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Metformin inhibits the proliferation of benign prostatic epithelial cells

Thu, 06/08/2017 - 4:12pm

OBJECTIVE: Benign prostatic hyperplasia (BPH) is the most common proliferative abnormality of the prostate affecting elderly men throughout the world. Epidemiologic studies have shown that diabetes significantly increases the risk of developing BPH, although whether anti-diabetic medications preventing the development of BPH remains to be defined. We have previously found that stromally expressed insulin-like growth factor 1 (IGF-1) promotes benign prostatic epithelial cell proliferation through paracrine mechanisms. Here, we seek to understand if metformin, a first line medication for the treatment of type 2 diabetes, inhibits the proliferation of benign prostatic epithelial cells through reducing the expression of IGF-1 receptor (IGF-1R) and regulating cell cycle.

METHODS: BPE cell lines BPH-1 and P69, murine fibroblasts3T3 and primary human prostatic fibroblasts were cultured and tested in this study. Cell proliferation and the cell cycle were analyzed by MTS assay and flow cytometry, respectively. The expression of IGF-1R was determined by western-blot and immunocytochemistry. The level of IGF-1 secretion in culture medium was measured by ELISA.

RESULTS: Metformin (0.5-10mM, 6-48h) significantly inhibited the proliferation of BPH-1 and P69 cells in a dose-dependent and time-dependent manner. Treatment with metformin for 24 hours lowered the G2/M cell population by 43.24% in P69 cells and 24.22% in BPH-1 cells. On the other hand, IGF-1 (100ng/mL, 24h) stimulated the cell proliferation (increased by 28.81% in P69 cells and 20.95% in BPH-1 cells) and significantly enhanced the expression of IGF-1R in benign prostatic epithelial cells. Metformin (5mM) abrogated the proliferation of benign prostatic epithelial cells induced by IGF-1. In 3T3 cells, the secretion of IGF-1 was significantly inhibited by metformin from 574.31pg/ml to 197.61pg/ml. The conditioned media of 3T3 cells and human prostatic fibroblasts promoted the proliferation of epithelial cells and the expression of IGF-1R in epithelial cells. Metformin abrogated the proliferation of benign prostatic epithelial cells promoted by 3T3 conditioned medium.

CONCLUSIONS: Our study demonstrates that metformin inhibits the proliferation of benign prostatic epithelial cells by suppressing the expression of IGF-1R and IGF-1 secretion in stromal cells. Metformin lowers the G2/M cell population and simultaneously increases the G0/G1 population. Findings here might have significant clinical implications in management of BPH patients treated with metformin.

Characterization of a new oda3 allele, oda3-6, defective in assembly of the outer dynein arm-docking complex in Chlamydomonas reinhardtii

Thu, 06/08/2017 - 4:12pm

We have used an insertional mutagenesis approach to generate new C. reinhardtii motility mutants. Of 56 mutants isolated, one is a new allele at the ODA3 locus, called oda3-6. Similar to the previously characterized oda3 alleles, oda3-6 has a slow-jerky swimming phenotype and reduced swimming speed. The oda3-6 mutant fails to assemble the outer dynein arm motor and outer dynein arm-docking complex (ODA-DC) in the ciliary axoneme due to an insertion in the 5' end of the DCC1 gene, which encodes the DC1 subunit of the ODA-DC. Transformation of oda3-6 with the wild-type DCC1 gene rescues the mutant swimming phenotype and restores assembly of the ODA-DC and the outer dynein arm in the cilium. This is the first oda3 mutant to be characterized at the molecular level and is likely to be very useful for further analysis of DC1 function.

Alberta Stroke Program Early CT Score Infarct Location Predicts Outcome Following M2 Occlusion

Thu, 06/08/2017 - 4:12pm

BACKGROUND: Although it is generally thought that patients with distal middle cerebral artery (M2) occlusion have a favorable outcome, it has previously been demonstrated that a substantial minority will have a poor outcome by 90 days. We sought to determine whether assessing the Alberta Stroke Program Early CT Score (ASPECTS) infarct location allows for identifying patients at risk for a poor 90-day outcome.

