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Exposures to heavy metals have been linked to prostate cancer risk. The relationship of these exposures with serum prostate-specific antigen (PSA), a marker used for prostate cancer screening, is unknown. We examined whether total urinary arsenic, urinary dimethylarsonic acid, blood cadmium, blood lead, and total blood mercury levels are associated with elevated PSA among presumably healthy U.S. men. Prostate cancer-free men, aged ≥40 years, were identified from the 2003-2010 National Health and Nutrition Examination Survey. Logistic regression analyses with survey sample weights were used to examine the association between heavy metal levels and elevated PSA for the total population and stratified by black and white race, after adjusting for confounders. There were 5,477 men included. Approximately 7% had elevated PSA. Men with an elevated PSA had statistically significantly higher levels of blood cadmium and blood lead compared to men with a normal PSA (p-values ≤ 0.02), with black men having higher levels. After adjusting for age, race/ethnicity, body mass index, smoking, and education, there was no association found between any of the heavy metal levels and elevated PSA for the total population. In addition, there was no association found when stratified by black and white race. Further investigation is warranted in a larger cohort of men who persistently are exposed to these heavy metals.

BackgroundThe survival rates from breast cancer in Africa are poor and yet the incidence rates are on the rise. In this study, we hypothesized that, in Africa, a continent with great disparities in socio-economic status, race, tumor biology, and cultural characteristics, the survival rates from breast cancer vary greatly based on region, tumor biology (hormone receptor), gender, and race. We aimed to conduct the first comprehensive systematic review and meta-analysis on region, gender, tumor-biology and race-specific 5-year breast cancer survival rates in Africa and compared them to 20-year survival trends in the United States.MethodsWe searched MEDLINE, EMBASE, and Cochrane Library to identify studies on breast cancer survival in African published before October 17, 2018. Pooled 5-year survival rates of breast cancer were estimated by random-effects models. We explored sources of heterogeneity through subgroup meta-analyses and meta-regression. Results were reported as absolute difference (AD) in percentages. We compared the survival rates of breast cancer in Africa and the United States.FindingsThere were 54 studies included, consisting of 18,970 breast cancer cases. There was substantial heterogeneity in the survival rates (mean 52.9%, range 7-91%, I2 = 99.1%; p for heterogeneity ConclusionRegional, sub-regional, gender, and racial disparities exist, influencing the survival rates of breast cancer in Africa. Therefore, region and race-specific public health interventions coupled with prospective genetic studies are urgently needed to improve breast cancer survival in this region.

Cerebral structural and functional alterations have been reported after chemotherapy for non-CNS cancers, yet the causative mechanism behind these changes remains unclear. This study employed a novel, non-invasive, MRI-based neuroimaging measure to provide the first direct longitudinal measurement of resting cerebral perfusion in breast cancer patients, which was tested for association with changes in cognitive function and gray matter density. Perfusion was measured using pulsed arterial spin labeling MRI in women with breast cancer treated with (N = 27) or without (N = 26) chemotherapy and matched healthy controls (N = 26) after surgery before other treatments (baseline), and one month after chemotherapy completion or yoked intervals. Voxel-based analysis was employed to assess perfusion in gray matter; changes were examined in relation to overall neuropsychological test performance and frontal gray matter density changes measured by structural MRI. Baseline perfusion was not significantly different across groups. Unlike control groups, chemotherapy-treated patients demonstrated significantly increased perfusion post-treatment relative to baseline, which was statistically significant relative to controls in the right precentral gyrus. This perfusion increase was negatively correlated with baseline overall neuropsychological performance, but was not associated with frontal gray matter density reduction. However, decreased frontal gray matter density was associated with decreased perfusion in bilateral frontal and parietal lobes in the chemotherapy-treated group. These findings indicate that chemotherapy is associated with alterations in cerebral perfusion which are both related to and independent of gray matter changes. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. Additionally, lower baseline cognitive function may be a risk factor for treatment-associated perfusion dysregulation. Future research is needed to clarify these mechanisms, identify individual differences in susceptibility to treatment-associated changes, and further examine perfusion change over time in survivors.

