Virio- and Bacterioplankton Microscale Distributions at the Sediment-Water Interface

The marine sediment-water interface is an important location for microbially controlled nutrient and gas exchange processes. While microbial distributions on the sediment side of the interface are well established in many locations, the distributions of microbes on the water side of the interface are less well known. Here, we measured that distribution for marine virio- and bacterioplankton with a new two-dimensional technique. Our results revealed higher heterogeneity in sediment-water interface biomass distributions than previously reported with a greater than 45– and 2500-fold change cm⁻¹ found within bacterial and viral subpopulations compared to previous maxima of 1.5- and 1.4-fold cm⁻¹ in bacteria and viruses in the same environments. The 45-fold and 2500-fold changes were due to patches of elevated and patches of reduced viral and bacterial abundance. The bacterial and viral hotspots were found over single and multiple sample points and the two groups often coincided whilst the coldspots only occurred over single sample points and the bacterial and viral abundances showed no correlation. The total mean abundances of viruses strongly correlated with bacteria (r = 0.90, p<0.0001, n = 12) for all three microplates (n = 1350). Spatial autocorrelation analysis via Moran’s I and Geary’s C revealed non-random distributions in bacterial subpopulations and random distributions in viral subpopulations. The variable distributions of viral and bacterial abundance over centimetre-scale distances suggest that competition and the likelihood of viral infection are higher in the small volumes important for individual cell encounters than bulk measurements indicate. We conclude that large scale measurements are not an accurate measurement of the conditions under which microbial dynamics exist. The high variability we report indicates that few microbes experience the ‘average’ concentrations that are frequently measured.     

A Correlate of HIV-1 Control Consisting of Both Innate and Adaptive Immune Parameters Best Predicts Viral Load by Multivariable Analysis in HIV-1 Infected Viremic Controllers and Chronically-Infected Non-Controllers

HIV-1 infected viremic controllers maintain durable viral suppression below 2000 copies viral RNA/ml without anti-retroviral therapy (ART), and the immunological factor(s) associated with host control in presence of low but detectable viral replication are of considerable interest. Here, we utilized a multivariable analysis to identify which innate and adaptive immune parameters best correlated with viral control utilizing a cohort of viremic controllers (median 704 viral RNA/ml) and non-controllers (median 21,932 viral RNA/ml) that were matched for similar CD4⁺ T cell counts in the absence of ART. We observed that HIV-1 Gag-specific CD8⁺ T cell responses were preferentially targeted over Pol-specific responses in viremic controllers (p = 0.0137), while Pol-specific responses were positively associated with viral load (rho = 0.7753, p = 0.0001, n = 23). Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05). Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8⁺ T cell activation and spontaneous NK cell degranulation compared to uninfected donors. Overall, we identified that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8⁺ T cell responses) immune parameters best predicted viral load (R² = 0.5864, p = 0.0021, n = 17) by a multivariable analysis. Together, this data indicates that preferential Gag-specific over Pol-specific CD8⁺ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.     

The Fitness Landscape of HIV-1 Gag: Advanced Modeling Approaches and Validation of Model Predictions by In Vitro Testing

Viral immune evasion by sequence variation is a major hindrance to HIV-1 vaccine design. To address this challenge, our group has developed a computational model, rooted in physics, that aims to predict the fitness landscape of HIV-1 proteins in order to design vaccine immunogens that lead to impaired viral fitness, thus blocking viable escape routes. Here, we advance the computational models to address previous limitations, and directly test model predictions against in vitro fitness measurements of HIV-1 strains containing multiple Gag mutations. We incorporated regularization into the model fitting procedure to address finite sampling. Further, we developed a model that accounts for the specific identity of mutant amino acids (Potts model), generalizing our previous approach (Ising model) that is unable to distinguish between different mutant amino acids. Gag mutation combinations (17 pairs, 1 triple and 25 single mutations within these) predicted to be either harmful to HIV-1 viability or fitness-neutral were introduced into HIV-1 NL4-3 by site-directed mutagenesis and replication capacities of these mutants were assayed in vitro. The predicted and measured fitness of the corresponding mutants for the original Ising model (r = −0.74, p = 3.6×10⁻⁶) are strongly correlated, and this was further strengthened in the regularized Ising model (r = −0.83, p = 3.7×10⁻¹²). Performance of the Potts model (r = −0.73, p = 9.7×10⁻⁹) was similar to that of the Ising model, indicating that the binary approximation is sufficient for capturing fitness effects of common mutants at sites of low amino acid diversity. However, we show that the Potts model is expected to improve predictive power for more variable proteins. Overall, our results support the ability of the computational models to robustly predict the relative fitness of mutant viral strains, and indicate the potential value of this approach for understanding viral immune evasion, and harnessing this knowledge for immunogen design.     

