Persistent metabolic changes in HIV-infected patients during the first year of combination antiretroviral therapy

The HIV-human metabolic relationship is a complex interaction convoluted even more by antiretroviral therapy (cART) and comorbidities. The ability of cART to undo the HIV induced metabolic dysregulation is unclear and under-investigated. Using targeted metabolomics and multiplex immune biomarker analysis, we characterized plasma samples obtained from 18 untreated HIV-1-infected adult patients and compared these to a non-HIV infected (n = 23) control population. The biogenic amine perturbations during an untreated HIV infection implicated altered tryptophan- nitrogen- and muscle metabolism. Furthermore, the lipid profiles of untreated patients were also significantly altered compared to controls. In untreated HIV infection, the sphingomyelins and phospholipids correlated negatively to markers of infection IP-10 and sIL-2R whereas a strong association was found between triglycerides and MCP-1. In a second cohort, we characterized plasma samples obtained from 28 HIV-1-infected adult patients before and 12 months after the start of cART, to investigate the immune-metabolic changes associated with cART. The identified altered immune-metabolic pathways of an untreated HIV infection showed minimal change after 12 months of cART. In conclusion, 12 months of cART impacts only mildly on the metabolic dysregulation underlying an untreated HIV infection and provide insights into the comorbidities present in virally suppressed HIV patients

Are motor inhibition and cognitive flexibility dead ends in ADHD?

Contains fulltext : 53518.pdf (publisher's version ) (Closed access)Executive dysfunction has been postulated as the core deficit in ADHD, although many deficits in lower order cognitive processes have also been identified. By obtaining an appropriate baseline of lower order cognitive functioning light may be shed on as to whether executive deficits result from problems in lower order and/or higher order cognitive processes. We examined motor inhibition and cognitive flexibility in relation to a baseline measure in 816 children from ADHD and control families. Multiple children in a family were tested in order to examine the familiality of the measures. No evidence was found for deficits in motor inhibition or cognitive flexibility in children with ADHD or their nonaffected siblings: Compared to their baseline speed and accuracy of responding, children with ADHD and their (non)affected siblings were not disproportionally slower or inaccurate when demands for motor inhibition or cognitive flexibility were added to the task. However, children with ADHD and their (non)affected siblings were overall less accurate than controls, which could not be attributed to differences in response speed. This suggests that inaccuracy of responding is characteristic of children having (a familial risk for) ADHD. Motor inhibition and cognitive flexibility as operationalized with mean reaction time were found to be familial. It is concluded that poorer performance on executive tasks in children with ADHD and their (non)affected siblings may result from deficiencies in lower order cognitive processes and not (only) from higher order cognitive processes/executive functions

Does methylphenidate improve inhibition and other cognitive abilities in adults with childhood-onset ADHD?

Contains fulltext : 48908.pdf (publisher's version ) (Closed access)We examined the effect of methylphenidate (Mph) on inhibition and several other cognitive abilities in 43 adults with Attention Deficit Hyperactivity Disorder (ADHD) by use of Conners' Continuous Performance Test (CPT) and the Change Task (ChT), an extension of the Stop Signal Test (SST). In a double blind, cross-over, placebo controlled study with Mph, tests were administered during the third week of individually titrated treatment with Mph (maximum dose 1 mg / kg / day) and during the third week of treatment with placebo. We established large medication effects for commission errors, standard error of mean reaction time, and attentiveness on the CPT, as well as moderate medication effects for mean reaction time on the CPT and response re-engagement speed on the ChT. For Stop Signal Reaction Time (SSRT) on the ChT, we also established large effects of Mph, but only in a group of participants who showed slow SSRTs on placebo. Mph indeed ameliorates inhibition, which is the core problem of ADHD, and certain other cognitive abilities in adults with ADHD

The impact of societal cultural values and individual social beliefs on the perceived effectiveness of managerial influence strategies: a meso approach

This paper reports the findings of a 12-nation study designed to test empirically the relationships between societal cultural values, individual social beliefs, and the perceived effectiveness of different influence strategies. The relationships between three types of broad influence strategy (persuasive, assertive, and relationship based) and four dimensions of individual beliefs (cynicism, fate control, reward for application, and religiosity) were examined. Three of Project GLOBE's cultural values (in-group collectivism, uncertainty avoidance, and future orientation) were selected to investigate their direct effects on the rated effectiveness of influence strategies, and their possible interaction with dimensions of individual beliefs. Results showed that different dimensions of individual social beliefs predict the perceived effectiveness of the three types of influence strategy, and that cultural values can moderate the strength of the relationship between these dimensions of individual social beliefs and the perceived effectiveness of influence strategies

Kupffer cells interact with hepatitis B surface antigen in vivo and in vitro, leading to proinflammatory cytokine production and natural killer cell function

BACKGROUND: Based on their localization, Kupffer cells (KCs) likely interact with hepatitis B virus (HBV). However, the role of KCs in inducing immunity toward HBV is poorly understood. Therefore, the interaction of hepatitis B surface antigen (HBsAg) and KCs, and possible functional consequences, were assessed. METHODS: KCs in liver tissue from patients with chronic HBV were analyzed for presence of HBsAg and their phenotype, and compared with KCs in control liver tissue. Liver graft perfusate-derived KCs and in vitro-generated monocyte-derived macrophages were investigated for functional interaction with patient-derived HBsAg. RESULTS: Intrahepatic KCs were HBsAg positive and more activated than those from control livers. KCs internalized HBsAg in vitro, which did not change their phenotype, but strongly induced proinflammatory cytokine production. Additionally, monocyte-derived macrophages also interacted with HBsAg, leading to activation and cytokine production. Furthermore, HBsAg-exposed macrophages and KC activated natural killer (NK) cells, resulting in increased CD69 expression and interferon-γ production. CONCLUSIONS: KCs directly interact with HBsAg in vivo and in vitro. HBsAg-induced cytokine production by KCs and monocyte-derived macrophages and subsequent NK cell activation may be an early event in viral containment and may support induction of HBV-specific immunity upon HBV infection, but may also contribute to liver pathology

