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Biomedical subjects

B Shah

Publications and source records attributed to B Shah.

At least 19 recordsLinked to original sources

Oral submucous fibrosis in a 11-year-old Bangladeshi girl living in the United Kingdom.

A case of oral submucous fibrosis occurring in a 11-year-old Bangladeshi girl is presented. This paper reviews the aetiology, clinical presentation and treatment modalities of oral submucous fibrosis. This case highlights the link between oral submucous fibrosis and the regular use of areca-nut (paan) and the newer transcultural oral tobacco products. This association has been reported among children resident in the Indian sub-continent but is unrecorded for United Kingdom residents. The case report underlines the danger that children face with products which are clearly targeted at them by the tobacco industry.

Areca↗

The schistosome egg: development and secretions.

We have investigated the development of the schistosome egg and its secretions in order to understand how it migrates through gut tissues and also initiates pathology in the liver. We show by electron microscopy that the subshell envelope is absent in the newly deposited egg, but appears very early and differentiates as development progresses. In the mature egg, this nucleated envelope contains extensive endoplasmic reticulum, suggestive of a protein synthetic capacity. Furthermore, Reynolds' layer only appears between the envelope and the egg-shell in the mature egg and may represent its accumulated secretions. We have biosynthetically labelled and collected the secretions (ESP) released by mature but not immature eggs during culture. Their fractionation by SDS-PAGE reveals a simple pattern of 6 bands, differing markedly in composition from soluble egg antigen preparations. Electrophoresis in casein substrate gels demonstrates the presence of 2 distinct proteases in the egg secretions. By immunocytochemistry, ESP localized predominantly to the envelope of the mature egg, suggesting that this layer rather than the miracidium is the source of egg secretions.

Animals↗

Tubulin stimulates adenylyl cyclase activity in C6 glioma cells by bypassing the beta-adrenergic receptor: a potential mechanism of G protein activation.

While the cytoskeleton is known to play several roles in the biology of the cell, one role, which has been revealed only recently, is that of a participant in the signal transduction process. Tubulin binds specifically to the alpha subunits of Gs (stimulatory GTP-binding regulatory protein of adenylyl cyclase), Gi1 (inhibitory protein of adenylyl cyclase), and Gq and transactivates those molecules through direct transfer of GTP. The relevance of this transactivation process to G proteins which are normally activated by a neurotransmitter-occupied receptor is the subject of this study. C6 glioma cells, made permeable with saponin, retained tight coupling between Gs and the beta-adrenergic receptor. Although 5-guanylylimidodiphosphate (GppNHp) was incapable of activating Gs (and subsequently, adenylyl cyclase) in the absence of agonist, tubulin with GppNHp bound (tubulin-GppNHp) activated adenylyl cyclase with an EC(50) of 30 nM. Desensitization of beta-adrenergic receptors by isoproterenol exposure had no effect on the ability of tubulin-GppNHp to activate Gs and adenylyl cyclase. When the photoaffinity GTP analog, azidoanilido GTP (AAGTP; P3(4-azidoanilido)-P1-5'-GTP), was added to C6 membranes or permeable C6 cells, it was only weakly incorporated by G alpha s in the absence of isoproterenol. When the same concentration of dimeric tubulin with AAGTP bound was introduced, AAGTP was transferred from tubulin to G alpha s, activating the latter species. Similar 'preferential' activation of G alpha s by tubulin-AAGTP versus the free nucleotide was seen using purified components. Thus, membrane-associated tubulin may serve to activate G alpha s, independent of signals not normally coupled to that protein. Tubulin may act as an agent to link a variety of membrane-associated signalling systems.