METHODS: We retrospectively analyzed patients with isolated acute M2 occlusion admitted to a single academic center between January 2010 and August 2012. Infarct regions were defined according to ASPECTS system on the initial head computed tomography. Discriminant function analysis was used to define specific ASPECTS regions that are predictive of the 90-day functional outcome as defined as a modified Rankin Scale score of 3-6. In addition, logistic regression was used to model the relationship between each individual ASPECT region with poor outcome; for evaluation and comparison, odds ratios, c-statistics, and Akaike information criterion values were estimated for each region.

RESULTS: Ninety patients with isolated M2 were included in the final analysis. ASPECTS score

CONCLUSION: Infarction in ASPECTS regions M3 and M6 are key predictors of functional outcome following isolated distal M2 occlusion. These findings will be helpful in stratifying outcomes if validated in future studies.

Chromatin dynamics regulate mesenchymal stem cell lineage specification and differentiation to osteogenesis

Thu, 06/08/2017 - 4:12pm

Multipotent mesenchymal stromal cells (MSCs) are critical for regeneration of multiple tissues. Epigenetic mechanisms are fundamental regulators of lineage specification and cell fate, and as such, we addressed the question of which epigenetic modifications characterize the transition of nascent MSCs to a tissue specific MSC-derived phenotype. By profiling the temporal changes of seven histone marks correlated to gene expression during proliferation, early commitment, matrix deposition, and mineralization stages, we identified distinct epigenetic mechanisms that regulate transcriptional programs necessary for tissue-specific phenotype development. Patterns of stage-specific enrichment of histone modifications revealed distinct modes of repression and activation of gene expression that would not be detected using single endpoint analysis. We discovered that at commitment, H3K27me3 is removed from genes that are upregulated and is not acquired on downregulated genes. Additionally, we found that the absence of H3K4me3 modification at promoters defined a subset of osteoblast-specific upregulated genes, indicating that acquisition of acetyl modifications drive activation of these genes. Significantly, loss or gain of H3K36me3 was the primary predictor of dynamic changes in temporal gene expression. Using unsupervised pattern discovery analysis the signature of osteogenic-related histone modifications identified novel functional cis regulatory modules associated with enhancer regions that control tissue-specific genes. Our work provides a cornerstone to understand the epigenetic regulation of transcriptional programs that are important for MSC lineage commitment and lineage, as well as insights to facilitate MSC-based therapeutic interventions.

Vibrotactile stimulation: A non-pharmacological intervention for opioid-exposed newborns

Thu, 06/08/2017 - 4:12pm

OBJECTIVE: To examine the therapeutic potential of stochastic vibrotactile stimulation (SVS) as a complementary non-pharmacological intervention for withdrawal in opioid-exposed newborns. STUDY DESIGN: A prospective, within-subjects single-center study was conducted in 26 opioid-exposed newborns ( > 37 weeks; 16 male) hospitalized since birth and treated pharmacologically for Neonatal Abstinence Syndrome. A specially-constructed mattress delivered low-level SVS (30-60Hz, 10-12mum RMS), alternated in 30-min intervals between continuous vibration (ON) and no vibration (OFF) over a 6-8 hr session. Movement activity, heart rate, respiratory rate, axillary temperature and blood-oxygen saturation were calculated separately for ON and OFF. RESULTS: There was a 35% reduction in movement activity with SVS (p<0.001), with significantly fewer movement periods > 30 sec duration for ON than OFF (p = 0.003). Incidents of tachypneic breaths and tachycardic heart beats were each significantly reduced with SVS, whereas incidents of eupneic breaths and eucardic heart beats each significantly increased with SVS (p<0.03). Infants maintained body temperature and arterial-blood oxygen level independent of stimulation condition. CONCLUSIONS: SVS reduced hyperirritability and pathophysiological instabilities commonly observed in pharmacologically-managed opioid-exposed newborns. SVS may provide an effective complementary therapeutic intervention for improving autonomic function in newborns with Neonatal Abstinence Syndrome.