CTLA4 Gene Polymorphisms Influence the Incidence of Infection after Renal Transplantation in Chinese Recipients

Background

Immunosuppressive therapy is usually administered following renal transplantation to protect the graft from rejection. However, this often causes complications such as infections to occur. Single nucleotide polymorphisms (SNPs) within the CTLA4 gene, such as −1772T/C (rs733618), +49A/G (rs231775) and +6230 G/A (rs3087243), can affect graft rejection and the long-term clinical outcome of organ transplantation. The role of CTLA4 SNPs in T cell-mediated immunity in renal transplantation and association with infection after transplantation is unknown.

Methods

In this study, the risk of infection according to CTLA4 SNPs was investigated in 304 patients who received kidney graft transplants between 2008 and 2012.

Results

The frequency of the rs4553808 GG genotype was significantly higher in recipients with viral infection (14.89%) than in those without infections (3.50%) (Bonferroni-adjusted p = 0.005). A significant difference (p = 0.001) in patients with the rs4553808 GG genotype from those with the AA+AG genotypes was found in the viral cohort using the log-rank test. A significant association was found between the rs4553808 genotype and onset of viral infection in transplant recipients (p = 0.001). The frequencies of the CGTAG and CGCAG haplotypes were significantly higher in the viral infection group (9.6% and 5.3%) than in the non-viral infection group (3.8% and 1.4%) (p = 0.0149 and p = 0.0111). No association between any CTLA4 SNP and bacterial infection was found. Multivariate analyses revealed that one risk factor, the use of antibody induction therapy (p = 0.007), was associated with bacterial infection, and two risk factors, antibody use (p = 0.015) and recipient rs4553808 genotype (p = 0.001), were associated with viral infection.

Conclusions

The rs4553808 GG genotype may be a risk factor for viral infection in kidney transplantation. The CTLA4 haplotypes CGTAG and CGCAG were partially associated with the development of viral infection in Chinese kidney transplant recipients.     

The Outcome of Prophylactic Intravenous Cefazolin and Ceftriaxone in Cirrhotic Patients at Different Clinical Stages of Disease after Endoscopic Interventions for Acute Variceal Hemorrhage

Antibiotic prophylaxis with norfloxacin, intravenous ciprofloxacin, or ceftriaxone has been recommended for cirrhotic patients with gastrointestinal hemorrhage but little is known about intravenous cefazolin. This study aimed to compare the outcome of intravenous cefazolin and ceftriaxone as prophylactic antibiotics among cirrhotic patients at different clinical stages, and to identify the associated risk factors. The medical records of 713 patients with acute variceal bleeding who had received endoscopic procedures from were reviewed. Three hundred and eleven patients were entered for age-matched adjustment after strict exclusion criteria. After the adjustment, a total of 102 patients were enrolled and sorted into 2 groups according to the severity of cirrhosis: group A (Child’s A patients, n = 51) and group B (Child’s B and C patients, n = 51). The outcomes were prevention of infection, time of rebleeding, and death. Our subgroup analysis results failed to show a significant difference in infection prevention between patients who received prophylactic cefazolin and those who received ceftriaxone among Child’s A patients (93.1% vs. 90.9%, p = 0.641); however, a trend of significance in favor of ceftriaxone prophylaxis (77.8% vs. 87.5%, p = 0.072) was seen among Child’s B and C patients. More rebleeding cases were observed in patients who received cefazolin than in those who received ceftriaxone among Child’s B and C patients (66.7% vs. 25.0%, p = 0.011) but not in Child’s A patients (32% vs. 40.9%, p = 0.376). The risk factors associated with rebleeding were history of bleeding and use of prophylactic cefazolin among Child’s B and C patients. In conclusion, this study suggests that prophylactic intravenous cefazolin may not be inferior to ceftriaxone in preventing infections and reducing rebleeding among Child’s A cirrhotic patients after endoscopic interventions for acute variceal bleeding. Prophylactic intravenous ceftriaxone yields better outcome among Child’s B and C patients.     

