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Biomedical subjects

A Ismail

Publications and source records attributed to A Ismail.

At least 19 recordsLinked to original sources
PubMed2000

Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study.

Patients with primary sclerosing cholangitis (PSC) have a significantly increased risk of developing cholangiocarcinoma (CCA). Risk factors for developing such a complication are not well defined. We conducted a multicenter, case-control study to determine the risk factors and possible predictors for CCA in patients with PSC. The demographic, clinical, and laboratory features of 26 PSC patients with CCA diagnosed over a 7-year period at eight academic centers were compared with 87 patients with PSC but no CCA (controls). There was no statistically significant difference in demographics, smoking, signs or symptoms or complications of PSC, indices of disease severity (Mayo Risk score or Child-Pugh score), frequency or duration or complications of inflammatory bowel disease (IBD), frequency of biliary surgery, or therapeutic endoscopy between the two groups. Alcohol consumption was significantly associated with CCA in patients with PSC (odds ratio: 2.95; 95% CI: 1.04-8.3). Serum carbohydrate antigen 19-9 (CA 19-9) was significantly higher in patients with CCA than those without (177 +/- 89 and 61 +/- 58 U/mL, respectively; P =.002). A serum CA 19-9 level > 100 U/mL had 75% sensitivity and 80% specificity in identifying PSC patients with CCA. In conclusion, alcohol consumption was a risk factor for having CCA in PSC patients. The indices of severity of liver disease were not associated with CCA in patients with PSC. Serum CA 19-9 appeared to have good ability to discriminate PSC patients with and without CCA.

Alcohol Drinking↗
PubMed2000

Impaired glucose tolerance in vitamin D deficiency can be corrected by calcium.

Vitamin D(3), via its active metabolite 1alpha,25-dihydroxyvitamin D(3), helps maintain normal calcium levels in the body. Apart from the maintenance of calcium homeostasis, the active form of vitamin D(3) is now known to be involved in a number of other functions including that of pancreatic beta cells. Low serum insulin levels and impaired glucose tolerance in a vitamin D-deficient state have been reported in experimental animals. Hypocalcemia is a major consequence of vitamin D deficiency. Whether the impairment observed is due to vitamin D deficiency per se or is secondary to low calcium is still a matter of controversy. The present study was conducted to delineate the roles of vitamin D and calcium in glucose intolerance associated with vitamin D deficiency in vivo. It was found that supplementation with either vitamin D(3) or high calcium alone to vitamin D-deficient rats could correct the defects. In addition, insulin sensitivity was found to be enhanced in the vitamin D-deficient group compared with vitamin D control or calcium-supplemented groups. Hence the present study demonstrates that calcium per se in the absence of vitamin D increases insulin secretion and normalizes intolerance to glucose seen in vitamin D deficiency.

Journal Article↗
PubMed2000

The development of post-kala-azar dermal leishmaniasis (PKDL) is associated with acquisition of Leishmania reactivity by peripheral blood mononuclear cells (PBMC).

PKDL develops in about 50% of Sudanese patients treated for visceral leishmaniasis (kala-azar). Patients with kala-azar were entered into this study and followed for a period of up to 2 years. During follow up 12 patients developed PKDL and eight did not. Proliferative responses and cytokine production to Leishmania donovani and control antigens were measured in vitro using PBMC isolated at the time of diagnosis of kala-azar, after treatment of visceral leishmaniasis, during follow up, and at the time of diagnosis of PKDL. Proliferative responses and interferon-gamma (IFN-gamma) production were low at diagnosis and increased after treatment of kala-azar in both patients who developed (group 1) and those who did not develop PKDL later (group 2). In group 1, development of PKDL was always associated by an increased PBMC response to Leishmania antigen in proliferation and IFN-gamma production assays. There were no differences in Leishmania antigen-induced production of IL-4, IL-5 and IL-10 between or within the two groups. We have previously shown that Leishmania parasites spread to the skin during visceral leishmaniasis and proposed that PKDL was the result of an immunological attack on parasites, which have survived in the skin despite the drug treatment. The finding that PKDL develops after treatment of kala-azar as Leishmania-reactive T cells start to circulate in peripheral blood in sufficient numbers to be detected in in vitro assays supports this hypothesis.

