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)

Cryptococcus neoformans is an important opportunist pathogen in human immunodeficiency virus (HIV) infection. Cryptococcal meningitis (CM) 3rd after primary HIV neuropathy an Toxoplasma gondii among infectious neurological diseases in AIDS patients. Extrapulmonary infection due to C. neoformans has occurred in up to 13% of patients. 86% of the Cryptococcus spp isolates in the US, Canada, and Japan are serotype A. Thousands of infection due to var neoformans have been reported in AIDS patients but only 3 cases of var gattii. Cryptococcal pneumonia meningitis appears in 63-84% of AIDS patients with symptoms of fever, headache, meningism, and photophobia. 17-37% of AIDS patients with Cm die during therapy, and only 18-30% live over 12 months. Treatment in patients without immunodeficiency deficit is with a combination of .3 mg/kg/day of amphotericin B and 150 mg/kg/day of flucytosine for 4 weeks. A dose of .5-.8 mg/kg/day amphotericin was most effective although renal toxicity occurred in 80% of patients. Fluconazole has been used since 1987: cerebrospinal fluid concentrations reached 60-80% in serum. Treatment in 8 of 14 patients receiving 400 mg/day fluconazole failed while it did not in 6 patients treated with .7 mg/kg/day of amphotericin for 7 days and flucytosine 100 mg/kg/day. 200 mg/bid itraconazole was given to 32 patients with cryptococcosis (24 CM cases and 26 AIDS victims) and 65% of CM patients improved clinically with negative cultures. The relapse of 2 of 106 patients taking 200 mg/day fluconazole and 13 of 77 patients taking 1 mg/kg/week amphotericin B occurred in maintenance therapy. CM was suppressed in 10 of 15 patients with 400 mg/kg itrazonazole. Prophylactic use of azole drugs in AIDS does not protect completely from CM although it reduced systemic fungal infections such as cryptococcosis.
Int J STD AIDS
PMID:Cryptococcal infection in AIDS. 161 62

During the clinical trials 8,861 patients have been treated with ciprofloxacin worldwide. 3,822 of the therapeutic courses were valid for analysis of efficacy according to FDA standards. The following dosages were usually administered: UTI: 100 to 500 mg twice daily orally or 100 mg twice daily intravenously; RTI: 250 to 1000 mg twice daily orally or 200 mg twice daily intravenously; septicemia: 200 mg intravenously twice daily; gonorrhea: 250 to 500 mg single tablet orally; all other infections: 500 to 1000 mg twice daily orally or 200 mg twice daily intravenously. Ciprofloxacin was administered to 762 courses of lower RTI, 88 courses of upper RTI, 108 courses of bacteremia, 766 courses of skin structure infection, 142 courses of bone and joint infections, 149 courses of intra-abdominal infections, 33 courses of gastrointestinal infections, 1,633 courses of UTI, 49 courses of pelvic infections, 279 courses of STD, mainly gonorrhea, and three courses of meningitis. The clinical response was resolution in 76%, improvement in 18% and failure in only 6%. Bacteriologic response by all sites evaluable: pathogens were eradicated from 74%, markedly reduced in 2%, persisted in 10%. Relapse occurred in 4% and reinfection was observed in another 6%. The overall response was favourable for 90% of the patients. Drug safety was established on a data base of 8,861 courses worldwide. The following side-effects according to COSTART terminology were observed: digestive 5%, metabolic nutritional 4.6%, central nervous 1.6%, skin 1.4%, hemic and lymphatic 1%, cardiovascular 0.4%, body as a whole 0.4%, urogenital 0.3%, special senses 0.3%, musculo-skeletal 0.1%, respiratory 0.08%. Several courses had more than one reaction. Thus the total incidence of side-effects for the treated patient population was 10.2%. Ciprofloxacin is a highly effective drug and a breakthrough in several areas of medical interest. It is relatively safe and side-effects are usually mild or moderate in intensity and transient.
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PMID:Worldwide clinical data on efficacy and safety of ciprofloxacin. 328 11

