Clinical subtypes of depression are associated with specific metabolic parameters and circadian endocrine profiles in women: the power study

Background

Major depressive disorder (MDD) has been associated with adverse medical consequences, including cardiovascular disease and osteoporosis. Patients with MDD may be classified as having melancholic, atypical, or undifferentiated features. The goal of the present study was to assess whether these clinical subtypes of depression have different endocrine and metabolic features and consequently, varying medical outcomes.

Methods

Premenopausal women, ages 21 to 45 years, with MDD (N = 89) and healthy controls (N = 44) were recruited for a prospective study of bone turnover. Women with MDD were classified as having melancholic (N = 51), atypical (N = 16), or undifferentiated (N = 22) features. Outcome measures included: metabolic parameters, body composition, bone mineral density (BMD), and 24 hourly sampling of plasma adrenocorticotropin (ACTH), cortisol, and leptin.

Results

Compared with control subjects, women with undifferentiated and atypical features of MDD exhibited greater BMI, waist/hip ratio, and whole body and abdominal fat mass. Women with undifferentiated MDD characteristics also had higher lipid and fasting glucose levels in addition to a greater prevalence of low BMD at the femoral neck compared to controls. Elevated ACTH levels were demonstrated in women with atypical features of depression, whereas higher mean 24-hour leptin levels were observed in the melancholic subgroup.

Conclusions

Pre-menopausal women with various features of MDD exhibit metabolic, endocrine, and BMD features that may be associated with different health consequences.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00006180","term_id":"NCT00006180"}}NCT00006180     

Marked reduction of AKT1 expression and deregulation of AKT1-associated pathways in peripheral blood mononuclear cells of schizophrenia patients

Background

Recent studies have suggested that deregulated AKT1 signaling is associated with schizophrenia. We hypothesized that if this is indeed the case, we should observe both decreased AKT1 expression as well as deregulation of AKT1 regulated pathways in Peripheral Blood Mononuclear Cells (PBMCs) of schizophrenia patients.

Objectives

To examine PBMC expression levels of AKT1 in schizophrenia patients versus controls, and to examine whether functional biological processes in which AKT1 plays an important role are deregulated in schizophrenia patients.

Methods/Results

A case-control study, investigating whole-genome PBMC gene expression in male, recent onset (<5 years) schizophrenia patients (N = 41) as compared to controls (N = 29). Genes, differentially expressed between patients and controls were identified using ANOVA with Benjamini-Hochberg correction (false discovery rate (FDR) = 0.05). Functional aspects of the deregulated set of genes were investigated with the Ingenuity Pathway Analysis (IPA) Software Tool. We found significantly decreased PBMC expression of AKT1 (p<0.001, t = −4.25) in the patients. AKT1 expression was decreased in antipsychotic-free or -naive patients (N = 11), in florid psychotic (N = 20) and in remitted (N = 21) patients. A total of 1224 genes were differentially expressed between patients and controls (FDR = 0.05). Functional analysis of the entire deregulated gene set indicated deregulated canonical pathways involved in a large number of cellular processes: immune system, cell adhesion and neuronal guidance, neurotrophins and (neural) growth factors, oxidative stress and glucose metabolism, and apoptosis and cell-cycle regulation. Many of these processes are associated with AKT1.

Conclusions

We show significantly decreased PBMC gene expression of AKT1 in male, recent-onset schizophrenia patients. Our observations suggest that decreased PBMC AKT1 expression is a stable trait in recent onset, male schizophrenia patients. We identified several AKT related cellular processes which are potentially affected in these patients, a majority of which play a prominent role in current schizophrenia hypotheses.     

T Cell Activation Markers and African Mitochondrial DNA Haplogroups among Non-Hispanic Black Participants in AIDS Clinical Trials Group Study 384

Introduction

Mitochondrial function influences T cell dynamics and is affected by mitochondrial DNA (mtDNA) variation. We previously reported an association between African mtDNA haplogroup L2 and less robust CD4 cell recovery on antiretroviral therapy (ART) in non-Hispanic black ACTG 384 subjects. We explored whether additional T cell parameters in this cohort differed by mtDNA haplogroup.