BackgroundAbuse of prescription opioid analgesics is a serious threat to public health, resulting in rising numbers of overdose deaths and admissions to emergency departments and treatment facilities. Absent adequate patient information systems, "doctor shopping" patients can obtain multiple opioid prescriptions for nonmedical use from different unknowing physicians. Our study estimates the prevalence of doctor shopping in the US and the amounts and types of opioids involved.Methods and findingsThe sample included records for 146.1 million opioid prescriptions dispensed during 2008 by 76% of US retail pharmacies. Prescriptions were linked to unique patients and weighted to estimate all prescriptions and patients in the nation. Finite mixture models were used to estimate different latent patient populations having different patterns of using prescribers. On average, patients in the extreme outlying population (0.7% of purchasers), presumed to be doctor shoppers, obtained 32 opioid prescriptions from 10 different prescribers. They bought 1.9% of all opioid prescriptions, constituting 4% of weighed amounts dispensed.ConclusionsOur data did not provide information to make a clinical diagnosis of individuals. Very few of these patients can be classified with certainty as diverting drugs for nonmedical purposes. However, even patients with legitimate medical need for opioids who use large numbers of prescribers may signal dangerously uncoordinated care. To close the information gap that makes doctor shopping and uncoordinated care possible, states have created prescription drug monitoring programs to collect records of scheduled drugs dispensed, but the majority of physicians do not access this information. To facilitate use by busy practitioners, most monitoring programs should improve access and response time, scan prescription data to flag suspicious purchasing patterns and alert physicians and pharmacists. Physicians could also prevent doctor shopping by adopting procedures to screen new patients for their risk of abuse and to monitor patients' adherence to prescribed treatments.

Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p=2.44×10(-5)) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p

ObjectiveLarge studies describing the profile of high-risk Human papillomavirus (hrHPV) genotypes among women in sub-Saharan Africa are lacking. Here we describe the prevalence and distribution of hrHPV genotypes among HIV-negative women in South Africa, with and without cervical intraepithelial neoplasia (CIN).MethodsWe report data on 8,050 HIV-negative women, aged 17-65 years, recruited into three sequential studies undertaken in Cape Town, South Africa. Women had no history of previous cervical cancer screening. Cervical samples were tested for hrHPV DNA using the Hybrid Capture 2 (HC2) assay and all positive samples were genotyped using a PCR-based assay (Line Blot). Women underwent colposcopy and biopsy/endocervical curettage to determine CIN status. The prevalence and distribution of specific hrHPV genotypes were examined by age and CIN status.ResultsOverall, 20.7% (95% CI, 19.9-21.6%) of women were hrHPV-positive by HC2, with women with CIN having the highest rates of positivity. Prevalence decreased with increasing age among women without CIN; but, a bimodal age curve was observed among women with CIN. HPV 16 and 35 were the most common hrHPV genotypes in all age and CIN groups. HPV 45 became more frequent among older women with CIN grade 2 or 3 (CIN2,3). Younger women (17-29 years) had more multiple hrHPV genotypes overall and in each cervical disease group than older women (40-65 years).ConclusionHPV 16, 35, and 45 were the leading contributors to CIN 2,3. The current HPV vaccines could significantly reduce HPV-related cervical disease; however, next generation vaccines that include HPV 35 and 45 would further reduce cervical disease in this population.

