Determinants of sustained viral suppression in HIV-infected patients with self-reported poor adherence to antiretroviral therapy.

BACKGROUND: Good adherence to antiretroviral therapy (ART) is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels. METHODS: Eligible individuals were Caucasians treated with efavirenz (EFV) and/or boosted lopinavir (LPV/r) with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV (rs3745274, rs35303484, rs35979566 in CYP2B6) and LPV/r clearance (rs4149056 in SLCO1B1, rs6945984 in CYP3A, rs717620 in ABCC2). Viral suppression was defined as having HIV-1 RNA <400 copies/ml throughout the study period. RESULTS: From January 2003 until May 2009, 37 individuals on EFV (28 suppressed and 9 not suppressed) and 69 on LPV/r (38 suppressed and 31 not suppressed) were eligible. The poor adherence period was a median of 32 weeks with 18.9% of EFV and 20.3% of LPV/r patients reporting missed doses on a daily basis. The tested SNPs were not determinant for viral suppression. Reporting missing >1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR) 0.11, 95% confidence interval (CI): 0.01-0.99; LPV/r: OR 0.29, 95% CI: 0.09-0.94). In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period (EFV: OR 3.40, 95% CI: 0.62-18.75; LPV/r: OR 5.65, 95% CI: 1.82-17.56). CONCLUSIONS: The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population.

The evolution of information suppression in communicating robots with conflicting interests.

Reliable information is a crucial factor influencing decision-making and, thus, fitness in all animals. A common source of information comes from inadvertent cues produced by the behavior of conspecifics. Here we use a system of experimental evolution with robots foraging in an arena containing a food source to study how communication strategies can evolve to regulate information provided by such cues. The robots could produce information by emitting blue light, which the other robots could perceive with their cameras. Over the first few generations, the robots quickly evolved to successfully locate the food, while emitting light randomly. This behavior resulted in a high intensity of light near food, which provided social information allowing other robots to more rapidly find the food. Because robots were competing for food, they were quickly selected to conceal this information. However, they never completely ceased to produce information. Detailed analyses revealed that this somewhat surprising result was due to the strength of selection on suppressing information declining concomitantly with the reduction in information content. Accordingly, a stable equilibrium with low information and considerable variation in communicative behaviors was attained by mutation selection. Because a similar coevolutionary process should be common in natural systems, this may explain why communicative strategies are so variable in many animal species.

Suppression of short interfering RNA-mediated gene silencing by the structural proteins of hepatitis C virus.

Viruses have evolved strategies to overcome the antiviral effects of the host at different levels. Besides specific defence mechanisms, the host responds to viral infection via the interferon pathway and also by RNA interference (RNAi). However, several viruses have been identified that suppress RNAi. We addressed the question of whether hepatitis C virus (HCV) suppresses RNAi, using cell lines constitutively expressing green fluorescent protein (GFP) and inducibly expressing HCV proteins. It was found that short interfering RNA-mediated GFP gene silencing was inhibited when the entire HCV polyprotein was expressed. Further studies showed that HCV structural proteins, and in particular envelope protein 2 (E2), were responsible for this inhibition. Co-precipitation assays demonstrated that E2 bound to Argonaute-2 (Ago-2), a member of the RNA-induced silencing complex, RISC. Thus, HCV E2 that interacts with Ago-2 is able to suppress RNAi.

Cognitive dysfunction in HIV patients despite long-standing suppression of viremia.

OBJECTIVE:: To determine the prevalence of cognitive complaints and HIV-associated neurocognitive disorders (HANDs) in a cohort of aviremic HIV-positive patients. To evaluate the relevance of the HIV dementia scale to detect HANDs. DESIGN:: Assessment of HANDs with neuropsychological tests. METHODS:: Two hundred HIV-infected patients with undetectable HIV-1 RNA concentrations in the plasma, no history of major opportunistic infection of the central nervous system in the past 3 years, no current use of intravenous drugs, and no major depression answered a questionnaire designed to elicit cognitive complaints. Cognitive functions of 50 complaining and 50 noncomplaining HIV-positive patients were assessed. RESULTS:: Patients had undetectable HIV-1 RNA concentrations for a median time of 48 months (range 3.2-136.6). The prevalence of cognitive complaints was 27%. The prevalence of HANDs was 84% among patients with cognitive complaints (asymptomatic neurocognitive impairment 24%, mild neurocognitive disorders 52%, and HIV-associated dementia 8%) and 64% among noncomplainers (asymptomatic neurocognitive impairment 60%, mild neurocognitive disorders 4%, and HIV-associated dementia 0%; P < 0.001). A score of 14 points or less on the HIV dementia scale yielded a positive predictive value of HANDs of 92% in complainers and 82% in noncomplainers. CONCLUSION:: The prevalence of HANDs is high even in long-standing aviremic HIV-positive patients. However, HANDs without functional repercussion in daily life (asymptomatic neurocognitive impairment) is the most frequent subtype observed. In this population, the HIV dementia scale with a cutoff of 14 points or less seems to provide a useful tool to screen for the presence of HANDs.