Quantitative microvascular analysis of retinal venous occlusions by spectral domain optical coherence tomography angiography

Thu, 06/08/2017 - 4:12pm

PURPOSE: To quantitatively evaluate the retinal microvasculature in human subjects with retinal venous occlusions (RVO) using optical coherence tomography angiography (OCTA). DESIGN: Retrospective, cross-sectional, observational case series. PARTICIPANTS: Sixty subjects (84 eyes) were included (20 BRVO, 14 CRVO, 24 unaffected fellow eyes, and 26 controls). METHODS: OCTA was performed on a prototype, spectral domain-OCTA system in the 3x3mm central macular region. Custom software was used to quantify morphology and density of retinal capillaries using four quantitative parameters. The vasculature of the segmented retinal layers and nonsegmented whole retina were analyzed. MAIN OUTCOME MEASURES: Fractal dimension (FD), vessel density (VD), skeletal density (SD), and vessel diameter index (VDI) within the segmented retinal layers and nonsegmented whole retina vasculature. RESULTS: Nonsegmented analysis of RVO eyes demonstrated significantly lower FD (1.64+/-0.01 vs 1.715+/-0.002; p<0.001), VD (0.32+/-0.01 vs 0.432+/-0.002; p<0.001), and SD (0.073+/-0.004 vs 0.099+/-0.001; p<0.001) compared to controls. Compared to the fellow eye, FD, VD and SD were lower (p<0.001), and VDI was higher (p<0.001). FD, VD, and SD progressively decreased as the extent (or type) of RVO increased (control vs BRVO vs CRVO; p<0.001). In the unaffected fellow eye FD, VD and SD showed significant differences when compared to control eyes or affected RVO eyes (p<0.001). CONCLUSIONS: Quantitative OCTA of the central 3x3mm macular region demonstrates significant differences in capillary density and morphology among subjects with BRVO and CRVO compared to controls or unaffected fellow eyes in all vascular layers. The unaffected fellow eyes also demonstrate significant differences when compared to controls. OCTA allows for noninvasive, layer-specific, quantitative evaluation of RVO-associated microvascular changes.

Cannabis use is associated with reduced prevalence of non-alcoholic fatty liver disease: A cross-sectional study

Thu, 06/08/2017 - 4:11pm

Cannabis use is associated with reduced prevalence of obesity and diabetes mellitus (DM) in humans and mouse disease models. Obesity and DM are a well-established independent risk factor for non-alcoholic fatty liver disease (NAFLD), the most prevalent liver disease globally. The effects of cannabis use on NAFLD prevalence in humans remains ill-defined. Our objective is to determine the relationship between cannabis use and the prevalence of NAFLD in humans. We conducted a population-based case-control study of 5,950,391 patients using the 2014 Healthcare Cost and Utilization Project (HCUP), Nationwide Inpatient Survey (NIS) discharge records of patients 18 years and older. After identifying patients with NAFLD (1% of all patients), we next identified three exposure groups: non-cannabis users (98.04%), non-dependent cannabis users (1.74%), and dependent cannabis users (0.22%). We adjusted for potential demographics and patient related confounders and used multivariate logistic regression (SAS 9.4) to determine the odds of developing NAFLD with respects to cannabis use. Our findings revealed that cannabis users (dependent and non-dependent) showed significantly lower NAFLD prevalence compared to non-users (AOR: 0.82[0.76-0.88]; p<0.0001). The prevalence of NAFLD was 15% lower in non-dependent users (AOR: 0.85[0.79-0.92]; p<0.0001) and 52% lower in dependent users (AOR: 0.49[0.36-0.65]; p<0.0001). Among cannabis users, dependent patients had 43% significantly lower prevalence of NAFLD compared to non-dependent patients (AOR: 0.57[0.42-0.77]; p<0.0001). Our observations suggest that cannabis use is associated with lower prevalence of NAFLD in patients. These novel findings suggest additional molecular mechanistic studies to explore the potential role of cannabis use in NAFLD development.

Altered resting-state intra- and inter- network functional connectivity in patients with persistent somatoform pain disorder

