The placebo enigma in antidepressant clinical trials.
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Antidepressive Agents↗
Biomedical subjects
A Khan
Publications and source records attributed to A Khan.
Acetabular fractures with associated vascular injury: a report of two cases.
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Acetabulum↗
Enterolith-induced perforation in small bowel carcinoid tumor.
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Aged↗
Prevalence and correlates of smoking on the roof of the world.
OBJECTIVE: To determine the prevalence and correlates of cigarette smoking among adults in high mountain rural areas of northern Pakistan. DESIGN: Cross sectional survey. PARTICIPANTS: A sample of 4203 adults (aged 18 years and over) were selected by stratified random sampling from 16 villages. MAIN OUTCOME MEASURE: Self reported smoking prevalence; age of smoking initiation; daily cigarette consumption and association between current smoking and sociodemographic variables, use of snuff, wine, body mass index, blood pressure, family history of stroke, and hypertension. RESULTS: 614/1406 men (43.7%) and 154/2797 (5.5%) women reported smoking cigarettes. The age standardised prevalence of smoking was 40.5% for men and 6.3% for women. Men were more likely (odds ratio (OR) 6.5, 95% confidence interval (CI) 4.75 to 8.79) to be smokers. Smokers were more likely to use snuff (OR 1.39, 95% CI 1.12 to 1.73), drink wine (OR 3.47, 95% CI 2.81 to 4.29), and were more likely to work as farmers (OR 1.55, 95% CI 1.05 to 2.29) or shopkeepers (OR 2.63, 95% CI 1.67 to 4.14). Individuals with college level education and with desirable body mass index were less likely to smoke (OR 0.55, 95% CI 0.35 to 0.87; OR 0.74, 95% CI 0.57 to 0.96). CONCLUSION: Cigarette smoking is a major public health problem in this high mountain community of Pakistan, particularly among the male population, the majority of whom begin to smoke quite early in life. A comprehensive tobacco control effort incorporated into the existing community based health infrastructure is needed.
Adolescent↗
Osteonecrosis in a patient with Crohn's disease unrelated to corticosteroid use.
Osteonecrosis is a feared complication of corticosteroid use. However, a direct association between corticosteroid use and osteonecrosis has never been proven. The present report examines the case of a patient with longstanding Crohn's disease who had never been treated with corticosteroids and who developed osteonecrosis of the talus. The association of systemic inflammatory disorders with osteonecrosis and the possible association with vascular thrombosis are discussed.
Acute Disease↗
Symptom reduction and suicide risk among patients treated with placebo in antipsychotic clinical trials: an analysis of the food and drug administration database.
OBJECTIVE: The assumption that psychotic patients assigned to placebo in clinical trials of antipsychotics are exposed to substantial morbidity and mortality is not based on data about what actually happens to such patients. This study assesses symptoms and risks of suicide and suicide attempts in psychotic patients assigned to receive placebo in clinical trials. METHOD: The authors used the Food and Drug Administration database to assess suicides, suicide attempts, and psychotic symptom reduction in clinical trials of three new antipsychotics. RESULTS: Among 10,118 participating patients, 26 committed suicide and 51 attempted suicide. Rates of suicide and attempted suicide did not differ significantly between the placebo-treated and the drug-treated groups. Annual rates of suicide and attempted suicide based on patient exposure years were 1.8% and 3.3%, respectively, with placebo; 0.9% and 5.7% with an established antipsychotic; and 0.7% and 5.0% with a new antipsychotic. Symptom reduction was 16.6% with new antipsychotics (N=1,203), 17.3% with established antipsychotics (N=261), and 1.1% with placebo (N=462). CONCLUSIONS: These data may help inform discussions about the use of placebo in antipsychotic clinical trials.
Antipsychotic Agents↗
Insulin-like growth factor-1 selectively increases glucose utilization in brains of aged animals.