Adolescent↗
PubMed1999

Rapid and reliable serological diagnosis of enteric fever: comparative sensitivity and specificity of Typhidot and Typhidot-M tests in febrile Malaysian children.

The Typhidot test, which detects IgM and IgG antibodies to a Salmonella typhi-specific outer membrane protein, is as sensitive as, and more specific than, the Widal test in the diagnosis of enteric fever in Malaysian children. It is easier and quicker to perform. In order to increase diagnostic accuracy in an area of high endemicity, the Typhidot-M test has been developed in which IgG is first removed. This theoretically allows improved detection of IgM, and thus would differentiate new from recent infections. We evaluated both tests in 134 unselected febrile children admitted to the General Hospital Kota Bharu, Malaysia. The children were divided into two groups: (i) those who were blood and/or stool culture positive for S. typhi and/or who had clinical features strongly suggestive of enteric fever (n = 62); and (ii) those who were both culture-negative and had clinical evidence of another diagnosis (n = 72). The sensitivity and specificity of the Typhidot and Typhidot-M tests were identical at 90.3 and 93.1%, respectively. Both tests had comparable sensitivity but greater specificity than those of the Widal test (91.9 and 80.6%, respectively). When used together, a positive result for Typhidot and/or Typhidot-M was more specific than either test alone (95.2%) but specificity was lower (87.5%). We conclude that the Typhidot and Typhidot-M tests have comparatively high diagnostic accuracy, suggesting that IgM can be detected in children who may have a predominant IgG response to S. typhi. Using these tests in combination increases the negative predictive value but at the cost of a lower positive predictive value.

Antibodies, Bacterial↗
PubMed1999

Immunopathology of post kala-azar dermal leishmaniasis (PKDL): T-cell phenotypes and cytokine profile.

In Sudan, post kala-azar dermal leishmaniasis (PKDL) caused by Leishmania donovani develops in half of the patients treated for visceral leishmaniasis (kala-azar). In most patients lesions heal spontaneously, but in others symptoms are severe and persist for years. This study examined the immunological response in lesions of PKDL patients by immunohistochemistry and compared the findings with results obtained using peripheral blood mononuclear cells (PBMCs). In all lesions, parasites or parasite antigen were present and provoked the formation of an inflammatory infiltrate consisting of a mixture of macrophages, lymphocytes, and plasma cells. In patients who had high interferon-gamma (IFNgamma) responses to Leishmania antigen in vitro, compact epithelioid granulomas were formed. The inflammatory cells were mainly CD3(+) and interleukin-10 (IL10) was the most prominent cytokine in the lesions. However, IFNgamma was found in all and IL4 in most lesions, in varying amounts. PBMCs from all patients responded to Leishmania antigen by IFNgamma production or proliferation. The results indicate that PKDL develops as a result of an influx of immunocompetent cells into skin, which harbours parasites. The inflammatory response to the parasites is complex. It involves several cell types and cytokines, of which some are antagonistic. It is conceivable that the balance between these cytokines determines the outcome of the disease.

Adolescent↗
PubMed1999

T-cell response in human leishmaniasis.

In the present communication we provide evidence for the existence of a Th1/Th2 dichotomy in the T-cell response to Leishmania antigens in human leishmaniasis. Our data suggest that the pattern of IL-4 and IFN-gamma response is polarised in these patients. Lymphocytes from individuals recovered from cutaneous leishmaniasis (CL) responded by IFN-gamma production following stimulation with Leishmania antigens whereas cells from patients recovered from visceral leishmaniasis (VL) showed a mixed pattern of IFN-gamma and IL-4 responses. The cells producing these cytokines were predominantly CD4+. Furthermore, IL-10 plays an important role in the development of post kala azar dermal leishmaniasis (PKDL) from VL. The balance between the parasitic-specific T-cell response plays an important regulatory role in determining the outcome of Leishmania infections in humans.

