Towards a combined prognostic index for survival in HIV infection: the role of 'non-HIV' biomarkers.

BACKGROUND: As those with HIV infection live longer, 'non-AIDS' condition associated with immunodeficiency and chronic inflammation are more common. We ask whether 'non-HIV' biomarkers improve differentiation of mortality risk among individuals initiating combination antiretroviral therapy (cART). METHODS: Using Poisson models, we analysed data from the Veterans Aging Cohort Study (VACS) on HIV-infected veterans initiating cART between 1 January 1997 and 1 August 2002. Measurements included: HIV biomarkers (CD4 cell count, HIV RNA and AIDS-defining conditions); 'non-HIV' biomarkers (haemoglobin, transaminases, platelets, creatinine, and hepatitis B and C serology); substance abuse or dependence (alcohol or drug); and age. Outcome was all cause mortality. We tested the discrimination (C statistics) of each biomarker group alone and in combination in development and validation data sets, over a range of survival intervals, and adjusting for missing data. RESULTS: Of veterans initiating cART, 9784 (72%) had complete data. Of these, 2566 died. Subjects were middle-aged (median age 45 years), mainly male (98%) and predominantly black (51%). HIV and 'non-HIV' markers were associated with each other (P < 0.0001) and discriminated mortality (C statistics 0.68-0.73); when combined, discrimination improved (P < 0.0001). Discrimination for the VACS Index was greater for shorter survival intervals [30-day C statistic 0.86, 95% confidence interval (CI) 0.80-0.91], but good for intervals of up to 8 years (C statistic 0.73, 95% CI 0.72-0.74). Results were robust to adjustment for missing data. CONCLUSIONS: When added to HIV biomarkers, 'non-HIV' biomarkers improve differentiation of mortality. When evaluated over similar intervals, the VACS Index discriminates as well as other established indices. After further validation, the VACS Index may provide a useful, integrated risk assessment for management and research.

Growth performance of stocker calves backgrounded on sod-seeded winter annuals or hay and grain.

Economically viable options for retaining ownership of spring-born calves through a winter backgrounding program are somewhat limited in the southeastern United States. Although sod-seeded winter annual forages produce less forage than those same forages planted using conventional tillage practices, sod-seeded winter annual forages have the potential to provide a low-cost, rapid-gain, ecologically and economically viable option for retaining ownership of fall-weaned calves. A study was conducted during the winters of 1998, 1999, and 2000 using 180 crossbred calves (261 +/- 2.8 kg initial BW; n = 60 each year) to compare sod-seeded winter annual forages with conventional hay and supplement backgrounding programs in southeast Arkansas. Calves were provided bermudagrass hay (ad libitum) and a grain sorghum-based supplement (2.7 kg/d) on 1-ha dormant bermudagrass pastures or were grazed on 2-ha pastures of bermudagrass/dallisgrass overseeded with 1) annual ryegrass, 2) wheat plus annual ryegrass, or 3) rye plus annual ryegrass at a set stocking rate of 2.5 calves/ha. Calves grazed from mid-December until mid-April but were fed bermudagrass hay during times of low forage mass. Mean CP and IVDMD concentrations were 19.0 and 71.1%, respectively, across sampling dates and winter annual forages, but three-way interactions among forage treatments, year, and sampling date were detected (P < 0.01) for forage mass, concentrations of CP, and IVDMD. The IVDMD of rye plus ryegrass was greater (P < 0.05) than that of ryegrass in yr 2. A forage treatment x sampling date interaction was detected for forage CP in yr 1 (P < 0.05) and 2 (P = 0.05) but not in yr 3 (P = 0.40). Forage mass did not differ (P > or = 0.22) among winter annual treatments on any sampling date. During the first 2 yr, calves fed hay plus supplement gained less (P < 0.05) BW than calves that grazed winter annual forages; gains did not differ (P > or = 0.23) among winter annual treatments. During the 3rd yr, undesirable environmental conditions limited growth of the winter annual forages; total gain did not differ (P = 0.66) among the four treatments. Winter annual forages offer potential to provide high-quality forage for calves retained until spring, but consistent forage production and quality are a concern when sod-seeding techniques are used.

A novel approach to the design of inhibitors of human secreted phospholipase A2 based on native peptide inhibition.