Measuring Turnover of SIV DNA in Resting CD4+ T Cells Using Pyrosequencing: Implications for the Timing of HIV Eradication Therapies

Resting CD4+ T cells are a reservoir of latent HIV-1. Understanding the turnover of HIV DNA in these cells has implications for the development of eradication strategies. Most studies of viral latency focus on viral persistence under antiretroviral therapy (ART). We studied the turnover of SIV DNA resting CD4+ T cells during active infection in a cohort of 20 SIV-infected pigtail macaques. We compared SIV sequences at two Mane-A1*084:01-restricted CTL epitopes using serial plasma RNA and resting CD4+ T cell DNA samples by pyrosequencing, and used a mathematical modeling approach to estimate SIV DNA turnover. We found SIV DNA turnover in resting CD4+ T cells was slow in animals with low chronic viral loads, consistent with the long persistence of latency seen under ART. However, in animals with high levels of chronic viral replication, turnover was high. SIV DNA half-life within resting CD4 cells correleated with viral load (p = 0.0052) at the Gag KP9 CTL epitope. At a second CTL epitope in Tat (KVA10) there was a trend towards an association of SIV DNA half-life in resting CD4 cells and viral load (p = 0.0971). Further, we found that the turnover of resting CD4+ T cell SIV DNA was higher for escape during early infection than for escape later in infection (p = 0.0084). Our results suggest viral DNA within resting CD4 T cells is more labile and may be more susceptible to reactivation/eradication treatments when there are higher levels of virus replication and during early/acute infection.     

Factors Associated with Results and Conclusions of Trials of Thiazolidinediones

Background

When a sponsor funds a study of two competing drugs in a head-to-head comparison, the results and conclusions are likely to favor the sponsor’s drug. Thiazolidinediones, oral medications used for the treatment of type 2 diabetes, are one of the most costly choices of oral anti-diabetic medications, yet they do not demonstrate clinically relevant differences in achieving lower glycosylated hemoglobin levels compared to other oral antidiabetic drugs. Our aim is to examine associations between research funding source, study design characteristics aimed at reducing bias, and other factors with the results and conclusions of randomized controlled trials (RCTs) of thiazolidinediones compared to other oral hypoglycemic agents.

Methods and Findings

This is a cross-sectional study of 61 published RCTs comparing a thiazolidinedione (glitazone) to another anti-diabetic drug or placebo for treatment of type 2 diabetes. Data on study design characteristics, funding source, author’s financial ties, results for primary outcomes, and author conclusions were extracted. Univariate logistic regression identified associations between independent variables and results and conclusions that favored the glitazone. Of the RCTs, 59% (36/61) were funded by industry, 39% (24/61) did not disclose any funding. Common study design weaknesses included inadequate blinding and lack of concealment of allocation. Trials that reported favorable glycemic control results for the glitazone were more likely to have adequate blinding (OR (95% CI)  = 5.42 (1.46, 21.19), p = 0.008) and have a corresponding author with financial ties to the glitazone manufacturer (OR (95% CI)  = 4.12 (1.05, 19.53); p = 0.04). Trials with conclusions favoring the glitazone were less likely to be funded by a comparator drug company than a glitazone company (OR (95% CI)  = 0.026 (0, 0.40), p = 0.003) and less likely to be published in journals with higher impact factors (OR (95% CI)  = 0.79 (0.62, 0.97), p = 0.011). One limitation of our study is that we categorized studies as funded by industry based on each article’s disclosure which could underestimate the number of industry sponsored studies and personal ties of investigators. Additionally, our study did not include any head-to-head comparisons of one glitazone to another.