Adenylyl Cyclases↗

Direct inhibition of c-Jun N-terminal kinase in sympathetic neurones prevents c-jun promoter activation and NGF withdrawal-induced death.

c-Jun N-terminal kinases (JNKs) regulate gene expression by phosphorylating transcription factors, such as c-Jun. Studies with JNK: knockout mice suggest that JNK activity may be required for excitotoxin-induced apoptosis in the adult hippocampus and for apoptosis in the developing embryonic neural tube. Here we investigate the role of JNKs in classical neurotrophin-regulated developmental neuronal death by using nerve growth factor (NGF)-dependent sympathetic neurones. In this system, NGF withdrawal leads to an increase in JNK activity, an increase in c-Jun protein levels and c-Jun N-terminal phosphorylation before the cell death commitment point, and c-Jun activity is required for cell death. To inhibit JNK activity in sympathetic neurones we have used two different JNK inhibitors that act by distinct mechanisms: the compound SB 203580 and the JNK binding domain (JBD) of JNK interacting protein 1 (JIP-1). We demonstrate that JNK activity is required for c-Jun phosphorylation, c-jun promoter activation and NGF withdrawal-induced apoptosis. We also show that ATF-2, a c-Jun dimerization partner that can regulate c-jun gene expression, is activated following NGF deprivation. Finally, by co-expressing the JBD and a regulatable c-Jun dominant negative mutant we demonstrate that JNK and AP-1 function in the same pro-apoptotic signalling pathway after NGF withdrawal.

Animals↗

c-Jun and the transcriptional control of neuronal apoptosis.

There has been considerable interest in the molecular mechanisms of apoptosis in mammalian neurons because this form of neuronal cell death is important for the normal development of the nervous system and because inappropriate neuronal apoptosis may contribute to the pathology of human neurodegenerative diseases. The aim of recent research has been to identify the key components of the cell death machinery in neurons and understand how the cell death programme is regulated by intracellular signalling pathways activated by the binding of neurotrophins or death factors to specific cell surface receptors. The aim of this commentary was to review research that has investigated the role of the Jun N-terminal kinase (JNK)/c-Jun signalling pathway in neuronal apoptosis, focusing in particular on work carried out with developing sympathetic neurons. Experiments with sympathetic neurons cultured in vitro, as well as with cerebellar granule neurons and differentiated PC12 cells, have demonstrated that JNK/c-Jun signalling can promote apoptosis following survival factor withdrawal. In addition, experiments with Jnk(-/-) knockout mice have provided evidence that Jnk3 may be required for apoptosis in the hippocampus in vivo following injection of kainic acid, an excitotoxin, and that Jnk1 and Jnk2 are required for apoptosis in the developing embryonic neural tube. However, in the embryonic forebrain, Jnk1 and Jnk2 have the opposite function and are necessary for the survival of developing cortical neurons. These results suggest that JNKs and c-Jun are important regulators of the cell death programme in the mammalian nervous system, but that their biological effects depend on the neuronal type and stage of development.

Animals↗

beta 3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics.

The voltage-sensitive sodium channel confers electrical excitability on neurons, a fundamental property required for higher processes including cognition. The ion-conducting alpha-subunit of the channel is regulated by two known auxiliary subunits, beta1 and beta2. We have identified rat and human forms of an additional subunit, beta3. It is most closely related to beta1 and is the product of a separate gene localized to human chromosome 11q23.3. When expressed in Xenopus oocytes, beta3 inactivates sodium channel opening more slowly than beta1 does. Structural modeling has identified an amino acid residue in the putative alpha-subunit binding site of beta3 that may play a role in this difference. The expression of beta3 within the central nervous system differs significantly from beta1. Our results strongly suggest that beta3 performs a distinct neurophysiological function.

Amino Acid Sequence↗

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Journal Article↗

Association of naphthalene with acute hemolytic anemia.