Antigens, Protozoan↗
PubMed1999

Leishmania-specific T cells expressing interferon-gamma (IFN-gamma) and IL-10 upon activation are expanded in individuals cured of visceral leishmaniasis.

Peripheral blood mononuclear cells (PBMC) from patients who have recovered from visceral leishmaniasis often respond to Leishmania antigens in vitro by production of both IL-4, IFN-gamma and IL-10. In order to establish the cellular sources of these cytokines, we activated cells from individuals with a history of visceral leishmaniasis with Leishmania antigen for 6 days in culture, and identified cytokine production at the single-cell level by flow cytometry. The cytokines were only found in CD3+ cells and among these mainly within the CD4+ subset. The percentage of cytokine-producing cells was compared in Leishmania-activated PBMC cultures from the previous patients and from individuals living in a village where leishmaniasis does not occur. The percentage of IL-10- and IFN-gamma-containing cells was significantly higher in the previous patients than in the controls, indicating that Leishmania-specific T cells producing IL-10 and/or IFN-gamma had been expanded as a result of the infection. The cytokine-producing cells in the previous patients could be divided into three types: (i) cells producing IFN-gamma only; (ii) cells producing IL-4 only; and (iii) cells producing IFN-gamma and IL-10 simultaneously. The first and second group of cells can be described as Th1- and Th2-type cells, respectively. The third group could be a regulatory subset of T cells important for maintaining a balance between Th1- and Th2-type cells in these individuals.

Animals↗
PubMed1999

Predictors of large esophageal varices in patients with cirrhosis.

OBJECTIVE: Recent guidelines recommend that all cirrhotics undergo screening upper endoscopy to identify those patients at risk for bleeding from varices. However, this practice may not be cost effective as large esophageal varices are seen only in 9-36% of these patients. The aim of this study was to determine whether clinical variables were predictive of the presence of large esophageal varices. METHODS: This is a retrospective analysis of cirrhotics who had a screening upper endoscopy during an evaluation for liver transplantation at three different centers and who had not previously bled from varices. A multivariate model was derived on the combined cohort using logistic regression. Three hundred forty-six patients were eligible for the study. RESULTS: The prevalence of large esophageal varices was 20%. On multivariate analysis, splenomegaly detected by computed tomographic scan (odds ratio: 4.3; 95% confidence interval: 1.6-11.5) or by physical examination (odds ratio: 2.0; 95% confidence interval: 1.1-3.8), and low platelet count were independent predictors of large esophageal varices. On the basis of these variables, cirrhotics were stratified into high- and low-risk groups for the presence of large esophageal varices. Patients with a platelet count of > or = 88,000/mm3 (median value) and no splenomegaly by physical examination had a risk of large esophageal varices of 7.2%. Those with splenomegaly or platelet count < 88,000/mm3 had a risk of large esophageal varices of 28% (p < 0.0001). CONCLUSIONS: Our data show that clinical predictors could be used to stratify cirrhotic patients for the risk of large esophageal varices and such stratification could be used to improve the cost effectiveness of screening endoscopy.

Adrenergic beta-Antagonists↗
PubMed1999

Kala-azar in a high transmission focus: an ethnic and geographic dimension.

In 1994-1996, we studied a group of 58 game wardens stationed in an area known to be highly endemic for visceral leishmaniasis (kala-azar) for evidence of infection with Leishmania donovani. Leishmania DNA was detected by the polymerase chain reaction in the peripheral blood of cases of active kala-azar, former patients with visceral leishmaniasis, patients, and asymptomatic subjects. Using the cloned antigen rk39, antibodies were detected in 44.2% of the game wardens while leishmanin skin test result was positive in 77% of our sample. It was shown that certain tribes from northern Sudan were more likely to develop subclinical infections, while those of the Baria tribe from southern Sudan and those of the Nuba tribe from western Sudan were more likely to develop visceral leishmaniasis. Whether this is due to genetic factors or previous exposure to Leishmania parasites remains to be elucidated.

