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Biomedical subjects

A Khan

Publications and source records attributed to A Khan.

At least 145 records · Page 8Linked to original sources
PubMed2002

Role of outer ring carboxylates of the rat skeletal muscle sodium channel pore in proton block.

Voltage-gated Na+ current is reduced by acid solution. Protons reduce peak Na+ conductance by lowering single channel conductance and shift the voltage range of gating by neutralizing surface charges. Structure-function studies identify six carboxyls and a lysine in the channel's outer vestibule. We examined the roles of the superficial ring of carboxyls in acid block of Na(v)1.4 (the rat skeletal muscle Na+ channel isoform) by measuring the effects of their neutralization or their substitution by lysine on sensitivity to acid solutions, using the two-micropipette voltage clamp in Xenopus oocytes. Alteration of the outer ring of carboxylates had little effect on the voltage for half-activation of Na+ current, as if they are distant from the channels' voltage sensors. The mutations did not abolish proton block; rather, they all shifted the pK(a) (-log of the dissociation constant) in the acid direction. Effects of neutralization on pK(a) were not identical for different mutations, with E758Q > D1241A > D1532N > E403Q. E758K showed double the effect of E758Q, and the other lysine mutations all produced larger effects than the neutralizing mutations. Calculation of the electrostatic potential produced by these carboxylates using a pore model showed that the pK(a) values of carboxylates of Glu-403, Glu-758, and Asp-1532 are shifted to values similar to the experimentally measured pK(a). Calculations also predict the experimentally observed changes in pK(a) that result from mutational neutralization or introduction of a positive charge. We propose that proton block results from partial protonation of these outer ring carboxylates and that all of the carboxylates contribute to a composite Na+ site.

Animals↗
PubMed2002

Relative sensitivity of the Montgomery-Asberg Depression Rating Scale, the Hamilton Depression rating scale and the Clinical Global Impressions rating scale in antidepressant clinical trials.

Although early antidepressant clinical trials simply relied on a clinician's judgment as to whether a depressed patient clinically improved or not, the Hamilton Depression (HAM-D) rating scale has become the 'gold standard' to assess the efficacy of new antidepressants. The alternative Montgomery-Asberg Depression Rating Scale (MADRS) has not achieved general acceptance. However, its ease of use warrants evaluation as to whether it is comparable to HAM-D in its sensitivity in detecting antidepressant-placebo differences in antidepressant clinical trials. A retrospective chart review was performed on the records of 208 depressed adult patients that participated in eight randomized, placebo-controlled, double-blind antidepressant clinical trials at the Northwest Clinical Research Center between 1996 and 2000. We compared the effect sizes of the HAM-D, MADRS and Clinical Impressions Rating Scale (CGI-S for severity and CGI-I for improvement) for patients assigned to placebo or an established antidepressant. The effect size (measured as the mean change in rating with antidepressants minus the mean change for placebo divided by the pooled SD of change, adjusted for age, gender and initial scores) was 0.49 with MADRS, 0.53 with HAM-D, 0.55 with CGI-S and 0.59 with CGI-I. The four rating scales had similar effect sizes regardless of the type of antidepressant evaluated. These data suggest that MADRS is as sensitive an instrument as HAM-D for detecting antidepressant efficacy in clinical trials. Thus, MADRS may be a desirable tool in large-scale, pivotal antidepressant clinical trials.

Adolescent↗
PubMed2002

A molecular linkage map of tomato displaying chromosomal locations of resistance gene analogs based on a Lycopersicon esculentum x Lycopersicon hirsutum cross.