Methods

ACTG 384 randomized ART-naïve subjects to two different nucleoside regimens with efavirenz, nelfinavir, or both. CD4 and CD8 memory and activation markers were available at baseline and week 48 on most subjects. mtDNA sequencing was performed on whole blood DNA, and haplogroups were determined. We studied non-Hispanic black subjects with HIV RNA <400 copies/mL at week 48. Analyses included Wilcoxon ranksum test and linear regression.

Results

Data from 104 subjects were included. Major African mtDNA haplogroups included L1 (N = 25), L2 (N = 31), and L3 (N = 32). Baseline age, HIV RNA, and CD4 cells did not differ between L2 and non-L2 haplogroups. Compared to non-L2 haplogroups, L2 subjects had lower baseline activated CD4 cells (median 12% vs. 17%; p = 0.03) and tended toward lower activated CD8 cells (41% vs. 47%; p = 0.06). At 48 weeks of ART, L2 subjects had smaller decreases in activated CD4 cells (−4% vs. −11%; p = 0.01), and smaller CD4 cell increases (+95 vs. +178; p = 0.002). In models adjusting for baseline age, CD4 cells, HIV RNA, and naïve-to-memory CD4 cell ratio, haplogroup L2 was associated with lower baseline (p = 0.04) and 48-week change in (p = 0.01) activated CD4 cells.

Conclusions

Among ART-naïve non-Hispanic blacks, mtDNA haplogroup L2 was associated with baseline and 48-week change in T cell activation, and poorer CD4 cell recovery. These data suggest mtDNA variation may influence CD4 T cell dynamics by modulating T cell activation. Further study is needed to replicate these associations and identify mechanisms.     

Characterization of genome-wide association-identified variants for atrial fibrillation in African Americans

Background

Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown.

Methodology/Principal Findings

We studied 73 African Americans with AF from the Vanderbilt-Meharry AF registry and 71 African American controls, with no history of AF including after cardiac surgery. Tests of association were performed for 148 SNPs across the three regions associated with AF, and 22 SNPs were significantly associated with AF (P<0.05). The SNPs with the strongest associations in African Americans were both different from the index SNPs identified in European-descent populations and independent from the index European-descent population SNPs (r²<0.40 in HapMap CEU): 1q21 rs4845396 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13–0.67, P = 0.003), 4q25 rs4631108 (OR 3.43, 95% CI 1.59–7.42, P = 0.002), and 16q22 rs16971547 (OR 8.1, 95% CI 1.46–45.4, P = 0.016). Estimates of European ancestry were similar among cases (23.6%) and controls (23.8%). Accordingly, the probability of having two copies of the European derived chromosomes at each region did not differ between cases and controls.

Conclusions/Significance

Variable European admixture at known AF loci does not explain decreased AF susceptibility in African Americans. These data support the role of 1q21, 4q25, and 16q22 variants in AF risk for African Americans, although the index SNPs differ from those identified in European-descent populations.     

High-Throughput Genotyping in Metastatic Esophageal Squamous Cell Carcinoma Identifies Phosphoinositide-3-Kinase and BRAF Mutations

Background

Given the high incidence of metastatic esophageal squamous cell carcinoma, especially in Asia, we screened for the presence of somatic mutations using OncoMap platform with the aim of defining subsets of patients who may be potential candidate for targeted therapy.

Methods and Materials

We analyzed 87 tissue specimens obtained from 80 patients who were pathologically confirmed with esophageal squamous cell carcinoma and received 5-fluoropyrimidine/platinum-based chemotherapy. OncoMap 4.0, a mass-spectrometry based assay, was used to interrogate 471 oncogenic mutations in 41 commonly mutated genes. Tumor specimens were prepared from primary cancer sites in 70 patients and from metastatic sites in 17 patients. In order to test the concordance between primary and metastatic sites from the patient for mutations, we analyzed 7 paired (primary-metastatic) specimens. All specimens were formalin-fixed paraffin embedded tissues and tumor content was >70%.

Results

In total, we have detected 20 hotspot mutations out of 80 patients screened. The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L) (N = 10, 11.5%) followed by MLH1 V384D (N = 7, 8.0%), TP53 (R306, R175H and R273C) (N = 3, 3.5%), BRAF V600E (N = 1, 1.2%), CTNNB1 D32N (N = 1, 1.2%), and EGFR P733L (N = 1, 1.2%). Distributions of somatic mutations were not different according to anatomic sites of esophageal cancer (cervical/upper, mid, lower). In addition, there was no difference in frequency of mutations between primary-metastasis paired samples.

