Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals

HIV-associated neurocognitive disorders (HANDs) continue to be common and are associated with increased morbidity and mortality. However, the underlying mechanisms in the combination antiretroviral therapy (cART) era are not fully understood. Interferon alpha (IFNα) is an antiviral cytokine found to be elevated in the cerebrospinal fluid (CSF) of individuals with advanced HIV-associated dementia in the pre-cART era. In this cross-sectional study, we investigated the association between IFNα and neurocognitive performance in ambulatory HIV-infected individuals with milder impairment. An eight-test neuropsychological battery representing six cognitive domains was administered. Individual scores were adjusted for demographic characteristics, and a composite neuropsychological score (NPT-8) was calculated. IFNα and CSF neurofilament light chain (NFL) levels were measured using enzyme-linked immunosorbent assay (ELISA). There were 15 chronically infected participants with a history of significant immunocompromise (median nadir CD4+ of 49 cells/μl). Most participants were neurocognitively impaired (mean global deficit score of 0.86). CSF IFNα negatively correlated with three individual tests (Trailmaking A, Trailmaking B, and Stroop Color-Word) as well as the composite NPT-8 score (r = −0.67, p = 0.006). These negative correlations persisted in multivariable analyses adjusting for chronic hepatitis B and C. Additionally, CSF IFNα correlated strongly with CSF NFL, a marker of neuronal damage (rho = 0.748, p = 0.0013). These results extend findings from individuals with severe HIV-associated dementia in the pre-cART era and suggest that IFNα may continue to play a role in HAND pathogenesis during the cART era. Further investigation into the role of IFNα is indicated

Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission.

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.This study was funded by the Mason Medical Research Trust, the Stanley Medical Research Institute, the GlaxoSmithKlein and the Pinsent Darwin funding.This is the final published version. It first appeared at http://www.nature.com/tp/journal/v5/n3/full/tp201526a.html

Clinical use of HIV integrase inhibitors : a systematic review and meta-analysis

Background: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. Methods: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. Results: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. Conclusion: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment

Intramolecular Epistasis and the Evolution of a New Enzymatic Function

Atrazine chlorohydrolase (AtzA) and its close relative melamine deaminase (TriA) differ by just nine amino acid substitutions but have distinct catalytic activities. Together, they offer an informative model system to study the molecular processes that underpin the emergence of new enzymatic function. Here we have constructed the potential evolutionary trajectories between AtzA and TriA, and characterized the catalytic activities and biophysical properties of the intermediates along those trajectories. The order in which the nine amino acid substitutions that separate the enzymes could be introduced to either enzyme, while maintaining significant catalytic activity, was dictated by epistatic interactions, principally between three amino acids within the active site: namely, S331C, N328D and F84L. The mechanistic basis for the epistatic relationships is consistent with a model for the catalytic mechanisms in which protonation is required for hydrolysis of melamine, but not atrazine

Rate and determinants of treatment response to different antiretroviral combination strategies in subjects presenting at HIV-1 diagnosis with advanced disease

