Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis of murine thymocytes was examined either in intact fetal thymus lobes or in thymus cell suspensions, both cultured alone or in the presence of either a cortical (TEC 1.4) or a medullary (TEC 2.3) thymic epithelial cell line. Both TECs induced a pronounced increase of apoptosis in 24-h cultivated single thymus cell suspensions but not in spleen or bone marrow cell cultures. Co-culture of thymocytes with murine fibroblasts did not enhance apoptosis of the thymus cells. A similar enhancement of thymocyte apoptosis was observed with dialysed culture supernatants derived from both TEC lines, the active component(s) having a molecular weight of > 30 kDa. In contrast, the cortical TEC 1.4 had a pronounced apoptosis inducing effect on intact fetal thymus lobes cultivated for six days, whereas the medullary TEC 2.3 had only a marginal influence. TEC 1.4 also induced a significant alteration in the ratio of CD4+CD8+ to CD4-CD8- cells. It is concluded that both the cortical and medullary epithelial cell lines are able to induce thymocyte apoptosis but that a large proportion of the cells within the intact thymus stroma is refractory to the respective signal(s) of the medullary epithelial cell line.
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PMID:Thymocyte-directed enhancement of apoptosis via soluble factor(s) derived from a cortical and a medullary thymic epithelial cell line. 862 98

The fate of developing CD4+CD8+ thymocytes is determined by signals transduced through surface TCR complexes. Here, we report that cross-linking of TCR on CD4+ CD8+ thymocytes fails to activate ZAP70 protein tyrosine kinase and fails to initiate downstream signaling events, unless the TCR are coaggregated with surface coreceptor molecules. TCR signaling in CD4+CD8+ thymocytes is impaired because the number of available p56lck molecules is diminished by intrathymic CD4-Ia interactions that initially activate p56lck molecules, which are subsequently degraded. As a consequence of intrathymic CD4-Ia interactions, TCR zeta chains are initially phosphorylated to recruit ZAP70 molecules, but the recruited ZAP70 molecules are not subsequently phosphorylated, resulting in TCR complexes that are stably associated with inactive ZAP70 molecules. Thus, intrathymic interactions that diminish p56lck regulate TCR signaling thresholds and affect TCR structure in developing CD4+CD8+ thymocytes.
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PMID:TCR activation of ZAP70 is impaired in CD4+CD8+ thymocytes as a consequence of intrathymic interactions that diminish available p56lck. 863 Jul 34

A retrospective study of 55 HIV-1 seropositive African patients living in the UK, seen between January 1986 and November 1993, showed a total of 26 (47%) patients with AIDS. Thirty-one (56%) had symptomatic HIV disease at the time of presentation of whom 19 (34.5%) had an AIDS defining condition. Tuberculosis was the most common AIDS defining illness, accounting for 27% of all initial AIDS diagnoses, followed by by Pneumocystis carinii pneumonia and oesophageal candidiasis in 19% each and chronic mucocutaneous genital herpes in 15%. The mean CD4 count at the time of the first AIDS defining event was 91 x 10/mm3 (range 4-320 x 10/mm3). The profile of AIDS defining illnesses was different to published data of homosexual men and injecting drug users in the UK. This has practical implications when considering differential diagnoses and screening as well as prophylaxis for opportunistic infections in this group of patients.
Int J STD AIDS
PMID:AIDS defining conditions in Africans resident in the United Kingdom. 865 11

The most common pathogens involved in disseminated bacterial infection in people with acquired immunodeficiency syndrome (AIDS) are organisms of the Mycobacterium avium-intracellulare complex (MAC). Azithromycin and clarithromycin, a new azalide and macrolide, respectively, are among the most potent monotherapies for MAC bacteraemia, Although many bloodstream isolates demonstrate increased minimum inhibitory concentrations after 4 months of treatment. Current recommended prophylaxis, based on the results of two randomized, double-blind, prospective studies, is rifabutin 300 mg daily for people with AIDS with < 100 CD4 lymphocytes/mm3. In the beige mouse model, we have shown that both azithromycin and clarithromycin prevent MAC bacteraemia following repetitive oral challenge. Clinical trails are now underway to confirm these effects in man; comparative treatments include placebo, rifabutin and an azalide/macrolide plus rifabutin. While combinations might be more effective and reduce the emergence of resistance, the spectre of cytochrome P-450 drug interactions necessitates careful study before combination prophylactic approaches are accepted. Such interactions are associated with rifabutin and some macrolides, although azithromycin may be less problematic in this respect as it appears to have little potential to interact with other antimicrobial agents.
Int J STD AIDS 1996
PMID:Treatment and prophylaxis of Mycobacterium avium complex. 865 24