OBJECTIVES: To describe the prevalence and severity of naphthalene-associated hemolysis (NA1) and infection-associated hemolysis (IAH) in children with glucose-6-phosphate dehydrogenase (G6-PD) deficiency. To survey the rationale for naphthalene-containing moth repellent (mothball) use in the study population and to compare this with that of a more diverse population. METHODS: A ten-year retrospective chart review of 160 patients with G-6-PD deficiency and/or anemia and an analysis of 24 hospitalized African-American children with an episode of acute hemolysis associated with G-6-PD deficiency were conducted. The parents of 330 children cared for in the pediatric emergency departments (EDs) of two tertiary care centers were questioned regarding domestic mothball (naphthalene) use. RESULTS: Fourteen of 24 (58.3%) of the children identified with G-6-PD deficiency presented with hemolysis associated with exposure to naphthalene-containing moth repellents. The remaining ten had IAH. Seventy-nine percent of the NAH group required transfusion, compared with 60% of the IAH group. Mothballs were reportedly used by 27% of the families surveyed in one inner-city population with a 2-13% incidence of G-6-PD deficiency and by 15% in a more culturally diverse city. The main reported motivation for use was the fresh scent, not as a moth repellent. CONCLUSIONS: Mothballs are used for previously unrecognized reasons. Naphthalene-containing mothballs can pose a hematologic threat to vulnerable populations.

Acute Disease↗

A study comparing the clinical pharmacokinetics, pharmacodynamics, and tolerability of triamcinolone acetonide HFA-134a metered-dose inhaler and budesonide dry-powder inhaler following inhalation administration.

The impending phaseout of chlorofluorocarbons as propellants in pressurized metered-dose inhalers used in the treatment of asthma has resulted in the development of alternative devices to deliver drug to the pulmonary airways. These alternative devices include metered-dose inhalers using environmentally friendly hydroflurocarbon propellants and breath-actuated dry-powder inhalers. The purpose of this study was to compare the single- and multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of a newly developed hydroflurocarbon formulation of triamcinolone acetonide (Azmacort HFA 225 mcg Inhalation Aerosol) to that of the dry-powder formulation of budesonide (Pulmicort Turbuhaler 200 mcg). This three-way crossover study used 18 normal healthy subjects each receiving a 675 mcg dose of triamcinolone acetonide, 600 mcg dose of budesonide, or placebo twice a day for 5 days. Serial plasma samples were collected after the first and last dose of test medication for pharmacokinetic analysis. Pharmacodynamics were assessed by changes in hypothalamic-pituitary-adrenal axis function as measured by 8 a.m. serum cortisol, 24-hour overnight serum cortisol AUC(0-24), and 24-hour urinary-free cortisol after the last evening dose of test drug. Tolerability was assessed through physical examinations, vital signs, 12-lead ECG, routine clinical labs, and adverse events recording. Both compounds were systemically absorbed. However, no significant drug accumulation was noted with chronic dosing. Chronic dosing did result in a statistically significant 20% reduction in basal 24-hour serum cortisol AUC(0-24) for both compounds. There were no clinically significant abnormalities in physical examination, vital signs, 12-lead ECG, or routine clinical labs noted during the study. Overall, the study drugs were well tolerated, with adverse events characterized as mild to moderate in severity.

Administration, Inhalation↗

Admission serum potassium in patients with acute myocardial infarction: its correlates and value as a determinant of in-hospital outcome.

