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A Non-Restrictive Weight Loss Diet Focused on Increasing Fiber and Lean Protein: Results of a Pilot Trial

Fri, 05/20/2016 - 3:30pm

Objective. The vast majority of diets are not only multicomponent but also restrictive. Dietary fiber or protein can reduce hunger and enhance satiety; they also exert clinical benefits. We examined feasibility and acceptability of a non-restrictive diet combining the two for weight loss.

Population and Methods. Fifteen patients were enrolled in the trial (2 men, 13 women, mean age=48 y and mean BMI = 36 kg/m2) to attend 6 bi-weekly individual counselling sessions for the diet during the 12-week study period. The goals of the intervention were to attain a daily goal of higher fiber (>35g)/ and lean protein (120g). 24-hour diet recalls and body weight were collected at baseline, 6- and 12-week assessments.

Results. All participants completed 6-week assessment, one participant dropped from the study before 12-week assessment. At 12 weeks, 93% of participants liked the diet much/very much, 92% were very/extremely confident in adhering to the diet and 85% did not feel hungry on the diet. Mean fiber intake increased by 9.4 g/day (95% CI: 5.9, 12.8) at 6 weeks, and by 6.9 g/day (CI: 3.3, 10.5) at 12 weeks. Protein intake increased by a mean of 13.7 g/day (CI: 4.8, 22.6) at 6 weeks, and by 6.0 g/day (CI: -3.3, 15.3) at 12 weeks. % of calories from saturated fat decreased by 2.0% (CI: 0.5, 3.4) at 6 weeks and by 2.7% (CI: 0.5, 3.4) at 12 weeks. Alternative Healthy Eating Index score increased by 9.7 (CI: 5.3, 14.0) at 6 weeks and by 6.1 (CI: 1.5, 10.7) at 12 weeks. Mean weight loss was -2.7 lbs (CI: -4.9, 0.6) at 6 weeks and -4.7 lbs (CI: -8.0, -1.4) at 12 weeks.

Conclusion. Participants liked the diet prescribed, and significantly increased their fiber and lean protein intake, resulting in significant weight loss with improvement to dietary quality.

Optimization of the Design of an Amphiphilic Biodegradable Polymer for Tissue-engineering Application

Fri, 05/20/2016 - 3:30pm

Biodegradable polymers have been widely utilized as drug delivery vehicles and tissue engineering scaffolds. We previously designed amphiphilic triblock copolymer poly(lactic acid)-b-poly(ethylene glycol)-b-poly(lactic acid) (PELA) and its hydroxyapatite (HA) composites for bone tissue engineering applications. The hydrophilic electrospun PELA-HA composite exhibited aqueous stability and elastic handling characteristics, and was able to template the proliferation and osteogenesis of bone marrow stromal cells (BMSCs) in vitro and in vivo when spiral-wrapped into cylinders and press-fit into critical size femoral segmental defects in rats. However, the slow degradation of PELA has prevented timely disappearance of the scaffold and impeded more effective restoration of biomechanical integrity of the defect. To accelerate degradation, in this work we designed poly(lactic/glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic/glycolic acid) (PELGA) with varying ratios of glycolide and lactide and confirmed their more accelerated degradations as compared to PELA. Processing conditions (e.g. solvent-casting vs. electrospinning, with or without hydration) significantly impacted the structural characteristics of PELGA and their HA composites. The PEG crystallization in PELGA was not as strong as in PEG homopolymers, giving rise to a lower Tm. HA could be well dispersed in PELGA and electrospun to give a uniform composite where the crystallization of PEG was promoted by water resulting in enhanced mechanical strength upon hydration. These HA-contained electrospun meshes exhibited excellent cytocompatibility and efficacy in templating osteogenesis of rat BMSCs in vitro.

Structural Activity Relationship Study on Dual PLK1 /BRD4 Inhibitor, BI- 2536

Fri, 05/20/2016 - 3:30pm

Polo-like kinase 1 (PLK1) and BRD4 are two different therapeutic targets in cancer drug discovery. Recently it has been reported that PLK1 inhibitor, BI-2536, is also a potent inhibitor of BRD4. The simultaneous inhibition of PLK1 and BRD4 by a single drug molecule is interesting because this could lead to the development of effective therapeutic strategy for different types of disease conditions in which PLK1 and BRD4 are implicated. Structural activity relationship studies has been carried out on BI-2536 to generate analogs with enhanced dual inhibitory activity against BRD4 and PLK1 as well as to render the molecule selective to one target over the other. UMB101 and 160 have been found to exhibit enhanced dual inhibitory activity with selectivity fold of less than 30, UMB160 being the most potent dual-kinase bromodomain inhibitor (BRD4 IC50 = 28 nM, PLK1 IC50 = 40 nM). UMB131 was found to be the most selective PLK1 inhibitor over BRD4.

Statistical Analysis for Hospital Length-of-Stay and Readmission Rate Study

Fri, 05/20/2016 - 3:30pm

Hospital readmission rate has become a major indicator of quality of care, with penalties given to hospitals that have high rates of readmission. At the same time, insurers are applying increasing pressure to improve efficiency and reduce costs, including decreasing hospital lengths of stay. We analyze these trends to determine if reducing lengths of stay (LOS) may actually worsen readmission rates. All records of patients admitted to the neurosurgical service at one hospital from October 2007 through June 2014 were aggregated and analyzed for several variables, including initial length of stay, readmission occurrence, and length of stay, admitting diagnosis, admission priority and discharge disposition. Any trends over time were also noted. 925 out of 9,409 patient encounters are readmissions. Readmission rate and average length of stay were found significantly negative correlated. Besides linear regression which directly connecting average length of stay and readmission rate, survival analysis methods with Cox proportional hazard ratio model were employed to determine which factors were associated with a higher risk of readmission. There was a clear increase in readmissions over the study period, but LOS remained relatively constant, suggesting that increasing medical complexity confounded efforts to decrease LOS and was responsible for increased readmission rates. This study can help providers avoid readmissions by focusing on effective management of comorbidities.