Conclusions

Published RCT comparisons of glitazones with other anti-diabetic drugs or placebo are predominantly industry supported and this support, as well as the financial ties of study authors, appears to be associated with favorable findings.     

Predictors of Bisexual Behaviour among MSM Attending Intervention Sites May Help in Prevention Interventions for This Bridge to the Heterosexual Epidemic in India: Data from HIV Sentinel Surveillance

Background

Indian cultural tradition demanding marriage, many MSM howsoever they self-identify are likely to be married or have sex with women. To consolidate India''s HIV prevention gains, it is important to understand and address the interaction between the MSM and heterosexual epidemics in India and create specific interventions for bisexual MSM. The challenge is to identify and intervene this hard to reach population. Data from HIV Sentinel Surveillance 2011 among MSM in four Indian states were analyzed to assess predictors and prevalence of bisexual behaviour in MSM.

Methods

Between March-May 2011, 4682 men (15–49 years) who had anal/oral sex with a male partner in the past month, attending intervention sites and consenting for an un-linked anonymous survey answered an 11- item questionnaire and provided blood for HIV test by finger stick at 19 designated surveillance sites.

Results

Of 4682 MSM tested overall, 5% were illiterate, 51% reported only receptive anal intercourse, 21% only penetrative and 28% both. 36% MSM had ever received money for sex. Overall 6.8% were HIV infected. 44% MSM were bisexual in the last six months. On multivariate analysis, ‘being bisexual’ was found to be independently associated with ‘older age’: 26–30 years [AOR = 3.1, 95% CI(2.7, 3.7)], >30 years [AOR = 6.5, 95% CI(5.5, 7.7)]; ‘reporting penetrative behaviour alone’ with other men [AOR = 5.8, 95% CI(4.8, 7.0), p<0.01] and ‘reporting both penetrative and receptive behaviour’ [AOR = 2.7, 95% CI(2.3, 3.1) p<0.01]. Those who both paid and received money for sex [AOR = 0.49, 95% CI (0.38, 0.62)] were significantly less likely to be bisexual.

Conclusions

A substantial proportion of men receiving services from Targeted Intervention programs are bisexual and the easy opportunity for intervention in this setting should be capitalised upon. Focusing on older MSM, as well as MSM who show penetrative behaviour with other men, could help in reaching this population.     

In Nonagenarians,Acute Kidney Injury Predicts In-Hospital Mortality,while Heart Failure Predicts Hospital Length of Stay

Background/Aims

The elderly constitute an increasing proportion of admitted patients worldwide. We investigate the determinants of hospital length of stay and outcomes in patients aged 90 years and older.

Methods

We retrospectively analyzed all admitted patients aged >90 years from the general medical wards in a tertiary referral medical center between August 31, 2009 and August 31, 2012. Patients’ clinical characteristics, admission diagnosis, concomitant illnesses at admission, and discharge diagnosis were collected. Each patient was followed until discharge or death. Multivariate logistic regression analysis was utilized to study factors associated with longer hospital length of stay (>7 days) and in-hospital mortality.

Results

A total of 283 nonagenarian in-patients were recruited, with 118 (41.7%) hospitalized longer than one week. Nonagenarians admitted with pneumonia (p = 0.04) and those with lower Barthel Index (p = 0.012) were more likely to be hospitalized longer than one week. Multivariate logistic regression analysis revealed that patients with lower Barthel Index (odds ratio [OR] 0.98; p = 0.021) and those with heart failure (OR 3.05; p = 0.046) had hospital stays >7 days, while patients with lower Barthel Index (OR 0.93; p = 0.005), main admission nephrologic diagnosis (OR 4.83; p = 0.016) or acute kidney injury (OR 30.7; p = 0.007) had higher in-hospital mortality.