Conclusions

Our study led to the detection of potentially druggable mutations in esophageal SCC which may guide novel therapies in small subsets of esophageal cancer patients.     

Autoantibodies against a 43 KDa muscle protein in inclusion body myositis

Background

Inclusion body myositis (IBM) is a poorly understood and refractory autoimmune muscle disease. Though widely believed to have no significant humoral autoimmunity, we sought to identify novel autoantibodies with high specificity for this disease.

Methodology/Principal Findings

Plasma autoantibodies from 65 people, including 25 with IBM, were analyzed by immunoblots against normal human muscle. Thirteen of 25 (52%) IBM patient samples recognized an approximately 43 kDa muscle protein. No other disease (N = 25) or healthy volunteer (N = 15) samples recognized this protein.

Conclusions

Circulating antibodies against a 43-kDa muscle autoantigen may lead to the discovery of a novel biomarker for IBM. Its high specificity for IBM among patients with autoimmune myopathies furthermore suggests a relationship to disease pathogenesis.     

Prevalence of drug-resistant tuberculosis in mainland China: systematic review and meta-analysis

Background

The spread of drug-resistant tuberculosis (TB) is one of the major public health problems in the world. Surveillance of anti-TB drug resistance is important for monitoring TB control strategies. However, the status of drug-resistant TB in China has been reported inconsistently.

Methods

We systematically reviewed published studies on drug-resistant TB in China until March 31, 2011, and quantitatively summarized prevalence and patterns of anti-TB drug resistance among new cases and previously treated cases, respectively.

Results

Ninety-five eligible articles, published during 1993–2011, were included in this review. The meta-analyses showed that the prevalence of drug-resistant TB in new cases was 27.9% (95% CI, 25.6%–30.2%) (n/N = 27360/104356) and in previously treated cases was 60.3% (95% CI, 56.2%–64.2%) (n/N = 30350/45858). Furthermore, in these two study populations, the prevalence of multiple drug resistance was found to be 5.3% (95% CI, 4.4%–6.4%) (n/N = 8810/101718) and 27.4% (95% CI, 24.1%–30.9%) (n/N = 10486/44530) respectively. However, the results were found to be frequently heterogeneous (p for Q tests <0.001). The most common resistance was observed for isoniazid among both study populations. Different patterns of drug resistance were observed in the subgroup analysis with respect to geographic areas, drug susceptibility testing methods and subject enrollment time.

Conclusions

Results of meta-analyses indicated a severe status of drug-resistant TB in China, which attaches an importance to strength TB prevention and control.     

Paternal Age and Risk of Autism in an Ethnically Diverse, Non-Industrialized Setting: Aruba

Objective

The aim of this study was to examine paternal age in relation to risk of autism spectrum disorders (ASDs) in a setting other than the industrialized west.

Design

A case-control study of Aruban-born children (1990–2003). Cases (N = 95) were identified at the Child and Adolescent Psychiatry Clinic, the only such clinic in Aruba; gender and age matched controls (N = 347) were gathered from public health records. Parental age was defined categorically (≤29, 30–39, 40–49, ≥50y). The analysis was made, using conditional logistic regression.

Results

Advanced paternal age was associated with increased risk of ASDs in offspring. In comparison to the youngest paternal age group (≤29y), risk of autism increased 2.18 times for children born from fathers in their thirties, 2.71 times for fathers in their forties, and 3.22 thereafter.

Conclusion

This study, part of the first epidemiologic study of autism in the Caribbean, contributes additional evidence, from a distinctive sociocultural setting, of the risk of ASD associated with increased paternal age.     

Intake of Gnetum Africanum and Dacryodes Edulis, Imbalance of Oxidant/Antioxidant Status and Prevalence of Diabetic Retinopathy in Central Africans

Objective

To estimate the prevalence of DR and to correlate cardiometabolic, sociodemographic, and oxidant/antioxidant imbalance data to the prevalence of DR.

