Neuroendocrine markers and psychological features in patients with irritable bowel syndrome

Background and aims

The key role of the brain-gut axis in the pathophysiology of irritable bowel syndrome (IBS) has been recognized. The aim of this study was to assess the possible association between IBS, neuroendocrine markers, and psychological features.

Methods

One hundred and twenty-five consecutive IBS patients and 105 healthy subjects were enrolled. Plasma serotonin, plasma and urinary cortisol, and plasma neuropeptide Y levels were evaluated. All patients were given a questionnaire to assess IBS symptom severity. In 66 patients, a psychodiagnostic assessment was carried out.

Results

A high incidence of specific psychological features, including state anxiety (69.69 %), trait anxiety (54.54 %), obsessions and compulsions (28.78 %), was observed in IBS patients. A positive correlation between neuropeptide Y and state anxiety (r?=?0.287, p?=?0.024) and simulation/social ingenuity (r?=?0.269, p?=?0.039) was found in these patients. In diarrhea-predominant IBS, plasma cortisol was linearly related to plasma serotonin (r?=?0.5663, p?<?0.001).

Conclusions

In IBS patients, a significant correlation was found between specific psychological features and neuroendocrine markers, especially plasma cortisol and neuropeptide Y; in diarrhea-predominant IBS, a correlation between plasma cortisol and serotonin was found, although it needs to be confirmed in more extensive cohorts.     

Canada's Contribution to Global Research in Cardiovascular Diseases

The burden of cardiovascular disease (CVD) in Canada and other developed countries is growing, in part because of the aging of the population and the alarming rise of obesity. Studying Canada's contribution to the global body of CVD research output will shed light on the effectiveness of investments in Canadian CVD research and inform if Canada has been responding to its CVD burden. Search was conducted using the Web-of-Science database for publications during 1981 through 2010 on major areas and specific interventions in CVD. Search was also conducted using Canadian and US online databases for patents issued between 1981 and 2010. Search data were used to estimate the proportions of the world's pool of research publications and of patents conducted by researchers based in Canada. The results indicate that Canada contributed 6% of global research in CVD during 1981 through 2010. Further, Canada's contribution shows a strong upward trend during the period. Based on patent data, Canada's contribution level was similar (5%-7%). Canada's contribution to the global pool of CVD research is on par with France and close to the UK, Japan, and Germany. Canada's contribution in global CVD research is higher than its average contribution in all fields of research (6% vs 3%). As the burden of chronic diseases including CVD rises with Canada's aging population, the increase in Canadian research into CVD is encouraging.     

Defining a 0.5-mb region of genomic gain on chromosome 6p22 in bladder cancer by quantitative-multiplex polymerase chain reaction

Metaphase-based comparative genomic hybridization (CGH) has identified recurrent regions of gain on different chromosomes in bladder cancer, including 6p22. These regions may contain activated oncogenes important in disease progression. Using quantitative multiplex polymerase chain reaction (QM-PCR) to study DNA from 59 bladder tumors, we precisely mapped the focal region of genomic gain on 6p22. The marker STS-X64229 had copy number increases in 38 of 59 (64%) tumors and the flanking markers, RH122450 and A009N14, had copy number gains in 33 of 59 (56%) and 26 of 59 (45%) respectively. Contiguous gain was present for all three markers in 14 of 59 (24%) and for two (RH122450 and STS-X64229) in 25 of 59 (42%). The genomic distance between the markers flanking STS-X64229 is 0.5 megabases, defining the minimal region of gain on 6p22. Locus-specific interphase fluorescence in situ hybridization confirmed the increased copy numbers detected by QM-PCR. Current human genomic mapping data indicates that an oncogene, DEK, is centrally placed within this minimal region. Our findings demonstrate the power of QM-PCR to narrow the regions identified by CGH to facilitate identifying specific candidate oncogenes. This also represents the first study identifying DNA copy number increases for DEK in bladder cancer.     

Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1

Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC^min polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC^min polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action.     

Latent class analysis of polysubstance use,sexual risk behaviors,and infectious disease among South African drug users

Background

HIV transmission risk among non-injection drug users is high due to the co-occurrence of drug use and sexual risk behaviors. The purpose of the current study was to identify patterns of drug use among polysubstance users within a high HIV prevalence population.