A molecular linkage map of tomato was constructed based on a BC1 population (N = 145) of a cross between Lycopersicon esculentum Mill. line NC84173 (maternal and recurrent parent) and Lycopersicon hirsutum Humb. and Bonpl. accession PI126445. NC84173 is an advanced breeding line that is resistant to several tomato diseases, not including early blight (EB) and late blight (LB). PI126445 is a self-incompatible accession that is resistant to many tomato diseases, including EB and LB. The map included 142 restriction fragment length polymorphism (RFLP) markers and 29 resistance gene analogs (RGAs). RGA loci were identified by PCR amplification of genomic DNA from the BC1 population, using ten pairs of degenerate oligonucleotide primers designed based on conserved leucine-rich repeat (LRR), nucleotide binding site (NBS), and serine (threonine) protein kinase (PtoKin) domains of known resistance genes (R genes). The PCR-amplified DNAs were separated by denaturing polyacrylamide gel electrophoresis (PAGE), which allowed separation of heterogeneous products and identification and mapping of individual RGA loci. The map spanned 1469 cM of the 12 tomato chromosomes with an average marker distance of 8.6 cM. The RGA loci were mapped to 9 of the 12 tomato chromosomes. Locations of some RGAs coincided with locations of several known tomato R genes or quantitative resistance loci (QRLs), including Cf-1, Cf-4, Cf-9, Cf-ECP2, rx-1, and Cm1.1 (chromosome 1); Tm-1 (chromosome 2); Asc (chrromosme 3); Pto, Fen, and Prf (chromosome 5); 01-1, Mi, Ty-1, Cm6.1, Cf-2, CF-5, Bw-5, and Bw-1 (chromosome 6); I-1, 1-3, and Ph-1 (chromosome 7); Tm-2a and Fr1 (chromosome 9); and Lv (chromosome 12). These co-localizations indicate that the RGA loci were either linked to or part of the known R genes. Furthermore, similar to that for many R gene families, several RGA loci were found in clusters, suggesting their potential evolutionary relationship with R genes. Comparisons of the present map with other molecular linkage maps of tomato, including the high density L. esculentum x Lycopersicon pennellii map, indicated that the lengths of the maps and linear order of RFLP markers were in good agreement, though certain chromosomal regions were less consistent than others in terms of the frequency of recombination. The present map provides a basis for identification and mapping of genes and QTLs for disease resistance and other desirable traits in PI126445 and other L. hirsutum accessions, and will be useful for marker-assisted selection and map-based gene cloning in tomato.

Chromosome Mapping↗
PubMed2002

The pathogenesis of oral lichen planus.

Both antigen-specific and non-specific mechanisms may be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8(+) cytotoxic T-cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase (MMP) activation in OLP lesions. These mechanisms may combine to cause T-cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T-cell migration, and keratinocyte apoptosis in OLP. OLP chronicity may be due, in part, to deficient antigen-specific TGF-beta1-mediated immunosuppression. The normal oral mucosa may be an immune privileged site (similar to the eye, testis, and placenta), and breakdown of immune privilege could result in OLP and possibly other autoimmune oral mucosal diseases. Recent findings in mucocutaneous graft-versus-host disease, a clinical and histological correlate of lichen planus, suggest the involvement of TNF-alpha, CD40, Fas, MMPs, and mast cell degranulation in disease pathogenesis. Potential roles for oral Langerhans cells and the regional lymphatics in OLP lesion formation and chronicity are discussed. Carcinogenesis in OLP may be regulated by the integrated signal from various tumor inhibitors (TGF-beta 1, TNF-alpha, IFN-gamma, IL-12) and promoters (MIF, MMP-9). We present our recent data implicating antigen-specific and non-specific mechanisms in the pathogenesis of OLP and propose a unifying hypothesis suggesting that both may be involved in lesion development. The initial event in OLP lesion formation and the factors that determine OLP susceptibility are unknown.

Animals↗
PubMed2002

A neural network approach to burst detection.

This paper describes how hydraulic and water quality data from a distribution network may be used to provide a more efficient leakage management capability for the water industry. The research presented concerns the application of artificial neural networks to the issue of detection and location of leakage in treated water distribution systems. An architecture for an Artificial Neural Network (ANN) based system is outlined. The neural network uses time series data produced by sensors to directly construct an empirical model for predication and classification of leaks. Results are presented using data from an experimental site in Yorkshire Water's Keighley distribution system.

Algorithms↗
PubMed2002

Predictors of inpatient mortality in 190 adult patients with tuberculous meningitis.

