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Biomedical subjects

S Ali

Publications and source records attributed to S Ali.

At least 127 records · Page 7Linked to original sources
PubMed1999

Disabled infectious single-cycle herpes simplex virus as an oncolytic vector for immunotherapy of colorectal cancer.

New modalities of treatment for colorectal cancer are required to support and improve those currently available. One such approach is immunotherapy by transfer of immunostimulatory genes to tumor cells. Here, we report the use of a herpes simplex virus (HSV) vector that is capable of a single round of infection (disabled infectious single-cycle [DISC]-HSV) as a gene transfer vehicle for colorectal cancer. This vector has potential advantages over other vectors for cancer immunotherapy in that it lyses infected tumor cells. Infection with DISC-HSV inhibited tumor cell growth both in vitro and in vivo. In addition, DISC-HSV-mediated cell killing occurs by both apoptotic and necrotic mechanisms. A range of colorectal tumor cell lines could be rapidly transduced with DISC-HSV/lacZ (14-90% in 4 hr). Both tumor prevention and tumor therapy protocols showed clear antitumor effects with DISC-HSV/mGM-CSF. In the prophylactic approach, an infected/irradiated whole cell vaccine protected up to 80% of mice from rechallenge. In addition, intratumoral injection of established tumors with DISC-HSV/GM-CSF caused rejection in 40% of mice and generated some protection from subsequent rechallenge. In both cases, however, it is clear that a dominant therapeutic effect of the DISC-HSV vector derives from its oncolytic properties, irrespective of the transduced gene. As a prelude to taking these studies forward to human clinical trials, we demonstrate that tumor cells could be successfully grown from freshly obtained human colorectal cancer resections (within 1 week of surgery), were transduced with DISC-HSV/hGM-CSF, and secreted the cytokine. This study provides the preclinical basis for trials of immunotherapy of colorectal cancer using DISC-HSV.

Animals↗
PubMed1999

Ecological analysis of ethnic differences in relation between tuberculosis and poverty.

OBJECTIVE: To examine the effect of ethnicity on the relation between tuberculosis and deprivation. DESIGN: Retrospective ecological study comparing incidence of tuberculosis in white and south Asian residents of the 39 electoral wards in Birmingham with ethnic specific indices of deprivation. SETTING: Birmingham, 1989-93. SUBJECTS: 1516 notified cases of tuberculosis. MAIN OUTCOME MEASURES: Rates of tuberculosis and measures of deprivation. RESULTS: Univariate analysis showed significant associations of tuberculosis rates for the whole population with several indices of deprivation (P<0.01) and with the proportion of the population of south Asian origin (P<0.01). All deprivation covariates were positively associated with each other but on multiple regression, higher level of overcrowding was independently associated with tuberculosis rates. For the white population, overcrowding was associated with tuberculosis rates independently of other variables (P=0.0036). No relation with deprivation was found for the south Asian population in either single or multivariable analyses. CONCLUSIONS: Poverty is significantly associated with tuberculosis in the white population, but no such relation exists for those of Asian ethnicity. These findings suggest that causal factors, and therefore potential interventions, will also differ by ethnic group.

Adolescent↗
PubMed1999

Characteristics of EGFR family-mediated HRG signals in human ovarian cancer.

The ability of the epidermal growth factor receptor (EGFR) family members, EGFR, HER2, HER3, and HER4, to form homo- and heterodimers after interaction with different ligands expands the signal diversity of these proteins. We investigated their mechanism of activation by exogenous EGF and heregulin (HRG) in human ovarian carcinoma cell lines which express different amounts and combinations of the four receptors. Consistently the predominant interaction after EGF treatment was between EGFR and HER2, whereas activation of HER3 and HER4 depended on the relative abundance of the four receptors in the cells. Remarkably HER3 activation by HRG could occurs independent of HER2, and in one cell line almost no HER4 activation by HRG was detected despite high levels expression. Both EGF and HRG induced activation of mitogen-activated protein kinase (MAPK), but the time course of MAPK activation differed depending on the hetero-dimers induced. EGF and HRG mediated cell growth through the EGFR/HER2 heterodimer and HER4, respectively, but not through HER3 when it was the only HRG receptor expressed and phosphorylated in the cells. These findings reveal a distinct pattern of HRG induced EGFR family interaction in ovarian cancer that is distinct from that described in human breast cancer. Moreover EGF and HRG can exert distinct biological functions depending on the receptor complexes induced in a given ovarian cancer cell line.

DNA Replication↗
PubMed1999

Bacterial xylanase expression in mammalian cells and transgenic mice.