Cryptosporidium parvum is a protozoan which can cause severe debilitating disease in immunocompromised individuals. Animal models have shown that cellular immunity is the most important factor against the development of the disease. Individuals with a humoral immune deficiency are also at risk. In HIV-infected patients there is a clear relationship between disease severity and CD4 cell counts. Insight into the pathogenesis and development of new agents is hampered by the lack of an in vitro culture system. Prevention is of the utmost importance due to the difficulties of therapy and the severity of clinical disease which can develop. Oocysts are highly resistant to commonly used disinfectants. In HIV-infected patients with cryptosporidiosis, antiretroviral therapy should be instituted or modified. Moreover, non-specific therapy with antidiarrhoeal agents should also be instituted. If no effect is seen, therapy with paromomycin 500 mg 4 times daily for 2-3 weeks should be initiated, followed by maintenance therapy with 500 mg twice daily to prevent relapse.
Int J STD AIDS 1996
PMID:Human cryptosporidiosis. 865 25

Signal transduction through integrin molecules expressed on platelets and nonlymphoid cells involves activation of the intracellular focal adhesion kinase ppI25FAK (FAK) to phosphorylate substrate proteins on tyrosine residues. Similar mechanisms are also functional in T-lymphocytes through the beta 1-integrin VLA-4. A putative FAK-related phosphoprotein (fakB) was identified that is responsive to intracellular signals induced through ligation of antigen receptors on both T- and B-lymphocytes, and whose induced tyrosine phosphorylation is augmented by TCR costimulation through the adhesion/costimulatory receptors CD2 and CD4. In this report, fakB is shown to respond to extracellular signals through the beta 2-integrin LFA-1 in the absence of primary signals through the TCR. Protein-protein complex formation was observed involving an association between fakB, phospholipase C gamma 1 (PLC gamma 1), and the tyrosine phosphoprotein pp35-36. Evidence is provided here that fakB interacts with PLC gamma 1 through its SH3 domain. The association between fakB and PLC gamma 1 does not appear to require T-cell activation, whereas the induced tyrosine phosphorylation of the protein complex components occurs following engagement of LFA-1. These data indicate that the beta2-integrin LFA-1 expressed on T-lymphocytes stimulates a novel, FAK-related molecule that may function in the interplay between adhesion receptors and intracellular signaling enzymes responsible for downstream second messenger generation.
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PMID:Focal adhesion kinase-related fakB is regulated by the integrin LFA-1 and interacts with the SH3 domain of phospholipase C gamma 1. 866 Aug 53

Nineteen cases of cerebral toxoplasmosis (CTOX) are reported from a group of Edinburgh AIDS patients. All patients were severely immunodeficient at the time of presentation with CD4 count < 50 cells/mm3. Thirteen patients had suffered a previous AIDS-defining illness. In Edinburgh, CTOX has developed in 48% of patients who are seropositive for toxoplasma and have a CD4 count < 50 cells/mm3. It is estimated that at least half of the toxoplasma seropositive patients will develop CTOX if they survive for 21 months after reaching a time in their illness when the CD4 count = 50 cells/mm3. The incidence of CTOX in toxoplasma-seronegative patients with a CD4 count < 50 cells/mm3 is 1.3%. All patients showed improvement on treatment and there was no correlation between clinical or radiological features and patient survival. Those patients unable to tolerate first choice anti-toxoplasma therapy had a significantly shorter survival than the remainder but there was no single therapeutic regimen which conferred a survival advantage. Eighteen patients had died at the time of study and the median survival following diagnosis of cerebral toxoplasmosis was 10 months (range 3-38 months). Postmortem examination of the brain was available in 8, 4 of whom had concomitant cerebral lymphoma. The survival from AIDS or CD4 count = 50 cells/mm3 did not differ significantly between those with treated CTOX and a control group who had no toxoplasma infection, suggesting that treatment is reasonably effective. CTOX is a disease associated with severe HIV-related immunodeficiency and, in those with a CD4 count < 50 cells/mm3, occurs more than 35 times as frequently in toxoplasma-seropositive than toxoplasma-seronegative patients. Treatment is effective but the outcome of treated disease cannot be predicted from presenting clinical or radiological features. Concomitant space-occupying cerebral pathology is evident in 50% of post-mortem examinations.
Int J STD AIDS 1996 Jul
PMID:Clinical features, outcome and survival from cerebral toxoplasmosis in Edinburgh AIDS patients. 887 56