Integrin-linked kinase (ILK) is a highly evolutionarily conserved, multi-domain signaling protein that localizes to focal adhesions, myofilaments and centrosomes where it forms distinct multi-protein complexes to regulate cell adhesion, cell contraction, actin cytoskeletal organization and mitotic spindle assembly. Numerous studies have demonstrated that ILK can regulate the phosphorylation of various protein and peptide substrates in vitro, as well as the phosphorylation of potential substrates and various signaling pathways in cultured cell systems. Nevertheless, the ability of ILK to function as a protein kinase has been questioned because of its atypical kinase domain.Here, we have expressed full-length recombinant ILK, purified it to >94% homogeneity, and characterized its kinase activity. Recombinant ILK readily phosphorylates glycogen synthase kinase-3 (GSK-3) peptide and the 20-kDa regulatory light chains of myosin (LC(20)). Phosphorylation kinetics are similar to those of other active kinases, and mutation of the ATP-binding lysine (K220 within subdomain 2) causes marked reduction in enzymatic activity. We show that ILK is a Mn-dependent kinase (the K(m) for MnATP is approximately 150-fold less than that for MgATP).Taken together, our data demonstrate that ILK is a bona fide protein kinase with enzyme kinetic properties similar to other active protein kinases.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: Francesco Muntoni is a member of the Rare Disease Scientific Advisory Group for Pfizer and of Dyne Therapeutics SAB, and has participated to SAB meetings for PTC, Sarepta, Santhera, Wave Therapeutics. UCL and Great Ormond Street Hospital are recipient of grants from Pfizer, Italfarmaco, Wave, Santhera, Sarepta regarding clinical trials. James Signorovitch co-founded the collaborative Trajectory Analysis Project (cTAP) and is an employee of Analysis Group, Inc., a consulting firm that received funding from the membership of cTAP to conduct this study. Gautam Sajeev, Nicolae Done, and Henry Lane are employees of Analysis Group, Inc., a consulting firm that received funding from the membership of cTAP to conduct this study. Ibrahima Dieye and Zhiwen Yao were employees of Analysis Group, Inc. at the time this study was conducted. Nathalie Goemans has served on clinical steering committees and/or as a consultant and received compensation from Eli Lilly, Italfarmaco, PTC Therapeutics, and BioMarin Pharmaceutical; has served as site investigator for GlaxoSmithKline, Prosensa, BioMarin Pharmaceutical, Italfarmaco, Roche, and Eli Lilly. Craig McDonald has served as a consultant for PTC Therapeutics, BioMarin Pharmaceutical, Sarepta Therapeutics, Eli Lilly, Pfizer Inc, Santhera Pharmaceuticals, Cardero Therapeutics, Inc, Catabasis Pharmaceuticals, Capricor Therapeutics, Astellas Pharma (Mitobridge), and FibroGen, Inc; serves on external advisory boards related to DMD for PTC Therapeutics, Sarepta Therapeutics, Santhera Pharmaceuticals, and Capricor Therapeutics; and reports grants from US Department of Education/National Institute on Disability and Rehabilitation Research, the National Institute on Disability, Independent Living, and Rehabilitation Research, US NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH/National Institute of Neurologic Disorders and Stroke, US Department of Defense, and Parent Project Muscular Dystrophy US. Eugenio Mercuri has served on clinical steering committees and/or as a consultant for Eli Lilly, Italfarmaco, PTC Therapeutics, Sarepta, Santhera, and Pfizer; has served as PI for GlaxoSmithKline, Prosensa, BioMarin Pharmaceutical, Italfarmaco, Roche, PTC, Pfizer, Sarepta, Santhera, Wave, NS and Eli Lilly. EM reports personal fees as consultant, PI or member on advisory board form BIOGEN S.R.L. outside the submitted work; EM reports personal fees consultant, PI or member on advisory board from ROCHE; EM reports personal fees consultant, PI or member on advisory board form AVEXIS outside the submitted work; EM reports personal fees consultant, PI or member on advisory board from SCHOLAR ROCK outside the submitted work; EM is part of an institution that receives funding from Biogen for a SMA disease registry (ISMAR). Erik H. Niks is a member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO‐NMD). EN report grants from Duchenne Parent Project, ZonMW and AFM, consultancies for BioMarin and Summit, and