Design

This case-control study included type 2 DM (T2 DM) patients with DR (n = 66), T2 DM patients without DR (N = 84), and healthy controls (n = 45) without DR, in Kinshasa town. Diet, albuminemia, serum vitamins, and 8-isoprostane were examined.

Results

No intake of safou (OR = 2.7 95% CI 1.2–5.8; P = 0.014), low serum albumin <4.5 g/dL (OR-2.9 95% CI 1.4–5.9; P = 0.003), no intake of fumbwa (OR = 2.8 95% CI 1.2–6.5; P = 0.014), high 8-isoprostane (OR = 14.3 95% CI 4.5–46; P<0.0001), DM duration ≥5 years (OR = 3.8 95% CI 1.6–9.1; P = 0.003), and low serum vitamin C (OR = 4.5 95% CI 1.3–15.5; P = 0.016) were identified as the significant independent determinants of DR.

Conclusion

The important role of oxidant/antioxidant status imbalance and diet is demonstrated in DR.     

Anti-retroviral treatment outcomes among older adults in Zomba district, Malawi

Background

There are approximately 3 million people aged 50 and older in sub-Saharan Africa who are HIV-positive. Despite this, little is known about the characteristics of older adults who are on treatment and their treatment outcomes.

Methods

A retrospective cohort analysis was performed using routinely collected data with Malawi Ministry of Health monitoring tools from facilities providing antiretroviral therapy services in Zomba district. Patients aged 25 years and older initiated on treatment from July 2005 to June 2010 were included. Differences in survival, by age group, were determined using Kaplan–Meier survival plots and Cox proportional hazards regression models.

Results

There were 10,888 patients aged 25 and older. Patients aged 50 and older (N = 1419) were more likely to be male (P<0.0001) and located in rural areas (P = 0.003) than those aged 25–49. Crude survival estimates among those aged 50–59 were not statistically different from those aged 25–49 (P = 0.925). However, survival among those aged 60 and older (N = 345) was worse (P = 0.019) than among those 25–59. In the proportional hazards model, after controlling for sex and stage at initiation, survival in those aged 50–59 did not differ significantly from those aged 25–49 (hazard ratio 1.00 (95% CI: 0.79 to 1.27; P = 0.998) but the hazard ratio was 1.46 (95% CI: 1.03 to 2.06; P = 0.032) for those aged 60 and older compared to those aged 25–49.

Conclusions

Treatment outcomes of those aged 50–59 are similar to those aged 25–49. A better understanding of how older adults present for and respond to treatment is critical to improving HIV services.     

Genotypic diversity and drug susceptibility patterns among M. tuberculosis complex isolates from South-Western Ghana

Objective

The aim of this study was to use spoligotyping and large sequence polymorphism (LSP) to study the population structure of M. tuberculosis complex (MTBC) isolates.

Methods

MTBC isolates were identified using standard biochemical procedures, IS6110 PCR, and large sequence polymorphisms. Isolates were further typed using spoligotyping, and the phenotypic drug susceptibility patterns were determined by the proportion method.

Result

One hundred and sixty-two isolates were characterised by LSP typing. Of these, 130 (80.25%) were identified as Mycobacterium tuberculosis sensu stricto (MTBss), with the Cameroon sub-lineage being dominant (N = 59/130, 45.38%). Thirty-two (19.75%) isolates were classified as Mycobacterium africanum type 1, and of these 26 (81.25%) were identified as West-Africa I, and 6 (18.75%) as West-Africa II. Spoligotyping sub-lineages identified among the MTBss included Haarlem (N = 15, 11.53%), Ghana (N = 22, 16.92%), Beijing (4, 3.08%), EAI (4, 3.08%), Uganda I (4, 3.08%), LAM (2, 1.54%), X (N = 1, 0.77%) and S (2, 1.54%). Nine isolates had SIT numbers with no identified sub-lineages while 17 had no SIT numbers. MTBss isolates were more likely to be resistant to streptomycin (p<0.008) and to any drug resistance (p<0.03) when compared to M. africanum.

Conclusion

This study demonstrated that overall 36.4% of TB in South-Western Ghana is caused by the Cameroon sub-lineage of MTBC and 20% by M. africanum type 1, including both the West-Africa 1 and West-Africa 2 lineages. The diversity of MTBC in Ghana should be considered when evaluating new TB vaccines.     