Methods

The study sample included 409 substance users from the Pretoria region of South Africa. Substances used by 20% or more the sample included: cigarettes, alcohol, marijuana and heroin in combination, marijuana and cigarettes in combination, and crack cocaine. Latent class analysis was used to identify patterns of polysubstance use based on types of drugs used. Multivariate logistic regression analyses compared classes on demographics, sexual risk behavior, and disease status.

Results

Four classes of substance use were found: MJ + Cig (40.8%), MJ + Her (30.8%), Crack (24.7%), and Low Use (3.7%). The MJ + Cig class was 6.7 times more likely to use alcohol and 3 times more likely to use drugs before/during sex with steady partners than the Crack class. The MJ + Cig class was 16 times more likely to use alcohol before/during sex with steady partners than the MJ + Her class. The Crack class was 6.1 times more likely to engage in transactional sex and less likely to use drugs before/during steady sex than the MJ + Her class.

Conclusions

Findings illustrate patterns of drug use among a polysubstance using population that differ in sexual risk behavior. Intervention strategies should address substance use, particularly smoking as a route of administration (ROA), and sexual risk behaviors that best fit this high-risk population.     

Low Level of Exposure to Pesticides Leads to Lung Dysfunction in Occupationally Exposed Subjects

Pesticides may contribute to adverse respiratory health effects among farmers and have been considered one causal factor for the rise in asthma prevalence. This cross-sectional study was conducted to evaluate potential respiratory function abnormalities following long-term pesticide exposure by means of a complete pulmonary function testing, including spirometry, lung volumes, and diffusing capacity for carbon monoxide. The study population was comprised by workers from a prominent intensive agriculture area of southern Spain that relied on pesticides for the control of plagues. Eighty-nine pesticide sprayers of plastic greenhouse farming and a control group of 25 nonspraying control farmers from the same area were interviewed by a general practitioner asking about sociodemographic factors, occupational exposure, and clinical symptoms by using a structured questionnaire. Multiple regression analyses showed a relationship of short-term exposure to pesticides (as indicated by a drop in serum cholinesterase > 25% of baseline levels) with reduced forced expired volume in 1 s, and of long-term exposure (as indicated by a cumulative pesticide exposure index) with reduced forced expiratory flow rate. Exposure to bipyridilium-class herbicides was a determinant of a fall in the diffusing capacity of the lungs, and neonicotinoid insecticides showed a relationship with lower pulmonary volumes (total lung capacity, residual volume, and functional residual capacity), suggestive of restrictive lung disease, and with an increased risk of reporting irritative symptoms.     

Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity

Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines. We show here that PCPA treatment induces the expression of E-cadherin and other epithelial markers and markedly suppresses migration and invasion of TNBC cell lines MDA-MB-231 and BT-549. These effects were phenocopied by Slug or LSD1 silencing. In two models of orthotopic breast cancer, PCPA treatment reduced local tumor growth and the number of lung metastases. In mice injected directly in the blood circulation with MDA-MB-231 cells, PCPA treatment or Slug silencing markedly inhibited bone metastases but had no effect on lung infiltration. Thus, blocking Slug activity may suppress the metastatic spread of TNBC and, perhaps, specifically inhibit homing/colonization to the bone.     

Effectiveness and tolerability of dolutegravir and abacavir/lamivudine administered as two separate pills compared to their equivalent single‐tablet regimen in a multicentre cohort in Spain