<p>Abstract</p> <p>Background</p> <p>The optimal therapeutic strategies for patients presenting with advanced disease at HIV-1 diagnosis are as yet incompletely defined.</p> <p>Methods</p> <p>All patients presenting at two outpatient clinics in 2000-2009 with an AIDS-defining clinical condition or a CD4+ T cell count < 200/μL at HIV-1 diagnosis were analyzed for the presence of combined immunovirological response, defined by the concomitant presence of an absolute number of CD4+ T cells > 200 cells/μL and a plasma HIV-1 RNA copy number < 50/mL after 12 months of HAART.</p> <p>Results</p> <p>Among 102 evaluable patients, first-line regimens were protease inhibitors [PI]-based in 78 cases (77%) and efavirenz-based in 24 cases (23%). The overall response rate was 65% (95% CI: 55-74), with no differences by gender, age, nationality, route of transmission, hepatitis virus coinfections, presence of AIDS-defining clinical events, baseline HIV-1 viral load, or type of regimen (response rates with PI-based and efavirenz-based therapy: 63% and 71%, respectively, p = 0.474). Response rate was significantly better with higher baseline CD4+ T cell counts (78% with CD4+ ≥ 100/μL, compared to 50% with CD4+ < 100/μL; odds ratio: 3.5; 95% CI: 1.49-8.23, p = 0.003). Median time on first-line antiretroviral therapy was 24 months (interquartile range: 12-48). Switch to a second line treatment occurred in 57% of patients, mainly for simplification (57%), and was significantly more common with PI-based regimens [adjusted hazard ratios (AHR) with respect to efavirenz-based regimens: 3.88 for unboosted PIs (95% CI: 1.40-10.7, p = 0.009) and 4.21 for ritonavir-boosted PI (95%CI 1.7-10.4, p = 0.002)] and in older subjects (≥ 50 years) (AHR: 1.83; 95% CI: 1.02-3.31, p = 0.044). Overall mortality was low (3% after a median follow up of 48 months).</p> <p>Conclusions</p> <p>Our data indicate that a favorable immunovirological response is possible in the majority of naive patients presenting at HIV-1 diagnosis with AIDS or low CD4+ T cell counts, and confirm that starting HAART with a more compromised immune system may be associated with a delayed and sometimes partial immune recovery. Simpler regimens may be preferable in this particular population.</p

The ability of analysts’ recommendations to predict optimistic and pessimistic forecasts

Previous researches show that buy (growth) companies conduct income increasing earnings management in order to meet forecasts and generate positive forecast Errors (FEs). This behavior however, is not inherent in sell (non-growth) companies. Using the aforementioned background, this research hypothesizes that since sell companies are pressured to avoid income increasing earnings management, they are capable, and in fact more inclined, to pursue income decreasing Forecast Management (FM) with the purpose of generating positive FEs. Using a sample of 6553 firm-years of companies that are listed in the NYSE between the years 2005–2010, the study determines that sell companies conduct income decreasing FM to generate positive FEs. However, the frequency of positive FEs of sell companies does not exceed that of buy companies. Using the efficiency perspective, the study suggests that even though buy and sell companies have immense motivation in avoiding negative FEs, they exploit different but efficient strategies, respectively, in order to meet forecasts. Furthermore, the findings illuminated the complexities behind informative and opportunistic forecasts that falls under the efficiency versus opportunistic theories in literature

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial

In a double-blind trial, Rajesh Gandhi and colleagues detect no significant reduction in viral load after people with low-level HIV viremia added an integrase inhibitor to their treatment regimen

Is web interviewing a good alternative to telephone interviewing? Findings from the International Tobacco Control (ITC) Netherlands Survey

<p>Abstract</p> <p>Background</p> <p>Web interviewing is becoming increasingly popular worldwide, because it has several advantages over telephone interviewing such as lower costs and shorter fieldwork periods. However, there are also concerns about data quality of web surveys. The aim of this study was to compare the International Tobacco Control (ITC) Netherlands web and telephone samples on demographic and smoking related variables to assess differences in data quality.</p> <p>Methods</p> <p>Wave 1 of the ITC Netherlands Survey was completed by 1,668 web respondents and 404 telephone respondents of 18 years and older. The two surveys were conducted in parallel among adults who reported smoking at least monthly and had smoked at least 100 cigarettes over their lifetime.</p> <p>Results</p> <p>Both the web and telephone survey had a cooperation rate of 78%. Web respondents with a fixed line telephone were significantly more often married, had a lower educational level, and were older than web respondents without a fixed line telephone. Telephone respondents with internet access were significantly more often married, had a higher educational level, and were younger than telephone respondents without internet. Web respondents were significantly less often married and lower educated than the Dutch population of smokers. Telephone respondents were significantly less often married and higher educated than the Dutch population of smokers. Web respondents used the "don't know" options more often than telephone respondents. Telephone respondents were somewhat more negative about smoking, had less intention to quit smoking, and had more self efficacy for quitting. The known association between educational level and self efficacy was present only in the web survey.</p> <p>Conclusions</p> <p>Differences between the web and telephone sample were present, but the differences were small and not consistently favourable for either web or telephone interviewing. Our study findings suggested sometimes a better data quality in the web than in the telephone survey. Therefore, web interviewing can be a good alternative to telephone interviewing.</p

