CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study.

CINAMMON is a phase IV, open-label, single-arm, pilot study assessing maraviroc (MVC) in the central nervous system (CNS) when added to darunavir/ritonavir monotherapy (DRV/r) in virologically suppressed HIV-infected subjects. CCR5 tropic participants on DRV/r were recruited. Participants remained on DRV/r for 12 week (w) (control phase). MVC 150 mg qd was added w12-w36 (intervention phase). Lumbar puncture (LP) and neurocognitive function (Cogstate) examinations scheduled at baseline, w12 and w36; MRI before w12, again at w36. Primary endpoint was CSF inflammatory marker changes during intervention phase. Secondary endpoints included changes in NC function and MRI parameters. CSF/plasma DRV/r concentrations measured at w12 and w36, MVC at w36. Nineteen patients recruited, 15 completed (17M, 2F). Dropouts: headache (2), knee problem (could not attend, 1), personal reasons (1). Mean age (range) 45.4 years (27.2-65.1), 13/19 white, 10/19 MSM. No changes in selected CSF markers were seen w12-w36. Overall NC function did not improve w12-w36: total age adjusted z score improved by 0.27 (weighted paired t test; p = 0.11); for executive function only, age adjusted z score improved by 0.54 (p = 0.03). MRI brain parameters unchanged. DRV plasma:CSF concentration ratio unchanged between w12 (132) and w36 (112; p = 0.577, Wilcoxon signed-rank). MVC plasma:CSF concentration ratio was 35 at w36. No changes in neuroinflammatory markers seen. In this small study, addition of 24w MVC 150 mg qd to stable DRV/r monotherapy showed possible improvement in executive function with no global NC effect. Learning effect cannot be excluded. This effect should be further evaluated.

Correction to: CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study.

Due to a production error the bottom portion of Figure 1 was omitted. The corrected figure is given below.

The Localized Hemodynamics of Drug-Eluting Stents Are Not Improved by the Presence of Magnetic Struts.

The feasibility of implementing magnetic struts into drug-eluting stents (DESs) to mitigate the adverse hemodynamics which precipitate stent thrombosis is examined. These adverse hemodynamics include platelet-activating high wall shear stresses (WSS) and endothelial dysfunction-inducing low wall shear stresses. By magnetizing the stent struts, two forces are induced on the surrounding blood: (1) magnetization forces which reorient red blood cells to align with the magnetic field and (2) Lorentz forces which oppose the motion of the conducting fluid. The aim of this study was to investigate whether these forces can be used to locally alter blood flow in a manner that alleviates the thrombogenicity of stented vessels. Two-dimensional steady-state computational fluid dynamics (CFD) simulations were used to numerically model blood flow over a single magnetic drug-eluting stent strut with a square cross section. The effects of magnet orientation and magnetic flux density on the hemodynamics of the stented vessel were elucidated in vessels transporting oxygenated and deoxygenated blood. The simulations are compared in terms of the size of separated flow regions. The results indicate that unrealistically strong magnets would be required to achieve even modest hemodynamic improvements and that the magnetic strut concept is ill-suited to mitigate stent thrombosis.

A cross-sectional study to evaluate the association of hyperbilirubinaemia on markers of cardiovascular disease, neurocognitive function, bone mineral density and renal markers in HIV-1 infected subjects on protease inhibitors.