Presence of IgM anti-topoisomerase I antibodies is associated with disease progression in anti-topoisomerase I IgG positive systemic sclerosis

BACKGROUND: Anti-topoisomerase I auto-antibodies (ATA) in systemic sclerosis (SSc) are associated with diffuse skin involvement and interstitial lung fibrosis. Thus far, however, the relations between the ATA response and disease course have not yet been fully evaluated. OBJECTIVES: To gain insight into the relation between characteristics of the ATA immune response and clinical disease course in ATA+ SSc. METHODS: ATA-IgG, -IgM and -IgA levels were assessed in consecutive serum samples of baseline ATA-IgG+ patients from the Leiden Combined Care In Systemic Sclerosis cohort (CCISS). One-year disease progression was defined by a relevant increase in modified Rodnan Skin Score (mRSS), decline in pulmonary function tests, development of digital ulcers, renal crisis, pulmonary hypertension and/or mortality. Validation was performed in ATA+ SSc patients from the Oslo University Hospital and University Hospital Zurich RESULTS: Of 103 ATA-IgG+ patients available in the CCISS cohort, 81 patients had clinical data available to assess one-year disease progression. Of these 81 patients, 23 patients (28%) showed disease progression. At baseline, disease-progressors were significantly more often ATA-IgM+ compared to non-progressors (21/23 [91%] vs 33/58 [57%], p<0.01). This finding was confirmed in the independent validation samples. CONCLUSION: In ATA-IgG+ SSc patients, presence of ATA-IgM, which might be taken as a surrogate for an ongoing auto-reactive B cell immune response, is associated with disease progression

Anti-centromere antibody levels and isotypes and the development of systemic sclerosis

OBJECTIVES Little is known on the disease course of very early systemic sclerosis (SSc). It is unknown whether anti-centromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. We aim to evaluate whether ACA-IgG, -IgM and -IgA levels in ACA-IgG positive patients associate with disease severity and/or progression from very early SSc to definite SSc. METHODS ACA-IgG positive patients with very early SSc and ACA-IgG positive patients fulfilling the 2013 ACR/EULAR criteria for SSc from five different cohorts were included. A diagnosis of very early SSc was based on the presence of ACA-IgG AND Raynaud and/or puffy fingers and/or abnormal nailfold capillaroscopy but not fulfilling the 2013 ACR/EULAR criteria. Multivariable regression analyses were performed to determine the association between baseline isotype levels and progression to SSc and organ involvement. RESULTS Six hundred twenty-five ACA-IgG positive patients were included of whom 138 (22%) fulfilled very early SSc criteria and 487 (78%) had definite SSc. ACA-IgG (Odds Ratio (OR) 2.5 (1.8-3.7)) and ACA-IgM (OR 1.8 (1.3 -2.3)) levels were significantly higher in definite SSc patients. Of 115 very early SSc patients with follow-up, 48 (42%) progressed to definite SSc within five years. Progression to definite SSc was associated with higher ACA-IgG levels at baseline (OR 4.3 (1.7-10.7)). CONCLUSION ACA isotype levels might serve as a biomarker to identify very early SSc patients at risk for progression to definite SSc

Anticentromere Antibody Levels and Isotypes and the Development of Systemic Sclerosis

Objective: Little is known on the disease course of very early systemic sclerosis (SSc). Among the information yet to be elucidated is whether anticentromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. This study was undertaken to evaluate whether IgG, IgM, and IgA ACA levels in IgG ACA–positive patients are associated with disease severity and/or progression from very early SSc to definite SSc. Methods: IgG ACA–positive patients from 5 different cohorts who had very early SSc or SSc fulfilling the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria were included. A diagnosis of very early SSc was based on the presence of IgG ACAs and Raynaud’s phenomenon, and/or puffy fingers and/or abnormal nailfold capillaroscopy, but not fulfilling the ACR/EULAR 2013 criteria for SSc. Multivariable regression analyses were performed to determine the association between baseline ACA isotype levels and progression to definite SSc with organ involvement. Results: Six hundred twenty-five IgG ACA–positive patients were included, of whom 138 (22%) fulfilled the criteria for very early SSc and 487 (78%) had definite SSc. Levels of IgG ACAs (odds ratio 2.5 [95% confidence interval 1.8–3.7]) and IgM ACAs (odds ratio 1.8 [95% confidence interval 1.3–2.3]) were significantly higher in patients with definite SSc. Of 115 patients with very early SSc with follow-up, progression to definite SSc occurred within 5 years in 48 (42%). Progression to definite SSc was associated with higher IgG ACA levels at baseline (odds ratio 4.3 [95% confidence interval 1.7–10.7]). Conclusion: ACA isotype levels may serve as biomarkers to identify patients with very early SSc who are at risk for disease progression to definite SSc