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Biomedical subjects

S Malik

Publications and source records attributed to S Malik.

At least 55 records · Page 3Linked to original sources
PubMed2000

Evaluation of the clinical usefulness of C. difficile toxin testing in hospitalized patients with diarrhea.

Although numerous studies have evaluated the sensitivity and specificity of different assays for Clostridium difficile toxin, none has evaluated how physicians utilize these tests or respond to test results. Therefore, we assessed patient characteristics, clinical findings, and physician responses to positive and negative assay results at two university-affiliated hospitals, one of which used a cell cytotoxicity assay to test for C. difficile toxin and the other of which used an enzyme immunoassay. Two hundred one patient samples at Hospital A and 199 samples at Hospital B were assessed. Positive toxin assays were more frequent at Hospital A than at Hospital B (p < 0.001), at least in part due to the fact that patients tested at Hospital A were more likely to have fever (p < 0.001), an abnormal abdominal exam (p < 0.001), an abnormal leukocyte count (p < 0.001), and a history of prior antibiotic use (p < 0.001). Empiric therapy for C. difficile before results of the toxin assay was more common (p < 0.001) at Hospital A (83/201, 41. 3%) than at Hospital B (25/199, 12.5%). Once empiric therapy was started, most physicians continued therapy despite negative test results (Hospital A, 76%; Hospital B, 69%). Patients who were treated empirically were more likely than patients not treated empirically to have positive toxin assay results and to have fever (p < 0.001), an abnormal abdominal exam (p = 0.003), or an abnormal leukocyte count (p < 0.05). Physicians seldom ordered repeat toxin assays (Hospital A, 14%; Hospital B, 10%) if the initial assay result was negative. In logistic regression analysis, predictors of a positive toxin assay were prior antibiotic therapy, an abnormal abdominal exam, residence at Hospital A, and age >/= 60 years. Predictors of empiric therapy were residence at Hospital A and prior antibiotic therapy. Because physicians electing to empirically treat inpatients with diarrhea rarely alter therapy based on C. difficile toxin assay results, a more cost-effective management strategy may be not to obtain a toxin assay at all in such situations. Testing should be limited to patients who have received antibiotics within the prior month and who have significant diarrhea and/or abdominal pain.

Bacterial Toxins↗
PubMed2000

Transcriptional regulation through Mediator-like coactivators in yeast and metazoan cells.

A novel multiprotein complex has recently been identified as a coactivator for transcriptional control of protein-encoding genes by RNA polymerase II in higher eukaryotic cells. This complex is evolutionarily related to the Mediator complex from yeast and, on the basis of its structural and functional characteristics, promises to be a key target of diverse regulatory circuits.

Animals↗
PubMed2000

The USA-derived transcriptional coactivator PC2 is a submodule of TRAP/SMCC and acts synergistically with other PCs.

PC2, the high-molecular weight constituent of the potent USA transcriptional coactivator fraction, was identified as a Mediator-like complex. Its composition resembles that of the TRAP/SMCC complex, but PC2 is distinguished by the prominent absence of the SRB10 and SRB11 kinase/cyclin pair, as well as several additional polypeptides. Furthermore, affinity-purified PC2, which lacks independent activity, acts in synergy with USA-derived coactivators PC3/topoisomerase I and PC4 to mediate the effects of a variety of activators (including VP16, the synthetic activator GAL4-AH, and the orphan nuclear receptor HNF4) and thus recapitulates partial USA coactivator function.

HeLa Cells↗
PubMed2000

Microphotometric analysis of NADH-tetrazolium reductase deficiency in fibroblasts of patients with Leber hereditary optic neuropathy.