Hydrogen Peroxide Acts on Sensitive Mitochondrial Proteins to Induce Death of a Fungal Pathogen Revealed by Proteomic Analysis

How the host cells of plants and animals protect themselves against fungal invasion is a biologically interesting and economically important problem. Here we investigate the mechanistic process that leads to death of Penicillium expansum, a widespread phytopathogenic fungus, by identifying the cellular compounds affected by hydrogen peroxide (H2O2) that is frequently produced as a response of the host cells. We show that plasma membrane damage was not the main reason for H2O2-induced death of the fungal pathogen. Proteomic analysis of the changes of total cellular proteins in P. expansum showed that a large proportion of the differentially expressed proteins appeared to be of mitochondrial origin, implying that mitochondria may be involved in this process. We then performed mitochondrial sub-proteomic analysis to seek the H2O2-sensitive proteins in P. expansum. A set of mitochondrial proteins were identified, including respiratory chain complexes I and III, F1F0 ATP synthase, and mitochondrial phosphate carrier protein. The functions of several proteins were further investigated to determine their effects on the H2O2-induced fungal death. Through fluorescent co-localization and the use of specific inhibitor, we provide evidence that complex III of the mitochondrial respiratory chain contributes to ROS generation in fungal mitochondria under H2O2 stress. The undesirable accumulation of ROS caused oxidative damage of mitochondrial proteins and led to the collapse of mitochondrial membrane potential. Meanwhile, we demonstrate that ATP synthase is involved in the response of fungal pathogen to oxidative stress, because inhibition of ATP synthase by oligomycin decreases survival. Our data suggest that mitochondrial impairment due to functional alteration of oxidative stress-sensitive proteins is associated with fungal death caused by H2O2

Spatio-structural granularity of biological material entities

<p>Abstract</p> <p>Background</p> <p>With the continuously increasing demands on knowledge- and data-management that databases have to meet, ontologies and the theories of granularity they use become more and more important. Unfortunately, currently used theories and schemes of granularity unnecessarily limit the performance of ontologies due to two shortcomings: (i) they do not allow the integration of multiple granularity perspectives into one granularity framework; (ii) they are not applicable to cumulative-constitutively organized material entities, which cover most of the biomedical material entities.</p> <p>Results</p> <p>The above mentioned shortcomings are responsible for the major inconsistencies in currently used spatio-structural granularity schemes. By using the Basic Formal Ontology (BFO) as a top-level ontology and Keet's general theory of granularity, a granularity framework is presented that is applicable to cumulative-constitutively organized material entities. It provides a scheme for granulating complex material entities into their constitutive and regional parts by integrating various compositional and spatial granularity perspectives. Within a scale dependent resolution perspective, it even allows distinguishing different types of representations of the same material entity. Within other scale dependent perspectives, which are based on specific types of measurements (e.g. weight, volume, etc.), the possibility of organizing instances of material entities independent of their parthood relations and only according to increasing measures is provided as well. All granularity perspectives are connected to one another through overcrossing granularity levels, together forming an integrated whole that uses the <it>compositional object perspective </it>as an integrating backbone. This granularity framework allows to consistently assign structural granularity values to all different types of material entities.</p> <p>Conclusions</p> <p>The here presented framework provides a spatio-structural granularity framework for all domain reference ontologies that model cumulative-constitutively organized material entities. With its multi-perspectives approach it allows querying an ontology stored in a database at one's own desired different levels of detail: The contents of a database can be organized according to diverse granularity perspectives, which in their turn provide different <it>views </it>on its content (i.e. data, knowledge), each organized into different levels of detail.</p