STUDY OBJECTIVES: Although controversial, hypokalemia (LK) in patients with acute myocardial infarction (MI) is thought to predict increased in-hospital morbidity, particularly cardiac arrhythmias, and mortality. Also, the mechanism of low serum potassium in the setting of MI has not been delineated. We evaluated the frequency, attributes, and outcome, and speculated on the mechanism of LK in patients with MI. DESIGN: This was a prospective cross-sectional study of 517 consecutive patients with MI admitted to the coronary care unit (CCU). Serum potassium was measured in the emergency department and repeatedly thereafter throughout hospitalization, and was used in the analysis, along with a large array of clinical and laboratory variables. RESULTS: The patients were allocated to a LK and a normokalemic (NK) cohort, based on the emergency department serum potassium measurement. The 41 patients with LK (3.16+/-0.24 mEq/L; 7.9% of total) were comparable on admission in their baseline assessment to the 476 patients with normal serum potassium (4.28+/-0.56 mEq/L), except for lower emergency department magnesium (1.48+/-0.15 mg/dL vs. 1.96+/-0.26 mg/dL; p = 0.0005) and earlier presentation after onset of symptoms (3.0+/-4.1 h vs. 4.4+/- 6.2 h; p = 0.05). There was a poor correlation between serum potassium and magnesium on admission (r = 0.14). Peak creatine kinase (CK) and myocardial isomer of CK were higher in the LK patients (3,870+/-3, 840 IU/L vs. 2,359+/-2,653 IU/L [p = 0.018] and 358+/-312 IU/L vs. 228 +/- 258 IU/L [p = 0.013], respectively). Management of the two cohorts was the same, except for a higher rate of use of magnesium (14.6% vs. 4.6%; p = 0.007), serum potassium supplements (90.2% vs 43. 1%; p = 0.000005), and antiarrhythmic drugs (78.0% vs 50.4%; p = 0. 0007) in the LK patients. No difference was detected between the LK and NK patients in total mortality (24.4% vs. 18.3%; p = 0.34), cardiac mortality (17.1% vs. 15.3%; p = 0.52), atrial fibrillation (14.6% vs 13.9%; p = 0.89), and ventricular tachycardia (22.0% vs. 16.0%; p = 0.32), but ventricular fibrillation (VF) occurred more often (24.4% vs 13.0%; p = 0.04) in the LK patients. However, proportions of VF occurring in the emergency department, CCU, or wards in the two cohorts were not different, but they were higher during the time interval prior to emergency department admission in LK patients (17.1% vs 2.1%; p = 0.00001). CONCLUSIONS: LK is seen in approximately 8% of patients with MI in the emergency department; LK is associated with low emergency department magnesium, and low serum potassium levels in the CCU and throughout hospitalization. LK has no relationship to preadmission use of diuretics, it is associated with early presentation to the emergency department, and it is not a predictor of increased morbidity or mortality.

Biomarkers↗

Effect of food and gender on the pharmacokinetics of RP 73401, a phosphodiesterase IV inhibitor.

OBJECTIVE: Early exploratory clinical pharmacokinetic studies can provide valuable information for the design and control of subsequent phase 2 studies. This philosophy was instituted for the compound RP 73401, a specific phosphodiesterase IV inhibitor, that was being developed simultaneously for delivery by both oral and pulmonary routes of administration. The objective of these studies was to separately evaluate the effect of food and gender on the pharmacokinetics of RP 73401 using small-scale focused pilot studies. METHODS: In the first study, 400 mcg of inhaled RP 73401 were administered to male and female healthy volunteers (n = 8 f, 8 m. In the second study, 400 mcg oral RP 73401 were administered to healthy male volunteers (n = 8) in the fed and fasted state in a crossover fashion. Serial plasma samples were collected for 24 hours and analyzed for RP 73401 using an HPLC method with post-column photochemical reaction and fluorescence detection that had a minimum quantifiable limit of 10 pg/ml. Pharmacokinetic parameters were calculated using non-compartmental techniques. RESULTS: Comparison of male and female pharmacokinetics following inhalation administration showed no statistically significant differences in the absorption and disposition of RP 73401 with respect to AUC, Cmax, tmax, and t1,2 values. Conversely, RP 73401 administered subsequently to a high fat meal showed a 51% reduction in Cmax and a 5-fold prolongation in tmax as compared to the fasted state. However, there was no statistically significant difference in the systemic availability of RP 73401 as assessed through AUC0-infinity comparisons. CONCLUSIONS: These results successfully allowed the uncomplicated inclusion of females in oral and inhalation studies with RP 73401 and indicated the need to address oral drug dosing conditions in order to minimize sources of pharmacokinetic variability in subsequent phase 2 studies.

3',5'-Cyclic-AMP Phosphodiesterases↗

Clinical trials of Chitra band material.