We employed a microphotometric approach to examine whether a defect in the mitochondrial respiratory complex I expected in Leber hereditary optic neuropathy (LHON) as the consequence of a mtDNA (11778G>A) mutation in the ND4 gene coding for a subunit of the respiratory complex I can be detected at the single-cell level. Genetically stable fibroblast cell lines were established from skin biopsies of two members of a Chinese Indonesian family with LHON. The fibroblasts were homoplasmic for the 11778G>A mutation. The activity of the respiratory complex I was examined histochemically by staining for NADH-tetrazolium reductase. The histochemical staining showed a typical pattern with an apparent concentration of the activity around the nucleus, suggested as the reflection of the gradient in the thickness of the unsectioned fibroblast cells. Microphotometric quantification of the staining intensity showed that the activity is linear for at least 60 min. The activity shows a discontinuity in its Arrhenius kinetics with a break point at 13.0-13.5 degrees C (activation energy at 50-58 J/mol and 209-238 J/mol above and below the break temperature, respectively), indicating the membrane association of the NADH-tetrazolium reductase activity. Both patients showed lower fibroblast NADH-tetrazolium reductase activity, with a reduction of degrees 30%. Our results demonstrate the utility of microphotometric analysis in the study of biochemical defects associated with mutations in the mtDNA.

Cell Line↗
PubMed2000

Students, tutors and relationships: the ingredients of a successful student support scheme.

BACKGROUND: Medical students suffer from stress and psychological morbidity. Much of this stress is related to uncertainty about course work and workload. Although several student support systems are on offer at various medical schools, few have been shown to meet the needs of students. OBJECTIVE: To evaluate one student support scheme and determine the factors which are essential for success. METHOD: A total of 144 second- and third-year medical students were randomly selected at the University of Dundee. They were asked to complete questionnaires regarding contact with their personal tutors, frequency of meetings, activities during meetings, opinions on how to improve the system and how satisfied they were with the present system. In addition 28 tutors were also asked to complete a questionnaire which matched as far as possible that for students. Qualitative data was collected from semi-structured interviews, free-text responses from questionnaires, email communications with student group representatives and telephone interviews. RESULTS: The scheme was rated as successful or very successful by 25 (18.4%) students and five (29.4%) tutors. A high success rating was associated with regular and frequent meetings, with tutors actively seeking their students and taking part in social as well as academic activities. CONCLUSIONS: The relationship that is formed between students and tutors is the most important factor contributing to the success of the scheme. Taking part in social activities encourages the relationship to develop, whilst addressing academic problems helps to meet the needs of students. Those students who fail exams appear to have the same needs as those who pass.

Education, Medical, Undergraduate↗
PubMed2000

World-wide genetic differentiation of Eubalaena: questioning the number of right whale species.

Few studies have examined systematic relationships of right whales (Eubalaena spp.) since the original species descriptions, even though they are one of the most endangered large whales. Little morphological evidence exists to support the current species designations for Eubalaena glacialis in the northern hemisphere and E. australis in the southern hemisphere. Differences in migratory behaviour or antitropical distribution between right whales in each hemisphere are considered a barrier to gene flow and maintain the current species distinctions and geographical populations. However, these distinctions between populations have remained controversial and no study has included an analysis of all right whales from the three major ocean basins. To address issues of genetic differentiation and relationships among right whales, we have compiled a database of mitochondrial DNA control region sequences from right whales representing populations in all three ocean basins that consist of: western North Atlantic E. glacialis, multiple geographically distributed populations of E. australis and the first molecular analysis of historical and recent samples of E. glacialis from the western and eastern North Pacific Ocean. Diagnostic characters, as well as phylogenetic and phylogeographic analyses, support the possibility that three distinct maternal lineages exist in right whales, with North Pacific E. glacialis being more closely related to E. australis than to North Atlantic E. glacialis. Our genetic results provide unequivocal character support for the two usually recognized species and a third distinct genetic lineage in the North Pacific under the Phylogenetic Species Concept, as well as levels of genetic diversity among right whales world-wide.

Animals↗
PubMed2000

Contribution of Ras GTPase/MAP kinase and cytochrome P450 metabolites to deoxycorticosterone-salt-induced hypertension.