BACKGROUND: Ongoing inflammation in controlled HIV infection contributes to non-AIDS comorbidities. High bilirubin appears to exhibit an anti-inflammatory effect in vivo. We therefore examined whether increased bilirubin in persons with HIV was associated with differences in markers of inflammation and cardiovascular, bone, renal disease, and neurocognitive (NC) impairment. METHODS: This cross-sectional study examined inflammatory markers in individuals with stable HIV infection treated with two nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor. Individuals recruited were those with a normal bilirubin (NBR; 0-17 µmol/L) or high bilirubin (>2.5 × upper limit of normal). Demographic and anthropological data were recorded. Blood and urine samples were taken for analyses. Pulse wave velocity (PWV) measurement, carotid intimal thickness (CIT), and calcaneal stiffness (CSI) were measured. Males were asked to answer a questionnaire about sexual function; NC testing was performed using CogState. RESULTS: 101 patients were screened, 78 enrolled (43 NBR and 35 HBR). Atazanavir use was significantly higher in HBR. Whilst a trend for lower CIT was seen in those with HBR, no significant differences were seen in PWV, bone markers, calculated cardiovascular risk (Framingham), or erectile dysfunction score. VCAM-1 levels were significantly lower in the HBR group. HBR was associated with lower LDL and triglyceride levels. NBR was associated with a calculated FRAX significantly lower than HBR although no associations were found after adjusting for tenofovir use. No difference in renal markers was observed. Component tests of NC testing revealed differences favouring HBR but overall composite scores were similar. DISCUSSION: High bilirubin in the context of boosted PI therapy was found not to be associated with differences in with the markers examined in this study. Some trends were noted and, on the basis of these, a larger, clinical end point study is warranted.

HIV-related neurocognitive impairment screening: the patient's perspective on its utility and psychological impact.

Despite ever improving advances in antiretroviral therapy, neurocognitive impairments such as asymptomatic and mild neurocognitive impairment remain a significant problem for the HIV-positive population. We distributed a post-neurocognitive impairment screening service evaluation questionnaire to assess satisfaction and anxiety. Subjects were HIV positive and aged 18-50. They were screened using the Brief Neurocognitive Score and International HIV Dementia Score as well as undergoing screening for anxiety (Generalised Anxiety Disorder Assessment [GAD-7]), depression (Participant Health Questionnaire Mood Scale [PHQ-9]) and memory (Everyday Memory Questionnaire [EMQ-R]). On completion, they were either reassured that the tests were normal or were referred for further investigation. Following assessment, subjects were asked to complete an anonymous satisfaction survey; 101 surveys were analysed. Forty-nine per cent of participants stated that they "felt better" following screening, 43% said it "made no difference", 6% stated it "worried me" and 1% "did not understand". On a scale of 0-10 of helpfulness, the mean score was 7.53. Forty-seven subjects indicated that they were referred for further investigation and 46 subjects that nothing else was needed; 8 reported they did not know. Those referred on rated satisfaction at a mean of 7.54/10 and those with normal screen as 7.09/10 (p = 0.46). Of the groups that were referred for further investigation, 6% said the test "worried them" compared to 4% in the non-referred group. Forty-nine per cent said they "felt better" despite an abnormal result compared to 50% in a normal screening result (p = 0.76). The results of this survey show that screening for neurocognitive impairment by this method is acceptable and helpful to participants. It did not lead to an increase in anxiety and there was no correlation between referred for further investigations and anxiety suggesting concerns about creating undue anxiety by screening and referral are unfounded.

Screening for HIV-related neurocognitive impairment in clinical practice: challenges and opportunities.

With increasingly successful management of HIV, focus has shifted away from AIDS-related complications to other chronic co-morbidities. For HIV-related cognitive problems, the true aetiopathogenesis and epidemiology remains unclear. Rather than a systematic review, this paper presents the challenges and the opportunities we faced in establishing our own clinical service. Papers were identified using Pubmed and the terms "screening", "HIV" and "neurocognitive". This article covers the background of HIV-associated neurocognitive disorders (HAND) with a focus on HIV-related neurocognitive impairment (NCI), detailing classification, prevalence, diagnostic categories and diagnostic uncertainties. Screening is discussed, including a comparison of the available screening tools for cognitive deficits in HIV-infected patients and the importance of practice effects. Discussed also are the normal ranges and the lack thereof and potential investigations for those found to have impairments. We conclude by discussing the role of NCI screening in routine clinical care at the current time.

How does HIV impact on non-AIDS events in the era of HAART?

Death rates from AIDS-related events in HIV-positive individuals have declined in the era of highly active antiretroviral therapy (HAART). It has also been shown that deaths from non-AIDS events have declined in this cohort since the advent of HAART. We review these data, as well as discussing some of the possible effects HAART might have on non-AIDS diagnoses and deaths in HIV-positive individuals with successfully treated HIV.

