim files and their possible prevention. Files from February 1, 1977, to February 1, 1992, were reviewed.

Adult↗

PubMed1993

Kinetic characterization of Na+/D-mannose cotransport in dog kidney: comparison with Na+/D-glucose cotransport.

Brush-border membrane vesicles (BBMV) prepared from whole dog kidney cortex, or separately from outer cortex (OC) and outer medulla (OM), were used to study the kinetics and inhibition specificity of Na(+)-dependent D-mannose cotransport. In BBMV from whole cortex the measured parameters for Na+/D-mannose uptake were Km = 0.07 +/- 0.01 mM and Vmax = 4.19 +/- 0.24 nmol/mg protein per min (n = 36). In OC BBMV the Km for Na+/D-mannose was 0.04 mM, Vmax = 3.41 nmol/mg per min. In OM the Km was 0.06 +/- 0.02 mM Vmax = 0.18 nmol/mg per min. Thus only about 5% of Na+/D-mannose activity occurs in OM. Both mannoheptulose (Ki = 5.6 mM) and methyl alpha-D-mannoside (Ki = 0.05 mM) are competitive inhibitors of Na+/D-mannose uptake, but at comparable concentrations have little effect on Na+/D-glucose uptake. Phlorizin is a noncompetitive inhibitor of Na+/D-mannose uptake (Ki = 4.45 microM) but a more potent and competitive inhibitor (Ki = 0.58 microM) of Na+/D-glucose uptake. Phloretin (Ki = 104 microM) is a noncompetitive inhibitor of Na+/D-mannose uptake in BBMV. We conclude that Na+/D-mannose uptake is mediated by a unique high-affinity carrier located in the OC presumably at the luminal surface of the proximal convoluted tubule, with strong specificity requirements for sugars with mannose-like structures (i.e., axial C-2 hydroxyl group). Phlorizin is an inhibitor of both Na+/D-mannose and Na+/D-glucose cotransporters but is approx. 10 times less potent for the Na+/D-mannose system and also has a different mode of inhibition (i.e., noncompetitive vs. competitive). The different phlorizin inhibitory mechanisms on the Na+/D-glucose and Na+/D-mannose cotransporters may be mediated by distinct hydrophobic and sugar binding sites that characterize phlorizin-carrier interaction.

Animals↗

PubMed1993

Identification of two unique polypeptides from dog kidney outer cortex and outer medulla that exhibit different Na+/D-glucose cotransport functional properties.

The cloned Na+/D-glucose cotransporter SGLT1 and an additional recently isolated human kidney cDNA Hu14/K15 belong to a family of similar cotransport proteins including the Na(+)-dependent nucleoside and Na(+)-dependent myo-inositol carrier SMIT1. For the present study we used two different polyclonal antibodies raised against the amino acid sequence 402-420 (Ab-E) and 565-574 (Ab-P) of SGLT1 to probe brush-border membrane fractions from different regions (outer cortex-->outer medulla) of dog kidney. In Western blots both Ab-E and Ab-P react specifically (peptide blockable) with two distinct bands migrating on SDS-PAGE under reducing conditions at 75.5 kDa and 72.5 kDa. The higher molecular mass polypeptide is greatly enriched (13:1) in outer cortex and diminishes progressively towards outer medulla, whereas the lower molecular mass band is barely detectable in outer cortex but is enriched in outer medulla (4:1). Brush-border membrane vesicles (BBMV) prepared from the same outer cortical and outer medullary regions that were probed with Ab-E and Ab-P exhibit strikingly different Na+/D-glucose functional transport behavior. The Na+/D-glucose cotransport activity in outer cortical BBMV is a low-affinity system with Km = 5.98 +/- 1.01 mM, Vmax = 13.05 +/- 0.55 nmol/mg protein per min, and with 1:1 Na+:D-glucose stoichiometry. Outer medulla BBMV exhibit high-affinity Km = 0.27 +/- 0.03 mM Vmax = 0.97 +/- 0.04 nmol/mg protein per min and 2:1 Na+:D-glucose stoichiometry. Comparison of SGLT1, Hu14/K15, SNST1 and SMIT indicates that Ab-E could cross react with all four, but Ab-P would recognize SGLT1, Hu14/K15, SNST1 but not SMIT. Also SNST1 is not expressed in outer cortex. Based on currently available sequence data, and its marked enrichment in outer cortex, the 75.5 kDa band is a likely candidate protein responsible for low-affinity and 1:1 Na+:D-glucose stoichiometric Na+/D-glucose cotransport activity (Hu14/K15) while the minor 72.5 kDa band in outer cortex is probably SGLT1. In outer medulla, the predominant band recognized by both Ab-E and Ab-P is the 72.5 kDa protein and this could be either SGLT1 or SNST1.