worked as local investigator of clinical trials of BioMarin, GSK, Lilly, Santhera, Givinostat, and Roche outside the submitted work. E.H.N. reports ad hoc consultancies for WAVE, Santhera, Regenxbio, and PTC, and he worked as investigator of clinical trials of Italfarmaco, NS Pharma, Reveragen, Roche, WAVE, and Sarepta outside the submitted work. Brenda Wong has participated in advisory committee meetings for Prosensa and Biomarin and has received compensation for consultancy services for Gilead Sciences, Pfizer, GSK, RegenXBio, and PepGen. Krista Vandenborne has received grants from NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institute of Neurologic Disorders and Stroke, Parent Project Muscular Dystrophy, and the Muscular Dystrophy Association. She has also received funding from ltalfarmaco SpA, Sarepta Therapeutics, Summit Therapeutics plc, Catabasis Pharmaceuticals, Pfizer Inc, ldera Pharmaceuticals, Bristol-Myers Squibb, and Eli Lilly through grant awards to the University of Florida. Volker Straub has participated in advisory boards for Audentes Therapeutics, Biogen, Exonics Therapeutics, Italfarmaco S.p.A., Roche, Sanofi Genzyme, Sarepta Therapeutics, Summit Therapeutics, UCB, and Wave Therapeutics. He has research collaborations with Ultragenyx and Sanofi Genzyme. Imelda JM de Groot has no disclosures. Cuixia Tian has participated as the site principal investigator for trials sponsored by PTC Therapeutics, Eli Lilly, GSK, Prosensa/Biomarin, Bristol Myers Squibb, Roche, Pfizer. Santhera, Sarepta, Fibrogen, Capricor, Pfizer, Avexis, and Catabasis. Adnan Manzur has no disclosures. Susan J. Ward co-founded and manages the collaborative Trajectory Analysis Project and has received funding from the membership of cTAP to facilitate this study. Laurent Servais is member of the SAB or has performed consultancy for Sarepta, Dynacure, Santhera, Avexis, Biogen, Cytokinetics and Roche, Audentes Therapeutics and Affinia Therapeutics; LS has given lectures and has served as a consultant for Roche, Biogen, Avexis, and Cytokinetics. LS is the project leader of the newborn screening in Southern Belgium funded by Avexis, Roche, and Biogen.]. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Muntoni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Bevacizumab-related imaging abnormality (BRIA), appearing as areas of restricted diffusion on magnetic resonance imaging (MRI) and representing atypical coagulative necrosis pathologically, has been observed in patients with brain tumors receiving radiotherapy and bevacizumab. We investigated the role of cumulative radiation dose in BRIA development in a voxel-wise analysis., Methods: Patients (n = 18) with BRIA were identified. All had high-grade gliomas or brain metastases treated with radiotherapy and bevacizumab. Areas of BRIA were segmented semi-automatically on diffusion-weighted MRI with apparent diffusion coefficient (ADC) images. To avoid confounding by possible tumor, hypoperfusion was confirmed with perfusion imaging. ADC images and radiation dose maps were co-registered to a high-resolution T1-weighted MRI and registration accuracy was verified. Voxel-wise normal tissue complication probability analyses were performed using a logistic model analyzing the relationship between cumulative voxel equivalent total dose in 2 Gy fractions (EQD2) and BRIA development at each voxel. Confidence intervals for regression model predictions were estimated with bootstrapping., Results: Among 18 patients, 39 brain tumors were treated. Patients received a median of 4.5 cycles of bevacizumab and 1-4 radiation courses prior to BRIA appearance. Most (64%) treated tumors overlapped with areas of BRIA. The median proportion of each BRIA region of interest volume overlapping with tumor was 98%. We found a dose-dependent association between cumulative voxel EQD2 and the relative probability of BRIA (β0 = -5.1, β1 = 0.03 Gy-1, γ = 1.3)., Conclusions: BRIA is likely a radiation dose-dependent phenomenon in patients with brain tumors receiving bevacizumab and radiotherapy. The combination of radiation effects and tumor microenvironmental factors in potentiating BRIA in this population should be further investigated., Competing Interests: JAH-G and TMS report grant funding from Varian Medical Systems, unrelated to the present study. CRM and AD receive research funding from GE Healthcare, unrelated to the