INTRODUCTION: Tuberculous meningitis (TBM), a tuberculous infection of the leptomeninges, carries significant morbidity and mortality. To date, little literature is available regarding TBM in Pakistan. METHODS: All adult patients with TBM admitted to a tertiary care teaching hospital in Karachi, were reviewed retrospectively. AIMS: To describe the demographic profile, clinical features, laboratory and radiological picture of these patients and to identify predictors of mortality. RESULTS: Among the 190 patients analyzed, majority (28%) were between 21-30 years of age. Fever (90%), impaired consciousness (63%) and nausea/vomiting (50%) were the most common presenting symptoms. Thirty four percent were categorized as clinical stage III. CSF cultures were positive in only 5%. Thirty seven percent had an associated lung pathology on a chest X-ray. Neuroimaging revealed meningeal enhancement in 27% and hydrocephalus in 23%. All patients were treated with antituberculous therapy; 79% received concomitant steroid therapy. Neurosurgical intervention was required in 13% and mechanical ventilation support in 12%. Overall mortality was 20% and neurological sequelae were seen in 42% of the survivors. Univariate analysis showed age greater than sixty years, clinical stage III and mechanical ventilation as predictors of mortality. The logistic regression model, however, revealed that stage III presentation was not an independent predictor. CONCLUSION: We continue to see late presentations of TBM in our setting. The current study has shown that age greater than sixty years and the need for mechanical ventilation are significant independent predictors of mortality.

Adolescent↗
PubMed2002

Streptococcal antibodies among rural school children in Bangladesh.

The upper limit of normal values of group A streptococcal antibodies should be known for a population concerned because it is influenced by many local conditions. As yet the reference value of the these antibodies has not been determined by using a quantitative method among Bangladeshi children. We determined the reference value of anti-streptolysin O and anti-deoxyribonuclease B among 361 apparently healthy rural Bangladeshi primary school children (aged 5 to 14 years, mean 9.2 years). Anti-streptolysin O was measured by an auto-analyzer and antideoxyribonuclease B was measured by microtitre method. The geometric mean titres for the entire group was 241 IU/ml and 222 IU/ml for anti-streptolysin O and anti-deoxyribonuclease B respectively. The upper limit of normal values (80th percentile) was 390 and 340 for anti-streptolysin O and anti-deoxyribonuclease B, respectively. These limits should be of value to physicians, epidemiologists and clinical laboratory personnel as well.

Adolescent↗
PubMed2001

The changed histologic paradigm of colorectal polyps.

BACKGROUND: Previous literature has recorded the preponderance of hyperplastic over neoplastic polyps. This study evaluated the histopathologic characteristics of colonic polyps, excised during colonoscopic polypectomy, and further determined their relationship to age, location, and gender. METHODS: Of 5132 colonoscopies reviewed between 1976 and 1999, 757 were performed on 582 patients who had polyp removal. Patients with previous colon resection or incomplete cecal intubation were excluded. RESULTS: The mean age was 67 +/- 11 years for men and 66 +/- 11 years for women. Of the 1050 lesions histologically analyzed, 871 (83.0%) were neoplastic, 129 (12.3%) were hyperplastic, and 50 (4.8%) were miscellaneous lesions (29 inflammatory polyps, 14 lipomas, 2 leiomyomas, 1 juvenile polyp, and 4 no pathology identified). Hyperplastic polyps were always less than 1 cm (with one exception) and were located predominantly in the left colon, the majority residing in the sigmoid colon. Peak prevalence of hyperplastic polyps occurred in the 50-70 years old age group. Of the neoplastic polyps, 566 (65.0%) were tubular, 225 (25.8%) villotubular, 63 (7.2%) villous adenomas, 4 (0.5%) mixed adenomatous hyperplastic polyps, and 12 (1.4%) invasive carcinomas. The peak prevalence of neoplastic polyps occurred in the same age group as did hyperplastic polyps. Even though adenomatous polyps outnumbered hyperplastic polyps throughout the colon and within each age group, a greater percentage of hyperplastic polyps were found distally and in younger patients compared to location and age groups for neoplastic polyps. CONCLUSION: Adenomatous polyps outnumber hyperplastic polyps 7:1, even in the distal colon. Even small polyps seen during colonoscopy should be removed and subjected to histologic analysis because of the advisability of follow-up examinations of patients with neoplastic polyps. The increase in the incidence of neoplastic polyps beginning at the age of 50 years supports the need for colonoscopy in these individuals.