Animals↗
PubMed1999

Detrimental subtype-specific endothelin-1 (ET-1) signaling in myocardial cells: the ET(A) mediated proliferation and ET(B)receptor down-regulation.

Many physiological and pathological processes in the cardiac tissue have been shown to be associated with a release of endothelin (ET) peptides and with induction of specific ET-receptors and G-protein-coupled ion channels. However, the exact mechanism regulating ET-receptors in the myocardium is controversial. The response to ET-1, the most important member of the ET family, is rapidly attenuated by down-regulation of ET-receptors. The internalization of ET-1 bound to two subclasses of specific receptors (ET(A) and ET(B)) that are abundant in the myocardium has been hypothesized to activate and/or inhibit a variety of intracellular signal transducing systems. The [125I]ET-1, BQ-3020 and selective ET-antagonists were used to study the subtype-selective component of regulation of ET-1 receptors in myocardial membranes. We determined the characteristics of [125I]ET-1 binding and [3H]thymidine incorporation in whole cell saturation studies and measured Ca2+ channel induction and the total number of inactive Ca2+ channels in photoaffinity studies with [3H]azidopine. Here we demonstrate four important components of the complex ET-1 response in human, porcine and rat myocardium, leading to aberrant responses of cells. After ET-1 induction, adaptive subtype-ETB selective down-regulation predominated in human embryonic fibroblasts, in porcine membrane vesicles and in microsomal membranes of renal hypertensive rats, with preferential high affinity ET-1 binding to ETA receptors and with the resultant ETA mediated proliferative and mitogenic activation of human fibroblasts. The ET-1 induction was also accompanied by profound inactivation of Ca2+ channels in myocardial membranes.

Animals↗
PubMed1998

Increased osteoclast-like cells formation in long-term bone marrow cultures from patients with a spinal cord injury.

Patients with a spinal cord section loose a significant amount of bone. After paraplegia, bone loss occurs below the lesional level and is the more dramatic in iliac bones and in the metaphyseal area of long bones. A peak of urinary calcium and hydroxyprolinuria is observed approximately 6 weeks after their lesion. To further understand the mechanisms underlying the bone damage, we used long-term bone marrow cultures to compare osteoclast-like (OCL-like) cell formation above and below the lesional level. Seven paraplegic, one quadriparetic, one quadriplegic patients and five normal subjects were investigated. Six weeks after their spinal cord section, the number of OCL-like cells formed in iliac bone marrow cultures was significantly greater than those formed in sternal bone marrow cultures for all paraplegic patients tested. No significant differences were seen between iliac and sternal bone marrow cultures for the quadriparetic, the quadriplegic patient, or for the five normal subjects. Conditioned media (CM) from iliac marrow of paraplegic patients increased OCL-like cell formation in normal bone marrow cultures. IL-1, TNF-alpha, IL-6, and PGE2 were measured in the CM after 3 weeks of culture. IL-6 was found to be significantly higher in iliac CM compared with sternal CM in six out of seven paraplegic patients. In two patients, addition of an anti-IL-6 monoclonal antibody to the marrow cultures significantly decreased the number of OCL-like cells formed at 3 weeks. We conclude that paraplegia caused by a cord section locally induces an increase in the capacity of progenitors to form OCL-like cells in long-term bone marrow cultures. A locally increased IL-6 production in the marrow below the lesional level could be partly responsible for this observation.