Conclusion

In nonagenarians, presence of heart failure at admission was associated with longer hospital length of stay, while acute kidney injury at admission predicted higher hospitalization mortality. Poorer functional status was associated with both prolonged admission and higher in-hospital mortality.     

LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection

Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8⁺ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10⁻²). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10⁻¹¹–10⁻⁹) and African (p = 10⁻⁵–10⁻³) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.     

Herpes Virus Infection Is Associated with Vascular Remodeling and Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

Background

Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed.

Methods

Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice.

Results

A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients.

Conclusion

Herpesviral infections may contribute to the development of PH in IPF patients.     

Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda

Introduction

Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS.

Methods

Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR).

Results

78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7–6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7–9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0–2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8–5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs).

Conclusions

HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda.     

Natural Killer KIR3DS1 Is Closely Associated with HCV Viral Clearance and Sustained Virological Response in HIV/HCV Patients

Aim

To evaluate the influence of the presence of the killer cell immunoglobulin-like receptor (KIR) 3DS1 on HCV treatment response in HIV/HCV genotype 1 co-infected patients

Methods

HIV/HCV co-infected patients were included. KIR3DS1, their specific HLA-B ligands and IL28B gene were genotyped. Reductions of plasma HCV RNA levels between baseline and week 1, week 2 and week 4 were analyzed for IL28B genotype and KIR3DS1 (HLA Bw4 or Bw6). Rapid and sustained virological response (RVR and SVR) rates were also analyzed.

Results

Sixty HIV/HCV genotype 1 co-infected patients were included. Patients with KIR3DS1 and Bw4 had higher rates of HCV viral decline than those who were not carriers of KIR3DS1 (week1: p = 0.01; week2: p = 0.038; week 4: p = 0.03). Patients carrying KIR3DS1/Bw4 had higher rates of RVR and SVR than those who did not carry KIR3DS1 (RVR: 46.15% versus 17.02%, p = 0.012; SVR: 63.6% versus 13 26.5%, p = 0.031). With respect to patients carrying the IL28B-CC genotype, those with KIR3DS1/Bw4 had greater rates of HCV viral clearance (week1: p<0.001; week2: p = 0.01; week 4: p = 0.02), RVR (p = 0.015) and SVR (p = 0.029) than those not carrying KIR3DS1.

Conclusion

Our results show that the KIR3DS1 genotype has a positive effect on HCV viral clearance during the first weeks of Peg-IFN/RBV treatment in HCV/HCV co-infected patients bearing genotype 1, and higher RVR and SVR rates.     

Evidence That Multiple Defects in Lipid Regulation Occur before Hyperglycemia during the Prodrome of Type-2 Diabetes

Background

Blood-vessel dysfunction arises before overt hyperglycemia in type-2 diabetes (T2DM). We hypothesised that a metabolomic approach might identify metabolites/pathways perturbed in this pre-hyperglycemic phase. To test this hypothesis and for specific metabolite hypothesis generation, serum metabolic profiling was performed in young women at increased, intermediate and low risk of subsequent T2DM.

Methods

Participants were stratified by glucose tolerance during a previous index pregnancy into three risk-groups: overt gestational diabetes (GDM; n = 18); those with glucose values in the upper quartile but below GDM levels (UQ group; n = 45); and controls (n = 43, below the median glucose values). Follow-up serum samples were collected at a mean 22 months postnatally. Samples were analysed in a random order using Ultra Performance Liquid Chromatography coupled to an electrospray hybrid LTQ-Orbitrap mass spectrometer. Statistical analysis included principal component (PCA) and multivariate methods.

Findings

Significant between-group differences were observed at follow-up in waist circumference (86, 95%CI (79–91) vs 80 (76–84) cm for GDM vs controls, p<0.05), adiponectin (about 33% lower in GDM group, p = 0.004), fasting glucose, post-prandial glucose and HbA_1c, but the latter 3 all remained within the ‘normal’ range. Substantial differences in metabolite profiles were apparent between the 2 ‘at-risk’ groups and controls, particularly in concentrations of phospholipids (4 metabolites with p≤0.01), acylcarnitines (3 with p≤0.02), short- and long-chain fatty acids (3 with p< = 0.03), and diglycerides (4 with p≤0.05).