Adenomatous Polyps↗
PubMed2001

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report.

BACKGROUND: Tacrolimus (TAC) and mycophenolate mofetil (MMF) are currently approved immunosuppressants for prevention of rejection in liver transplantation (LTx). They have different modes of action and toxicity profiles, but the efficacy and safety of MMF in primary liver transplantation with TAC has not been determined. METHODS: An Institutional Review Board-approved, open-label, single-center, prospective randomized trial was initiated to study the efficacy and toxicity of TAC and steroids (double-drug therapy (D)) versus TAC, steroids, and MMF (triple-drug therapy (T)) in primary adult LTx recipients. Both groups of patients were started on the same doses of TAC and steroids. Patients randomized to T also received 1 gm MMF twice a day. RESULTS: Between August 1995 and May 1998, 350 patients were enrolled at a single center-175 in the D and 175 in the T groups. All patients were followed until May 1998, with a mean follow-up of 33.8+/-9.1 months. Using an intention-to-treat analysis, the 1-, 2-, 3-, and 4-year patient survival was 85.1%, 81.6%, 78.6%, and 75.8%, respectively, for D and 87.4%, 85.4%, 81.3%, and 79.9%, respectively, for T. The 4-year graft survival was 70% for D and 72.1% for T. Although the rate of acute rejection in the first 3 months was significantly lower for T than for D (28% for triple vs. 38.9% for double, P=0.03), the overall rate of rejection for T at the end of 1 year was not significantly lower than for the D (38.9% triple vs. 45.2% double). The median time to the first episode of rejection was 14 days for D versus 24 days for T (P=0.008). During the study period, 38 of 175 patients in D received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 103 patients in the T discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. The need for corticosteroids was less after 6 months for T and the perioperative need for dialysis was lower with use of MMF. CONCLUSION: This final report confirms similar patient survival and graft survival up to 4 years with a trend towards fewer episodes of rejection, lower need for steroids, and better perioperative renal function. However, the complex nature of LTx patients and their posttransplantation course prevents the routine application of MMF.

Adult↗
PubMed2001

Multiple tactile maps in the human cerebellum.

Functional imaging studies of the cerebellum have mostly investigated motor performance or have been limited to the anterior lobe and therefore the somatosensory representations in the human cerebellum have not been fully demonstrated. We used fMRI of the entire cerebellum during tactile stimulation of the hand and foot in six normal subjects. Our results demonstrate that the tactile projections to the cerebellum in humans are represented in both the anterior and posterior lobes. in agreement with previous functional imaging studies, our results show a large-scale, between-limb somatotopy comparable to that shown in early animal studies.

Adult↗
PubMed2001

Stereocontrolled formation of epoxy peroxide functionality appended to a lactam ring.

The action of tert-butyl hydroperoxide and tin(IV) chloride upon allylic alcohols containing a lactam ring leads mainly to epoxy alkyl peroxides with high diastereoselection. Both the stereochemistry and the products formed are in marked contrast to the reactions of the analogous carbocyclic allylic alcohols with tert-butyl hydroperoxide-VO(acac)2.

Journal Article↗
PubMed2001

Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions.