With the FACSCount flow cytometer, counts of CD4, CD8 and CD3 lymphocytes and CD4/CD8 ratios were performed in a rural hospital in Tanzania. A total of 168 subjects (21 HIV-1 seropositive and 147 HIV-1 seronegative) were tested as part of a population-based serosurvey and AIDS education programme; 134 other subjects were hospitalized patients who had signs and symptoms suggestive of AIDS (69 HIV-1 seropositive and 65 HIV-seronegative). Mean values for the 147 HIV-1 seronegative subjects from the local population were 980 CD4 cells (95% CI 930, 1031), 598 CD8 cells (560, 635) and CD4/CD8 ratio 1.78 (1.68, 1.89). Seropositive subjects from the local population had significantly lower CD4 cell counts, higher CD8 counts and a lower CD4/CD8 ratio. CD4 cells were significantly lower and CD8 cells significantly higher in HIV-1 seropositive hospital patients compared to HIV-1 seronegative patients. However, 23 (35%) seronegative hospital patients had CD4 counts lower than 600. These results establish baseline values for the lymphocyte subsets in this population and indicate that this technique can be used in remote areas to monitor progress of HIV-infected individuals.
Int J STD AIDS 1996 Jul
PMID:Determination of T-lymphocyte subsets on site in rural Tanzania: results in HIV-1 infected and non-infected individuals. 887 62

The aim of this study was to assess the correlation and average cost of total lymphocyte count compared with CD4 count as a broad estimate of immunosuppression in HIV-1 infected individuals. Spearman's partial rank correlation were calculated between total lymphocyte count, absolute CD4 count and CD4 per cent stratified by stage of HIV-1 infection for routinely collected samples. Data were collected prospectively from a T cell-subset register combined with clinical data obtained retrospectively from case notes of HIV-infected patients managed at St Mary's Hospital, London 1982-1991. Costing data were obtained through a survey of the departments of haematology and immunology (1989/90 prices). The correlation between 1534 paired absolute lymphocyte count and CD4 lymphocyte count was found to be high (R = 0.76). When analysed by stage of HIV infection, the correlation increased from R = 0.64 for asymptomatic patients, to R = 0.72 for patients with symptomatic non-AIDS HIV infection and R = 0.73 for AIDS patients. Correlations between absolute lymphocyte count and CD4 per cent were considerably weaker: R = 0.41 all paired counts; R = 0.32 for asymptomatic patients; R = 0.25 for symptomatic non-AIDS patients; R = 0.32 for AIDS patients. Average cost was pounds 8 per full blood count compared with pounds 38 per T-cell subset analysis. The high correlation between total and CD4 lymphocyte counts, especially for patients with symptomatic HIV disease, demonstrates the suitability of the use of total lymphocyte count in the absence of CD4 counts. Given the considerably lower prices of total lymphocyte counts compared with T-cell subset analysis, this is particularly relevant for developing countries.
Int J STD AIDS 1996 Oct
PMID:Correlation between total and CD4 lymphocyte counts in HIV infection: not making the good an enemy of the not so perfect. 894 Jun 71

Ligation of the CD2 cell surface glycoprotein expressed on T lymphocytes and NK cells induces protein tyrosine phosphorylation and activation of the Src kinases, LCK and FYN. We show here that in Jurkat T leukemia cells and in peripheral blood T cells, CD2 stimulation also leads to tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK. Activation of EMT by CD2 was induced by mitogenic pairs of CD2 mAb, certain single CD2 mAb followed by secondary antibody cross-linking, and CD58-bearing sheep red blood cells. With the use of different Jurkat cell mutants it was demonstrated that CD2-mediated activation of EMT required expression of LCK, but not require surface expression of the CD3 zeta chain. Receptor-mediated activation of LCK does not in itself lead to activation of this Tec kinase since induction of LCK by ligation of CD4 or CD5 did not result in activation of EMT. The activation of EMT during CD2 signaling suggests an important role for this kinase in CD2 co-stimulation of T cell responses.
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PMID:CD2 signaling in T cells involves tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK. 894 65


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