Interpretation

Defects in adipocyte function from excess energy storage as relatively hypoxic visceral and hepatic fat, and impaired mitochondrial fatty acid oxidation may initiate the observed perturbations in lipid metabolism. Together with evidence from the failure of glucose-directed treatments to improve cardiovascular outcomes, these data and those of others indicate that a new, quite different definition of type-2 diabetes is required. This definition would incorporate disturbed lipid metabolism prior to hyperglycemia.     

A Parameter for IL-10 and TGF-? Mediated Regulation of HIV-1 Specific T Cell Activation Provides Novel Information and Relates to Progression Markers

HIV replication is only partially controlled by HIV-specific activated effector T cells in chronic HIV infection and strategies are warranted to improve their efficacy. Chronic T cell activation is generally accompanied by regulation of antigen-specific T cell responses which may impair an effective control of chronic infections. The impact of HIV-induced T cell regulation on individual patients’ disease progression is largely unknown, since classical T cell activation assays reflect net activation with regulation as unknown contributing factor. We here explore a quantitative parameter for antigen-induced cytokine-mediated regulation (R_AC) of HIV-specific effector T cell activation by functional antibody-blockade of IL-10 and transforming growth factor-β. HIV Env- and Gag-specific T cell activation and R_AC were estimated in peripheral blood mononuclear cells from 30 treatment-naïve asymptomatic HIV-infected progressors (CD4 count 472/µl, HIV RNA 37500 copies/ml) stimulated with overlapping peptide panels for 6 days. R_AC was estimated from differences in T cell activation between normal and blocked cultures, and related to annual CD4 loss, immune activation (CD38) and microbial translocation (plasma lipopolysaccharides). R_AC was heterogeneously distributed between individual patients and the two HIV antigens. Notably, R_AC did not correlate to corresponding classical activation. Env R_AC correlated with CD38 and CD4 loss rates (r> = 0.37, p = <0.046) whereas classical Gag activation tended to correlate with HIV RNA (r = −0.35, p = 0.06). 14 patients (47%) with low R_AC’s to both Env and Gag had higher CD8 counts (p = 0.014) and trends towards lower annual CD4 loss (p = 0.056) and later start with antiretroviral treatment (p = 0.07) than the others. In contrast, patients with high R_AC to both Env and Gag (n = 8) had higher annual CD4 loss (p = 0.034) and lower CD8 counts (p = 0.014). R_AC to Env and Gag was not predicted by classical activation parameters and may thus provide additional information on HIV-specific immunity. R_AC and other assessments of regulation deserve further in-depth exploration.     

Low Muscle Strength Is Associated with Metabolic Risk Factors in Colombian Children: The ACFIES Study

Purpose

In youth, poor cardiorespiratory and muscular strength are associated with elevated metabolic risk factors. However, studies examining associations between strength and risk factors have been done exclusively in high income countries, and largely in Caucasian cohorts. The aim of this study was to assess these interactions in schoolchildren in Colombia, a middle income Latin American country.

Methods

We measured body mass index, body composition, handgrip strength (HG), cardiorespiratory fitness (CRF) and metabolic risk factors in 669 low-middle socioeconomic status Colombian schoolchildren (mean age 11.52±1.13, 47% female). Associations between HG, CRF and metabolic risk factors were evaluated.

Results

HG and CRF were inversely associated with blood pressure, HOMA index and a composite metabolic risk score (p<0.001 for all) and HG was also inversely associated with triglycerides and C-reactive protein (CRP) (both p<0.05). Associations between HG and risk factors were marginally weakened after adjusting for CRF, while associations between CRF and these factors were substantially weakened after adjusting for HG. Linear regression analyses showed inverse associations between HG and systolic BP (β = −0.101; p = 0.047), diastolic BP (β = −0.241; p> = 0.001), HOMA (β = −0.164; p = 0.005), triglycerides (β = −0.583; p = 0.026) and CRP (β = −0.183; p = 0.037) but not glucose (p = 0.698) or HDL cholesterol (p = 0.132). The odds ratios for having clustered risk in the weakest quartile compared with the strongest quartile were 3.0 (95% confidence interval: 1.81–4.95).