Antibodies↗

PubMed1993

Exhaustive conformational search and simulated annealing for models of lattice peptides.

We consider simple lattice models for short peptide chains whose states can be exhaustively enumerated to find the lowest energy conformation. Using these exact results and numerical simulations, we compute the distributions for the mean time tN, required to find the global minimum energy state by simulated annealing (SA), as a function of N, the number of units in the chain. On the basis of scaling arguments, the time tN, to find the global minimum energy of longer chains, beyond the range covered by exhaustive enumeration, can be estimated. On the basis of the observed exponential increase in folding time of the standard SA algorithms, it is imperative that better algorithms be found for minimizing longer chains.

Algorithms↗

PubMed1993

Comparison of the squeeze technique and transcutaneous oxygen tension for measuring the response to bronchial challenge in normal and wheezy infants.

The aim of this study was to compare the fall in transcutaneous oxygen tension (PtcO2) as an outcome measure during bronchial provocation with histamine, with changes in airway function measured by the squeeze technique in healthy infants and those with wheezing disorders. PtcO2 was measured during histamine challenge in 20 infants, aged 6-16 months, of whom 14 had recurrent cough or wheeze (lower respiratory illness, LRI), and 6 were healthy. All were symptom free at the time of testing. The minimum value of PtcO2 after each nebulization was compared with the minimum baseline value. The response to increasing concentrations of histamine was also assessed by measuring maximal flow at functional residual capacity (VmaxFRC) by the squeeze technique. The inhaled concentration of histamine causing a 30% fall in VmaxFRC was calculated to give the provoking concentration (PC30). Baseline VmaxFRC was lower in symptomatic infants (117 mL/s) than the normal infants (322 mL/s; P < 0.005), but the PC30 was not significantly different (7.7 and 5.7 g/L, respectively). There was no difference in baseline PtcO2 between the two groups. The infants with LRI had significant reductions in PtcO2 at both the final and preceding concentrations of histamine, whereas the normal infants had a significant and smaller reduction in PtcO2 only at the provoking concentration. Reduction in PtcO2 during bronchial challenge was a less sensitive index of bronchial response in healthy infants than in infants with a history of recurrent LRI.

Asthma↗

PubMed1993

Association between pulmonary and gastric inflammatory cells on the first day of life in preterm infants.

It has been shown that inflammatory cells in the newborn lung are fetal in origin, whereas those in the amniotic fluid are maternal. In order to explore the relationship between fetal amnionitis and neonatal pneumonitis, we collected paired samples of gastric aspirate within 2 hours of birth, and bronchoalveolar lavage fluid within 24 hours of birth from intubated preterm infants. Leukocyte counts in bronchoalveolar lavage fluid correlated with the duration of membrane rupture (r = 0.68, P = 0.0001). There was a high degree of correlation between leukocyte counts in the two fluids (r = 0.86, P = 0.0001). The factors responsible for this association are unknown.

Bronchoalveolar Lavage Fluid↗

PubMed1993

Autosomal dominant polycystic kidney disease in Toronto.

This study describes the Toronto, Ontario experience with autosomal dominant polycystic kidney disease (ADPKD). Patients were divided into three groups: Group 1, 19 families studied with genetic markers; Group 2, 80 pre-dialysis ADPKD patients followed by Toronto nephrologists in whom the incidence of non-renal complications and the mean age of onset of symptomatology is documented; Group 3, 4,449 individuals who entered end-stage renal failure (ESRF) in the Toronto region between the years 1981 and 1992, 320 with ADPKD and 4129 with other diseases. In this third group age of onset of ESRF, frequency, age and cause of death is compared between ADPKD and non-ADPKD. ADPKD caused by a gene different from that linked to chromosome 16 short-arm probes occurred at a frequency of between 8 and 17%. Incidence of hepatic cysts in ADPKD was similar to that of previous series, other organ involvement was underdiagnosed without deliberate screening, and incidence of symptomatic intracranial aneurysm was 1.25%. A 5% excess of patients with ADPKD died of cerebro-vascular accident. Years of survival after ESRF measured by life table analysis was significantly greater for ADPKD patients than for non-ADPKD patients. A high frequency of death due to infection still exists in ADPKD despite the reduction of invasive procedures in diagnosis and treatment, and despite the presumably improved recent methods of managing infection. The average age of onset of ESRF has been delayed by over six years, and average age of death of ADPKD patients at 63.9 years-old by 12.4 years since 1960.