BACKGROUND: Thyroid cancer is the most common endocrine malignant disease, but preoperative diagnosis remains a challenge. Fine-needle aspiration cytology has greatly improved the clinical management of thyroid nodules, but the preoperative characterisation of follicular lesions is very difficult. Many patients are thus referred to surgery more for diagnosis than for therapeutic necessity. We undertook an international multicentre study to assess the usefulness of immunohistocytochemical staining for two potential markers of malignant thyrocytes. METHODS: Expression of galectin-3 and CD44v6 was tested on 1009 thyroid lesions (tissue specimens and cytological cell-blocks) and 226 fresh cytological samples obtained preoperatively by ultrasound-guided fine-needle aspiration of thyroid nodules (prospective analysis). The test used monoclonal antibodies specific for CD44v6 and galectin-3, the indirect avidin-biotin complex immunoperoxidase method, and 3-amino-9-ethyl-carbazole as substrate. FINDINGS: The sensitivity, specificity, positive predictive value, and diagnostic accuracy of this test method (for coexpression of the two markers) in the prospective analysis were 88%, 98%, 91%, and 97%, respectively. The sensitivity and specificity of galectin-3 immunodetection alone in discriminating benign from malignant thyroid lesions were more than 99% and 98% respectively, and the positive predictive value and diagnostic accuracy were 92% and 99%. INTERPRETATION: The integration of galectin-3 immunostaining with conventional cytomorphological and clinical diagnostic procedures represents a sensitive and reliable diagnostic approach for preoperative identification of thyroid carcinomas. This test method improves the diagnostic accuracy of conventional cytology and provides the molecular basis for a new nosological assignation of the not yet classified thyroid neoplasms of indeterminate malignant behaviour.

Antigens, Differentiation↗
PubMed2001

Serotonin activates S6 kinase in a rapamycin-sensitive manner in Aplysia synaptosomes.

The identification of tags that can specifically mark activated synapses is important for understanding how long-term synaptic changes can be restricted to specific synapses. The maintenance of synapse-specific facilitation in Aplysia sensory to motor neuron cultures can be blocked by inhibitors of translation and by the drug rapamycin, which specifically blocks a signaling pathway that regulates phosphorylation of translational regulators. One important target of rapamycin is the phosphorylation and subsequent activation of S6 kinase. To test whether S6 kinase is the target for the ability of rapamycin to block synapse-specific facilitation in Aplysia, we cloned Aplysia S6 kinase, its substrate S6, and the S6 kinase kinase phosphoinositide-dependent kinase 1 (PDK-1). Serotonin, which induces synapse-specific facilitation, increased phosphorylation of Aplysia S6 kinase at threonine 399 in a rapamycin-sensitive manner in Aplysia synaptosomes. The phosphorylation of threonine 399 by 5-HT was independent of phosphoinositide-3 kinase, dependent on PKA and PKC, and occluded by the phosphatase inhibitor calyculin-A. 5-HT also increased S6 kinase activity and led to increased phosphorylation of S6 in synaptosomes. 5-HT increased levels of S6 in synaptosomes because of a rapamycin-sensitive increase in translation-stabilization of S6. Aplysia PDK-1 bound to and phosphorylated Aplysia S6 kinase but only modulated phosphorylation of threonine 399 indirectly. These results suggest a mechanism by which the levels of translation factors can be increased specifically at activated synapses generating a long-lasting synaptic tag.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2001

Sonographic appearance of primary liver liposarcoma.

Primary malignant mesenchymal tumors of the liver are extremely rare. We report a case of a primary liposarcoma in the right hepatic lobe of a 50-year-old man. Sonography showed a poorly defined, lobulated, infiltrating echogenic tumor with shadowing. Within the tumor were hyperechoic and hypoechoic foci thought to represent areas of hemorrhage and necrosis. Color Doppler sonography showed the mass to be avascular. A low-attenuation mass of fat density was confirmed on CT. The resected tumor was reasonably well circumscribed, with demonstrable infiltration of the liver parenchyma. Histologic analysis showed liposarcoma with high-grade sarcomatous features.

Humans↗
PubMed2001

Transradial renal angioplasty: initial experience.

We report our early experience of a new technique of renal angioplasty utilizing the radial approach. Certain anatomic considerations continue to make access from above via the arm the preferable approach in selected patients in renal artery stenosis. We have utilized the transradial technique for renal artery angioplasty and stenting successfully in four patients. The development of coronary guidewire (0.014")-based peripheral balloons and stent delivery systems has miniaturized equipment sufficiently to make the transradial approach attractive. Present equipment allows for stenting of renal arteries of up to 7 mm with the use of 6 Fr guiding catheters. Present equipment length remains a limitation in taller patients. The transradial approach should be considered in those patients with renal artery or aortoiliac anatomy favoring an approach from the arm.

Aged↗