Human Type IIA secreted phospholipase A(2) (sPLA(2)-IIA) is an important modulator of cytokine-dependent inflammatory responses and a member of a growing superfamily of structurally related phospholipases. We have previously shown that sPLA(2)-IIA is inhibited by a pentapeptide sequence comprising residues 70-74 of the native sPLA(2)-IIA protein and that peptides derived from the equivalent region of different sPLA(2)-IIA species specifically inhibit the enzyme from which they are derived. We have now used an analogue screen of the human pentapeptide (70)FLSYK(74) in which side-chain residues were substituted, together with molecular docking approaches that modeled low-energy conformations of (70)FLSYK(74) bound to human sPLA(2)-IIA, to generate inhibitors with improved potency. Importantly, the modeling studies showed a close association between the NH(2) and COOH termini of the peptide, predicting significant enhancement of the potency of inhibition by cyclization. Cyclic compounds were synthesized and indeed showed 5-50-fold increased potency over the linear peptide in an Escherichia coli membrane assay. Furthermore, the potency of inhibition correlated with steady-state binding of the cyclic peptides to sPLA(2)-IIA as determined by surface plasmon resonance studies. Two potential peptide interaction sites were identified on sPLA(2)-IIA from the modeling studies, one in the NH(2)-terminal helix and the other in the beta-wing region, and in vitro association assays support the potential for interaction of the peptides with these sites. The inhibitors were effective at nanomolar concentrations in blocking sPLA(2)-IIA-mediated amplification of cytokine-induced prostaglandin synthesis in human rheumatoid synoviocytes in culture. These studies provide an example where native peptide sequences can be used for the development of potent and selective inhibitors of enzyme function.

Functional coupling and differential regulation of the phospholipase A2-cyclooxygenase pathways in inflammation.

Prostaglandins generated by the phospholipase A2 (PLA2)/cyclooxygenase (COX) pathway are well known to mediate diverse intracellular and extracellular effects that regulate mammalian development, vascular function, renal physiology, parturition, and immune responses to infection or wounding. In immune-mediated diseases and in certain cancers, this pathway is aberrantly up-regulated and excessive prostaglandin production contributes to the pathology. It is now known that there are two isoforms of COX and multiple secreted and intracellular PLA2 enzymes. The use of isoform-specific inhibitors, coupled with antisense and in vivo gene deletion experiments, has identified independent pathways of arachidonic acid metabolism, which are differentially regulated at the levels of gene expression, protein phosphorylation, and cellular localization. There is cross-talk between the pathways at the level of PLA2 and substrate supply to the two isoforms of COX is apparently compartmentalized. Knockout studies have shown that the two COX isoforms play independent roles in immediate and delayed agonist-induced prostaglandin synthesis. Cytosolic PLA2-alpha is essential for both responses. Inducible secreted forms of PLA2 are, as yet, not essential for either response with the exception of the in vitro murine mast cell immediate response and instances of murine macrophage prostaglandin synthesis. These enzymes amplify the delayed response and are likely to modulate the severity of immune-mediated diseases.

Drinking and HIV: knowledge and context.

AIDS: The unique role of alcohol consumption on the AIDS epidemic is examined, as are the gaps in knowledge that exist among patients, practitioners, and researchers. Research on how alcohol abuse enhances unsafe sex practices and nonadherence to AIDS medication regimens is discussed. In addition, the effects of drinking, with respect to HIV infection and the need for interventions, which may be particularly important to women, particularly to women of color, reasons why male-oriented intervention models may not be appropriate for alcohol-abusing women, and the need for effective interventions to include issues such as child care, family and partner roles, and other potential barriers are discussed. Other topics include treatment problems among seropositive alcohol abusers, and the needs of populations at high risk for alcohol abuse and HIV infection such as prison inmates, homeless youth, and women with histories of victimization to be addressed.^ieng

Decreasing HIV / STD risk in relation to alcohol use: a research agenda.

PIP: Alcohol consumption has been consistently associated with HIV-risk behaviors over time, with significantly higher rates of HIV infection generally found among samples of alcoholics and individuals who meet the criteria for alcohol dependence than in the general public. Research on HIV infection among alcoholics in treatment who use few other drugs has found 2.5-10% to be HIV-infected in cities where HIV is prevalent. Alcohol use and abuse may particularly compound the HIV-infection risk of those already in situations of high risk for HIV/STD infection in developing countries, such as women in households where alcohol abuse is common, prostitutes, runaway and homeless youth, and men in occupations which require them to travel long distances. HIV/STD prevention interventions should include alcohol harm reduction while alcohol treatment interventions should be bolstered with HIV/STD risk reduction measures. Harm reduction strategies and research opportunities are described.^ieng

Design and characterisation of long-R3-insulin-like growth factor-I muteins which show resistance to pepsin digestion.

