Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals

Chemokines influence HIV neuropathogenesis by affecting the HIV life cycle, trafficking of macrophages into the nervous system, glial activation, and neuronal signaling and repair processes; however, knowledge of their relationship to in vivo measures of cerebral injury is limited. The primary objective of this study was to determine the relationship between a panel of chemokines in cerebrospinal fluid (CSF) and cerebral metabolites measured by proton magnetic resonance spectroscopy (MRS) in a cohort of HIV-infected individuals. One hundred seventy-one stored CSF specimens were assayed from HIV-infected individuals who were enrolled in two ACTG studies that evaluated the relationship between neuropsychological performance and cerebral metabolites. Concentrations of six chemokines (fractalkine, IL-8, IP-10, MCP-1, MIP-1β, and SDF-1) were measured and compared with cerebral metabolites individually and as composite neuronal, basal ganglia, and inflammatory patterns. IP-10 and MCP-1 were the chemokines most strongly associated with individual cerebral metabolites. Specifically, (1) higher IP-10 levels correlated with lower N-acetyl aspartate (NAA)/creatine (Cr) ratios in the frontal white matter and higher MI/Cr ratios in all three brain regions considered and (2) higher MCP-1 levels correlated with lower NAA/Cr ratios in frontal white matter and the parietal cortex. IP-10, MCP-1, and IL-8 had the strongest associations with patterns of cerebral metabolites. In particular, higher levels of IP-10 correlated with lower neuronal pattern scores and higher basal ganglia and inflammatory pattern scores, the same pattern which has been associated with HIV-associated neurocognitive disorders (HAND). Subgroup analysis indicated that the effects of IP-10 and IL-8 were influenced by effective antiretroviral therapy and that memantine treatment may mitigate the neuronal effects of IP-10. This study supports the role of chemokines in HAND and the validity of MRS as an assessment tool. In particular, the findings identify relationships between the immune response—particularly an interferon-inducible chemokine, IP-10—and cerebral metabolites and suggest that antiretroviral therapy and memantine modify the impact of the immune response on neurons

A novel application of capnography during controlled human exposure to air pollution

BACKGROUND: The objective was to determine the repeatability and stability of capnography interfaced with human exposure facility. METHODS: Capnographic wave signals were obtained from five healthy volunteers exposed to particle-free, filtered air during two consecutive 5 min intervals, 10 min apart, within the open and then the sealed and operational human exposure facility (HEF). Using a customized setup comprised of the Oridion Microcap(® )portable capnograph, DA converter and AD card, the signal was acquired and saved as an ASCII file for subsequent processing. The minute ventilation (VE), respiratory rate (RR) and expiratory tidal volume (V(TE)) were recorded before and after capnographic recording and then averaged. Each capnographic tracing was analyzed for acceptable waves. From each recorded interval, 8 to 19 acceptable waves were selected and measured. The following wave parameters were obtained: total length and length of phase II and III, slope of phase II and III, area under the curve and area under phase III. In addition, we recorded signal measures including the mean, standard deviation, mode, minimum, maximum – which equals end-tidal CO(2 )(EtCO(2)), zero-corrected maximum and true RMS. RESULTS: Statistical analysis using a paired t-test for means showed no statistically significant changes of any wave parameters and wave signal measures, corrected for RR and V(TE), comparing the measures when the HEF was open vs. sealed and operational. The coefficients of variation of the zero-corrected and uncorrected EtCO(2), phase II absolute difference, signal mean, standard deviation and RMS were less than 10% despite a sub-atmospheric barometric pressure, and slightly higher temperature and relative humidity within the HEF when operational. CONCLUSION: We showed that a customized setup for the acquisition and processing of the capnographic wave signal, interfaced with HEF was stable and repeatable. Thus, we expect that analysis of capnographic waves in controlled human air pollution exposure studies is a feasible tool for characterization of cardio-pulmonary effects of such exposures

Hepatic profile analyses of tipranavir in Phase II and III clinical trials

<p>Abstract</p> <p>Background</p> <p>The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.</p> <p>Methods</p> <p>Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.</p> <p>Results</p> <p>Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade ≤ 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.</p> <p>Conclusion</p> <p>Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline.</p> <p>Trial registration</p> <p>US-NIH Trial registration number: NCT00144170</p

General practitioners knowledge and management of whiplash associated disorders and post-traumatic stress disorder: Implications for patient care