current study. TMS reports honoraria from Multimodal Imaging Services Corporation and WebMD. AD is a Founder of, holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. AD is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI). There are no other financial or other relationships that might lead to a perceived conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Salans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Visual and cognitive dysfunction are common in Parkinson's disease and relate to balance and gait impairment, as well as increased falls risk and reduced quality of life. Vision and cognition are interrelated (termed visuo-cognition) which makes intervention complex in people with Parkinson's (PwP). Non-pharmacological interventions for visuo-cognitive deficits are possible with modern technology, such as combined mobile applications and stroboscopic glasses, but evidence for their effectiveness in PwP is lacking. We aim to investigate whether technological visuo-cognitive training (TVT) can improve visuo-cognitive function in PwP. We will use a parallel group randomised controlled trial to evaluate the feasibility and acceptability of TVT versus standard care in PwP. Forty PwP who meet our inclusion criteria will be randomly assigned to one of two visuo-cognitive training interventions. Both interventions will be carried out by a qualified physiotherapist in participants own homes (1-hour sessions, twice a week, for 4 weeks). Outcome measures will be assessed on anti-parkinsonian medication at baseline and at the end of the 4-week intervention. Feasibility of the TVT intervention will be assessed in relation to safety and acceptability of the technological intervention, compliance and adherence to the intervention and usability of equipment in participants homes. Additionally, semi structured interviews will be conducted to explore participants' experience of the technology. Exploratory efficacy outcomes will include change in visual attention measured using the Trail Making Test as well as changes in balance, gait, quality of life, fear of falling and levels of activity. This pilot study will focus on the feasibility and acceptability of TVT in PwP and provide preliminary data to support the design of a larger, multi-centre randomised controlled trial. This trial is registered at isrctn.com (ISRCTN46164906)., Competing Interests: The authors have declared that no competing interests exist.

Introduction: An estimated 1 billion people with disabilities live in low and middle income countries, a population that includes people with communication disabilities (PwCD). PwCD are a heterogenous group with a wide range of abilities who may be underrepresented in research due to the communication demands involved in research participation., Methods: A critical analysis of 145 studies from a previously published systematic review was undertaken with the aim of documenting the opportunities for direct participation of PwCD in research on poverty and disability in low- and middle- income countries., Results: The key finding was the high risk of underrepresentation of PwCD in research on poverty and disability in LMICs, despite low rates of explicit exclusion (n = 8; 5.5%). A total of 366 uses of data collection tools were analysed (255 unique tools). The majority of data collection tools had high communication demands (92.9%), including those measuring disability (88.6%) and those assessing poverty (100%). Only 22 studies (15.2%) specifically included PwCD. A subset of these studies (n = 14) presented disaggregated data in a way that allowed for analysis of outcomes for PwCD, suggesting a clear intersection between poverty and communication disability, with findings related to general poverty indicators, reduced access to education, low levels of employment, and additional expenditure., Conclusions: The findings suggest a systematic underrepresentation of PwCD in research on poverty and disability with substantial implications for future policy and program planning, directly affecting the availability and provision of services and resources for this population. A failure to provide adequate opportunity for participation of PwCD in research risks leaving those with communication disabilities behind in the pursuit of global poverty eradication., Competing Interests: The authors have declared that no competing interests exist.

