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Largest Decrease (largest + decrease)
Selected AbstractsProbing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analysesPROTEIN SCIENCE, Issue 8 2007Qing Xia Abstract Nonnucleoside reverse transcriptase inhibitors (NNRTI) are a group of structurally diverse compounds that bind to a single site in HIV-1 reverse transcriptase (RT), termed the NNRTI-binding pocket (NNRTI-BP). NNRTI binding to RT induces conformational changes in the enzyme that affect key elements of the polymerase active site and also the association between the two protein subunits. To determine which conformational changes contribute to the mechanism of inhibition of HIV-1 reverse transcription, we used transient kinetic analyses to probe the catalytic events that occur directly at the enzyme's polymerase active site when the NNRTI-BP was occupied by nevirapine, efavirenz, or delavirdine. Our results demonstrate that all NNRTI,RT,template/primer (NNRTI,RT,T/P) complexes displayed a metal-dependent increase in dNTP binding affinity (Kd) and a metal-independent decrease in the maximum rate of dNTP incorporation (kpol). The magnitude of the decrease in kpol was dependent on the NNRTI used in the assay: Efavirenz caused the largest decrease followed by delavirdine and then nevirapine. Analyses that were designed to probe direct effects on phosphodiester bond formation suggested that the NNRTI mediate their effects on the chemistry step of the DNA polymerization reaction via an indirect manner. Because each of the NNRTI analyzed in this study exerted largely similar phenotypic effects on single nucleotide addition reactions, whereas each of them are known to exert differential effects on RT dimerization, we conclude that the NNRTI effects on subunit association do not directly contribute to the kinetic mechanism of inhibition of DNA polymerization. [source] Effects of ovariectomy and oestrogen replacement on the function and expression of Rho-kinase in rat bladder smooth muscleBJU INTERNATIONAL, Issue 5 2006Sung K. Hong OBJECTIVE To investigate the effects of ovariectomy and oestrogen replacement on the function and expression of Rho-kinase in rat bladder smooth muscle, as the actual effects of oestrogen deprivation on bladder smooth muscle are unclear. MATERIALS AND METHODS Female Sprague,Dawley rats were placed into one of three groups: sham-operated, bilateral ovariectomy-only, and bilateral ovariectomy plus oestrogen replacement groups. In the last group, oestrogen was replaced by weekly injection of ,-estradiol 17-cypionate (250 µg/kg subcutaneously for 6 weeks) beginning at 1 week after ovariectomy, whereas the other groups received vehicle-only injections for 6 weeks. After treatment, the bladder was removed for muscle strip studies to evaluate the effects of Y-27632, a specific inhibitor of Rho-kinase, on baseline tension and carbachol-induced tonic contractions. Also, the protein expression of RhoA and Rho-kinase isoenzymes was assessed by Western blot analysis. RESULTS Of the three groups, incubation with 10 µm Y-27632 resulted in the largest decrease in baseline tension of strips from the bilateral ovariectomy-only group, but this was not statistically significant (P > 0.05). For carbachol-induced tonic contractions, strips from the bilateral ovariectomy-only group were attenuated the most among the three groups after adding Y-27632 (P < 0.05). However, there were no significant differences in the levels of RhoA and the two Rho-kinase isoenzymes in bladder tissues from the three groups. CONCLUSION Our data show that oestrogen might inhibit the function of Rho-kinase in bladder smooth muscle, while having no significant effect on its expression. This finding might help to explain the greater incidence of urinary tract symptoms suggestive of overactive bladder after the menopause in women. [source] Primary Care Quality and Addiction Severity: A Prospective Cohort StudyHEALTH SERVICES RESEARCH, Issue 2 2007Theresa W. Kim Background. Alcohol and drug use disorders are chronic diseases that require ongoing management of physical, psychiatric, and social consequences. While specific addiction-focused interventions in primary care are efficacious, the influence of overall primary care quality (PCQ) on addiction outcomes has not been studied. The aim of this study was to prospectively examine if higher PCQ is associated with lower addiction severity among patients with substance use disorders. Study Population. Subjects with alcohol, cocaine, and/or heroin use disorders who initiated primary care after being