Bone Marrow Cells↗
PubMed1998

Optimization of the enzymatic synthesis of butyl glucoside using response surface methodology

Enzymatic synthesis of butyl glucoside by beta-glucosidase from bitter almonds was optimized using response surface methodology (RSM). Empirical models were developed to describe relationships between the operating variables (temperature, water/butanol volume ratio, glucose concentration, enzyme concentration) and responses (butyl glucoside concentration, conversion yield). Statistical analysis indicated that the four factors had significant effects on the butyl glucoside synthesis. Optimal concentration (41.6 g/L) was reached when the operating conditions were temperature (44.7 degreesC), water/butanol volume ratio (17.6%), glucose concentration (199.2 g/L), and enzyme concentration (2.5 g/L). Good agreement between predicted and measured data at the predicted optimal conditions confirmed the usefulness of the model. Synthesis at a laboratory pilot scale was successful.

Journal Article↗
PubMed1998

High levels of plasma IL-10 and expression of IL-10 by keratinocytes during visceral leishmaniasis predict subsequent development of post-kala-azar dermal leishmaniasis.

Some patients develop post-kala-azar dermal leishmaniasis (PKDL) after they have been treated for the systemic infection kala-azar (visceral leishmaniasis). It has been an enigma why the parasites cause skin symptoms after the patients have been successfully treated for the systemic disease. We report here that PKDL development can be predicted before treatment of visceral leishmaniasis, and that IL-10 is involved in the pathogenesis. Before treatment of visceral leishmaniasis, Leishmania parasites were present in skin which appeared normal on all patients. However, IL-10 was detected in the keratinocytes and/or sweat glands of all patients who later developed PKDL (group 1) and not in any of the patients who did not develop PKDL (group 2). Furthermore, the levels of IL-10 in plasma as well as in peripheral blood mononuclear cell culture supernatants were higher in group 1 than in group 2.

Adolescent↗
PubMed1998

Humoral and cellular immune responses to synthetic peptides of the Leishmania donovani kinetoplastid membrane protein-11.

Native kinetoplastid membrane protein-11 (KMP-11), purified from crude extracts of Leishmania donovani parasites, activates T cells from individuals who have recovered from visceral leishmaniasis. In this work we used three 38-mer peptides spanning the amino acid sequence of the L. donovani KMP-11 as solid-phase ligands in enzyme-linked immunosorbent assays (ELISAs) and as stimulating antigens in lymphoproliferative assays in order to evaluate humoral and cellular immune responses to well-defined sequences of the protein. Antibody reactivity against the three peptides was measured in plasma from 63 Sudanese visceral leishmaniasis patients (VL) and the percentage of patients with anti-KMP-11 antibodies in ELISA were 37% (KMP-11-1), 30% (KMP-11-2) and 58% (KMP-11-3). The fraction of VL patients with measurable antibody reactivity in one or more of the three ELISAs was 79%. Cross-reactivity to the KMP-11 peptides was detected in plasma from Sudanese patients suffering from Leishmania major infections and in plasma from Sudanese and Danish patients infected with Plasmodium falciparum. In lymphoproliferative assays, 10 of 17 PBMC isolates from donors previously infected with L. donovani showed a response to one or more of the three KMP-11 peptides.

Adolescent↗
PubMed1998

Susceptibility pattern of Streptococcus pneumoniae among pre-school children in Kota Bharu, Malaysia.

Streptococcus pneumoniae (S. pneumoniae) is the most common bacterial cause of pneumonia, meningitis, and otitis media, with the highest incidence among young children and the elderly. S. pneumoniae was once routinely susceptible to penicillin, but since the mid-1980s the incidence of resistance to penicillin and other antimicrobial agents has been increasing all over the world. To optimize empirical regimens and initial therapy for S. pneumoniae infections, clinical healthcare providers must be informed about the prevalence and pattern of drug resistance among the isolates in their communities. No such data are available for the Malaysian population. Therefore, this study was designed to determine the antibiotic susceptibility pattern of S. pneumoniae among colonized pre-school children in Kota Bharu, Malaysia. Pharyngeal swabs were collected from children 1 month to 6 years of age. S. pneumoniae isolates were identified according to the standard and tested for penicillin resistance with a 1-microgram oxacillin disk by the Kirby-Bauer disk diffusion methods. Of 355 nasopharyngeal specimens obtained from kindergarten students, in-patients and pediatric clinics over a period of 1 year, S. pneumoniae was isolated from 36 (10 per cent). All isolates, except one, were susceptible to penicillin. The resistant isolates was susceptible to erythromycin, chloramphenicol and cephalosporins.