Thu, 06/08/2017 - 4:11pm

Patients with persistent somatoform pain disorder (PSPD) usually experience various functional impairments in pain, emotion, and cognition, which cannot be fully explained by a physiological process or a physical disorder. However, it is still not clear for the mechanism underlying the pathogenesis of PSPD. The present study aimed to explore the intra- and inter-network functional connectivity (FC) differences between PSPD patients and healthy controls (HCs). Functional magnetic resonance imaging (fMRI) was performed in 13 PSPD patients and 23 age- and gender-matched HCs. We used independent component analysis on resting-state fMRI data to calculate intra- and inter-network FCs, and we used the two-sample t-test to detect the FC differences between groups. Spearman correlation analysis was employed to evaluate the correlations between FCs and clinical assessments. As compared to HCs, PSPD patients showed decreased coactivations in the right superior temporal gyrus within the anterior default-mode network and the anterior cingulate cortex within the salience network, and increased coactivations in the bilateral supplementary motor areas within the sensorimotor network and both the left posterior cingulate cortex and the medial prefrontal cortex within the anterior default-mode network. In addition, we found that the PSPD patients showed decreased FNCs between sensorimotor network and audio network as well as visual network, between default-mode network and executive control network as well as audio network and between salience network and executive control network as well as right frontoparietal network, and increased FNCs between sensorimotor network and left frontoparietal network, salience network as well as cerebellum network, which were negatively correlated with the clinical assessments in PSPD patients. Our findings suggest that PSPD patients experience large-scale reorganization at the level of the functional networks, which suggests a possible mechanism underlying the pathogenesis of PSPD.

Culturally adaptive storytelling intervention versus didactic intervention to improve hypertension control in Vietnam: a cluster-randomized controlled feasibility trial

Thu, 06/08/2017 - 4:11pm

BACKGROUND: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. Novel, large-scale, effective, and sustainable interventions to control hypertension in Vietnam are needed. We report the results of a cluster-randomized feasibility trial at 3 months follow-up conducted in Hung Yen province, Vietnam, designed to evaluate the feasibility and acceptability of two community-based interventions to improve hypertension control: a "storytelling" intervention, "We Talk about Our Hypertension," and a didactic intervention.

METHODS: The storytelling intervention included stories about strategies for coping with hypertension, with patients speaking in their own words, and didactic content about the importance of healthy lifestyle behaviors including salt reduction and exercise. The didactic intervention included only didactic content. The storytelling intervention was delivered by two DVDs at 3-month intervals; the didactic intervention included only one installment. The trial was conducted in four communes, equally randomized to the two interventions.

RESULTS: The mean age of the 160 study patients was 66 years, and 54% were men. Most participants described both interventions as understandable, informative, and motivational. Between baseline and 3 months, mean systolic blood pressure declined by 8.2 mmHg (95% CI 4.1-12.2) in the storytelling group and by 5.5 mmHg (95% CI 1.4-9.5) in the didactic group. The storytelling group also reported a significant increase in hypertension medication adherence.

CONCLUSIONS: Both interventions were well accepted in several rural communities and were shown to be potentially effective in lowering blood pressure. A large-scale randomized trial is needed to compare the effectiveness of the two interventions in controlling hypertension.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02483780.

Circumstances of fall-related injuries by age and gender among community-dwelling adults in the United States

Thu, 06/08/2017 - 4:11pm

INTRODUCTION: Falls are the leading cause of injury in almost all age-strata in the U.S. However, fall-related injuries (FI) and their circumstances are under-studied at the population level, particularly among young and middle-aged adults. This study examined the circumstances of FI among community-dwelling U.S. adults, by age and gender.

METHODS: Narrative texts of FI from the National Health Interview Survey (1997-2010) were coded using a customized taxonomy to assess place, activity, initiating event, hazards, contributing factors, fall height, and work-relatedness of FI. Weighted proportions and incidence rates of FI were calculated across six age-gender groups (18-44, 45-64, 65+ years; women, men).

RESULTS: The proportion of FI occurring indoors increased with age in both genders (22%, 30%, and 48% among men, and 40%, 49% and 62% among women for 18-44, 45-64, 65+ age-groups, respectively). In each age group the proportion of indoor FI was higher among women as compared to men. Among women, using the stairs was the second leading activity (after walking) at the time of FI (19%, 14% and 10% for women in 18-44, 45-64, 65+ age groups, respectively). FI associated with tripping increased with age among both genders, and women were more likely to trip than men in every age group. Of all age-gender groups, the rate of FI while using ladders was the highest among middle-aged men (3.3 per 1000 person-year, 95% CI 2.0, 4.5). Large objects, stairs and steps, and surface contamination were the three most common hazards noted for 15%, 14% and 13% of fall-related injuries, respectively.