Urinary podocyte-associated mRNA profile in various stages of diabetic nephropathy

Background

Podocyte injury and subsequent excretion in urine play a crucial role in the pathogenesis and progression of diabetic nephropathy (DN). Quantification of messenger RNA (mRNA) expression in urinary sediment by real-time PCR is emerging as a noninvasive method of screening DN-associated biomarkers. We hypothesized that the urinary mRNA profile of podocyte-associated molecules may provide important clinical insight into the different stages of diabetic nephropathy.

Methods

DN patients (N = 51) and healthy controls (N = 13) were enrolled in this study. DN patients were divided into a normoalbuminuria group (UAE<30 mg/g, n = 17), a microalbuminuria group (UAE 30∼300 mg/g, n = 15), and a macroalbuminuria group (UAE>300 mg/g, n = 19), according to their urinary albumin excretion (UAE). Relative mRNA abundance of synaptopodin, podocalyxin, CD2-AP, α-actin4, and podocin were quantified, and correlations between target mRNAs and clinical parameters were examined.

Results

The urinary mRNA levels of all genes studied were significantly higher in the DN group compared with controls (p<0.05), and mRNA levels increased with DN progression. Urinary mRNA levels of all target genes positively correlated with both UAE and BUN. The expression of podocalyxin, CD2-AP, α-actin4, and podocin mRNA correlated with serum creatinine (r = 0.457, p = 0.001; r = 0.329, p = 0.01; r = 0.286, p = 0.021; r = 0.357, p = 0.006, respectively). Furthermore, podocalyxin mRNA was found to negatively correlate with eGFR (r = −0.349, p = 0.01).

Conclusion

The urinary mRNA profiles of synaptopodin, podocalyxin, CD2-AP, α-actin4, and podocin were found to increase with the progression of DN, which suggested that quantification of podocyte-associated molecules will be useful biomarkers of DN.     

The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy

Background

In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring.

Methods/Principal Findings

VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N = 32), macular hole (N = 13) or macular pucker (N = 23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment.

Conclusions/Significance

CTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy.     

Impact of non-HIV and HIV risk factors on survival in HIV-infected patients on HAART: a population-based nationwide cohort study

Background

We determined the impact of three factors on mortality in HIV-infected patients who had been on highly active antiretroviral therapy (HAART) for at least one year: (1) insufficient response to (HAART) and presence of AIDS-defining diseases, (2) comorbidity, and (3) drug and alcohol abuse and compared the mortality to that of the general population.

Methodology/Principal Findings

In a Danish nationwide, population-based cohort study, we used population based registries to identify (1) all Danish HIV-infected patients who started HAART in the period 1 January 1998–1 July 2009, and (2) a comparison cohort of individuals matched on date of birth and gender (N = 2,267 and 9,068, respectively). Study inclusion began 1 year after start of HAART. Patients were categorised hierarchically in four groups according to the three risk factors, which were identified before study inclusion. The main outcome measure was probability of survival from age 25 to 65 years. The probability of survival from age 25 to age 65 was substantially lower in HIV patients [0.48 (95% confidence interval (CI) 0.42–0.55)] compared to the comparison cohort [0.88 (0.86 to 0.90)]. However, in HIV patients with no risk factors (N = 871) the probability of survival was equivalent to that of the general population [0.86 (95% CI 0.77–0.92)]. In contrast, the probability of survival was 0.58 in patients with HIV risk factors (N = 704), 0.30 in patients with comorbidities (N = 479), and 0.03 in patients with drug or alcohol abuse (N = 313).

Conclusions

The increased risk of death in HIV-infected individuals is mainly attributable to risk factors that can be identified prior to or in the initial period of antiretroviral treatment. Mortality in patients without risk factors on a successful HAART is almost identical to that of the non–HIV-infected population.     

Estimation of daily energy expenditure in pregnant and non-pregnant women using a wrist-worn tri-axial accelerometer

Background

Few studies have compared the validity of objective measures of physical activity energy expenditure (PAEE) in pregnant and non-pregnant women. PAEE is commonly estimated with accelerometers attached to the hip or waist, but little is known about the validity and participant acceptability of wrist attachment. The objectives of the current study were to assess the validity of a simple summary measure derived from a wrist-worn accelerometer (GENEA, Unilever Discover, UK) to estimate PAEE in pregnant and non-pregnant women, and to evaluate participant acceptability.