Child, Preschool↗
PubMed1998

The Leishmania promastigote surface antigen-2 (PSA-2) is specifically recognised by Th1 cells in humans with naturally acquired immunity to L. major.

The promastigote surface antigen-2 (PSA-2) is a Leishmania parasite antigen, which can induce Th1-mediated protection against murine leishmaniasis when used as a vaccine. To evaluate PSA-2 as a human vaccine candidate the specific T-cell response to PSA-2 was characterised in individuals immune to cutaneous leishmaniasis. Peripheral blood mononuclear cells from Sudanese individuals with a past history of self-healing cutaneous leishmaniasis proliferated vigorously in response to PSA-2 isolated from Leishmania major, whereas the antigen did not activate cells from presumably unexposed Danes. Peripheral blood mononuclear cells from individuals with previous L. major infection had varying proliferative responses to PSA-2 derived from L. donovani promastigotes. Peripheral blood mononuclear cells activated by PSA-2 from L. major produced high amounts of interferon-gamma and tumour necrosis factor-beta, and little interleukin-4, thereby showing a Th1 cytokine pattern. Parallel cultures showed clear Th1 and Th2 response patterns to purified protein derivative of tuberculin or tetanus toxoid, respectively. Flow cytometric analysis revealed that PSA-2 induced blastogenesis in the CD3 positive population and that these cells were the major source of interferon-gamma. The results show that Th1-like cells recognising PSA-2 are expanded during infection by L. major and that they maintain their Th1-like cytokine profile upon reactivation in vitro. Since immunity to cutaneous leishmaniasis is mediated by antigen-specific Th1-like cells, PSA-2 might be considered a vaccine candidate for human leishmaniasis.

Animals↗
PubMed1998

Modulation of fluorouracil cytotoxicity by interferon-alpha and -gamma.

Because interferons (IFN)-alpha and -gamma individually have increased fluorouracil (FUra) cytotoxicity in several in vitro models, we studied the effects of FUra combined with IFN-alpha + gamma in HT29 colon cancer cells. A 96-hr exposure to IFN-alpha (500 units/ml) plus IFN-gamma (10 units/ml) and a 72-hr exposure to 0. 25-1 microM FUra (hr 24-96) inhibited cell growth and colony formation in an additive or more-than-additive fashion. When cells were exposed to IFN-alpha + gamma and FUra, free FdUMP levels became detectable, whereas [3H]FUra-RNA incorporation decreased. Exposure to IFN-alpha + gamma, FUra, or the combination decreased dTTP pools to 58%, 43%, and 17% of control, respectively. A marked increase in the dATP to dTTP ratio was seen with FUra with or without IFN-alpha + gamma. Thymidylate synthase catalytic activity was reduced to 28% and 24% of control with FUra with or without IFN-alpha + gamma, suggesting that the enhanced dTTP depletion must be due to another mechanism. FUra-mediated thymidylate synthase inhibition was accompanied by a 124-fold increase in total deoxyuridylate immunoreactivity and a 31-fold increase in dUTP pools, but the addition of IFN-alpha + gamma attenuated the accumulation. Treatment with IFN-alpha + gamma and FUra individually interfered with nascent DNA chain elongation, whereas the three-drug combination produced the most striking effects. IFN-alpha + gamma plus FUra produced the greatest amount of single-strand breaks in nascent DNA and dramatically decreased net DNA synthesis. IFN-alpha + gamma with or without FUra produced double-strand breaks in parental DNA. These results suggest that dTTP depletion, dATP/dTTP imbalance, pronounced inhibition of DNA synthesis, and damage to nascent and parental DNA contribute to the enhanced cytotoxicity with the triple combination.

DNA Fragmentation↗