This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals ...in the era of combination antiretroviral therapy (CART).
A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment).
Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups).
The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
Dysregulated iron transport and a compromised blood–brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport ...and/or angiogenesis—ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)—as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment odds ratio (OR) 2.17,
p
= 0.006 and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (
p
= 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (
p
= 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both
p
= 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both
p
< 0.05), and higher ceruloplasmin predicted worse impairment (higher cGDS values,
p
< 0.01). In the subgroup with undetectable viral load and minimal comorbidity, CSF ceruloplasmin and haptoglobin were strongly associated with GDS impairment (ORs 5.57 and 2.96, respectively; both
p
< 0.01) and HAND (both
p
< 0.01). Concurrently measured CSF IL-6 and TNF-α were only weakly correlated to these three biomarkers. Higher CSF ceruloplasmin, haptoglobin, and VEGF are associated with a significantly greater likelihood of HAND, suggesting that interventions aimed at disordered iron transport and angiogenesis may be beneficial in this disorder.
Background: Biological markers for optimal selection of patient to epidermal growth factor receptor (EGFR)-targeted therapies are not established in advanced non-small-cell lung cancer (NSCLC). ...Patients and methods: EGFR/HER2 gene copy number by FISH, EGFR protein and pAKT expression by immunohistochemistry (IHC) and EGFR and KRAS mutations were tested in 204 gefitinib-treated NSCLC patients. Results: Increased EGFR and HER2 gene copy number (FISH+), EGFR protein overexpression (IHC+), EGFR mutations and pAKT overexpression were all associated with significantly higher response rates (33%, 29%, 22%, 39% and 20% respectively). EGFR FISH+ (32%) and IHC+ (61%) correlated with improved survival, while EGFR mutations (27%), KRAS mutations (26%) and pAKT expression (69%) did not. In multivariate survival analysis EGFR FISH and IHC were independent predictive markers. EGFR FISH+/IHC+ patients (23%) had a median survival of 21 months versus 6 months for double-negative patients (30%). Conclusion: Combination of EGFR FISH and IHC is effective predictor for benefit from gefitinib. Patients with double-negative results are unlikely to benefit in western NSCLC populations.
Three types of HIV-associated neurocognitive disorders (HAND) exist that are distinguished by presence and severity of impairment in cognitive and everyday functioning. Although well-validated ...neurocognitive measures exist, determining impairment in everyday functioning remains a challenge. We aim to determine whether Self-Report measures of everyday functioning are as effective in characterizing HAND as Performance-Based measures. We assessed 674 HIV-infected participants with a comprehensive neurocognitive battery; 233 met criteria for a HAND diagnosis by having at least mild neurocognitive impairment. Functional decline was measured via Self-Report and Performance-Based measures. HAND diagnoses were determined according to published criteria using three approaches to assess functional decline: (1) Self-Report measures only, (2) Performance-Based measures only, and (3) Dual-method combining Self-Report and Performance-Based measures. The Dual-method classified the most symptomatic HAND, compared to either singular method. Singular method classifications were 76% concordant with each other. Participants classified as Performance-Based functionally impaired were more likely to be unemployed and more immunosuppressed, whereas those classified as Self-Report functionally impaired had more depressive symptoms. Multimodal methods of assessing everyday functioning facilitate detection of symptomatic HAND. Singular Performance-Based classifications were associated with objective functional and disease-related factors; reliance on Self-Report classifications may be biased by depressive symptoms.
Air pollution is a heterogeneous, complex mixture of gases, liquids, and particulate matter. Epidemiological studies have demonstrated a consistent increased risk for cardiovascular events in ...relation to both short- and long-term exposure to present-day concentrations of ambient particulate matter. Several plausible mechanistic pathways have been described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterial vasoconstriction, systemic inflammatory responses, and the chronic promotion of atherosclerosis. The purpose of this statement is to provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution and cardiovascular disease. In addition, the implications of these findings in relation to public health and regulatory policies are addressed. Practical recommendations for healthcare providers and their patients are outlined. In the final section, suggestions for future research are made to address a number of remaining scientific questions.