Methods

Non-pregnant (N = 73) and pregnant (N = 35) Swedish women (aged 20–35 yrs) wore the accelerometer on their wrist for 10 days during which total energy expenditure (TEE) was assessed using doubly-labelled water. PAEE was calculated as 0.9×TEE-REE. British participants (N = 99; aged 22–65 yrs) wore accelerometers on their non-dominant wrist and hip for seven days and were asked to score the acceptability of monitor placement (scored 1 [least] through 10 [most] acceptable).

Results

There was no significant correlation between body weight and PAEE. In non-pregnant women, acceleration explained 24% of the variation in PAEE, which decreased to 19% in leave-one-out cross-validation. In pregnant women, acceleration explained 11% of the variation in PAEE, which was not significant in leave-one-out cross-validation. Median (IQR) acceptability of wrist and hip placement was 9(8–10) and 9(7–10), respectively; there was a within-individual difference of 0.47 (p<.001).

Conclusions

A simple summary measure derived from a wrist-worn tri-axial accelerometer adds significantly to the prediction of energy expenditure in non-pregnant women and is scored acceptable by participants.     

Association of vitamin B12 deficiency with fatigue and depression after lacunar stroke

Background

In lacunar stroke patients vitamin B12 deficiency is often found and a relationship with the degree of periventricular white matter lesions (pWMLs) is suggested. Given the known relationships between WMLs and depression and between depression and fatigue after stroke, we studied both depression and fatigue in lacunar stroke patients with and without vitamin B12 deficiency.

Methods

In 40 first-ever lacunar stroke patients vitamin B12 levels were determined and self-report questionnaires for fatigue and depression were completed three months after stroke.

Results

Lacunar stroke patients with vitamin B12 deficiency (N = 13) reported significantly more fatigue (90.7 versus 59.4; p = .001) and depressive symptoms (6.62 versus 3.89; p<.05) than those without (N = 27). In regression analyses, vitamin B12 deficiency was significantly and independently associated with the presence of severe fatigue and clinically significant depression.

Conclusions

Our preliminary results suggest a relationship between vitamin B12 deficiency and increased levels of fatigue and depression in lacunar stroke patients. If these findings could be replicated in a larger and general stroke sample, this would open treatment options and may improve quality of life after stroke.     

A novel serum metabolomics-based diagnostic approach for colorectal cancer

Background

To improve the quality of life of colorectal cancer patients, it is important to establish new screening methods for early diagnosis of colorectal cancer.

Methodology/Principal Findings

We performed serum metabolome analysis using gas-chromatography/mass-spectrometry (GC/MS). First, the accuracy of our GC/MS-based serum metabolomic analytical method was evaluated by calculating the RSD% values of serum levels of various metabolites. Second, the intra-day (morning, daytime, and night) and inter-day (among 3 days) variances of serum metabolite levels were examined. Then, serum metabolite levels were compared between colorectal cancer patients (N = 60; N = 12 for each stage from 0 to 4) and age- and sex-matched healthy volunteers (N = 60) as a training set. The metabolites whose levels displayed significant changes were subjected to multiple logistic regression analysis using the stepwise variable selection method, and a colorectal cancer prediction model was established. The prediction model was composed of 2-hydroxybutyrate, aspartic acid, kynurenine, and cystamine, and its AUC, sensitivity, specificity, and accuracy were 0.9097, 85.0%, 85.0%, and 85.0%, respectively, according to the training set data. In contrast, the sensitivity, specificity, and accuracy of CEA were 35.0%, 96.7%, and 65.8%, respectively, and those of CA19-9 were 16.7%, 100%, and 58.3%, respectively. The validity of the prediction model was confirmed using colorectal cancer patients (N = 59) and healthy volunteers (N = 63) as a validation set. At the validation set, the sensitivity, specificity, and accuracy of the prediction model were 83.1%, 81.0%, and 82.0%, respectively, and these values were almost the same as those obtained with the training set. In addition, the model displayed high sensitivity for detecting stage 0–2 colorectal cancer (82.8%).