We recently reported that norepinephrine and angiotensin II activate the Ras/mitogen-activated protein (MAP) kinase pathway through generation of a cytochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this study was to determine the contribution of Ras/MAP kinase to deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Administration of DOCA and 1% saline drinking water to uninephrectomized rats for 6 weeks significantly elevated mean arterial blood pressure (MABP) (166+/-5 mm Hg, n=19) compared with that of normotensive controls (95+/-5 mm Hg, n=7) (P<0.05). The activity of Ras and MAP kinase measured in the heart was increased in DOCA-salt hypertensive rats. Infusion of the Ras farnesyl transferase inhibitors FPT III (138 ng/min) and BMS-191563 (694 ng/min) significantly (P<0.05) attenuated MABP to 139+/-4 mm Hg (n=14) and 126+/-1 mm Hg (n=4), respectively. Moreover, infusion of MAP kinase kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats. Morphological studies of the kidney showed that treatment of rats with FPT III, which reduced Ras activity, minimized the hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis observed in untreated hypertensive rats. In addition, the rise in CYP450 activity and MABP in hypertensive rats was prevented by the CYP450 inhibitor aminobenzotriazole (50 mg/kg) and was associated with a decrease in Ras and MAP kinase activity in the heart. These data suggest that the Ras/MAP kinase pathway contributes to DOCA-salt-induced hypertension and associated vascular pathology consequent to activation of CYP450.

Alkyl and Aryl Transferases↗
PubMed2000

Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia.

Endometrial growth and repair after menstruation are associated with profound angiogenesis. Abnormalities in these processes result in excessive or unpredictable bleeding patterns and are common in many women. It is therefore important to understand which factors regulate normal endometrial angiogenesis. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that plays an important role in normal and pathological angiogenesis. In this study we show that expression of VEGF is regulated by hypoxia in human endometrium. Culture in vitro for 24 h under hypoxic conditions resulted in a 2- to 6-fold increase in VEGF secretion by both stromal and epithelial cells isolated from human endometrium. Quantitative RT-PCR was used to measure VEGF messenger ribonucleic acid (mRNA) levels in these cells. After hypoxia, VEGF mRNA levels increased 1.8-fold in stromal cells and 3.4-fold in glandular epithelial cells. The mRNA for each VEGF splice variant increased to an equal extent. The increase in VEGF secretion by stromal and epithelial cells in response to hypoxia was not altered by treatment at the same time with estradiol or progesterone. In situ hybridization of human endometrium during menstruation, when steroid levels are low but the tissue is subject to ischemia, showed strong hybridization to VEGF mRNA in both stromal and glandular cells. These results show that local factors, such as hypoxia, can regulate VEGF expression in the endometrium. This may play an important part in normal endometrial repair after menstruation. The secretion of VEGF by endometrial cells under hypoxic conditions may also be important in the pathogenesis of endometriosis, because it would be predicted to assist revascularization of desquamated endometrial explants when they attach at ectopic sites.

Adult↗
PubMed2000

Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons.

Interleukin-1beta (IL-1beta), a polypeptide immune mediator, is induced within the central nervous system in response to a variety of pathological stimuli, including systemic infection, hypoxia, brain trauma, and seizure. IL-1beta action on the gamma-aminobutyric acid type A (GABA(A)) inhibitory neurotransmitter receptor was investigated in whole cell patch-clamped cultured hippocampal neurons. Application of IL-1beta at concentrations encountered in pathophysiological conditions (1-10 ng/ml; 59-590 pM) irreversibly decreased the peak magnitude of current elicited by 30 microM GABA. Current inhibition was IL-1beta concentration- and time-dependent and was prevented by a specific IL-1beta type I receptor antagonist. No significant changes in current kinetics or reversal potential were observed. The IL-1beta depression of GABA current was inhibited by high concentrations of nonspecific kinase inhibitors staurosporine (500 nM) and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7; 50 microM), but not by a protein kinase C selective inhibitor calphostin C (5 microM). We conclude that IL-1beta inhibits GABA(A) receptor function in hippocampal neurons by the involvement of an unidentified kinase. This blockade of the GABA(A) inhibitory neurotransmitter receptor may underlie the central nervous system hyperexcitability seen in many pathophysiological conditions.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2000

The efficacy and safety of cefaclor in respiratory infections amongst Pakistani children.