Previous studies indicate that insulin-like growth factor-1 is an important neurotrophic agent and that decreases in brain concentrations of IGF-1 and the type 1 IGF receptor have an important role in the age-related decline in memory, neuronal function and possibly dendritic architecture. In this study, we assessed the effects of age and IGF-1 replacement on local cerebral glucose utilization (LCGU). Three groups of male Brown-Norway rats (7, 18 and 28 months of age) were implanted with Alzet minipumps and either saline or IGF-1 (50ng/0.5 microliter/hour) was infused into the lateral ventricle for 28 days. On day 28, LCGU was measured by infusion of 2-[(14)C]deoxyglucose during the dark phase of the light/dark cycle. Results indicate that glucose utilization significantly decreased with age throughout the brain including the anterior cingulate, sensorimotor and retrosplenial cortex, CA1, CA3 and dentate gyrus of hippocampus and several regions of the hypothalamus. Administration of IGF-1 to aged animals increased rates of LCGU in the anterior cingulate of the cortex (14.2%), CA1 region of the hippocampus (11.0%) and the arcuate nucleus of the hypothalamus (12.0%). Our results indicate that although glucose utilization decreases with age throughout the brain, the effects of IGF-1 infusion are manifest only in specific brain regions. Since IGF-1 has been shown to reverse the age-related decrease in memory, these results suggest that despite the wide distribution of the type 1 IGF receptor the actions of IGF-1 on glucose utilization are highly localized. Additionally, the close association between glucose utilization and excitatory amino acid activity suggests that IGF-1 may act on specific neural pathways to increase glutamate activity in brain regions associated with learning and memory.
Aging↗
Conditional gene expression in human intracranial xenograft tumors.
In an initial effort to determine the effect of expressing potentially therapeutic gene products on the growth properties of glioma tumor xenografts, we describe the development of cell lines that can conditionally express beta-galactosidase (beta-gal). To achieve this, we generated stable cell lines that express the modified tetracycline repressor molecule (rtTA) and the beta-gal gene under control of tetracycline-responsive cis-elements. The resulting cell lines express functional beta-gal following treatment with the tetracycline analog doxycyclin (Dox). These cells were then used to form intracranial tumors after injection into the brain using an implantable guide-screw system. The xenografts were found to express beta-gal when the animals were fed drinking water containing Dox. From these studies, we conclude that the expression of a target gene in a human xenograft growing in the brain of a living mouse can be conditionally regulated.
Animals↗
Sonographic appearance of focal thyroiditis.
OBJECTIVE: The purpose of this study is to report the sonographic appearance of focal thyroid nodules that prove to be lymphocytic thyroiditis on fine-needle aspiration. CONCLUSION: In a patient population undergoing sonography for palpable nodular disease without known thyroiditis, focal nodules of thyroiditis had a wide variety of appearances. They most commonly appeared as solid hyperechoic nodules with ill-defined margins. However, the echogenicity was variable, and calcification and cystic-appearing regions were also noted. The vascularity of these nodules as assessed with color Doppler and power Doppler sonography also varied widely. Biopsy of these lesions is still necessary because there are no sonographic features that can reliably diagnose these lesions as thyroiditis and differentiate them from other lesions.
Biopsy, Needle↗
Defective stimulus-secretion coupling in islets of Psammomys obesus, an animal model for type 2 diabetes.
