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Biomedical subjects

L Westbrook

Publications and source records attributed to L Westbrook.

At least 19 recordsLinked to original sources
PubMed2006

Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells.

Fibroblast growth factor (FGF) signaling can bypass the requirement for estrogen receptor (ER) activation in the growth of ER-positive (ER+) breast cancer cells. Fibroblast growth factor-1 stimulation leads to phosphorylation of the adaptor protein Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target (SNT-1) on C-terminal tyrosine residues, whereas it is constitutively bound through its N-terminal phosphotyrosine-binding domain (PTB) to FGF receptors (FGFRs). By expressing the PTB domain of SNT-1 (SNT-1 PTB) in an inducible manner in an ER+ breast carcinoma line, ML20, we asked whether we could uncouple FGFR activation from its downstream signaling components and abrogate FGF-1-induced antiestrogen-resistant growth. Induction of SNT-1 PTB resulted in a significant decrease of FGF-1-dependent tyrosine phosphorylation of endogenous SNT-1, strong inhibition of complex formation between SNT-1, Gab-1 and Sos-1, and reduced activation of Ras, mitogen-activated protein kinase (MAP kinase), and Akt. SNT-1 PTB also inhibited the phosphorylation of p70S6K on Thr421/Ser424 and Ser411, which may result from the abrogation of MAP kinase activity. Moreover, we also observed a decreased phosphorylation of the MAP kinase-independent site Thr389. This may reflect both inhibition of PI-3 kinase pathways and mammalian target of rapamycin (mTOR)-dependent signaling, as the phosphorylation of Thr389 site was sensitive to treatment with the PI3-K and mTOR inhibitors, LY294002 and rapamycin, respectively. Collectively these results suggest that SNT-1 plays a pivotal role in FGF-dependent activation of the Ras-MAP kinase, PI-3 kinase, and mTOR pathways in these cells. Fibroblast growth factor-1 dependent colony formation of ML20 cells in media containing the pure antiestrogen ICI 182,780 was also markedly inhibited upon induction of SNT-1 PTB, suggesting that blockade of FGFR-SNT-1 interactions might abrogate FGF-mediated antiestrogen resistance in breast cancers.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Premorbid psychiatric risk factors for postictal psychosis.

Postictal psychosis (PIP) is a common and clinically significant sequela of inpatient epilepsy monitoring. A series of 622 patients with complex partial epilepsy undergoing video-EEG evaluations as candidates for epilepsy surgery were evaluated, by structured psychiatric interview, for individual and family psychiatric histories, depression, anxiety, and features of personality disorders. No patient had psychotic symptoms at baseline. Twenty-nine developed a PIP episode during monitoring. The a priori hypotheses were that patients with PIP would have higher baseline schizotypal and paranoid personality ratings and a greater prevalence of histories of psychiatric treatment and family history of psychotic illness. However, only a higher prevalence of mood disorder among first- and second-degree relatives distinguished the patients who developed PIP on logistic regression analyses (odds ratio=3.49, P=0.001). Possible mechanisms linking vulnerability toward mood disorders and the development of psychotic symptoms in epilepsy are discussed.

Adult↗
PubMed2000

Emotional outbursts and post-traumatic stress disorder during intracarotid amobarbital procedure.

Severe emotional outbursts (SEOs) during intracarotid amobarbital procedures (IAP) rarely jeopardize preoperative language and memory testing. Four of four patients (100%) with outbursts had experienced significant emotional trauma (three were raped and one witnessed a decapitation), compared with 26 of 546 patients (4.8%) without outbursts (chi2 = 69.8, p < 0. 0001). Evocative injections were ipsilateral to seizure focus. IAP may disrupt emotional balance in some traumatized patients. Counseling may prevent SEOs.

Adolescent↗
PubMed2000

Antimycobacterial activities of 2,4-diamino-5-deazapteridine derivatives and effects on mycobacterial dihydrofolate reductase.