Stainless steel band material was developed and tested for physico-chemical mechanical toxicological and in-vitro evaluation in dogs, at the Sree Chitra Thirunal Medical Institute, Trivandrum. Weld strength and tensile strength were measured with the Instron testing machine. A clinical pilot study was conducted at College of Dental Surgery, Manipal on 150 patients earlier. In the present study, Chitra bands were cemented on upper and lower molars on one side and Dentaurum bands on the other side, as controls in the same patient. The band was allocated to right and left molars at random. The study was a double blind trial. Thus fifty cases had Chitra bands on the left side and fifty on the tight side. Hundred cases were treated with fixed appliance treatment. The age, sex and technique of treatment were recorded. The spot welder and the cement used were also noted. The patients were recalled every month for nine months and the findings entered in the initial and follow-up proforma by another Orthodontist, making it a blind study. Loose bands, broken bands, broken tubes, broken welds, plaque accumulation, gingival bleeding and gingivitis were noted. The findings will be presented and the clinical applicability of Chitra Band Material discussed.

Animals↗

Adrenal function in premature infants during inhaled beclomethasone therapy.

OBJECTIVE: We tested the hypothesis that inhaled beclomethasone therapy for prevention of bronchopulmonary dysplasia does not cause adrenal suppression. STUDY DESIGN: Infants receiving ventilatory support with birth weights </=1250 g and born at <33 weeks' gestation, age 3 to 14 days, were enrolled in a multicenter randomized trial to study the efficacy and safety of beclomethasone therapy versus placebo for prevention of bronchopulmonary dysplasia. Adrenal function was assessed on study day 21 (+/- 2 days) by determination of basal and stimulated plasma cortisol levels. Initially, cortisol response was assessed with insulin-induced hypoglycemia test (IIHT) (n = 63) until an interim analysis revealed insignificant cortisol response in both study groups. Thereafter, cosyntropin stimulation was used (n = 85). RESULTS: Beclomethasone therapy was associated with lower median basal cortisol levels (5 microg/dL beclomethasone, 6 microg/dL placebo, P =.04). IIHT revealed insignificant change in cortisol response within each group. Cortisol response to cosyntropin stimulation was similar for each group (17 microg/dL beclomethasone, 18 microg/dL placebo, P =.86). CONCLUSION: Beclomethasone therapy was associated with a small decrease in basal cortisol levels. There was no evidence of adrenal suppression in response to cosyntropin stimulation during beclomethasone therapy. Lack of cortisol response to hypoglycemia may reflect missed timing and/or decreased response of the premature infants' hypothalamic-pituitary-adrenal axis to hypoglycemia.

Administration, Inhalation↗

A pharmacokinetic study to evaluate the absolute bioavailability of triamcinolone acetonide following inhalation administration.

Triamcinolone acetonide is a glucocorticoid administered by oral inhalation in the management of asthma. With oral inhalation of glucocorticoids, systemic absorption can come from oropharyngeal, gastrointestinal, or airway deposition of the drug. The objectives of this study were to determine the absolute bioavailability of triamcinolone acetonide following inhalation administration and to delineate the airway contribution of triamcinolone acetonide absorption relative to the absolute bioavailability. All subjects received a 5-minute 400 mcg intravenous infusion of triamcinolone acetonide and a single 800 mcg dose of inhaled triamcinolone acetonide with and without oral charcoal administration in a randomized three-way crossover fashion. The oral charcoal allowed for isolating the pulmonary component of absorption by adsorbing the oropharyngeal and gastrointestinal deposited drug. The mean (+/- SD) absolute bioavailability value for inhaled triamcinolone acetonide was 25% (8.75%). Delineation of the airway contribution of triamcinolone acetonide absorption showed that 10.4% of an inhaled dose is absorbed as triamcinolone acetonide from the lungs. Mean (+/- SD) total body clearance was rapid at 0.57 (0.12) L/hr/kg. The mean (+/- SD) apparent volume of distribution following the intravenous dose was a low 1.96 (0.31) L/kg. No significant differences were noted in the apparent terminal elimination half-life of triamcinolone acetonide (approximately 2.4 hr) between treatments.

Administration, Inhalation↗

Pharmacokinetics, safety, and tolerability of single intravenous infusions of an adenosine agonist, AMP 579, in healthy male volunteers.