The energy which simple-stomached livestock can derive from dietary plant material is limited by the lack of plant polysaccharide degrading enzymes in their gastro-intestinal (GI) tract and the inefficient microbial fermentation of such material in their hind-gut. In poultry the non-starch polysaccharides found in cereal grains can also impair normal digestive function as they form viscous gels in the GI tract inhibiting the breakdown and absorption of nutrients. The nutrition of such livestock could, therefore, be improved by the introduction of enzymes able to degrade plant polysaccharides in the small intestine. We describe the expression of a xylanase, XYLY', from the bacterium Clostridium thermocellum in mammalian cells and the exocrine pancreas of transgenic mice. The enzyme is synthesised, secreted and functionally active in the eukaryote system. This work demonstrates the feasibility of generating animals with the endogenous capacity to depolymerise the xylan component of hemi-cellulose.

Animals↗
PubMed1999

Characterization of a species-specific repetitive DNA from a highly endangered wild animal, Rhinoceros unicornis, and assessment of genetic polymorphism by microsatellite associated sequence amplification (MASA).

We have cloned and sequenced a 906bp EcoRI repeat DNA fraction from Rhinoceros unicornis genome. The contig pSS(R)2 is AT rich with 340 A (37.53%), 187 C (20.64%), 173 G (19.09%) and 206 T (22.74%). The sequence contains MALT box, NF-E1, Poly-A signal, lariat consensus sequences, TATA box, translational initiation sequences and several stop codons. Translation of the contig showed seven different types of protein motifs, among which, EGF-like domain cysteine pattern signatures and Bowman-Birk serine protease inhibitor family signatures were prominent. The presence of eukaryotic transcriptional elements, protein signatures and analysis of subset sequences in the 5' region from 1 to 165nt indicating coding potential (test code value=0.97) suggest possible regulatory and/or functional role(s) of these sequences in the rhino genome. Translation of the complementary strand from 906 to 706nt and 190 to 2nt showed proteins of more than 7kDa rich in non-polar residues. This suggests that pSS(R)2 is either a part of, or adjacent to, a functional gene. The contig contains mostly non-consecutive simple repeat units from 2 to 17nt with varying frequencies, of which four base motifs were found to be predominant. Zoo-blot hybridization revealed that pSS(R)2 sequences are unique to R. unicornis genome because they do not cross-hybridize, even with the genomic DNA of South African black rhino Diceros bicornis. Southern blot analysis of R. unicornis genomic DNA with pSS(R)2 and other synthetic oligo probes revealed a high level of genetic homogeneity, which was also substantiated by microsatellite associated sequence amplification (MASA). Owing to its uniqueness, the pSS(R)2 probe has a potential application in the area of conservation biology for unequivocal identification of horn or other body tissues of R. unicornis. The evolutionary aspect of this repeat fraction in the context of comparative genome analysis is discussed.

Animals↗
PubMed1999

Sub-national response in HIV/AIDS: a case study in AIDS prevention and control from Sindh province, Pakistan.

HIV/AIDS in Pakistan is slowly gaining recognition as a public health issue of great importance. However, the responses to the disease have been marred by lack of coordination and commitment. We examine, in this paper, the situation in the Sindh province of Pakistan, which is recognized as having the sole fully functioning AIDS prevention and control programme in the country. In discussing the results of the Sindh programme's activities we highlight progress made as well as gaps in data and surveillance. We also recommend strategies for implementation at the provincial and national levels. In addition this example of a sub-national government programme provides a case study for similar programmes in the region.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Bcl10 is not a target for frequent mutation in human carcinomas.

The recently described Bcl10 gene has been suggested to be a major target gene for inactivation in a variety of human cancers. In order to further evaluate the role of this gene in human adult malignancies, we have analysed a series of carcinomas for mutations in the Bcl10 gene. We have screened a panel of 174 carcinoma samples in total, comprised of 47 breast, 36 epithelial ovarian, 36 endometrial, 12 cervical, 23 colorectal and 20 head/neck carcinomas, all unselected for grade or stage. This panel reflects, in part, tumours reported to have involvement of the 1p22 region of chromosome 1, the region harbouring the Bcl10 gene. No deleterious mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not a common target for inactivation in adult malignancies and that BCL10 is not the gene targeted for frequent inactivation at 1p22.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Bladder cancer immunogenicity: expression of CD80 and CD86 is insufficient to allow primary CD4+ T cell activation in vitro.