Psammomys obesus is a model of type 2 diabetes that displays resistance to insulin and deranged beta-cell response to glucose. We examined the major signaling pathways for insulin release in P. obesus islets. Islets from hyperglycemic animals utilized twice as much glucose as islets from normoglycemic diabetes-prone or diabetes-resistant controls but exhibited similar rates of glucose oxidation. Fractional oxidation of glucose was constant in control islets over a range of concentrations, whereas islets from hyperglycemic P. obesus showed a decline at high glucose. The mitochondrial substrates alpha-ketoisocaproate and monomethyl succinate had no effect on insulin secretion in P. obesus islets. Basal insulin release in islets from diabetes-resistant P. obesus was unaffected by glucagon-like peptide 1 (GLP-1) or forskolin, whereas that of islets of the diabetic line was augmented by the drugs. GLP-1 and forskolin potentiated the insulin response to maximal (11.1 mmol/l) glucose in islets from all groups. The phorbol ester phorbol myristic acid (PMA) potentiated basal insulin release in islets from prediabetic animals, but not those from hyperglycemic or diabetes-resistant P. obesus. At the maximal stimulatory glucose concentration, PMA potentiated insulin response in islets from normoglycemic prediabetic and diabetes-resistant P. obesus but had no effect on islets from hyperglycemic P. obesus. Maintenance of islets from hyperglycemic P. obesus for 18 h in low (3.3 mmol/l) glucose in the presence of diazoxide (375 pmol/l) dramatically improved the insulin response to glucose and restored the responsiveness to PMA. Immunohistochemical analysis indicated that hyperglycemia was associated with reduced expression of alpha-protein kinase C (PKC) and diminished translocation of lambda-PKC. In summary, we found that 1) P. obesus islets have low oxidative capacity, probably resulting in limited ability to generate ATP to initiate and drive the insulin secretion; 2) insulin response potentiated by cyclic AMP-dependent protein kinase is intact in P. obesus islets, and increased sensitivity to GLP-1 or forskolin in the diabetic line may be secondary to increased sensitivity to glucose; and 3) islets of hyperglycemic P. obesus display reduced expression of alpha-PKC and diminished translocation of lambda-PKC associated with impaired response to PMA. We conclude that low beta-cell oxidative capacity coupled with impaired PKC-dependent signaling may contribute to the animals' poor adaptation to a high-energy diet.
Animals↗
Hyperglycemia contributes to impaired insulin response in GK rat islets.
Insulin secretion and glucose metabolism were compared in pancreatic islets from type 2 diabetic GK rats treated with phlorizin or vehicle. Treatment of control and GK rats with phlorizin for 30 days did not affect body weight, islet glucose utilization, or islet glucose oxidation. In phlorizin-treated GK rats, glucose-induced insulin release was about twofold higher at 11.0 and 16.7 mmol/l glucose compared with vehicle, treated GK rats, whereas phlorizin had no effect on control Wistar rats. However, also in phlorizin-treated GK rats, the amount of insulin released by the islets was significantly less than that from control rats (5.29+/-0.33 vs. 7.50+/-1.31 pmol x min(-1) islet(-1) at 16.7 mmol/l glucose; P<0.001). Islet glucose-6-phosphatase activity was significantly higher in GK rats than in control rats; phlorizin treatment significantly decreased this activity. These findings demonstrate that hyperglycemia per se constitutes an important factor for impaired insulin release in GK rats. Correction of hyperglycemia normalizes islet glucose-6-phosphatase activity, which may be an underlying factor for the partial improvement of glucose-induced insulin release.
Animals↗
Weight gain with risperidone among patients with mental retardation: effect of calorie restriction.
BACKGROUND: The atypical antipsychotics cause weight gain, which is poorly understood in terms of its mechanism and treatment. A usual recommendation for treatment of antipsychotic-induced weight gain includes calorie restriction and exercise. The authors describe their recent clinical experience with calorie restriction in adults with mental retardation treated with risperidone. METHOD: A retrospective chart review was performed on the records of 50 adult patients with mental retardation treated with risperidone while residing at a habilitation center. We assessed dose and duration of risperidone treatment, weight, changes in calorie intake, and frequency of aggressive behavior. RESULTS: Of the 50 patients, 39 had adequate data for analysis. Thirty-seven of the 39 patients gained weight with a mean of 18.8 lb (8.3 kg) over about 2 years. Twenty of the 37 patients were calorie restricted. Three of the 20 calorie-restricted patients lost weight at a rate of 0.2 lb (0.1 kg) per month. The other 17 calorie-restricted patients and the 17 patients who were not calorie restricted continued to gain weight at a rate of 0.8 lb (0.4 kg) per month over about another 2 years of treatment. The amount of weight gain was not dose related. Calorie restriction led to no deterioration in behavior. CONCLUSION: The current investigation lends support to data that note weight gain with risperidone in adults with mental retardation. It suggests that calorie restriction does not lead to weight loss or behavioral deterioration and that weight gain is not dose related.