Background: The optimal dose of simethicone before capsule endoscopy is unknown. Prior studies have reported inconsistent cleansing, with some showing improved visualization only in the proximal small intestine. We hypothesized a higher volume of simethicone may improve cleansing and diagnostic yield, especially in the distal small bowel., Methods: A phase III randomized controlled trial was conducted comparing high volume (1125 mg simethicone in 750 ml water) versus standard volume (300 mg simethicone in 200 ml water) solutions, both at 1.5 mg/ml. The primary outcome was adequate bowel preparation, defined as a KOrea-CanaDA (KODA) score >2.25, overall and stratified by the proximal and distal half of the small bowel. Secondary outcomes included mean KODA score, diagnostic yield, completion rate, and adverse events. All analyses were intention-to-treat., Results: A total of 167 patients were randomized (mean (SD) age 58.7 (15.7), 54% female) and the most common indication was obscure gastrointestinal bleeding (71.7%). Adequate cleansing was achieved in 39 (50%) patients in the high volume group and in 39 (48%) patients in the standard volume group (RR 1.04, 95% CI 0.76-1.43, p = 0.82), with no differences observed in the proximal half (71% vs 64%, p = 0.40) or the distal half -of the small bowel (36% vs. 37%, p = 0.88). There was no differences in the mean (SD) KODA score (2.20 (0.41) vs. 2.18 (0.44), p = 0.73), diagnostic yields (53% vs. 56%, p = 0.71), or completion rates (both 95%). One adverse event, nausea, occurred in the control group., Conclusion: High volume simethicone does not improve visualization during capsule endoscopy., Clinical Trial Registration: Clinical trial: NCT02334631., Competing Interests: Dr. Michael Sey has received arms-length research grants from Pharmascience Inc and educational funding from Medtronic. Cassandra McDonald, Klajdi Puka, Drs. Yan and Friedland have no competing interests. Dr. Dan Segal has received consulting fees from AbbVie and Takeda. Dr. Vipul Jairath has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena pharmaceuticals, BMS, Genentech, Pendopharm, Sandoz, Pfizer, Merck, Takeda, Janssen, Alimentiv Inc., Topivert, Celltrion, Applied Strategic, Sublimity Therapeutics, F. Hoffman-La Roche Ltd, Sigmatic Ltd.,; speaker’s fees from Takeda, Janssen, Ferring, Abbvie, Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Serum metabolite profiling in Duchenne muscular dystrophy (DMD) may enable discovery of valuable molecular markers for disease progression and treatment response. Serum samples from 51 DMD patients from a natural history study and 22 age-matched healthy volunteers were profiled using liquid chromatography coupled to mass spectrometry (LC-MS) for discovery of novel circulating serum metabolites associated with DMD. Fourteen metabolites were found significantly altered (1% false discovery rate) in their levels between DMD patients and healthy controls while adjusting for age and study site and allowing for an interaction between disease status and age. Increased metabolites included arginine, creatine and unknown compounds at m/z of 357 and 312 while decreased metabolites included creatinine, androgen derivatives and other unknown yet to be identified compounds. Furthermore, the creatine to creatinine ratio is significantly associated with disease progression in DMD patients. This ratio sharply increased with age in DMD patients while it decreased with age in healthy controls. Overall, this study yielded promising metabolic signatures that could prove useful to monitor DMD disease progression and response to therapies in the future.

The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut-brain axis, reflecting a bidirectional interaction between the central nervous system and the intestine. A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically, the archetypal model of plasticity, long-term potentiation (LTP), is reduced in hippocampus of middle-aged and aged rats. Because the intestinal microbiota might change with age, we have investigated whether the age-related deficit in LTP might be attenuated by changing the composition of intestinal microbiota with VSL#3, a probiotic mixture comprising 8 Gram-positive bacterial strains. Here, we report that treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota with an increase in the abundance of Actinobacteria and Bacterioidetes, which was reduced in control-treated aged rats. VSL#3 administration modulated the expression of a large group of genes in brain tissue as assessed by whole gene expression, with evidence of a change in genes that impact on inflammatory and neuronal plasticity processes. The age-related deficit in LTP was attenuated in VSL#3-treated aged rats and this was accompanied by a modest decrease in markers of microglial activation and an increase in expression of BDNF and synapsin. The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function.