PURPOSE: To evaluate the efficacy and safety of Cefaclor in respiratory tract infections amongst Pakistani children. PATIENTS AND METHODS: Multicenter, open label and non-comparative study was done to evaluate the response in terms of symptoms (In vivo) and bacterial cultures (In Vitro) to Cefaclor amongst children with respiratory tract infection between the ages 2 months to 12 years. Each patient was asked to visit the doctor on three occasions i.e., Day 0 (Initial evaluation prior to commencement of study), Day 4 (During therapy assessment and confirmation of compliance) and Day 10 (End of therapy assessment and compliance evaluation). Representative swab specimens (Throat swabs, Ear swabs or Sputum) were collected from the infected site on day 0 and day 10 for culture and sensitivity. Patients were also assessed by the evaluators on each visit in terms of clinical symptomatic response and information collected was documented on a prescribed data base form. RESULTS: A total of 160 patients were enrolled in the study, of whom 15 were lost to follow-up between the first and second visit and a further 38 were lost by the 3rd visit. Thus 107 patients completed the study as per protocol. Otitis media and Upper respiratory tract infection were the predominant ailments amongst the cases enrolled. One or more bacteria were isolated in 75 (46%) instances, the maximum number of isolates being from ear swabs of Otitis media patients. Beta haemolytic Streptococcus (group A,C,F,G) seen in 18 cases was the most common pathogen reported followed by Staphylococcus aureus, H. influenzae and Streptococcus pneumoniae in 13,12 and 11 cases respectively. Sensitivity of Cefaclor for bacteria commonly seen in the respiratory tract was greater than 90% in most of the cases. Evaluation of the 42 culture proven cases for patients who completed the study showed that Cefaclor had a 93% efficacy for indicated bacteria and 54% for non-indicated bacteria. In Vivo analysis of Cefaclor (i.e. on the basis of symptomatic response) showed that 96% cases had a symptomatic response by the second visit, which improved to 97% by the third visit. Only 15 non-serious adverse events were observed in 160 patients, none of the cases necessitated discontinuation of drug. Mild gastrointestinal symptom was the most common adverse event reported. CONCLUSION: Cefaclor was found to be a safe and efficacious drug in the treatment of bacterial respiratory tract infections amongst Pakistani children.

Bacterial Infections↗
PubMed1999

Solution and adsorption behaviour of lecithin surfactants in CFC suspensions: a light scattering study in aerosol propellants.

The behaviour of the lecithin Epikuron 200 was studied in solution in a chlorofluorocarbon (CFC) aerosol propellant (P113) using light scattering to determine the micellar structure as a function of temperature. At room temperature Epikuron 200 formed micelles with a radius of approximately 25 nm. The radius increased with decreasing temperature until a phase boundary was reached at 15-16 degrees C, below which the micellar radius increased rapidly to 150-250 nm. This was accompanied by a large increase in the viscosity and turbidity of the solution. We consider that this behaviour is due to the formation of large wormlike micelles similar to those reported for lecithin in cyclohexane. The adsorption of Epikuron 200 on salbutamol sulphate was measured over this temperature range. The adsorbed amount of Epikuron 200 increased with decreasing temperature, and the hemimicelle concentration decreased rapidly at a temperature corresponding to the threshold for the formation of wormlike micelles. It is likely that these structures do form in CFC-MDI systems (particularly during cold-fill formulation), and that the structure of the adsorbed surfactant layer changes at low temperature. This may have implications for the formulation of stable aerosol suspensions.

Adsorption↗
PubMed1999

Thyroid hormone receptor-associated proteins and general positive cofactors mediate thyroid hormone receptor function in the absence of the TATA box-binding protein-associated factors of TFIID.