Aggression↗
Effectiveness of pharmacotherapy for body dysmorphic disorder: a chart-review study.
BACKGROUND: Research on the pharmacotherapy of body dysmorphic disorder (BDD) is limited. No placebo-controlled, continuation, maintenance, or discontinuation studies have been published. Only one augmentation study has been published. METHOD: In this chart-review study of 90 patients with DSM-IV BDD treated for up to 8 years by the first 2 authors (K.A.P., R.S.A.) in their clinical practice, response to a variety of medications, including augmentation strategies, was assessed. The relapse rate with medication discontinuation was also determined. RESULTS: All subjects received a serotonin reuptake inhibitor (SRI), with 63.2% (55/87) of adequate SRI trials resulting in improvement in BDD symptoms; similar response rates were obtained for each type of SRI. Discontinuation of an effective SRI resulted in relapse in 83.8% (31/37) of cases. Response rates to selective SRI augmentation were clomipramine, 44.4% (4/9) of trials; buspirone, 33.3% (12/36) of trials; lithium, 20.0% (1/5); methylphenidate, 16.7% (1/6); and antipsychotics, 15.4% (2/13) of trials. CONCLUSION: These findings from a clinical setting suggest that a majority of BDD patients improve with an SRI and that all SRIs appear effective. Certain SRI augmentation strategies may be beneficial. The high relapse rate with SRI discontinuation suggests that long-term treatment is often necessary. These preliminary findings require confirmation in placebo-controlled efficacy studies and effectiveness studies.
Adolescent↗
Time course of pulmonary response of rats to inhalation of crystalline silica: histological results and biochemical indices of damage, lipidosis, and fibrosis.
Previous studies have determined that alpha-quartz (crystalline silica) can cause pulmonary inflammation, damage, and fibrosis. However, the temporal relationship between silica inhalation and pulmonary inflammation, damage, and fibrosis has not been fully examined. To address this gap in our knowledge of silica-induced pulmonary fibrosis, a chronic inhalation study using rats was designed. Specifically, rats were exposed to a silica aerosol (15 mg/m3 silica, 6 h/d, 5 d/wk, 116 d), and measurements of pulmonary inflammation, damage, and fibrosis were monitored throughout the study. We report (1) data demonstrating that the silica aerosol generation and exposure system produced a consistent silica aerosol of respirable size particles; (2) the time course of silica deposition in the lung; (3) calculations that demonstrate that the rats were not in pulmonary overload; (4) histopathological data demonstrating time-dependent enhancement of silica-induced alveolitis, epithelial hypertrophy and hyperplasia, alveolar lipoproteinosis, and pulmonary fibrosis in the absence of overload; and (5) biochemical data documenting the development of lipidosis, lung damage, and fibrosis.
Administration, Inhalation↗
The skin we are in--knowledge and practices regarding skin cancer in pre-clinical medical students.