Effect of Dexamethasone on cytolkine secretion in CD4+T cells in steroid refractori uveitis

Projecte de recerca elaborat a partir d’una estada a la facultat de Medical Sciences de la Universitat de Bristol, Alemanya, entre 2011 i 2012. Aquest treball s'ha realitzat a la facultat de Medical Sciences de la Universitat de Bristol, al laboratori del Prof. Andrew Di cks,o ta la seva supe1visi6. Ei treball s'ha realitzat amb els seus col.laboradors, el Dr Richard Lee i Lauren Schew:tz. Objectiu: Els glucocorticoids (GCs) tenen diversos efectes sobre les cèl.lules T CD4+ per modular la resposta immune principalment mitjançant els seus efectes anti-proliferatius. Tot i això la dexametasona (Dex, glucocorticoid sintètic) també indueix la secreció de la citocina immunosupressora IL-10 . L'objectiu d'aquest treball ha estat comparar la capacitat dels glucocorticoids en modular la producció de citocines en cèl.lules T CD4+ en pacients uveítics sensibles (SS), i resistents (SR) a esteroids. Metodologia: Es van aïllar cèl• lules T CD4+ de pacients uveítics SS i SR. Es va induir la producció de cèl.lules T regulatories (Tregs) i mitjançant I'estimulació amb anti- CD3/CD28 en presència d'lL-2 i Després del cultiu es van analitzar els nivells d’expressió intracel•lular de les citocines IL-10, IL-4, IL-9, IL-17 i IFN-y per citometria de flux. D'altra banda, també es van separar cèl.lules T CD4t de pacients uveïtis segons I'expressió de CCR6 i es van polaritzar per obtenir els fenotips ThO i Th17 per estudiar I'efecte de Dex i ciclosporina (CsA) en aquests subtipus cel.lulars. Resultats: Les cèl.lules T CD4+ de pacients SR no van ser capaces de produir IL-10 en resposta al tractament amb Dex. Dex no va afectar els nivells d'expressió d'11-17, però va reduir els nivells de IL-4 i IFN-V. Els nivells d'lL-9 (marcador d'un subtipus cel.lular recentment descrit, Th9) v ise r sempre inferiors a 11%. En canvi, el traclament a amb CsA va reduir significativament els nivells d'lL-17 i IFN-y en cèl.lules Th17 i ThO. Conclusions: La Dex no és capaç d'induir cèl.lules Treg funcionalment supresores en pacients veiticsS R. Aquest fenòmen és Independent dels efectes en I'expressió d'altres citocines. Aquests resultats suggereixen que I'efecte de la Dex sobre la funció de cél.lules Treg és clau en el desenvolupament del fenotip SR en la uveïtis . D'altra banda, al llarg d'aquest temps he iniciat un nou projecte que ha donat lloc a un futur projecte de col elaboració. Resumidament, degut a que els nivells elevats de proteïna C-reactiva (CRP) són un factor de risc en la degeneració macular, malaltia inflamatòria crònica principal causa de ceguera en països industrialitzats, I'objectiu d'aquest altre treball ha estat iniciar un projecte per avaluar els efectes de les diferents isoformes de la CRP sobre la resposta inflamatòria d’epiteli pigmentari retinià.

Édit du Roy, portant suppression des offices d'intendans & controlleurs généraux des écuries & livrées du Roy, & création de deux nouveaux offices d'intendans & controlleurs généraux desdites écuries & livrées . Donné au château de Bouchout au mois de May 1746

[Acte royal. 1746-05-00. Au château de Bouchout]

A systematic review and meta-analysis of perineural dexamethasone for peripheral nerve blocks.