Adult↗

PubMed1993

Histopathologic correlates of structures seen on dermoscopy (epiluminescence microscopy).

Dermoscopy (epiluminescence microscopy) is an in vivo technique that enables the clinician to visualize a variety of structures in pigmented cutaneous lesions that are not discernible by naked-eye examination. To identify the histologic correlates of these structures, a series of 71 pigmented neoplasms was documented photographically with and without dermoscopy. These lesions then underwent total excision and careful step-sectioning so that the resulting histologic slides could be correlated with the dermoscopic photographs. The histologic correlates of the pigment network, brown globules, black dots, blotches, hypopigmented areas, white areas, grey-blue areas, and whitish veil are identified. The structures seen under dermoscopy have specific histologic correlates. Understanding these histopathologic correlates will allow clinicians to better evaluate the dermoscopic features of pigmented lesions.

Biopsy↗

PubMed1993

Nasal IgA response in wheezy infants.

It is unknown why some infants wheeze during upper respiratory tract infections. One possibility is that secretory IgA, which has a major role in mucosal defence against viral infection, might be deficient in wheezy infants. The nasal IgA response to upper respiratory tract infection in 32 wheezy infants (median age 5.8 months) was compared with nine siblings (median age 2.6 years) who had nasal symptoms only. Nasal lavage was performed during infections and on follow up when free from symptoms, using inulin as a marker of dilution to determine absolute concentrations of IgA in the nasal secretions. The two groups showed a similar increase in total IgA and total protein levels during infection, but secretory IgA concentrations were unchanged. This study shows that wheezy infants have a normal nasal IgA response to infection and that the increase in total IgA during early infection is due to plasma exudation rather than increased production of secretory IgA.

Child, Preschool↗

PubMed1993

Increased airway responsiveness in children of low birth weight at school age: effect of topical corticosteroids.

The effect of treatment with topical inhaled corticosteroids was assessed in 15 children of low birth weight (mean (SD) birth weight 1435 (268) g, gestational age 30.5 (2.9) weeks, age at study 8.2 (0.4) years) who were symptomatic and showed a positive airway response to histamine aerosol. The study was of a double blind, placebo controlled, crossover design with four week long treatment periods with inhaled beclomethasone dipropionate (400 micrograms daily) or placebo. Daily symptom scores were recorded and physiological measurements were performed at the beginning and end of each treatment period. There was no significant difference in respiratory symptom score, baseline airway function, or the airway response to histamine between treatment periods. The findings argue against an inflammatory basis for airway hyper-responsiveness in these children and raise questions as to its pathophysiological basis.

Administration, Inhalation↗

PubMed1993

Delivery of salbutamol by metered dose inhaler and valved spacer to wheezy infants: effect on bronchial responsiveness.

The efficacy of a new valved spacer device, the Babyhaler inhaler (Glaxo) for administering metered dose inhaler treatment via a facemask to infants was assessed. In a double blind, single dose study, salbutamol (800 micrograms) or placebo were given on separate days to 12 sedated, sleeping, wheezy infants during a symptom free interval. Lung function was measured before and after administration and the bronchial response to aerosol challenge with methacholine was then assessed using the squeeze technique. A small increase in heart rate and a drop in arterial oxygen tension followed salbutamol administration. No other change in lung volume or air flow obstruction was detected. Bronchial responsiveness decreased significantly after the administration of salbutamol by Babyhaler, the PC30 (provoking concentration of methacholine causing a 30% fall in maximal flow at functional residual capacity by the squeeze technique) increasing from a median of 3.8 g/l after placebo to 12.5 g/l after salbutamol. The Babyhaler is an effective device for administering bronchodilator to wheezy infants. The small scale of the response may be attributable to the uncertain effect of beta agonists in this population. Furthermore, pulmonary deposition of inhaled aerosols may be reduced in nose breathing, sleeping infants.

Albuterol↗