Development of new antimycobacterial agents for Mycobacterium avium complex (MAC) infections is important particularly for persons coinfected with human immunodeficiency virus. The objectives of this study were to evaluate the in vitro activity of 2, 4-diamino-5-methyl-5-deazapteridines (DMDPs) against MAC and to assess their activities against MAC dihydrofolate reductase recombinant enzyme (rDHFR). Seventy-seven DMDP derivatives were evaluated initially for in vitro activity against one to three strains of MAC (NJ168, NJ211, and/or NJ3404). MICs were determined with 10-fold dilutions of drug and a colorimetric (Alamar Blue) microdilution broth assay. MAC rDHFR 50% inhibitory concentrations versus those of human rDHFR were also determined. Substitutions at position 5 of the pteridine moiety included -CH(3), -CH(2)CH(3), and -CH(2)OCH(3) groups. Additionally, different substituted and unsubstituted aryl groups were linked at position 6 through a two-atom bridge of either -CH(2)NH, -CH(2)N(CH(3)), -CH(2)CH(2), or -CH(2)S. All but 4 of the 77 derivatives were active against MAC NJ168 at concentrations of < or =13 microg/ml. Depending on the MAC strain used, 81 to 87% had MICs of < or =1.3 microg/ml. Twenty-one derivatives were >100-fold more active against MAC rDHFR than against human rDHFR. In general, selectivity was dependent on the composition of the two-atom bridge at position 6 and the attached aryl group with substitutions at the 2' and 5' positions on the phenyl ring. Using this assessment, a rational synthetic approach was implemented that resulted in a DMDP derivative that had significant intracellular activity against a MAC-infected Mono Mac 6 monocytic cell line. These results demonstrate that it is possible to synthesize pteridine derivatives that have selective activity against MAC.

Anti-Bacterial Agents↗
PubMed2000

Plant-derived and semi-synthetic calanolide compounds with in vitro activity against both human immunodeficiency virus type 1 and human cytomegalovirus.

Plant-derived and semi-synthetic calanolide compounds with anti-human immunodeficiency virus type 1 (HIV-1) activity were tested for anti-human cytomegalovirus (HCMV) activity in both cytopathic effect inhibition and plaque reduction assays. The results indicated that the anti-HCMV activity of calanolide compounds does not correlate with their activity against HIV-1. The semi-synthetic 12-keto derivatives tended to be more active against HCMV than the corresponding 12-OH congeners, which were more active against HIV-1. It appeared that the 7,8-unsaturated double bond in the chromene ring played a certain role in maintaining activities against both HCMV and HIV-1. Saturation of the double bond increased the EC50 values against both viruses, with concomitant increase in toxicity. The calanolide compounds reported here are the first non-nucleoside analogues capable of inhibiting both HIV-1 and HCMV and, therefore, may be useful chemoprophylactic agents for HCMV in HIV-infected people or vice versa.

Anti-HIV Agents↗
PubMed1999

Risk factors for poor health-related quality of life in adolescents with epilepsy.

PURPOSE: To examine potential risk factors for poor health-related quality of life (HRQOL) among adolescents with epilepsy by using the newly developed QOLIE-AD-48. Risk factors were derived from sociodemographic, social, academic, and epilepsy- and health-related domains. METHODS: The QOLIE-AD-48 was administered to 197 English-speaking adolescents (age 11-17 years from >20 sites in the United States and in Canada). The self-report instrument yields an overall HRQOL score and eight subscale scores. Other data were obtained from family interviews, physician reports, and health records. Multiple regression analyses were conducted to study risk factors for impairment of HRQOL. RESULTS: Older adolescents (age 14-17 years), those with more severe epilepsy and more symptoms of neurotoxicity, and those living in households with lower socioeconomic status were more likely to report poor overall HRQOL. Risk factors in the eight HRQOL domains were found as follows: (a) Epilepsy Impact: older age in adolescence, more severe epilepsy and neurotoxicity, more hospitalizations during the past year, and fewer hours of extracurricular activities; (b) Memory and Concentration: longer duration of epilepsy, special education classes, and history of repeating a grade in school; (c) Attitude Toward Illness: older age, female gender, and more severe epilepsy and neurotoxicity; (d) Social Support: younger age, male gender, and fewer hospitalizations in the last year; (e) Stigma: lower socioeconomic status and special-education classes; and (f) Health Perceptions: older age, female gender, and lower socioeconomic status. None of the factors examined was significantly associated with HRQOL in (g) Physical Functioning or (h) School Behavior subscales. CONCLUSIONS: We identified several risk factors for poor HRQOL outcomes in adolescents with epilepsy. Age, increased seizure severity, and neurotoxicity were most consistently associated with poor HRQOL across domains. Older adolescents, independent of epilepsy severity, reported worse overall HRQOL than did their younger counterparts. Older adolescents also were more likely to perceive a greater negative impact on life and general health, and had more negative attitudes toward epilepsy. Adolescent boys and girls may show different sensitivities to various quality-of-life domains.