We systematically reviewed the safety and efficacy of perineural dexamethasone as an adjunct for peripheral nerve blockade in 29 controlled trials of 1695 participants. We grouped trials by the duration of local anaesthetic action (short- or medium- vs long-term). Dexamethasone increased the mean (95% CI) duration of analgesia by 233 (172-295) min when injected with short- or medium-term action local anaesthetics and by 488 (419-557) min when injected with long-term action local anaesthetics, p < 0.00001 for both. However, these results should be interpreted with caution due to the extreme heterogeneity of results, with I2 exceeding 90% for both analyses. Meta-regression did not show an interaction between dose of perineural dexamethasone (4-10 mg) and duration of analgesia (r2 = 0.02, p = 0.54). There were no differences between 4 and 8 mg dexamethasone on subgroup analysis.

Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system.

Dietary obesity is a major factor in the development of type 2 diabetes and is associated with intra-adipose tissue hypoxia and activation of hypoxia-inducible factor 1α (HIF1α). Here we report that, in mice, Hif1α activation in visceral white adipocytes is critical to maintain dietary obesity and associated pathologies, including glucose intolerance, insulin resistance, and cardiomyopathy. This function of Hif1α is linked to its capacity to suppress β-oxidation, in part, through transcriptional repression of sirtuin 2 (Sirt2) NAD(+)-dependent deacetylase. Reduced Sirt2 function directly translates into diminished deacetylation of PPARγ coactivator 1α (Pgc1α) and expression of β-oxidation and mitochondrial genes. Importantly, visceral adipose tissue from human obese subjects is characterized by high levels of HIF1α and low levels of SIRT2. Thus, by negatively regulating the Sirt2-Pgc1α regulatory axis, Hif1α negates adipocyte-intrinsic pathways of fatty acid catabolism, thereby creating a metabolic state supporting the development of obesity.

Fat signal suppression for coronary MRA at 3T using a water-selective adiabatic T2 -preparation technique.

PURPOSE: To improve fat saturation in coronary MRA at 3T by using a spectrally selective adiabatic T2 -Prep (WSA-T2 -Prep). METHODS: A conventional adiabatic T2 -Prep (CA-T2 -Prep) was modified, such that the excitation and restoration pulses were of differing bandwidths. On-resonance spins are T2 -Prepared, whereas off-resonance spins, such as fat, are spoiled. This approach was combined with a CHEmically Selective Saturation (CHESS) pulse to achieve even greater fat suppression. Numerical simulations were followed by phantom validation and in vivo coronary MRA. RESULTS: Numerical simulations demonstrated that augmenting a CHESS pulse with a WSA-T2 -Prep improved robustness to B1 inhomogeneities and that this combined fat suppression was effective over a broader spectral range than that of a CHESS pulse in a conventional T2 -Prepared sequence. Phantom studies also demonstrated that the WSA-T2 -Prep+CHESS combination produced greater fat suppression across a range of B1 values than did a CA-T2 -Prep+CHESS combination. Lastly, in vivo measurements demonstrated that the contrast-to-noise ratio between blood and myocardium was not adversely affected by using a WSA-T2 -Prep, despite the improved abdominal and epicardial fat suppression. Additionally, vessel sharpness improved. CONCLUSION: The proposed WSA-T2 -Prep method was shown to improve fat suppression and vessel sharpness as compared to a CA-T2 -Prep technique, and to also increase fat suppression when combined with a CHESS pulse.

Selective suppression of cytokine secretion in whole blood cell cultures of patients with colorectal cancer.

We have investigated the secretion of interferon alpha (IFN-alpha), IFN-gamma, interleukin-1alpha (IL-1alpha), IL-1beta, IL-2 and tumour necrosis factor alpha (TNF-alpha) in whole blood cell cultures (WBCCs) of colorectal cancer patients upon mitogen stimulation. Whereas the values for IL-1beta and TNF-alpha remained virtually unchanged in comparison with healthy control subjects, WBCCs of colorectal cancer patients secreted significantly lower amounts of IFN-alpha (P < 0.005), IFN-gamma (P < 0.0001), IL-1alpha (P < 0.0001) and IL-2 (P < 0.05). This reduction correlated with the progression of the disease. The total leucocyte and monocyte population were almost identical in both groups. In contrast, a dramatic depletion of lymphocytes was observed in colorectal cancer patients, which affected both lymphocyte counts (P < 0.0005) and their distribution (P < 0.0001). Our results suggest a selective suppression of cytokines in colorectal cancer patients that is related to tumour burden. Several mechanisms might account for this phenomenon, one of which might be lymphocyte depletion.