IntroductionWe aimed to assess the effectiveness and tolerability of dolutegravir (DTG), abacavir (ABC) and lamivudine (3TC) administered as branded STR (DTG/ABC/3TC) or as two separate pills (DTG and either branded ABC/3TC [DTG+(ABC/3TC)b] or generic ABC/3TC [DTG+(ABC/3TC)g]).MethodsWe included individuals from the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) who received DTG/ABC/3TC, DTG+(ABC/3TC)b or DTG+(ABC/3TC)g during 2015 to 2018. We used multivariable logistic regression to compare the proportion of antiretroviral‐naïve individuals who achieved viral suppression (VS) (viral load ≤50 copies/mL) at 24 weeks of initiating with DTG+(ABC/3TC)b or DTG+(ABC/3TC)g versus DTG/ABC/3TC. We also calculated the proportion of virologically suppressed individuals who maintained VS at 24 weeks after switching from DTG/ABC/3TC to DTG+(ABC/3TC)g.ResultsDuring the study period, 829, 68 and 47 treatment‐naïve individuals started treatment with DTG/ABC/3TC, DTG+(ABC/3TC)b or DTG+(ABC/3TC)g respectively. The proportions of individuals who changed their regimens due to side effects during the first 24 weeks were 3.7%, 4.4% and 6.4% respectively (p = 0.646). We did not find significant differences in VS at 24 weeks among individuals starting with DTG+(ABC/3TC)b or DTG+(ABC/3TC)g compared to those initiating with DTG/ABC/3TC. Among 177 virologically suppressed individuals who switched from DTG/ABC/3TC to DTG+(ABC/3TC)g, 170 (96.0%) maintained VS at 24 weeks.ConclusionsIn naïve individuals, the effectiveness and tolerability at 24 weeks of DTG plus ABC/3TC administered as two separate pills, either as branded or generic ABC/3TC, was similar to the STR DTG/ABC/3TC. Switching the STR DTG/ABC/3TC to its separate components DTG+(ABC/3TC)g in virologically suppressed individuals did not seem to impair its effectiveness.     

Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study

Other than exposure to gluten and genetic compatibility, the gut microbiome has been suggested to be involved in celiac disease (CD) pathogenesis by mediating interactions between gluten/environmental factors and the host immune system. However, to establish disease progression markers, it is essential to assess alterations in the gut microbiota before disease onset. Here, a prospective metagenomic analysis of the gut microbiota of infants at risk of CD was done to track shifts in the microbiota before CD development. We performed cross-sectional and longitudinal analyses of gut microbiota, functional pathways, and metabolites, starting from 18 mo before CD onset, in 10 infants who developed CD and 10 matched nonaffected infants. Cross-sectional analysis at CD onset identified altered abundance of six microbial strains and several metabolites between cases and controls but no change in microbial species or pathway abundance. Conversely, results of longitudinal analysis revealed several microbial species/strains/pathways/metabolites occurring in increased abundance and detected before CD onset. These had previously been linked to autoimmune and inflammatory conditions (e.g., Dialister invisus, Parabacteroides sp., Lachnospiraceae, tryptophan metabolism, and metabolites serine and threonine). Others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects (e.g., Streptococcus thermophilus, Faecalibacterium prausnitzii, and Clostridium clostridioforme). Additionally, we uncovered previously unreported microbes/pathways/metabolites (e.g., Porphyromonas sp., high mannose–type N-glycan biosynthesis, and serine) that point to CD-specific biomarkers. Our study establishes a road map for prospective longitudinal study designs to better understand the role of gut microbiota in disease pathogenesis and therapeutic targets to reestablish tolerance and/or prevent autoimmunity.