Invasion of brain microvascular endothelial cells (BMEC) is a prerequisite for successful crossing of the blood-brain barrier by Escherichia coli K1. We have previously demonstrated the requirement of cytoskeletal rearrangements and activation of focal adhesion kinase (FAK) in E. coli K1 invasion of human BMEC (HBMEC). The current study investigated the role of phosphatidylinositol 3-kinase (PI3K) activation and PI3K interaction with FAK in E. coli invasion of HBMEC. PI3K inhibitor LY294002 blocked E. coli K1 invasion of HBMEC in a dose-dependent manner, whereas an inactive analogue LY303511 had no such effect. In HBMEC, E. coli K1 increased phosphorylation of Akt, a downstream effector of PI3K, which was completely blocked by LY294002. In contrast, non-invasive E. coli failed to activate PI3K. Overexpression of PI3K mutants Deltap85 and catalytically inactive p110 in HBMEC significantly inhibited both PI3K/Akt activation and E. coli K1 invasion of HBMEC. Stimulation of HBMEC with E. coli K1 increased PI3K association with FAK. Furthermore, PI3K/Akt activation was blocked in HBMEC-overexpressing FAK dominant-negative mutants (FRNK and Phe397FAK). These results demonstrated the involvement of PI3K signaling in E. coli K1 invasion of HBMEC and identified a novel role for PI3K interaction with FAK in the pathogenesis of E. coli meningitis.
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PMID:Phosphatidylinositol 3-kinase activation and interaction with focal adhesion kinase in Escherichia coli K1 invasion of human brain microvascular endothelial cells. 1097 83

Escherichia coli K1 traversal across the blood-brain barrier is an essential step in the pathogenesis of neonatal meningitis. We have previously shown that invasive E. coli promotes the actin rearrangement of brain microvascular endothelial cells (BMEC), which constitute a lining of the blood-brain barrier, for invasion. However, signal transduction mechanisms involved in E. coli invasion are not defined. In this report we show that tyrosine kinases play a major role in E. coli invasion of human BMEC (HBMEC). E. coli induced tyrosine phosphorylation of HBMEC cytoskeletal proteins, focal adhesion kinase (FAK), and paxillin, with a concomitant increase in the association of paxillin with FAK. Overexpression of a dominant interfering form of the FAK C-terminal domain, FRNK (FAK-related nonkinase), significantly inhibited E. coli invasion of HBMEC. Furthermore, we found that FAK kinase activity and the autophosphorylation site (Tyr397) are important in E. coli invasion of HBMEC, whereas the Grb2 binding site (Tyr925) is not required. Immunocytochemical studies demonstrated that FAK is recruited to focal plaques at the site of bacterial entry. Consistent with the invasion results, overexpression of FRNK, a kinase-negative mutant (Arg454 FAK), and a Src binding mutant (Phe397 FAK) inhibited the accumulation of FAK at the bacterial entry site. The overexpression of FAK mutants in HBMEC also blocked the E. coli-induced tyrosine phosphorylation of FAK and its association with paxillin. These observations provide evidence that FAK tyrosine phosphorylation and its recruitment to the cytoskeleton play a key role in E. coli invasion of HBMEC.
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PMID:Involvement of focal adhesion kinase in Escherichia coli invasion of human brain microvascular endothelial cells. 1103 55

Escherichia coli K1 invasion of brain microvascular endothelial cells (BMECs) is a prerequisite for penetration into the central nervous system and requires actin cytoskeletal rearrangements. Here, we demonstrate that E. coli K1 invasion of BMECs requires RhoA activation. In addition, we show that cytotoxic necrotizing factor-1 (CNF1) contributes to E. coli K1 invasion of brain endothelial cells in vitro and traversal of the blood-brain barrier in the experimental hematogenous meningitis animal model. These in vitro and in vivo effects of CNF1 were dependent upon RhoA activation as shown by (a) decreased invasion and RhoA activation with the Delta cnf1 mutant of E. coli K1 and (b) restoration of invasion frequency of the Delta cnf1 mutant to the level of the parent E. coli K1 strain in BMECs with constitutively active RhoA. In addition, CNF1-enhanced E. coli invasion of brain endothelial cells and stress fiber formation were independent of focal adhesion kinase and phosphatidylinositol 3-kinase activation. This is the first demonstration that CNF1 contributes to E. coli K1 invasion of BMECs.
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PMID:Cytotoxic necrotizing factor-1 contributes to Escherichia coli K1 invasion of the central nervous system. 1187 2

A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was present in 24 patients, in 15 already at diagnosis and in 9 more by 2000. The cumulative risk to present at diagnosis with CLD increased from 0.17 to 0.40 and 0.78 when the diagnosis was made at the ages of 5, 10, and 15 years respectively. For the 9 patients who developed CLD during follow-up, the duration of follow-up, rather than age at diagnosis; previous administration of intramuscular immunoglobulin; and residual IgG levels had a significant effect on the development of CLD. Chronic sinusitis was present in 35 patients (48%), in 15 already at diagnosis and in 20 by 2000. Sistemic infections such as sepsis and meningitis/meningoencephalitis decreased over follow-up, probably due to optimal protection provided by high circulating IgG levels reached with IVIG.
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PMID:Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. 1280 34