Objectives: Understanding mechanistic pathways linking airborne particle exposure to cardiovascular health is important for causal inference and setting environmental standards. We evaluated whether ...urinary albumin excretion, a subclinical marker of microvascular function which predicts cardiovascular events, was associated with ambient particle exposure. Methods: Urinary albumin and creatinine were measured among members of the Multi-Ethnic Study of Atherosclerosis at three visits during 2000–2004. Exposure to PM2.5 and PM10 (μg/m3) was estimated from ambient monitors for 1 month, 2 months and two decades before visit one. We regressed recent and chronic (20 year) particulate matter (PM) exposure on urinary albumin/creatinine ratio (UACR, mg/g) and microalbuminuria at first examination, controlling for age, race/ethnicity, sex, smoking, second-hand smoke exposure, body mass index and dietary protein (n = 3901). We also evaluated UACR changes and development of microalbuminuria between the first, and second and third visits which took place at 1.5- to 2-year intervals in relation to chronic PM exposure prior to baseline using mixed models. Results: Chronic and recent particle exposures were not associated with current UACR or microalbuminuria (per 10 μg/m3 increment of chronic PM10 exposure, mean difference in log UACR = −0.02 (95% CI −0.07 to 0.03) and relative probability of having microalbuminuria = 0.92 (95% CI 0.77 to 1.08)) We found only weak evidence that albuminuria was accelerated among those chronically exposed to particles: each 10 μg/m3 increment in chronic PM10 exposure was associated with a 1.14 relative probability of developing microalbuminuria over 3–4 years, although 95% confidence intervals included the null (95% CI 0.96 to 1.36). Conclusions: UACR is not a strong mechanistic marker for the possible influence of air pollution on cardiovascular health in this sample.
Reply to Haddow et al Heaton, Robert K.; Franklin, Donald R.; Deutsch, Reena ...
Clinical infectious diseases,
05/2015, Volume:
60, Issue:
9
Journal Article
Abstract Background Prior research has demonstrated neuropsychological (NP) impairment in persons with histories of injection drug use (IDU), hepatitis C virus (HCV) infection, and methadone ...maintenance treatment (MMT), individually, but little is known about the NP effects of these three risk factors in combination. This issue is particularly important in China, which is addressing its highly HCV-comorbid IDU epidemic with widespread government sponsored MMT, especially in light of recent evidence suggesting that methadone may be neuroprotective in some circumstances. Methods We administered a comprehensive NP test battery to 195 Chinese heroin IDU individuals taking MMT (IDU+ group), the majority of whom were also HCV+ (87%; n = 169), and compared their NP performance to that of 198 demographically comparable, non-IDU Chinese controls (IDU− group). All participants in both groups tested negative for HIV infection, which is also a common comorbidity in the Chinese IDU population. Results The IDU+ group did not have an increased rate of global NP impairment, or perform significantly worse on any individual NP test measure. Within the IDU+ group, liver disease characteristics and reported details of heroin use were not significantly associated with NP performance. Conclusion Failure to detect NP impairment in IDU+ subjects with or without HCV infection was surprising, particularly considering the previously demonstrated sensitivity of our NP battery to neurocognitive disorders associated with HIV infection in China. One possible explanation, which should be explored in future research, is the potential neuroprotective effect of methadone in the context of HCV infection and/or heroin withdrawal.
Background Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can ...identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3 / GSDMB variants with asthma (combined P = 2.9 × 10−8 ). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 ( FADS2 ; P = .002), N-acetyl-α-D-galactosaminidase ( NAGA ; P = .0002), and Factor XIII, A1 ( F13A1 ; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2 , NAGA , and F13A1 in the pathogenesis of asthma.
Data were collected from 1169 gay circuit party patrons in three North American circuit parties in three geographical locations in 1999. Questionnaires obtained reasons for attending circuit parties ...and drugs used at circuit parties. Factor analyses of the 10 major reasons for attending parties indicated that there were two significant moderately correlated dimensions: a social and celebratory one to be with friends and dance, and a sensation-seeking one, to have sex and drugs. Drug and sex on drugs predictors of the social dimension accounted for only 3.8% of its variance and included alcohol, ecstasy (methylenedioxymethamphetamine), GHB ( -hydroxybutyrate), and having sex while on alcohol as significant predictors. Drug predictors for the sensation-seeking dimension accounted for four times the variance of the first dimension and included poppers, alcohol, ecstasy, Special K, and GHB, and having sex while on methamphetamines and on GHB. Unsafe sex was significantly associated with the sensation-seeking dimension but not the social dimension. While 63% checked ≥3 of the social reasons for attendance, only 13% checked ≥3 of the sensation-seeking reasons for attendance. Age was significantly inversely associated with the social dimension. These data suggest that while drug use is significantly associated with both the sensation-seeking and social dimensions of circuit party attendance, a greater number of drugs, sexual activity while on drugs, and unsafe sex are more closely associated with the sensation-seeking dimension of attendance.
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