CONCLUSIONS: The rate and the circumstances of FI differ by age and gender. Understanding these differences and obtaining information about circumstances could be vital for developing effective interventions to prevent falls and FI.

Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness

Thu, 06/08/2017 - 4:11pm

Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.

An Open Conversation with Traditional Birth Attendants in Rural Uganda: The Potential for Collaborative Care

Wed, 06/07/2017 - 10:05pm

Background: Imaging the World-Africa (ITWA) is a registered non-governmental organization aimed at distributing low-cost ultrasound services at health centres in rural Uganda. Yet, studies demonstrate that the majority of mothers continue to deliver with unregulated traditional birth attendants (TBAs) in their local villages. It has been suggested that the unregulated practices of TBAs has contributed to the high rate of maternal and fetal mortality. A greater understanding of the roles of TBAs in the management of pregnancy and delivery is needed.

Purpose: The purpose of this report is to provide the international community with a greater understanding of TBA practices as well as an assessment of their willingness for future collaboration.

Methods: Three TBAs from different nearby villages attended a meeting with ITWA in Kamuli District, Uganda. The meeting included an interview and an educational session. A test on the management principles of common obstetric complications was administered at the beginning and end of the meeting to assess baseline knowledge and the effect of the interaction.

Results: The meeting with the TBAs provided valuable qualitative information about TBA clinical experience, the value of TBAs to the community and TBA understanding of ultrasound. On the pre-educational test, the TBAs had a limited understanding of pregnancy complications and conditions in which it would be safer for a mother to deliver at a hospital. After the educational session, the TBAs performed statistically significantly better on the post-test (p=0.03).

Conclusion: The open conversation with the TBAs provided valuable information on the current role of TBAs in rural Uganda. Our experience with the TBAs demonstrates that TBAs are willing to engage with trained healthcare providers. Collaboration between TBAs and health centers in Uganda has the potential to bring to light previously unknown barriers and create solutions to better maternal and fetal care.

The state and consequences of dermatology drug prices in the United States

Wed, 06/07/2017 - 12:13pm

In 2014, Medicare expenditures increased 12%, the largest increase reported since 2002, resulting in major concerns by both patients and physicians. Although costs are rising for both specialty drugs and generic medications,out-of-pocket costs, restrictive formularies,and health plan bureaucracies are limiting patients' access to necessary medications. In response, the Regulatory Policy Committee of the American Academy of Dermatology (AAD)/Association (AAD/A) convened a Task Force on Drug Pricing and Transparency. This editorial summarizes the issues addressed by the task force along with relevant AAD/A policy.

Predictors of Cigarette Smoking Initiation in Early, Middle, and Late Adolescence

Wed, 06/07/2017 - 12:13pm

PURPOSE: Little is known about age-related differences in risk factors for cigarette smoking initiation. We identified predictors of initiation in early, middle, and late adolescence from among sociodemographic factors, indicators of smoking in the social environment, psychological characteristics, lifestyle indicators, and perceived need for cigarettes.

METHODS: Data were drawn from a longitudinal study of 1,801 children recruited at age 10-11 years from 29 elementary schools in Montreal, Canada. Multivariable logistic regression within a generalized estimating equations framework was used to identify predictors among never smokers across three 2-year windows: age 11-13 years (n = 1,221); age 13-15 years (n = 737); and age 15-17 years (n = 690).

RESULTS: Among the 18 risk factors investigated, two differed across age. Friends' smoking, a strong risk factor in early adolescence (odds ratio [95% confidence interval] = 5.78 [3.90-8.58]), lost potency in late adolescence (1.83 [1.31-2.57]). Depressive symptoms, a risk factor in early and middle adolescence (1.60 [1.26-2.02] and 1.92 [1.45-2.54], respectively), were inversely associated in late adolescence (.76 [.58-1.00]). Sex, TV viewing, and weight-related goals were not associated with initiation at any age. All other factors were significant in two or three age groups.

CONCLUSIONS: Most risk factors for smoking initiation were stable across age. Tobacco control interventions may be robust for risk factors across age groups and may not need adjustment. At all ages, interventions should focus on eliminating smoking in the social environment and on reducing the availability of tobacco products.