Site-directed mutagenesis was used to construct pepsin-resistant, single-point mutations of the N-terminal extended IGF-I analogue, long-R3-IGF-I. In order to identify the most susceptible sites, the kinetics of long-R3-IGF-I digestion by purified porcine pepsin were determined. Pepsin initially cleaved the Leu10-Phe11 bond in the N-terminal extension peptide to generate FVN-R3-IGF-I, followed in rapid succession by cleavage at Gln15-Phe16, Tyr24-Phe25, Leu10-Val11 and Met59-Tyr60 in the IGF-I moiety. Single-point mutations at these sites were designed on the basis of the preferred cleavage bonds for pepsin, as well as amino acid substitutions less likely to disturb protein structure. These included Leu10Val, Phe16Ala, Phe25Leu, Asp53Glu and Met59Gln. All five muteins retained growth-promoting activity equivalent to or higher than that of IGF-I. In terms of pepsin susceptibility, Leu10Val and Asp53Glu were degraded as rapidly as the parent long-R3-IGF-I, Met59Gln and Phe25Leu were partially stabilised, and Phe16Ala showed a marked improvement in stability over a wide range of pepsin:substrate ratios. Accordingly, the Phe16Ala mutein, long-R3A16-IGF-I, has potential for oral applications to enhance gastric growth and repair.

Should tolerance and withdrawal be required for substance dependence disorders?

Despite the historical importance of tolerance and withdrawal in the substance abuse nomenclature, empirical evaluations of tolerance and withdrawal relative to other, non-physical, dependence criteria have been infrequent. Based on data from 521 subjects from a newly completed survey evaluating proposed options for DSM-IV substance use disorders, we found, first, across classes of drugs, requiring tolerance or withdrawal had little effect on rates of dependence, as most subjects who met dependence criteria for each drug class also reported tolerance. Second, tolerance and withdrawal did not emerge as superior to the other dependence criteria on several indicators of concurrent and predictive validity, including severity.

Emergency physicians' ratings of alcoholism treaters.

The purpose of this study is to identify treaters whom emergency physicians perceive to offer effective treatment of alcoholism. A random sample of 2,500 emergency physicians received a questionnaire comparing attitudes toward Alcoholics Anonymous (AA) and professional alcoholism treaters. Physician agreement on the efficacy of alcoholism treaters was greatest for AA (87%), moderate for mental health professionals (including psychiatrists and psychologists, 55%) and least for physicians and surgeons (excluding psychiatrists, 23%; chi-square = 1,024, p = .000000005, df = 2). Physician education about other alcoholism treaters may be necessary if all types of treatment are to be considered for the emergency room patient.

Psychiatric comorbidity in white and African-American cocaine addicts seeking substance abuse treatment.

OBJECTIVE: Few diagnostic studies have reported rates of psychiatric comorbidity among cocaine addicts according to race. This study examines psychiatric comorbidity in African-American and white cocaine addicts. METHODS: Rates of psychiatric comorbidity were assessed in 263 cocaine addicts seeking substance abuse treatment. The sample included 163 non-Hispanic whites and 100 African Americans. Diagnoses were based on patient interviews using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L). The SADS-L was supplemented to include DSM-III-R criteria for substance abuse or dependence and other psychiatric diagnoses and DSM-III criteria for attention deficit disorder. RESULTS: Overall, 55.7 percent of the cocaine addicts met Research Diagnostic Criteria for a current psychiatric diagnosis, and 73.5 percent met criteria for a lifetime psychiatric diagnosis. Whites and African Americans did not differ significantly in overall psychiatric comorbidity. However, whites had significantly higher rates of life-time major depression, alcohol dependence, attention deficit disorder, and conduct disorder. African-American addicts, particularly women, were more likely to meet criteria for a current diagnosis of phobia. CONCLUSIONS: Psychiatric comorbidity is common among cocaine addicts, and the rates for specific disorders vary by race. Differences in current and lifetime rates should be noted. Cocaine addicts seeking treatment should be assessed for comorbid alcohol dependence and other psychiatric disorders, including anxiety, affective, and personality disorders.

Alcoholism in treatment-seeking cocaine abusers: clinical and prognostic significance.