© 2016 The Author(s). Background: In Australia, general practitioners (GPs) see around two-thirds of people injured in road traffic crashes. Road traffic crash injuries are commonly associated with diverse physical and psychological symptoms that may be difficult to diagnose and manage. Clinical guidelines have been developed to assist in delivering quality, consistent care, however the extent to which GPs knowledge and practice in diagnosing and managing road traffic crash injuries concords with the guidelines is unknown. This study aimed to explore Australian GPs knowledge, attitudes and practices regarding the diagnosis and management of road traffic crash injuries, specifically whiplash associated disorders (WAD) and post-traumatic stress disorder (PTSD). Method: A cross-sectional survey of 423 GPs across Australia conducted between July and December 2014. We developed a questionnaire to assess their knowledge of WAD and PTSD, confidence in diagnosing and managing WAD and PTSD, frequency of referral to health providers, barriers to referral, and attitudes towards further education and training. Factor analysis, Spearman's correlation, and multiple ordered logistic regressions were performed. Results: Overall, GPs have good level knowledge of WAD and PTSD; only 9.6 % (95 % CI: 7.1 %, 12.8 %) and 23.9 % (95 % CI: 20.8 %, 28.2 %) of them were deemed to have lower level knowledge of WAD and PTSD respectively. Key knowledge gaps included imaging indicators for WAD and indicators for psychological referral for PTSD. GPs who were male, with more years of experience, working in the urban area and with higher knowledge level of WAD were more confident in diagnosing and managing WAD. Only GPs PTSD knowledge level predicted confidence in diagnosing and managing PTSD. GPs most commonly referred to physiotherapists and least commonly to vocational rehabilitation providers. Barriers to referral included out-of-pocket costs incurred by patients and long waiting times. Most GPs felt positive towards further education on road traffic crash injury management. Conclusion: This study has enhanced understanding of the knowledge skills and attitudes of GPs towards road traffic crash injury care in Australia, and has identified areas for further education and training. If delivered, this training has the potential to reduce unnecessary imaging for WAD and optimise the early referral of patients at risk of delayed recovery following a road traffic crash

Long-term air pollution exposure and self-reported morbidity: A longitudinal analysis from the Thai cohort study (TCS)

[Background] Several studies have shown the health effects of air pollutants, especially in China, North American and Western European countries. But longitudinal cohort studies focused on health effects of long-term air pollution exposure are still limited in Southeast Asian countries where sources of air pollution, weather conditions, and demographic characteristics are different. The present study examined the association between long-term exposure to air pollution and self-reported morbidities in participants of the Thai cohort study (TCS) in Bangkok metropolitan region (BMR), Thailand. [Methods] This longitudinal cohort study was conducted for 9 years from 2005 to 2013. Self-reported morbidities in this study included high blood pressure, high blood cholesterol, and diabetes. Air pollution data were obtained from the Thai government Pollution Control Department (PCD). Particles with diameters ≤10 μm (PM₁₀), sulfur dioxide (SO₂), nitrogen dioxide (NO₂), ozone (O₃), and carbon monoxide (CO) exposures were estimated with ordinary kriging method using 22 background and 7 traffic monitoring stations in BMR during 2005–2013. Long-term exposure periods to air pollution for each subject was averaged as the same period of person-time. Cox proportional hazards models were used to examine the association between long-term air pollution exposure with self-reported high blood pressure, high blood cholesterol, diabetes. Results of self-reported morbidity were presented as hazard ratios (HRs) per interquartile range (IQR) increase in PM₁₀, O₃, NO₂, SO₂, and CO. [Results] After controlling for potential confounders, we found that an IQR increase in PM₁₀ was significantly associated with self-reported high blood pressure (HR = 1.13, 95% CI: 1.04, 1.23) and high blood cholesterol (HR = 1.07, 95%CI: 1.02, 1.12), but not with diabetes (HR = 1.05, 95%CI: 0.91, 1.21). SO₂ was also positively associated with self-reported high blood pressure (HR = 1.22, 95%CI: 1.08, 1.38), high blood cholesterol (HR = 1.20, 95%CI: 1.11, 1.30), and diabetes (HR = 1.21, 95%CI: 0.92, 1.60). Moreover, we observed a positive association between CO and self-reported high blood pressure (HR = 1.07, 95%CI: 1.00, 1.15), but not for other diseases. However, self-reported morbidities were not associated with O₃ and NO₂. [Conclusions] Long-term exposure to air pollution, especially for PM₁₀ and SO₂ was associated with self-reported high blood pressure, high blood cholesterol, and diabetes in subjects of TCS. Our study supports that exposure to air pollution increases cardiovascular disease risk factors for younger population

HIV-1 Replication in the Central Nervous System Occurs in Two Distinct Cell Types

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to the development of HIV-1-associated dementia (HAD). We examined the virological characteristics of HIV-1 in the cerebrospinal fluid (CSF) of HAD subjects to explore the association between independent viral replication in the CNS and the development of overt dementia. We found that genetically compartmentalized CCR5-tropic (R5) T cell-tropic and macrophage-tropic HIV-1 populations were independently detected in the CSF of subjects diagnosed with HIV-1-associated dementia. Macrophage-tropic HIV-1 populations were genetically diverse, representing established CNS infections, while R5 T cell-tropic HIV-1 populations were clonally amplified and associated with pleocytosis. R5 T cell-tropic viruses required high levels of surface CD4 to enter cells, and their presence was correlated with rapid decay of virus in the CSF with therapy initiation (similar to virus in the blood that is replicating in activated T cells). Macrophage-tropic viruses could enter cells with low levels of CD4, and their presence was correlated with slow decay of virus in the CSF, demonstrating a separate long-lived cell as the source of the virus. These studies demonstrate two distinct virological states inferred from the CSF virus in subjects diagnosed with HAD. Finally, macrophage-tropic viruses were largely restricted to the CNS/CSF compartment and not the blood, and in one case we were able to identify the macrophage-tropic lineage as a minor variant nearly two years before its expansion in the CNS. These results suggest that HIV-1 variants in CSF can provide information about viral replication and evolution in the CNS, events that are likely to play an important role in HIV-associated neurocognitive disorders

Netherlands

The Netherlands traditionally had ample early retirement possibilities. Several reforms introduced from the late 1990s onward contributed to the successful reversal of this early exit trend. As a result, in 2018, employees o

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

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