Coactivators previously implicated in ligand-dependent activation functions by thyroid hormone receptor (TR) include p300 and CREB-binding protein (CBP), the steroid receptor coactivator-1 (SRC-1)-related family of proteins, and the multicomponent TR-associated protein (TRAP) complex. Here we show that two positive cofactors (PC2 and PC4) derived from the upstream stimulatory activity (USA) cofactor fraction act synergistically to mediate thyroid hormone (T3)-dependent activation either by TR or by a TR-TRAP complex in an in vitro system reconstituted with purified factors and DNA templates. Significantly, the TRAP-mediated enhancement of activation by TR does not require the TATA box-binding protein-associated factors of TFIID. Furthermore, neither the pleiotropic coactivators CBP and p300 nor members of the SRC-1 family were detected in either the TR-TRAP complex or the other components of the in vitro assay system. These results show that activation by TR at the level of naked DNA templates is enhanced by cooperative functions of the TRAP coactivators and the general coactivators PC2 and PC4, and they further indicate a potential functional redundancy between TRAPs and TATA box-binding protein-associated factors in TFIID. In conjunction with earlier studies on other nuclear receptor-interacting cofactors, the present study also suggests a multistep pathway, involving distinct sets of cofactors, for activation of hormone responsive genes.

Animals↗
PubMed1999

A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation.

A novel human complex that can either repress activator-dependent transcription mediated by PC4, or, at limiting TFIIH, act synergistically with PC4 to enhance activator-dependent transcription has been purified. This complex contains homologs of a subset of yeast mediator/holoenzyme components (including SRB7, SRB10, SRB11, MED6, and RGR1), homologs of other yeast transcriptional regulatory factors (SOH1 and NUT2), and, significantly, some components (TRAP220, TRAP170/hRGR1, and TRAP100) of a human thyroid hormone receptor-associated coactivator complex. The complex shows direct activator interactions but, unlike yeast mediator, can act independently of the RNA polymerase II CTD. These findings demonstrate both positive and negative functional capabilities for the human complex, emphasize novel (CTD-independent) regulatory mechanisms, and link the complex to other human coactivator complexes.

Cloning, Molecular↗
PubMed1999

Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators.

The human thyroid hormone receptor-associated protein (TRAP) complex, an earlier described coactivator for nuclear receptors, and an SRB- and MED-containing cofactor complex (SMCC) that mediates activation by Gal4-p53 are shown to be virtually the same with respect to specific polypeptide subunits, coactivator functions, and mechanisms of action (activator interactions). In parallel with ligand-dependent interactions of nuclear receptors with the TRAP220 subunit, p53 and VP16 activation domains interact directly with a newly cloned TRAP80 subunit. These results indicate novel pathways for the function of nuclear receptors and other activators (p53 and VP16) through a common coactivator complex that is likely to target RNA polymerase II. Identification of the TRAP230 subunit as a previously predicted gene product also suggests a coactivator-related transcription defect in certain disease states.

Amino Acid Sequence↗
PubMed1999

Rhinovirus infections in myelosuppressed adult blood and marrow transplant recipients.

Scant data are available on the clinical significance of rhinovirus infections in immunocompromised patients. We reviewed the clinical courses of and outcomes for 22 myelosuppressed adult blood and marrow transplant recipients with rhinovirus infections who were hospitalized at the M.D. Anderson Cancer Center (Houston) from January 1992 to January 1997. In 15 patients (68%), illnesses remained confined to the upper respiratory tract. Seven patients (32%) developed fatal pneumonia. These patients had profound respiratory failure a mean of 12 days (range, 3-21 days) after the onset of symptoms. In six of these seven cases, rhinovirus was isolated before death from a bronchoalveolar lavage fluid specimen and/or an endotracheal aspirate. Five patients underwent autopsies, one of which revealed disseminated aspergillosis and four of which revealed interstitial pneumonitis and/or acute respiratory distress syndrome and no other organisms. In conclusion, rhinovirus infections may be associated with considerable pulmonary-related morbidity and mortality in severely myelosuppressed immunocompromised patients.

Adult↗