Transitional cell carcinomas (TCC) of the urinary bladder are known to express proteins which can yield potentially immunogenic peptide epitopes for expression in the context of cell surface class I or class II MHC antigens. However, additional costimulatory ligands must also be expressed before such a cell might directly induce full activation and proliferation of resting, antigen-specific T lymphocytes. Intravesical therapy might be used to manipulate T cell costimulation in order to promote specific rejection of TCC cells. This in vitro study examined the potential of such a strategy by transfection of the prototypical TCC line J82 with the important costimulatory molecules CD80 (B7-1) and CD86 (B7-2). Untransfected J82 cells expressed class I and II MHC antigens, a range of cell adhesion molecules, though did not induce T cell proliferation in a robust, allogeneic co-culture system. Transfected J82 cells expressed CD80 or CD86 at levels comparable to an antigen-presenting B cell line. Furthermore, functional surface expression of CD80 and CD86 was demonstrated in a mitogen-dependent assay of costimulation. However, neither CD80+ nor CD86+ transfectant J82 cells could induce significant proliferation of antigen-specific CD4+ T cells. Further analysis showed that bystander J82 cells could inhibit independent T cell activation in an effect dependent on direct cell contact. This inhibitory effect was associated with increased cell death in the responding lymphocyte population and is concordant with surface expression of CD95L by the J82 cell line.

Antigens, CD↗
PubMed1999

Intracellular redox state determines whether nitric oxide is toxic or protective to rat oligodendrocytes in culture.

We found that several nitric oxide donors had similar potency in killing mature and immature forms of oligodendrocytes (OLs). Because of the possibility of interaction of nitric oxide with intracellular thiols, we tested the effect of the nitrosonium ion donor S-nitrosylglutathione (SNOG) in OL cultures in the setting of cystine deprivation, which has been shown to cause intracellular glutathione depletion. Surprisingly, the presence of 200 microM SNOG completely protected OLs against the toxicity of cystine depletion. This protection appeared to be due to nitric oxide, because it could be blocked by hemoglobin and potentiated by inclusion of superoxide dismutase. We tested the effect of three additional NO* donors and found that protection was not seen with diethylamine NONOate, a donor with a half-life measured in minutes, but was seen with dipropylenetriamine NONOate and diethylaminetriamine NONOate, donors with half-lives measured in hours. This need for donors with longer half-lives for the protective effect suggested that NO* was required when intracellular thiol concentrations were falling, a process evolving over hours in medium depleted of cystine. These studies suggest a novel protective role for nitric oxide in oxidative stress injury and raise the possibility that intracerebral nitric oxide production might be a mechanism of defense against oxidative stress injury in OLs.

Animals↗
PubMed1999

Prevalence of HLA sensitization in female apheresis donors.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a serious complication of plasma-containing blood components. Studies have implicated HLA antibodies along with biologically active lipids in stored blood in the pathogenesis of TRALI. It has been proposed that the exclusion of HLA-untested, multiparous donors of plasma-rich components, including plasma and single-donor apheresis platelets, would substantially reduce the risk of TRALI. STUDY DESIGN AND METHODS: To investigate the feasibility of such an exclusion, 332 female plateletpheresis donors with a record of over 9000 donations, none of which were associated with TRALI, were studied. RESULTS: Seventeen percent of female donors demonstrated HLA sensitization. Parity and HLA sensitization were significantly correlated (p<0.0001), with sensitized donors having an average of 2.9 (+/- 0.6 95% CI) prior pregnancies and unsensitized donors having an average of 1.8 (+/- 0.2 95% CI) prior pregnancies. The percentage of HLA-sensitized women with 0, 1 to 2, and > or = 3 pregnancies was 7.8, 14.6, and 26.3, respectively. CONCLUSION: These findings confirm the hypothesis that multiparous women (> or = 3 pregnancies) represent an increased potential risk for TRALI. However, the exclusion of multiparous plateletpheresis donors would eliminate one-third of our female donor pool. Screening such donors for HLA sensitization may represent the optimal approach for identifying donors at risk for causing TRALI, but this still would result in the deferral of 8 percent of female plateletpheresis donors. At present, prospective screening to identify donors at risk for causing TRALI is not justified.

Adult↗
PubMed1999

Analysis of conserved microsatellite sequences suggests closer relationship between water buffalo Bubalus bubalis and sheep Ovis aries.