Achievement↗
PubMed1996

Optimization of the reverse transcriptase assay for the detection of viral burden in mice infected with Rauscher murine leukemia virus.

Rauscher murine leukemia virus induces an erythroleukemia in susceptible strains of mice that is associated with splenomegaly and viremia. This animal model has been used for evaluating the in vivo efficacy of potential anti-HIV agents. The in vivo antiviral activity of therapeutic agents has usually been determined by measuring a reduction in the spleen weights of compound-treated mice or by quantitating viremia with the UV-XC plaque assay. The UV-XC assay, however, is time-consuming and labor-intensive. Virions of Rauscher murine leukemia virus, like other retroviruses, contain the enzyme reverse transcriptase. Quantitating the level of this enzyme in infected mouse sera provides a more rapid measure of viremia in the animal. We have examined the effects of several reagents, including detergent, KCl, EGTA, dGMP, spermine, as well as protease and RNase inhibitors, on the reverse transcriptase assay. The optimized assay method was effective in evaluating the antiviral activity of AZT in the Rauscher murine leukemia virus in vivo model. The assay is also amenable to automation if large numbers of assays are required.

Animals↗
PubMed1995

In vitro and in vivo enhancement of ddI activity against Rauscher murine leukemia virus by ribavirin.

Ribavirin has been reported to enhance the activity of ddI against HIV. We explored this enhancement of antiviral activity in Rauscher murine leukemia virus (RMuLV) models in vitro and in vivo. The significant finding in these studies was that combinations of the drugs exhibited virus titer reductions that were greater than would be expected if the drug interactions were simply additive. These effects were designated synergistic by the method of Prichard and Shipman (Prichard, M.N. and Shipman, C., Jr. (1990). A three-dimensional model to analyze drug-drug interaction, Antiviral Res. 14, 181-206). In addition to the antiviral synergy, we also observed some synergistic toxicity in the animal model.

Animals↗
PubMed1994

An estimate of the prevalence of asthma and wheezing among inner-city children.

OBJECTIVE: To estimate the prevalence of asthma and wheezing unassociated with a diagnosis of asthma among inner-city children. DESIGN: Cross-sectional survey of a sample of Bronx households. METHODS: Random digit dialing telephone survey using parental report. SETTING: Bronx County, NY. PARTICIPANTS: 662 self-designated heads-of-household who reported for all children 0 through 17 years of age living in their households. MEASUREMENTS: Questions from the Child Health Supplement to the 1988 National Health Interview Survey and the International Union Against Tuberculosis and Lung Disease Bronchial Symptoms Questionnaire were used to estimate the prevalence of asthma and wheezing-related illness. RESULTS: Information was gathered on 1285 children. Of this sample, 184 (14.3%) were reported to have ever had asthma (cumulative prevalence) and 111 (8.6%) were reported to have asthma in the last 12 months (period prevalence). The asthma period prevalence rate among Bronx children was twice the United States rate (4.3%). Among children 0 through 11 years of age, the prevalence rate was similar for boys and girls, although among children 12 through 17 years of age, asthma was significantly more prevalent among boys. Fifty-four children (4.2%) were reported to have had wheezing in the past 12 months unassociated with a diagnosis of asthma (wheeze only). The cumulative, but not the period, prevalence rate of asthma differed significantly by income and race/ethnicity. The cumulative prevalence was significantly higher among Hispanics and children from the lowest income families. The prevalence of wheeze only (no reported history of asthma) was higher among whites (6.4%) and blacks (5.8%) than Hispanics (2.9%) (P < .1). The reported number of wheezing attacks and the average number of nights per week that sleep was disturbed by wheezing during the past year were similar for those with asthma and those with wheeze only, although severe attacks (wheezing severe enough to limit speech) were significantly more likely among those reported to have asthma (P < .001). The total asthma prevalence (period prevalence of asthma plus wheeze only) was 12.8% and was quite consistent across subgroups. CONCLUSIONS: These data suggest that the prevalence of asthma among inner-city children may be substantially higher than the rates for this group estimated from national survey data. Some proportion of the wheeze only group may represent undiagnosed, and thereby undertreated, asthma. Public health efforts directed at reducing asthma morbidity and mortality need to address the possibility that asthma prevalence is higher within inner cities and that a large number of children with asthma may be inadequately diagnosed and treated.