Low levels of neurocognitive impairment detected in screening HIV-infected men who have sex with men: The MSM Neurocog Study.

This study aimed to determine the prevalence of HIV neurocognitive impairment in HIV-infected men who have sex with men aged 18-50 years, using a simple battery of screening tests in routine clinical appointments. Those with suspected abnormalities were referred on for further assessment. The cohort was also followed up over time to look at evolving changes. HIV-infected participants were recruited at three clinical sites in London during from routine clinical visits. They could be clinician or self-referred and did not need to be symptomatic. They completed questionnaires on anxiety, depression, and memory. They were then screened using the Brief Neurocognitive Screen (BNCS) and International HIV Dementia Scale (IHDS). Two hundred and five HIV-infected subjects were recruited. Of these, 59 patients were excluded as having a mood disorder and two patients were excluded due to insufficient data, leaving 144 patients for analysis. One hundred and twenty-four (86.1%) had a normal composite z score (within 1 SD of mean) calculated for their scores on the three component tests of the BNCS. Twenty (13.9%) had an abnormal z score, of which seven (35%) were symptomatic and 13 (65%) asymptomatic. Current employment and previous educational level were significantly associated with BNCS scores. Of those referred onwards for diagnostic testing, only one participant was found to have impairment likely related to HIV infection. We were able to easily screen for mood disorders and cognitive impairment in routine clinical practice. We identified a high level of depression and anxiety in our cohort. Using simple screening tests in clinic and an onward referral process for further testing, we were not able to identify neurocognitive impairment in this cohort at levels consistent with published data.

Assessing the role of peripheral CD8 T cells in neurocognitive impairment in HIV-infected men who have sex with men: data from the MSM Neurocog Study.

Studies have suggested CD8 lymphocytes may be a possible marker for inflammation, which is believed to be a contributing factor to neurocognitive impairment. Individuals enrolled in the MSM Neurocog Study were analysed. Those with depression, anxiety or mood disorders were excluded. Individuals with neurocognitive impairment were identified using the Brief NeuroCognitive Screen and compared to those with normal scores. CD4 and CD8 T cell values and CD4:CD8 ratios were compared between groups. In all, 144 men, aged 18-50 years, were included in the analysis. Twenty were diagnosed with neurocognitive impairment. We were unable to identify any significant difference between current, nadir or peak CD4 and CD8 counts. CD4:CD8 ratios and CD4:CD8 ratio inversion (<1) were also found to be similar between both groups. However, neurocognitive impairment subjects were 8% more likely to have inversion of CD4:CD8 ratio and higher median peak CD8 cell counts reported compared to non-impaired subjects. Analysis of data from the MSM Neurocog Study, demonstrated trends in peripheral CD8 counts and CD4:CD8 ratios. However, we are unable to demonstrate any significant benefit. Plasma biomarkers of neurocognitive impairment in HIV-infected subjects would be of great benefit over current methods of invasive CSF analysis and technical neuroimaging used in the diagnosis of neurocognitive impairment. Future, prospective, longitudinal work with large numbers of neurocognitive impairment subjects is required to further investigate the role of peripheral CD8 T cells as markers of neurocognitive impairment.

Structure and characterization of the murine p80 coilin gene, Coil.

Cajal bodies (coiled bodies, CBs) are nuclear organelles of unknown function and are characterized by a wide variety of components including various basal transcription and cell cycle proteins, the nucleolar proteins fibrillarin and Nopp140, numerous small nuclear ribonucleoproteins, the survival motor neuron protein complex, and the marker protein, p80 coilin. To gain insight into the role of p80 coilin in CBs, we have cloned the murine gene Coil and have mapped it to the distal portion of chromosome band 11D. The approximately 2.6-kb transcript is detectable in all tissues analyzed, with the highest levels in brain and testis. Sequence analysis shows that, like its human counterpart, the mouse coilin gene is composed of seven exons and spans nearly 30 kb of genomic DNA. The predicted amino acid sequence reveals two conserved N- and C-terminal domains, and comparison with the Xenopus SPH-1 protein reveals that these three genes are indeed orthologous. These results should facilitate gene disruption experiments aimed at creating a genetic model system to study CBs.