The distribution and evolutionary pattern of the conserved microsatellite repeat sequences (CA)n, (TGG)6, and (GGAT)4 were studied to determine the divergence time and phylogenetic position of the water buffalo, Bubalus bubalis. The mean allelic frequencies of these repeat loci showed a high level of heterozygosity among the euartiodactyls (buffalo, cattle, sheep, and goat). Genetic distances calculated from the allelic frequencies of these microsatellites were used to position Bubalus bubalis in the phylogenetic tree. The tree topology revealed a closer proximity of the Bubalus bubalis to the Ovis aries (sheep) genome than to other domestic species. The estimated time of divergence of the water buffalo genome relative to cattle, goat, sheep, pig, rabbit, and horse was found to be 21, 0.5, 0.7, 94, 20.3, and 408 million years (Myr), respectively. Although water buffaloes share morphological and biochemical similarities with cattle, our study using the microsatellite sequences places the bubaline species in an entirely new phylogenetic position. Our results also suggest that with respect to these repeat loci, the water buffalo genome shares a common ancestry with sheep and goat after the divergence of subfamily Bovinae (Bos taurus) from the family Bovidae.

Animals↗
PubMed1999

Phosphorylation of human estrogen receptor alpha by protein kinase A regulates dimerization.

Phosphorylation provides an important mechanism by which transcription factor activity is regulated. Estrogen receptor alpha (ERalpha) is phosphorylated on multiple sites, and stimulation of a number of growth factor receptors and/or protein kinases leads to ligand-independent and/or synergistic increase in transcriptional activation by ERalpha in the presence of estrogen. Here we show that ERalpha is phosphorylated by protein kinase A (PKA) on serine-236 within the DNA binding domain. Mutation of serine-236 to glutamic acid prevents DNA binding by inhibiting dimerization by ERalpha, whereas mutation to alanine has little effect on DNA binding or dimerization. Furthermore, PKA overexpression or activation of endogenous PKA inhibits dimerization in the absence of ligand. This inhibition is overcome by the addition of 17beta-estradiol or the partial agonist 4-hydroxy tamoxifen. Interestingly, treatment with the complete antagonist ICI 182,780 does not overcome the inhibitory effect of PKA activation. Our results indicate that in the absence of ligand ERalpha forms dimers through interaction between DNA binding domains and that dimerization mediated by the ligand binding domain only occurs upon ligand binding but that the complete antagonist ICI 182,780 prevents dimerization through the ligand-binding domain. Heterodimer formation between ERalpha and ERbeta is similarly affected by PKA phosphorylation of serine 236 of ERalpha. However, 4-hydroxytamoxifen is unable to overcome inhibition of dimerization by PKA. Thus, phosphorylation of ERalpha in the DNA binding domain provides a mechanism by which dimerization and thereby DNA binding by the estrogen receptor is regulated.

Amino Acid Sequence↗
PubMed1999

Economic impact of donor platelet count and platelet yield in apheresis products: relevance for emerging issues in platelet transfusion therapy.

INTRODUCTION: We analyzed donor platelet counts and platelet product yields in 708 consecutive platelet aphereses in our program in order to define the importance of this relationship for emerging issues in platelet transfusion therapy. METHODS: Aphereses performed on the Spectra 3.6 (COBE, Lakewood. Colo.) the CS-3000 Plus (Fenwall-Baxter, Deerfield, Ill.) were analyzed. RESULTS: Mean platelet count was 237+/-49x10(3)/mm3 (mean +/- SD), and mean yield was 4.24+/-1. 09x10(11) platelets. Eigthy-five (12%) procedures generated less that 3x10(11) platelets. Only thirty-eight (5.4%) procedures yielded >/=6x10(11) platelets, so that 'split products' could be obtained. Platelet yields were primarily related to the biologic contribution (baseline platelet count) of the donor. Procedure parameters selected for harvest, and the efficiency of the device also had a significant, but less important role in determining the final platelet yield. An increase in mean donor platelet count achieved with Mpl ligand therapy from 240,000 to 320,000/mm3 would reduce the cost from USD 378 to 267 for each apheresis product, since the fraction of split products would exceed 50% of apheresis procedures. CONCLUSION: Increasing the donor platelet count would have a significant economic impact on platelet apheresis programs, as well as important clinical consequences for the role of platelet apheresis products in future transfusion strategies.

Adult↗
PubMed1999

Effects of nisoldipine and lisinopril on left ventricular mass and function in diabetic nephropathy.