Conclusions/Significance

Our prediction model established via GC/MS-based serum metabolomic analysis is valuable for early detection of colorectal cancer and has the potential to become a novel screening test for colorectal cancer.     

Time-efficient black blood RCA wall imaging at 3T using improved motion sensitized driven equilibrium (iMSDE): feasibility and reproducibility

Background

The aim of this study was to explore the feasibility and reproducibility of a time-efficient coronary vessel wall measurement approach using an improved motion-sensitized driven equilibrium (iMSDE) pulse sequence.

Methodology

In this study, the iMSDE pulse sequence was first optimized and then applied on a group of healthy volunteers (N = 10) to evaluate its feasibility of vessel wall visualization. The same technique was also applied on a separate group of volunteers (N = 19) for a reproducibility study by scanning the same subject in two separate sessions. The iMSDE sequence was found to provide good coronary vessel wall delineation. It was also found to provide reproducible coronary vessel wall diameter and thickness measurements in both proximal and middle segments of the right coronary artery.

Conclusion

The feasibility and reproducibility of iMSDE based coronary vessel wall imaging were demonstrated for the first time, paving the way for further testing in a clinical environment for fast and accurate coronary artery disease detection.     

Soluble beta-amyloid precursor protein is related to disease progression in amyotrophic lateral sclerosis

Background

Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS) could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPPα and sAPPß) correlated with clinical subtypes of ALS and were of prognostic value.

Methodology/Principal Findings

In a cross-sectional study including patients with ALS (N = 68) with clinical follow-up data over 6 months, Parkinson''s disease (PD, N = 20), and age-matched controls (N = 40), cerebrospinal fluid (CSF) levels of sAPPα a, sAPPß and neurofilaments (NfH^SMI35) were measured by multiplex assay, Progranulin by ELISA. CSF sAPPα and sAPPß levels were lower in ALS with a rapidly-progressive disease course (p = 0.03, and p = 0.02) and with longer disease duration (p = 0.01 and p = 0.01, respectively). CSF NfH^SMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p<0.01). High CSF NfH^SMI3 was linked to low CSF sAPPα and sAPPß (p = 0.001, and p = 0.007, respectively). The ratios CSF NfH^SMI35/CSF sAPPα,-ß were elevated in patients with fast progression of disease (p = 0.002 each). CSF Progranulin decreased with ongoing disease (p = 0.04).

Conclusions

This study provides new CSF candidate markers associated with progression of disease in ALS. The data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP) is linked to progressive neuro-axonal damage (increase of NfH^SMI35) and to progression of disease.     

Relationship between Microbial Translocation and Endothelial Function in HIV Infected Patients

Background

Circulating levels of microbial products are increased in HIV infection, and provoke endothelial dysfunction in other disease settings.

Methodology/Principal Findings

We examined data from a cross-sectional single site study at Indiana University (Indiana, N = 85) and a 24- week multicenter prospective study of antiretroviral therapy (ART) initiation (ACTG 5152s, N = 75). Brachial artery flow-mediated dilation (FMD) was measured by ultrasound. Plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels were measured from stored specimens and correlated with FMD values using Pearson correlations. The Indiana subjects were 63% male with a mean age of 39 years and a median CD4 count of 406 cells/mm³ (388 not on ART, 464 on ART). The 5152s subjects were 92% were male with a mean age of 35 years and a median CD4 count of 251 cells/mm³ at entry which increased to 396 cells/mm³ on ART. When analyzing the two cohorts individually or in combination neither sCD14 nor LPS correlated significantly with FMD. In a pre-specified subgroup analysis of the Indiana subjects receiving ART (N = 46, mean ART duration 40 months) LPS was inversely correlated with FMD (r = −0.33, p = 0.02), but not sCD14 (r = −0.01, p = 0.9). Multivariate analysis confirmed LPS as an independent predictor of FMD in this subgroup (p = 0.02).

Conclusions/Significance

In HIV- infected individuals on prolonged ART, higher LPS levels are associated with worse endothelial function but not in untreated subjects or at 24 weeks after ART initiation. Persistent microbial translocation may contribute to arterial dysfunction and the increased cardiovascular disease risk observed in individuals on long-term ART.