Association between Dietary Energy Density and Incident Type 2 Diabetes in the Women's Health Initiative

Wed, 06/07/2017 - 12:13pm

BACKGROUND: Dietary energy density, or energy available in relation to gram intake, can inform disease risk.

OBJECTIVE: The objective of this study was to investigate the association between baseline dietary energy density and risk of incident type 2 diabetes in postmenopausal women.

DESIGN: Dietary energy density, weight status, and type 2 diabetes incidence were prospectively characterized in a large cohort of postmenopausal women participating in one or more clinical trials or an observational study.

PARTICIPANTS/SETTING: The study involved 161,808 postmenopausal women recruited to the Women's Health Initiative observational study or clinical trials at 40 centers across the United States between 1993 and 1998.

MAIN OUTCOME MEASURES: The primary outcome was incident type 2 diabetes.

STATISTICAL ANALYSES PERFORMED: The association between dietary energy density quintiles and incident diabetes was tested using Cox proportional hazards regression.

RESULTS: A total of 143,204 participants without self-reported diabetes at enrollment completed baseline dietary assessment and were followed for 12.7+/-4.6 years. Risk of diabetes developing was 24% greater for women in the highest dietary energy density quintile compared with the lowest after adjusting for confounders (95% CI 1.17 to 1.32). Body mass index (calculated as kg/m2) and waist circumference mediated the relationship between dietary energy density and diabetes. In waist circumference-stratified analysis, women in dietary energy density quintiles 2 to 5 with waist circumferences > 88 cm were at 9% to 12% greater risk of diabetes developing compared with women with waist circumference

CONCLUSIONS: In this prospective study, a higher baseline dietary energy density was associated with higher incidence of type 2 diabetes among postmenopausal women, both overall, and in women with elevated waist circumference.

ReaDAPting the Role of PGRP-SD in Bacterial Sensing and Immune Activation

Wed, 06/07/2017 - 12:13pm

Contradictory to previous reports, Iatsenko et al. (2016) reveal that PGRP-SD regulates the Imd signaling pathway rather than the Toll pathway in Drosophila and shed light on a decade-old mystery of conflicting structural and phenotypic data.

Regulatory and Exhausted T Cell Responses to AAV Capsid

Wed, 06/07/2017 - 12:13pm

Recombinant adeno-associated viruses (AAVs) are quickly becoming the preferred viral vector for viral gene delivery for the treatment of a wide variety of genetic disorders. However, since their use in a clinical trial targeting hemophilia B patients 10 years ago, immune responses to the AAV capsid appear to have hampered some of the early clinical gene transfer efficacy. Indeed, AAV-based gene transfer has been shown to reactivate capsid-specific memory T cells, which have correlated with a decline in AAV-transduced tissue in some patients. Importantly, clinical trials have also shown that this reactivation can be quelled by administering time-course taper of glucocorticoid steroids before or after dosing. More recently, two clinical studies have shown that AAV gene transfer is not only able to induce a deleterious immune response, but also can result in the initiation of a tolerance to the AAV capsid mediated by regulatory T cells and exhausted T cells. This article reviews clinical trials describing immune responses to AAV, as well as the mechanisms responsible for immune tolerance in chronic infections and how it could apply to AAV-based gene transfer. A better understanding of both cytotoxic and tolerogenic immune responses to recombinant AAV will lead to safer gene transfer protocols in patients.

Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma

Wed, 06/07/2017 - 12:12pm

Endemic Burkitt lymphoma (eBL) is an aggressive B cell lymphoma and is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria co-infections. Central to BL oncogenesis is the over-expression of the MYC proto-oncogene which is caused by a translocation of an Ig enhancer in approximation to the myc gene. While whole genome/transcriptome sequencing methods have been used to define driver mutations and transcriptional dysregulation, microRNA (miRNA) dysregulation and differential expression has yet to be fully characterized. We hypothesized that both human and EBV miRNAs contribute to eBL clinical presentation, disease progression, and poor outcomes. Using sensitive and precise deep sequencing, we identified miRNAs from 17 Kenyan eBL patient tumor samples and delineated the complement of both host and EBV miRNAs. One human miRNA, hsa-miR-10a-5p was found to be differentially expressed (DE), being down-regulated in jaw tumors relative to abdominal and in non-survivors compared to survivors. We also examined EBV miRNAs, which made up 2.7% of the miRNA composition in the eBL samples. However, we did not find any significant associations regarding initial patient outcome or anatomical presentation. Gene ontology analysis and pathway enrichment of previously validated targets of miR-10a-5p suggest that it can promote tumor cell survival as well as aid in evasion of apoptosis. To examine miR-10a-5p regulatory effect on gene expression in eBL, we performed a pairwise correlation coefficient analysis on the expression levels of all its validated targets. We found a significant enrichment of correlated target genes consistent with miR-10a-5p impacting expression. The functions of genes and their correlation fit with multiple target genes impacting tumor resilience. The observed downregulation of miR-10a and associated genes suggests a role for miRNA in eBL patient outcomes and has potential as a predictive biomarker that warrants further investigation.