discharged from an urban residential detoxification program. Measurements. We used the Primary Care Assessment Survey (PCAS), a well-validated, patient-completed survey that measures defining attributes of primary care named by the Institute of Medicine. Nine summary scales cover two broad areas of PCQ: the patient,physician relationship (communication, interpersonal treatment, thoroughness of the physical exam, whole-person knowledge, preventive counseling, and trust) and structural/organizational features of care (organizational access, financial access, and visit-based continuity). Each of the three addiction outcomes (alcohol addiction severity (ASI-alc), drug addiction severity (ASI-drug), and any drug or heavy alcohol use) were derived from the Addiction Severity Index and assessed 6,18 months after PCAS administration. Separate longitudinal regression models included a single PCAS scale as the main predictor variable as well as variables known to be associated with addiction outcomes. Main Results. Eight of the nine PCAS scales were associated with lower alcohol addiction severity at follow-up (p,.05). Two measures of relationship quality (communication and whole- person knowledge of the patient) were associated with the largest decreases in ASI-alc (,0.06). More whole-person knowledge, organizational access, and visit-based continuity predicted lower drug addiction severity (ASI-drug: ,0.02). Two PCAS scales (trust and whole-person knowledge of the patient) were associated with lower likelihood of subsequent substance use (adjusted odds ratio, [AOR]=0.76, 95 percent confidence interval [95% CI]=0.60, 0.96 and AOR=0.66, 95 percent CI=0.52, 0.85, respectively). Conclusion. Core features of PCQ, particularly those reflecting the quality of the physician,patient relationship, were associated with positive addiction outcomes. Our findings suggest that the provision of patient-centered, comprehensive care from a primary care clinician may be an important treatment component for substance use disorders. [source] SBIRT Outcomes in Houston: Final Report on InSight, a Hospital District-Based Program for Patients at Risk for Alcohol or Drug Use ProblemsALCOHOLISM, Issue 8 2009The InSight Project Research Group Background:, Screening, Brief Intervention, and Referral to Treatment (SBIRT) services have been implemented as the standard of care for patients in the Harris County Hospital District (HCHD). The present analysis addresses alcohol and drug use for patients admitted over a 39-month period from July 1, 2005 through September 30, 2008. Methods:, Patients were screened for alcohol and drug use at medical admission. Those who were positive received further assessment and were transitioned to receive services as appropriate. A sample of consenting patients who were positive and received services was contacted at 6 months for a follow-up interview. Using an intent-to-treat (ITT) protocol, the analysis included all patients who were assigned for follow-up, including those with completed follow-ups as well as those who could not be contacted at follow-up. Patients not contacted at follow-up were assumed to have maintained their baseline drug and alcohol consumption levels. Results:, Of 59,760 patients who were screened by generalists (primarily nurses, physicians, and medical care technicians), 15,241 (26%) were positive and received further assessment and services. The 6-month follow-up interview completion rate was 66%. The ITT sample consisted of all 1,937 patients who were assigned for follow-up. There was an overall reduction in the number of patients reporting any days of heavy drinking from 70% at intake to 37% at 6-month follow-up and a reduction in the mean number of days of heavy drinking from 7.8 days at intake to 4.1 days at follow-up. The number of patients reporting any days of drug use was 82% at intake versus 33% at follow-up, and the mean number of days of drug use declined from 8.3 days at intake to 4.2 days at follow-up. Conclusions:, The results were consistent with but of greater magnitude than most other studies reporting positive outcomes for SBIRT patients. Drug use and heavy alcohol use were found to decrease substantially from admission to follow-up. This finding holds good for all levels of drug or alcohol misuse severity, with the highest severity patients showing the largest decreases. Future studies are needed to control for potential regression to the mean effects and to develop improved understanding of differences in outcomes by race/ethnicity. 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