Celiac disease (CD) is a chronic systemic autoimmune disorder that occurs in genetically predisposed individuals and is characterized by loss of tolerance to dietary gluten protein. CD affects ∼1% of the global population, with regional variations depending on human leukocyte antigen (HLA) presence and dietary gluten consumption (1). The incidence of CD most likely will continue to increase, along with other autoimmune conditions, despite the fact that its associated genes, HLA, and the trigger, gluten, have not changed (1). Nevertheless, more than 30% of the population carries the predisposing gene and is exposed to gluten, yet only 2 to 3% develop CD in their lifetime (2). This suggests that other factors such as the intestinal microbiota may also contribute to CD pathogenesis.The inflammatory process underlying CD involves both innate and adaptive immune systems (3). While the adaptive immune response in CD has been described, less is known about the innate immune response following gluten exposure, which drives early steps in CD pathogenesis and eventually leads to loss of gluten tolerance (4). Previous work has linked the trigger of CD, gluten, the intestinal microbiota, and the innate immune response (5–8).Given the cross-talk between the gut microbiota and immune system, alterations in the gut microbiota have been linked to several autoimmune conditions (9) such as inflammatory bowel disease (10), type 1 diabetes (T1D) (11), multiple sclerosis (12), and CD (13–18). We, and others, have looked for changes in the gut microbiota of infants at risk for CD (15, 17–19). For example, using 16S ribsosomal ribonucelic acid (rRNA) amplicon sequencing, we previously reported higher abundance of Lactobacillus up to 12 mo of age in one infant who later developed CD compared with 15 at-risk infants who did not (15). Other studies of gut microbiota and CD assessed changes in gut microbiota composition of individuals during the first year after birth who later developed CD compared with controls (17, 18). For example, Olivares et al. (17) used a prospective cohort of 200 infants at risk for CD to compare, with 16S rRNA sequencing, the intestinal microbiota of 10 cases who developed CD during the 5-y study period and 10 matched controls at 4 and 6 mo of age. They reported increases in abundance of Firmicutes, Enterococcaceae, and Peptostreptococcaceae in controls from 4 to 6 mo (17). Rintala et al. (18) also examined intestinal microbiota of infants at risk for CD, using 16S rRNA sequencing, at 9 and 12 mo of age in nine subjects who developed CD by ages 4 and 18 and matched controls, but did not identify any significant differences in microbiota composition. Huang et al. (20) examined intestinal microbiota, using 16S rRNA sequencing, at ages 1, 2.5, and 5 y in 16 subjects with CD (11 of whom developed CD after age 5) and 16 controls and found significant differences in taxonomic composition of the microbiota in cases compared with controls at all of the time points. Finally, a recent study using 16S rRNA sequencing to examine differences in the gut microbiota of children with untreated CD compared with children with treated CD and healthy control subjects did not identify changes in alpha diversity at CD diagnosis (21) but did identify differences in taxonomic composition, such as a lower abundance in Alistipes in subjects with CD compared with healthy controls (21). A separate study utilizing 16S rRNA sequencing also identified significant differences in taxonomic composition between patients with newly diagnosed CD and healthy control subjects, with subjects with recently diagnosed CD having a lower abundance of Bacteroides–Prevotella, Akkermansia, and Staphylococcaceae (22).While these studies provide an important foundation concerning alterations in gut microbiota of subjects at risk for CD early in life, they analyzed only up to three time points in the first year after birth (17, 18, 20) or were restricted to only one subject with CD (15). In addition, the studies used 16S rRNA sequencing to analyze intestinal microbiota, which cannot provide information about functional characteristics of the microbiota nor provide taxonomic data at the strain level, both of which are necessary to design effective treatment for CD. Furthermore, metabolomic analysis (if any) in these studies was generally limited to serum (as opposed to fecal) metabolites, which do not provide direct information about metabolic activity of the gut microbiota. More importantly, here we argue that, to gain mechanistic insight into the pathogenesis of CD and other autoimmune diseases, we need to transition from case–control microbiome studies to prospective longitudinal studies, which prospectively examine subjects at multiple time points before disease development (23). Studies aimed at identifying changes in the microbiome (11, 24) and intestinal permeability (25) have been performed and identified taxonomic changes prior to T1D (11) and necrotizing enterocolitis (24) as well as increased intestinal permeability up to 3 y prior to the development of Crohn’s disease (25). However, longitudinal birth cohort studies focused on multiomic data collection and analysis are limited and have not been developed for CD.The first step toward achieving this goal was to establish a prospective cohort study for CD, the Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CDGEMM) study (26), where we have been following approximately 500 infants in the United States, Italy, and Spain who have a first-degree relative with CD and therefore, are at a high risk of developing CD. We have previously utilized other study subjects from this cohort and multiomics analysis to investigate the impact of genetic and environmental risk factors on the development of the gut microbiota in infants at risk for CD (19). In the current study, we present proof of concept intersubject and intrasubject analyses using fecal metagenomic and metabolomic data collected at multiple time points before onset of CD in 10 cases and 10 matched controls in order to identify alterations in the intestinal microbiota and metabolome, which may serve as markers of progression toward CD onset.