Adolescent↗
PubMed1993

Thiazolobenzimidazole: biological and biochemical anti-retroviral activity of a new nonnucleoside reverse transcriptase inhibitor.

Thiazolobenzimidazole (NSC 625487) was a highly potent inhibitor of human immunodeficiency virus-induced cell killing and viral replication in a variety of human cell lines, as well as fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2 and a pyridinone-resistant strain (A17) of HIV-1, a strain which is cross-resistant to several structurally diverse members of a common pharmacologic class of nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase but not HIV-2 reverse transcriptase. Combinations of thiazolobenzimidazole with either AZT or ddI synergistically inhibited HIV-1 induced cell killing in vitro. Thiazolobenzimidazole also inhibited the replication of the Rauscher murine leukemia retrovirus. Thus, thiazolobenzimidazole is a new active anti-HIV-1 chemotype and may represent a subclass of nonnucleoside reverse transcriptase inhibitors with an enhanced range of anti-retroviral activity.

Antiviral Agents↗
PubMed1993

Activity of triciribine and triciribine-5'-monophosphate against human immunodeficiency virus types 1 and 2.

Triciribine (TCN) and its 5'-monophosphate (TCN-P) are novel tricyclic compounds with known antitumor activity; TCN-P is currently in phase II human clinical trials. We now report that these compounds have potent and selective activity against HIV-1 and HIV-2. Using a syncytial plaque assay, TCN and TCN-P were active against HIV-1 at 0.01-0.02 microM and had differential selectivities of 2250 and 1900, respectively, compared to 1850 for AZT. In contrast, TCN and TCN-P had minimal selectivity against human cytomegalovirus (50 and 27, respectively). TCN and TCN-P markedly inhibited HIV-1-induced p24 core antigen production, reverse transcriptase, and infectious virus production in a dose-dependent manner using HIV-1 acutely infected CEM-SS, H9, and persistently infected H9IIIB and U1 cells. In acutely infected PBL cells, TCN and TCN-P inhibited reverse transcriptase and infectious virus production but not p24 core antigen production. Using a microtiter XTT assay, TCN and TCN-P were active against a panel of HIV-1 and HIV-2 strains at IC50 values ranging from 0.02 to 0.46 microM. Evaluation of matched pairs of predrug and postdrug therapy HIV-1 isolates established that AZT-resistant and TIBO-resistant variants of HIV-1 were sensitive to TCN or TCN-P. Furthermore, unlike AZT and other fraudulent nucleosides, neither TCN, TCN-P, nor TCN-TP inhibited the viral reverse transcriptase. Thus, even though triciribine is a nucleoside chemically, it does not act biologically by classic nucleoside modalities but rather by a unique mechanism yet to be elucidated.

Acenaphthenes↗
PubMed1992

An ELISA system for evaluating antiretroviral activity against Rauscher murine leukemia virus.