Conclusions

In Colombian schoolchildren both poorer handgrip strength/kg body mass and cardiorespiratory fitness were associated with a worse metabolic risk profile. Associations were stronger and more consistent between handgrip and risk factors than between cardiorespiratory fitness and these risk factors. Our findings indicate the addition of handgrip dynamometry to non-invasive youth health surveillance programs would improve the accuracy of the assessment of cardio-metabolic health.     

FDG PET and MRI in Logopenic Primary Progressive Aphasia versus Dementia of the Alzheimer’s Type

Objectives

The logopenic variant of primary progressive aphasia is an atypical clinical variant of Alzheimer’s disease which is typically characterized by left temporoparietal atrophy on magnetic resonance imaging and hypometabolism on F-18 fluorodeoxyglucose positron emission tomography. We aimed to characterize and compare patterns of atrophy and hypometabolism in logopenic primary progressive aphasia, and determine which brain regions and imaging modality best differentiates logopenic primary progressive aphasia from typical dementia of the Alzheimer’s type.

Methods

A total of 27 logopenic primary progressive aphasia subjects underwent fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging. These subjects were matched to 27 controls and 27 subjects with dementia of the Alzheimer’s type. Patterns of atrophy and hypometabolism were assessed at the voxel and region-level using Statistical Parametric Mapping. Penalized logistic regression analysis was used to determine what combinations of regions best discriminate between groups.

Results

Atrophy and hypometabolism was observed in lateral temporoparietal and medial parietal lobes, left greater than right, and left frontal lobe in the logopenic group. The logopenic group showed greater left inferior, middle and superior lateral temporal atrophy (inferior p = 0.02; middle p = 0.007, superior p = 0.002) and hypometabolism (inferior p = 0.006, middle p = 0.002, superior p = 0.001), and less right medial temporal atrophy (p = 0.02) and hypometabolism (p<0.001), and right posterior cingulate hypometabolism (p<0.001) than dementia of the Alzheimer’s type. An age-adjusted penalized logistic model incorporating atrophy and hypometabolism achieved excellent discrimination (area under the receiver operator characteristic curve = 0.89) between logopenic and dementia of the Alzheimer’s type subjects, with optimal discrimination achieved using right medial temporal and posterior cingulate hypometabolism, left inferior, middle and superior temporal hypometabolism, and left superior temporal volume.

Conclusions

Patterns of atrophy and hypometabolism both differ between logopenic primary progressive aphasia and dementia of the Alzheimer’s type and both modalities provide excellent discrimination between groups.     

Perfectionism in Anorexia Nervosa: Novel Performance Based Evidence

Existing research into perfectionism in Anorexia Nervosa (AN) is limited by a reliance upon self-report measures. This study used novel performance based measures to investigate whether there is behavioural evidence for elevated perfectionism in AN. 153 participants took part in the study – 81 with a diagnosis of AN and 72 healthy controls (HCs). Participants completed two performance based tasks assessing perfectionism – a text replication task and a bead sorting task – along with self-report measures of perfectionism. Significant group differences were observed on both tasks. In the text replication task the AN group took significantly longer compared with healthy controls (p = 0.03, d = 0.36) and produced significantly higher quality copies (p = <0.01, d = 0.45). In the bead sorting task, there was a trend towards more participants in the AN group choosing to check their work compared with the HC group (p = 0.07, d = 0.30) and the AN group took significantly longer checking than those in the HC group (p = <0.01, d = 0.45). Only copy quality uniquely predicted scores on self report measures of perfectionism. This study provides empirically tested evidence of elevated performance based perfectionism in AN compared with a healthy control group.