OBJECTIVE: To compare the effects of the calcium channel blocker, nisoldipine, and the ACE inhibitor, lisinopril, on left ventricular mass (LVM) and systolic function in type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: M-mode echocardiography was performed in 50 hypertensive type 1 diabetic patients with diabetic nephropathy enrolled in a 1-year, randomized, double-blind, parallel study of antihypertensive treatment with nisoldipine CC (20-40 mg/day) or lisinopril (10-20 mg/day). Ambulatory 24-h blood pressure was measured with the Takeda TM 2420 device (A & D, Tokyo, Japan) every 3 months. Three patients dropped out and seven patients were excluded due to technical difficulties. RESULTS: The 24-h diastolic blood pressure was reduced from 83 to 80 mmHg in the nisoldipine group (P = 0.06) and from 85 to 80 mmHg in the lisinopril group (P = 0.02). The decline in systolic blood pressure was not significant with any of the two treatments, and no difference in reduction of blood pressure was seen between groups. LVM corrected for body surface area (LVMI) was comparable between groups at baseline and increased from 96 +/- 5 to 107 +/- 6 g/m2 (mean +/- SEM; P = 0.007) in the nisoldipine group and from 95 +/- 4 to 103 +/- 5 g/m2 (P = 0.03) in the lisinopril group. The mean difference between the change in LVMI in the two groups was 2.9 (95% CI 6.8 to 12.7) g/m2. The prevalence of left ventricular hypertrophy rose from 18 (95% CI 6-30) to 30% (16-44) during the study period. A multiple linear regression analysis revealed that after 1 year of treatment, LVMI increased with higher systolic blood pressure level and declining glomerular filtration rate (R2 = 0.25). Fractional shortening was within normal range at baseline, 42 +/- 1 vs. 41 +/- 1% with nisoldipine and lisinopril, respectively, and did not change during follow-up. CONCLUSIONS: Antihypertensive treatment with nisoldipine or lisinopril to bring diastolic blood pressure level within the normal target range does not hinder a rise in LVMI in type 1 diabetic patients with diabetic nephropathy.

Adult↗
PubMed1999

Recurrent abdominal pain and Helicobacter pylori infection in children.

UNLABELLED: Recurrent chronic upper abdominal pain is a common problem in children and it has been associated with Helicobacter Pylori gastritis. AIMS AND OBJECTIVES: We under took this study, to find out the prevalence of Helicobacter pylori gastritis in children with recurrent chronic upper abdominal pain, in our set up. MATERIAL AND METHODS: This was prospective study carried out at KRL Hospital, Islamabad. Forty three children with chronic recurrent upper abdominal pain (age 3 to 14 years), underwent diagnostic gastroscopy and antral biopsies with histopathology, over a period of one year. Another 42 children of the same age group were taken as control group. Fifteen patients, who tested positive for H. pylori were tested for IgG antibodies in whole blood and compared with 15 patients having negative histology for H. pylori. RESULTS: Thirty two (75%) children tested positive for H. pylori, in the test group, as compared to 17 (40%) histological positives in the control group (P = < 0.1). The patients who were tested for IgG antibodies showed that this test has 93% sensitivity, 60% specificity and a negative predictive value of 90% as compared to histological identification. CONCLUSION: Recurrent chronic upper abdominal pain in children, in our population has a significant association with Helicobacter pylori gastritis. Testing of IgG antibodies for H. pylori in whole blood can be used as initial, non invasive screening test for this organism.

Abdominal Pain↗
PubMed1999

Clinical scoring system: a valuable tool for decision making in cases of acute appendicitis.

OBJECTIVE: Decision making in cases of acute appendicitis poses a clinical challenge specially in developing countries where advanced radiological investigations do not appear cost effective and so clinical parameters remain the mainstay of diagnosis. The aim of our study was to devise a scoring system from our local database and test its accuracy in the preoperative diagnosis of acute appendicitis. METHODS: Clinical data from 401 patients having undergone appendectomy were collected to identify predictive factors that distinguished those with appendicitis from those who had a negative appendectomy. Ten such factors were identified and using Bayesian probability a weight was assigned to each and the results summated to get an overall score. A cut-off point was identified to separate patients for surgery and those for observation. The scoring system was then retrospectively applied to a second population of 99 patients in order to compare suggested actions (derived from the scoring system) to those actually taken by surgeons. The sensitivity, specificity and accuracy for the level of decision was then calculated. RESULTS: Of the 99 patients, the method suggested immediate surgery for 65 patients, 63 of whom had acute appendicitis (3.1% diagnostic error rate). Of the 33 patients in whom the score suggested active observation, 18 had appendicitis. The accuracy of our scoring system was 82%. The method had a sensitivity of 78%, specificity 89% and a positive predictive value of 97%. The negative appendectomy rate determined by our study was 7% and the perforation rate 13%. CONCLUSION: Scoring system developed from a local database can work effectively in routine practice as an adjunct to surgical decision making in questionable cases of appendicitis.

Acute Disease↗