OBJECTIVE: To assess the level of knowledge about skin cancer in youth and to explore the influence of gender and system of education on their knowledge and practices. MATERIALS AND METHODS: A questionnaire-based study was conducted at The Aga Khan University Medical College (AKUMC), on Year 2 pre-clinical medical students. Descriptive analyses to examine the frequency distribution, chi-square test and factor analysis were applied using SPSS. RESULTS: Seventyone students participated in the study; 90% scored > 55% in the questions regarding knowledge of Malignant melanoma (MM), whereas in the questions assessing practice only 11% of the respondents scored > 52%. They were largely unaware that appearance of a new mole is a risk factor for MM (56% respondents incorrect) and that skin cancer is one of the most common cancers (54% respondents incorrect). 73% reported being sunburned at least once during childhood and 40% suffered sunburns at least once this summer, which points to the inadequacy of sun protection. The risk of MM may double if severe sunburns are experienced during childhood. Education system and gender did not affect the knowledge and practices. The popular sources of learning about skin cancer were magazines (52%) followed by television (42%). CONCLUSION: There is a need for epidemiological studies in Pakistani population regarding skin cancer. For preventing excessive solar exposure which leads to sunburns, we recommend interventions like a Pilot Program for photoprotection education and Sun Awareness Week to improve knowledge and sun protection behavior.
Adolescent↗
Influenza: recommendations for vaccination and treatment.
Influenza kills millions of people each year and has the potential to kill even more if proper vaccination and treatment protocols are not followed. This review provides the Louisiana State Office of Public Health and the Centers for Disease Control recommendations for vaccination and treatment of influenza.
Humans↗
Behavioral effects of 8-OH-DPAT in single and repeated haloperidol injected rats.
Haloperidol is an antipsychotic drug and shown to be antagonist at D2 receptors and found to cause severe impairment of locomotor performance. The serotonin (5HT1A) receptor agonist 8-OH-DPAT has been reported to attenuate extrapyramidal side effects of haloperidol. The present study was designed to examine the modulatory effect of serotonergic activities on haloperidol induced up-regulation of dopamine D2 receptors. In the acute phase of study, 8-OH-DPAT (0.5 mg/kg/ml) elicited behavioral syndrome was monitored in rats preinjected with haloperidol(5 mg/kg/ml). Results of single haloperidol administration revealed that 8-OH-DPAT induced forepaw treading (p < 0.05) and hyperlocomotion (p < 0.01) were smaller in haloperidol than saline preinjected rats. In repeated phase of study, 8-OH-DPAT (0.5 mg/kg/ml) induced behavioral syndrome was monitored in rats injected with haloperidol for 10 days (x2). The result of repeated haloperidol administration showed that 8-OH-DPAT elicited flat body posture (p < 0.01) was greater in repeated haloperidol injected rats than repeatedly saline injected rats. Relationship between 5HT1A receptors and D2 receptors has been discussed. It is suggested that combining neuroleptics with 5HT1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the development of new compounds that have greater therapeutic potential and/or better tolerated.
Journal Article↗
Type 1 11beta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets.
Metabolic transformation of glucocorticoid hormones constitutes a determinant of their cell-specific effects. The most important reaction for this class of steroids is the reversible C11 keto/beta-hydroxyl conversion between receptor-binding 11beta-OH steroids and the nonbinding 11-oxo compounds, carried out by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). In this study, we determined the role of glucocorticoid conversion by 11beta-HSD in pancreatic islets and its function in the regulation of insulin release. Pancreatic islets isolated from ob/ob mice display type 1 11beta-hydroxysteroid dehydrogenase activity, i.e. in intact cells the reductive reaction prevails, leading from dehydrocorticosterone to corticosterone. Expression of type 1 11beta-HSD mRNA was detected by reverse transcriptase-polymerase chain reaction in islets isolated from ob/ob mice and also from human tissue. Incubation of beta-cells in the presence of 11-dehydrocorticosterone leads to a dose-dependent inhibition of insulin release, indicating cellular activation of 11-dehydrocorticosterone to the receptor ligand, further confirmed by reporter gene assays. Inhibition of 11beta-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11beta-HSD in islets supports the concept that reactivation of inert circulating hormone precursors in a cell-specific manner plays a major role in glucocorticoid physiology in rodents and man.
11-beta-Hydroxysteroid Dehydrogenases↗