In the latter half of the 20th century, societal and technological changes led to a shift in the composition of the American diet to include a greater proportion of processed, pre-packaged foods high in fat and carbohydrates, and low in dietary fiber (a "Western diet"). Over the same time period, there have been parallel increases in Salmonella gastroenteritis cases and a broad range of chronic inflammatory diseases associated with intestinal dysbiosis. Several polysaccharide food additives are linked to bacterially-driven intestinal inflammation and may contribute to the pathogenic effects of a Western diet. Therefore, we examined the effect of a ubiquitous polysaccharide food additive, maltodextrin (MDX), on clearance of the enteric pathogen Salmonella using both in vitro and in vivo infection models. When examined in vitro, murine bone marrow-derived macrophages exposed to MDX had altered vesicular trafficking, suppressed NAPDH oxidase expression, and reduced recruitment of NADPH oxidase to Salmonella-containing vesicles, which resulted in persistence of Salmonella in enlarged Rab7+ late endosomal vesicles. In vivo, mice consuming MDX-supplemented water had a breakdown of the anti-microbial mucous layer separating gut bacteria from the intestinal epithelium surface. Additionally, oral infection of these mice with Salmonella resulted in increased cecal bacterial loads and enrichment of lamina propria cells harboring large Rab7+ vesicles. These findings indicate that consumption of processed foods containing the polysaccharide MDX contributes to suppression of intestinal anti-microbial defense mechanisms and may be an environmental priming factor for the development of chronic inflammatory disease.

Crohn's disease (CD) is associated with intestinal dysbiosis evidenced by an altered microbiome forming thick biofilms on the epithelium. Additionally, adherent-invasive E. coli (AIEC) strains are frequently isolated from ileal lesions of CD patients indicating a potential role for these strains in disease pathogenesis. The composition and characteristics of the host microbiome are influenced by environmental factors, particularly diet. Polysaccharides added to food as emulsifiers, stabilizers or bulking agents have been linked to bacteria-associated intestinal disorders. The escalating consumption of polysaccharides in Western diets parallels an increased incidence of CD during the latter 20(th) century. In this study, the effect of a polysaccharide panel on adhesiveness of the CD-associated AIEC strain LF82 was analyzed to determine if these food additives promote disease-associated bacterial phenotypes. Maltodextrin (MDX), a polysaccharide derived from starch hydrolysis, markedly enhanced LF82 specific biofilm formation. Biofilm formation of multiple other E. coli strains was also promoted by MDX. MDX-induced E. coli biofilm formation was independent of polysaccharide chain length indicating a requirement for MDX metabolism. MDX exposure induced type I pili expression, which was required for MDX-enhanced biofilm formation. MDX also increased bacterial adhesion to human intestinal epithelial cell monolayers in a mechanism dependent on type 1 pili and independent of the cellular receptor CEACAM6, suggesting a novel mechanism of epithelial cell adhesion. Analysis of mucosa-associated bacteria from individuals with and without CD showed increased prevalence of malX, a gene essential for MDX metabolism, uniquely in the ileum of CD patients. These findings demonstrate that the ubiquitous dietary component MDX enhances E. coli adhesion and suggests a mechanism by which Western diets rich in specific polysaccharides may promote dysbiosis of gut microbes and contribute to disease susceptibility.

Cystic fibrosis, an autosomal recessive disorder caused by a mutation in a gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), remains a leading cause of childhood respiratory morbidity and mortality. The respiratory consequences of cystic fibrosis include the generation of thick, tenacious mucus that impairs lung clearance, predisposing the individual to repeated and persistent infections, progressive lung damage and shortened lifespan. Currently there is no cure for cystic fibrosis. With this in mind, we investigated the ability of human amnion epithelial cells (hAECs) to express functional CFTR. We found that hAECs formed 3-dimensional structures and expressed the CFTR gene and protein after culture in Small Airway Growth Medium (SAGM). We also observed a polarized CFTR distribution on the membrane of hAECs cultured in SAGM, similar to that observed in polarized airway cells in vivo. Further, hAECs induced to express CFTR possessed functional iodide/chloride (I(-/)Cl(-)) ion channels that were inhibited by the CFTR-inhibitor CFTR-172, indicating the presence of functional CFTR ion channels. These data suggest that hAECs may be a promising source for the development of a cellular therapy for cystic fibrosis.