Two hundred ninety-eight treatment-seeking and 101 community cocaine abusers were interviewed using the Schedule for Affective Disorders and Research Diagnostic Criteria. Alcoholism was the most frequently diagnosed current and lifetime psychiatric disorder in both samples. Several findings from this study converge with recent evidence which suggests a particularly strong relationship between cocaine abuse and alcoholism that may differ from other types of alcohol-drug comorbidity. First, rates of alcoholism among cocaine abusers doubled those of comparable samples of opioid addicts. Second, while virtually all cocaine abusers in this sample reported some alcohol use during the past month, a lifetime diagnosis of alcoholism was associated with more severe cocaine dependence. Third, the onset of alcoholism followed the onset of drug dependence for the majority of alcoholic cocaine abusers, a pattern which contrasts that typically seen in other types of drug-alcohol comorbidity and suggests that cocaine abuse may increase vulnerability to secondary alcoholism. Prognostically, cocaine abusers who were alcoholic at baseline interview were more likely to remain alcoholic at 1-year follow-up but did not differ from nonalcoholic cocaine abusers on other measures of outcome.

Reliability of dual diagnosis. Substance dependence and psychiatric disorders.

The Structured Clinical Interview for DSM-III-R was used to examine the effects of the co-occurrence of psychiatric and substance dependence disorders on diagnostic reliability. The test-retest reliability over a 1-week period was studied in groups of: a) individuals with current substance abuse diagnoses (N = 97), b) individuals with past, but not current, drug histories (N = 146), and c) individuals without substance abuse diagnoses (N = 356; primarily psychiatric patients). A measurement of reliability (Kappa coefficients) was estimated for four general psychiatric categories (psychotic, mood, anxiety, and eating disorders), along with specific most-frequent diagnoses in each category (schizophrenia, major depression, panic disorders, and bulimia nervosa, respectively). Past use and non-drug-use groups were similar in their generally reliable reporting of current and past psychiatric disorders. However, current mood and psychotic disorders were less reliably diagnosed in the group with current substance use disorders.

Coherence of the dependence syndrome in cocaine users.

The method of diagnosing drug dependence introduced in DSM-III-R is largely untested for drugs other than alcohol. Cocaine, unlike alcohol, lacks clearly identifiable withdrawal symptoms, yet is also considered highly addictive. Can criteria derived from the dependence syndrome concept be generally applied to treatment seeking cocaine users? To evaluate the coherence of the dependence syndrome elements for cocaine, factor analysis models are applied to the nine dichotomous DSM-III-R drug-dependence criteria derived from structured clinical interviews with 399 cocaine users. A single factor model, in which both the centrality and severity of each criteria were assessed, adequately describes the criteria and supports the coherence of the dependence syndrome concept for cocaine. Pre-occupation was the most central criterion in defining cocaine dependence. However, avoiding withdrawal through the use of other drugs measured the most severe level of drug dependence. Inability to stop using the tolerance were only minimally related to the measurement of cocaine dependence.

Geographical/Spatial Orientation Ability Within Real-World and Simulated Large-Scale Environments.

Geographical/Spatial orientation ability is studied within real-world and simulated environments. Participants (n=1148), residents of San Francisco or Marin County, were assigned to one of four media presentation conditions, two of which are studied here: Auto Tour (a 25-minute tour of the research site) or Model Film (a color film of the tour route). The Embedded Figures Task, dispositional measures, slide-recognition, map-placement, and map-sketch tasks were administered. Simulation condition, previous exposure, visual-spatial ability, and dispositional measures significantly predicted performance on the general factor (Geographic/Spatial orientation ability). Structural equations models are developed, identifying different aspects of effective performance for Auto Tour and Model Film conditions. Differences in individual performance within presentation condition underscore the need for careful evaluation of the effectiveness o9f simulators as training devices.

Personality correlates of sense of direction and geographical orientation.

Personality measures were related to several dimensions of geographical orientation ability. Participants completed a questionnaire about their sense of direction and pointed to unseen locations on or near the Berkeley campus of the University of California. In addition, participants completed the Mental Rotations Test and the California Psychological Inventory (CPI). The CPI scales assessing interpersonal dimensions related both to pointing performance and to worrying about becoming lost but not to self-reports of sense of direction. In multiple regression analyses, personality scores on Capacity for Status, Sociability, and Self-Acceptance were found to account for a significant additional portion of the variance in pointing error even after various possible mediating variables (e.g., exploration, familiarity, spatial visualization) were taken into account. It is suggested that plans of action and attitudes toward the environment engage individuals differentially in building accurate real world representations.