A system for evaluating the activity of antiviral agents against Rauscher murine leukemia virus (R-MuLV) has been developed using an enzyme linked immunosorbent assay technique. The activity of various antiviral compounds demonstrated in this assay system has been compared to their activity in the UV-XC plaque reduction assay, which has been used historically for evaluating anti-R-MuLV compounds. The assay is based upon detection of R-MuLV encoded p30 protein production in virus infected murine cells. The assay reagents are readily available and the assay system is amenable to automated data collection systems. Cytotoxicity evaluations are conducted in parallel to the Rauscher MuLV ELISA assay in order to assess drug-induced reductions in cell viability. Cytotoxicity evaluations are important to interpretation of the ELISA results since reductions in cell viability reduce viral protein production which would indicate an antiviral drug effect. This system is less sensitive than the classical UV-XC plaque reduction assay; however, it does offer an alternative to the time-consuming and labor-intensive plaque assay.

Animals↗
PubMed1990

Effectiveness of alprazolam in the treatment of chronic pain: results of a preliminary study.

One hundred chronic pain patients were begun on alprazolam, 1.5 mg/day. No other medication changes or therapeutic interventions were made. Sixteen patients were lost to follow-up and 1 oncology patient died. Of the 83 patients who were evaluated at 12 weeks, 61 (73.5%) showed improvement, and only 5 had discontinued the medication because of side effects. The average score of all patients had decreased from 3.6 to 2.2 on a verbal analog scale that rated pain severity from 0 to 5. There was no difference in response among the various diagnostic groups represented in the study population.

Alprazolam↗
PubMed1989

Side effects and complications of cervical epidural steroid injections.

Two hundred and four cervical epidural injections of corticosteroids were performed on 142 patients for the treatment of cervical pain over a 1-yr period. Injections were performed at the C7-T1 interspace with 10-15 mL of 0.5% lidocaine containing 1 mg per kg of methylprednisone acetate. Four complications occurred: two dural punctures without sequelae; one episode of upper extremity weakness, which resolved in 24 hr; and one episode of nausea and vomiting lasting 12 hr. In addition, two side effects were frequently reported: stiff neck lasting 12-24 hr occurred in 13.2% of patients, and a mild facial flushing with subjective (but not objective) fever lasting about 12 hr occurred in 9.3% of patients. In this large series, the procedure appears safe to use in an outpatient setting.

Adrenal Cortex Hormones↗
PubMed1988

Cross-cultural and multi-ethnic dementia evaluation by mental status and memory testing.

Two studies investigated aspects of cross-cultural dementia evaluation. The first explored consequences of using different mental status tests; the second compared mental status and memory assessments for normal individuals aged 70-79 and 80-89 in Japan and in America. In a dementia screening clinic, scores from the Hasegawa mental status test could be converted to the Blessed scale without influencing patient classification (impaired vs. unimpaired). Younger subjects were slightly superior to older subjects in mental status in both comparison groups. Both Japanese groups performed better on the memory test than even the younger American group.

Aged↗
PubMed1985

Influence of 1-dodecylazacycloheptan-2-one (Azone) on the topical therapy of cutaneous herpes simplex virus type 1 infection in hairless mice with 2',3'-di-O-acetyl-9-beta-D-arabinofuranosyladenine and 5'-O-valeryl-9-beta-D-arabinofuranosyladenine.

The predictive value of a recently developed physical model was tested in the topical treatment of cutaneous infections caused by herpes simplex virus type 1 in hairless mice with two ester prodrugs of 9-beta-D-arabinofuranosyladenine (ara-A) (1). The tests were conducted with 2',3'-di-O-acetyl-ara-A (4) and 5'-O-valeryl-ara-A (3) topically applied with and without 15% 1-dodecylazacycloheptan-2-one (2) (Azone), a percutaneous penetration enhancer. In addition to the in vivo studies, in vitro diffusion cell experiments with excised, full-thickness skin from hairless mice were conducted to determine the penetration enhancement effects of 2. As previously observed, 2 was able to induce remarkably large (100- to 1000-fold) flux enhancements in these in vitro experiments. Consistent with predictions based on the physical model studies, formulations of 3 and 4 without 2 had little or no influence on the pathogenesis of the herpes simplex virus type 1 infections; when 2 was present in the formulations, both 3 and 4 had dramatic therapeutic effects consistent with the predictions made with the physical model. Prodrug 4 with 2 was especially efficacious in the prevention of virus-induced lesions and in the survival of all animals. Similar results were obtained with acyclovir plus 2 in this model system.

Acyclovir↗