The pharmacokinetics of an adenosine agonist, AMP 579, following intravenous administration were evaluated. Single AMP 579 doses of 20 to 150 micrograms/kg were infused intravenously over 6 hours using a constant-rate or two-step rate of infusion to healthy male volunteers. Plasma and urine samples were collected for measurement of AMP 579 concentration using a validated HPLC assay. An assessment of safety and tolerability was also performed. Based on a noncompartmental method of analysis, the pharmacokinetics of AMP 579 were characterized by rapid systemic clearance (0.77 to 0.85 L/h/kg), a moderate steady-state volume of distribution (0.80 to 0.94 L/kg), and a short terminal elimination half-life (0.84 to 1.13 h). AMP 579 exhibited dose (infusion rate)-proportional pharmacokinetics over the dose range. In addition, little or no unchanged AMP 579 was found in the urine. The primary cardiovascular pharmacodynamic response that was observed was a dose-related increase in mean ventricular heart rate. Fifteen minutes prior to the end of the infusion, volunteers administered the highest dose (150 micrograms/kg) exhibited a mean (range) 59% (36%-69%) increase in heart rate as compared to a mean (range) 18% (0%-73%) increase for the placebo group. No clinically relevant changes in the systolic or diastolic blood pressure were observed. The information obtained in this study should allow the design of AMP 579 dosage regimens that would maximize plasma AMP 579 concentrations and minimize the incidence of adverse events.

Adolescent↗

Ultrasound screening for hips at risk in developmental dysplasia. Is it worth it?

Between May 1992 and April 1997, there were 20,452 births in the Blackburn District. In the same period 1107 infants with hip 'at-risk' factors were screened prospectively by ultrasound. We recorded the presence of dislocation and dysplasia detected under the age of six months using Graf's alpha angle. Early dislocation was present in 36 hips (34 dislocatable and 2 irreducible). Of the 36 unstable hips, 30 (83%) were referred as being Ortolani-positive or unstable; 25 (69%) of these had at least one of the risk factors. Only 11 (31%) were identified from the 'at-risk' screening programme alone (0.54 per 1000 live births). Eight cases of 'late' dislocation presented after the age of six months (0.39 per 1000 live births). The overall rate of dislocation was 2.2 per 1000 live births. Only 31% of the dislocated hips belonged to a major 'at-risk' group. Statistical analysis confirmed that the risk factors had a relatively poor predictive value if used as a screening test for dislocation. In infants referred for doubtful clinical instability, one dislocation was detected for every 11 infants screened (95% confidence interval (CI) 8 to 17) whereas in infants referred because of the presence of any of the major 'at-risk' factors the rate was one in 75 (95% CI 42 to 149). Routine ultrasound screening of the 'at-risk' groups on their own is of little value in significantly reducing the rate of 'late' dislocation in DDH, but screening clinically unstable hips alone or associated with 'at-risk' factors has a high rate of detection.

Bone Diseases, Developmental↗

A rural population based case-control study of senile cataract in India.

PURPOSE: Senile cataract contributes to 75% of blindness in India and there is a growing backlog of cataract cases needing surgery. The present study seeks clues to the etiology of senile cataract, so that strategies to prevent or even delay cataract formation could be planned. METHODS: Using a community based case-control design, 258 cases & 308 controls from one centre and 301 cases & 591 controls from another were studied. The subjects were from rural areas and were aged 40-60 years. Logistic regression analysis technique was employed to study the associations between senile cataract and various variables. RESULTS: Systolic blood pressure, duration of exposure to sunlight per day were associated with senile cataract in both the centres (OR = 1.4 & 1.5 for systolic BP and 1.6 & 1.4 for exposure to sunlight). Utilization of rice gruel (OR = 0.5), duration of exposure to fire & dust per day (OR = 1.8), family history of cataract (OR = 5.0), use of cheap cooking fuels (OR = 1.8), increased height (OR = 0.7) and increased number of hours of work per day (OR = 0.7) were other variables that showed significant association in either of the centres. CONCLUSION: Senile cataract appears to have a multi factorial etiology. Though the study provided some clues to the etiology of senile cataract, further studies are needed to know the specific role of these factors in the causation of cataract, so that any preventive or control measures could be initiated in the community. Till such time, we have to fall back on the available surgical approach in control of senile cataract.

Adult↗