The morbidity and mortality associated with Escherichia coli K1 meningitis during the neonatal period have remained significant over the last decade and are once again on the rise. Transcytosis of brain microvascular endothelial cells (BMEC) by E. coli within an endosome to avoid lysosomal fusion is crucial for dissemination into the central nervous system. Central to E. coli internalization of BMEC is the expression of OmpA (outer membrane protein A), which interacts with its receptor for the actin reorganization that leads to invasion. However, nothing is known about the nature of the signaling events for the formation of endosomes containing E. coli K1. We show here that E. coli K1 infection of human BMEC (HBMEC) results in activation of caveolin-1 for bacterial uptake via caveolae. The interaction of caveolin-1 with phosphorylated protein kinase Calpha (PKCalpha) at the E. coli attachment site is critical for the invasion of HBMEC. Optical sectioning of confocal images of infected HBMEC indicates continuing association of caveolin-1 with E. coli during transcytosis. Overexpression of a dominant-negative form of caveolin-1 containing mutations in the scaffolding domain blocked the interaction of phospho-PKCalpha with caveolin-1 and the E. coli invasion of HBMEC, but not actin cytoskeleton rearrangement or the phosphorylation of PKCalpha. The interaction of caveolin-1 with phospho-PKCalpha was completely abrogated in HBMEC overexpressing dominant-negative forms of either focal adhesion kinase or PKCalpha. Treatment of HBMEC with a cell-permeable peptide that represents the scaffolding domain, which was coupled to an antennapedia motif of a Drosophila transcription factor significantly blocked the interaction of caveolin-1 with phospho-PKCalpha and E. coli invasion. These results show that E. coli K1 internalizes HBMEC via caveolae and that the scaffolding domain of caveolin-1 plays a significant role in the formation of endosomes.
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PMID:Escherichia coli K1 internalization via caveolae requires caveolin-1 and protein kinase Calpha interaction in human brain microvascular endothelial cells. 1238 63

We report a case of paradoxical recurrent meningitis in response to initiation of highly active antiretroviral therapy in a patient receiving maintenance fluconazole for a previous diagnosis of cryptococcal meningitis. We describe the unusual radiographic and histopathologic findings which are consistent with an immune reconstitution induced paradoxical inflammatory response to residual cryptococcal infection.
Int J STD AIDS 2002 Oct
PMID:Paradoxical recurrent meningitis following therapy of cryptococcal meningitis: an immune reconstitution syndrome after initiation of highly active antiretroviral therapy. 1239 46

Little is known about the effect of human immunodeficiency virus (HIV) infection on the Central American healthcare system. We describe HIV-related admissions in a Guatemalan medical service. The study was conducted at Guatemala City's largest public hospital. Data were derived from standardized data collection sheets maintained by the HIV testing service and by HIV clinic physicians. Data were collected for 295 medicine admissions of 257 HIV-infected adults during an 18-month period in 1999 and 2000; 30% of the patients were women. Average age was 33 years. Only 12.5% of the patients had been diagnosed with HIV infection prior to 1999 and nearly all had symptomatic AIDS. 60.3% of the patients were diagnosed with HIV infection during their hospitalization. The most common discharge diagnoses were tuberculosis (13.9%), toxoplasmosis, diarrhoea, candida and other fungal infections, and meningitis. Mean length of stay for HIV-positive patients was 17 days. 23.7% of the patients died during their hospitalization; this was double the mortality of non-HIV patients. HIV-infected patients represented 5.8% of the total admissions of the general medical wards. In a country where HIV prevalence is thought to be less than 1%, AIDS is now responsible for over 5% of admissions to a large medical service at a cost of $500,000 per year. These findings underline the importance of HIV infection in Central America and demonstrate the utility of tracking hospital admission data as a method of surveillance.
Int J STD AIDS 2003 Dec
PMID:The emergence of AIDS in Guatemala: inpatient experience at the Hospital General San Juan de Dios. 1467 88

The HIV epidemic in Cambodia is one of the most extensive in Asia. Meningitis accounts for a substantial proportion of HIV-related morbidity and mortality in Cambodia. A retrospective chart review was performed to identify the clinical and spinal fluid characteristics of patients undergoing spinal tap at an AIDS referral hospital in Phnom Penh, Cambodia during a 16-month period. Of 932 charts reviewed, 89 met criteria for analysis. Overall mortality was 49.4%. Cryptococcus was the most commonly identified pathogen (83%), followed by mycobacteria (8%). No pathogen was identified in 9% of charts reviewed. In hospital mortality was similar in all groups.
Int J STD AIDS 2004 Jan
PMID:Aetiology of meningitis in HIV-infected patients in a referral hospital in Phnom Penh, Cambodia. 1476 72


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