Effect of AHA dietary counselling on added sugar intake among participants with metabolic syndrome

Wed, 06/07/2017 - 12:12pm

BACKGROUND: High added sugar consumption has been associated with the development of metabolic syndrome (MetS). The American Heart Association (AHA) diet is designed to prevent and treat MetS; however, it remains unclear whether the AHA diet is effective on decreasing added sugar consumption. The aim of our study was to evaluate the effect of the AHA dietary counselling on added sugar consumption among participants with MetS.

METHODS: The AHA dietary counselling was conducted among 119 participants with MetS from June 2009 to January 2014 (ClinicalTrials.gov: NCT00911885). Unannounced 24-hour recalls were collected at baseline, 3, 6 and 12 months. Added sugar consumption patterns over time were examined using linear mixed models.

RESULTS: After 1-year dietary counselling, intake of added sugars decreased by 23.8 g/day (95% CI 15.1, 32.4 g/day); intake of nonalcoholic beverages dropped from the leading contributor of added sugar intake to number 7 (from 11.9 to 4.4%); the Alternative Healthy Eating Index (AHEI) score increased by 5.4 (95% CI 2.9, 8.0); however, added sugar intake for 48% participants still exceeded the recommendation. Added sugar intake per meal among different meal type was similar (24.2-25.8%) at baseline. After the 1-year dietary counselling, breakfast became the major resource of added sugar intake (33.3%); the proportion of added sugar intake from snacks decreased from 25.8% (CI 23.1, 28.5%) to 20.9% (CI 19.6, 22.3%).

CONCLUSION: Although the consumption of added sugars in participants with MetS decreased after the 1-year AHA dietary counselling, added sugar intake from majority of participants still exceeds recommended limits. Actions of successful public health strategies that focus on reducing added sugar intake are needed.

Comparison of control fasting plasma glucose of exercise-only versus exercise-diet among a pre-diabetic population: a meta-analysis

Wed, 06/07/2017 - 12:12pm

BACKGROUND/OBJECTIVES: Exercise is considered a protective factor in the prevention of type 2 diabetes, although its role as a sole treatment for pre-diabetes remains unknown. The present meta-analysis compared the effect of exercise-only with exercise-diet interventions on plasma glucose levels among a pre-diabetic population.

SUBJECTS/METHODS: A literature search was conducted using PubMed, EMBASE and Cochrane databases. The Cochrane Collaboration tool was used to assess the quality of each trial. Two reviewers independently performed quality assessment of all included articles. A random effects model was used to calculate the pooled effect.

RESULTS: A total of 4021 participants from 12 studies were included in this meta-analysis, 2045 of them were in the intervention group and 1976 were in the control group. Compared with the exercise-only interventions, the exercise-diet interventions showed a significant effect on decreasing fasting plasma glucose (FPG) levels, with a weighted mean difference (WMD) =-0.22 mmol/l, 95% confidence interval (CI): -0.25, -0.18 (Z=12.06, P 0.05). According to the intervention periods, the pooled effect in the 2-year group was the highest, and its WMD (95% CI) was -0.24 mmol/l (-0.43,-0.05). The pooled effects were statistically significant among the elderly and those of American and European descent, with WMD (95% CI) being -0.19 mmol/l (95% CI: -0.22, -0.15), -0.17 mmol/l (-0.21,-0.12) and -0.22 mmol/l (-0.27, -0.17), respectively.

CONCLUSIONS: Evidence from published trials indicates that exercise-diet interventions showed a significant effect on decreasing FPG levels.