Airway smooth muscle pathology in Pompe Disease

Fri, 05/20/2016 - 3:30pm

Pompe disease is a rare autosomal recessive disease which results from a deficiency of acid α-glucosidase (GAA) - an enzyme that degrades lysosomal glycogen. Patients with Pompe disease develop intra-lysosomal accumulation of glycogen in multiple tissues including skeletal muscle, CNS and smooth muscle.

Pulmonary dysfunction is a hallmark of Pompe disease and has classically been attributed to muscle weakness and CNS neuropathology. However, the potential role of respiratory smooth muscles in the respiratory pathology is unknown. Therefore we postulated that GAA deficiency results in airway smooth muscle glycogen accumulation that leads to airway smooth muscle dysfunction.

Using the Pompe mouse model, the Gaa-/- mouse, we examined the airway smooth muscle structure and function. We used in vivo forced oscillometry measurements (N=7WT, N=7 Gaa-/-) to examine pulmonary physiology and administered methacholine challenges to assess in vivo airway resistance. Also, we used ex-vivo contraction testing (N=6WT, N=5 Gaa-/-) to determine bronchi contractility. In response to the highest dose methacholine challenge (100mg/ml), there was a significant decrease in conducting airway resistance in Gaa-/- versus WT mice (p=0.007). Also, ex vivo bronchi contraction testing demonstrated a significantly weaker response to potassium chloride (p=0.008) and methacholine (2-way ANOVA p=0.005) in Pompe mice compared to WT mice, suggesting impaired smooth muscle contraction. Furtherly, we performed PAS staining on fresh-frozen tissue to examine the degree of glycogen accumulation as a result of GAA deficiency. PAS staining revealed robust glycogen accumulation in the trachea and bronchi of Pompe mice and a disruption of the airway smooth muscle architecture.

In conclusion, GAA deficiency results in glycogen accumulation and a disruption of the architecture in the airway smooth muscles of Gaa-/- mice. Furthermore, both in vivo and ex vivo tests reveal that Gaa-/- murine airways have impaired function as evidenced by decreased contractility and a decreased response to methacholine.

Text Mining From Drug Surveillance Report Narratives

Fri, 05/20/2016 - 3:30pm

Analysis of postmarket drug surveillance reports is imperative to ensure drug safety and effectiveness. FAERS (FDA Adverse Event Reporting System) is a surveillance system that monitors Adverse Events (AEs) from drugs and biologic products. The AEs are reported through MedWatch voluntary reports (initiated from patients and healthcare providers) and mandatory reports (initiated from manufacturers). Much of the information in the voluntary AE reports is narratives or unstructured text. The increasing volume of individual reports, estimated at more than one million per year, poses a challenge for the staff to review large volume of narratives for drug clinical review. We are developing a computational approach using Natural Language Processing and UMLS MetaMap biomedical software to parse the narratives, recognize named-entities in the text and extract consumer/patient and related drug indications and adverse drug reaction information. The goal is to develop a text mining tool that automatically extracts relevant information from the report narratives which can be stored in pre-defined data fields in the FAERS database for efficient searching and querying during clinical review process.

Comparison of Diabetic Remission Rates following Roux en-Y Gastric Bypass and Longitudinal Sleeve Gastrectomy

Fri, 05/20/2016 - 3:30pm

Introduction: Bariatric surgery is being increasingly investigated as treatment for Type II Diabetes Mellitus (T2DM). As Sleeve Gastrectomy (SG) surpasses Roux-en-Y Gastric Bypass (RYGB) as the new standard in bariatric surgery, it is still unknown if its efficacy in achieving remission is comparable to RYGB. This study compared diabetic remission rates between SG and RYGB in order to identify the predictive factors for remission and the mechanisms of achieving remission.

Methods: This was a retrospective cohort study comparing all diabetic patients undergoing RYGB and SG at an academic medical center from 1/1/11-7/1/15. Patients were followed preoperatively and at 6 week, 6 month, and 1, 2, and 3 year intervals. We defined diabetic remission as HbA1c under 7 without insulin or hypoglycemic use and excess body weight (EBW) as percent over ideal body weight. Data were analyzed using Cox analysis, Fisher’s Exact Tests, and Student T Tests.

Results: During the study, 96 patients underwent RYGB and 89 underwent SG. Preoperatively, patients from both groups had similar age, weight, gender, preoperative weight loss, HbA1c at onset and at surgery, oral hypoglycemic use, insulin use, and HOMA2 parameters. At one year postoperatively, patients who underwent RYGB showed a statistically greater postoperative EBW loss (62% vs. 36% p < 0.0001). Kaplan Meier analysis showed a significantly higher rate of remission, (83% vs. 66%) in patients who underwent SG (p=0.02). After using Cox analysis to account for differences in delta BMI (p=0.04), EBW loss (p=0.04), preoperative HOMA2 parameters (p=0.008-0.011), and preoperative factors such as HbA1c and insulin use (p=0.001 for both), there was no change in RYGB’s impact on diabetic remission compared to SG.

Conclusion: Our results confirm that RYGB achieves a significantly greater rate of diabetic remission and a significantly higher weight loss than SG. Additionally, the difference in rate of diabetic remission is not explained by weight loss or preoperative predictors of less reversible diabetes (HOMA2 parameters, use of insulin). Identification of the factor(s) responsible for this differential effect on diabetes may afford opportunity for therapeutic intervention.

Differences in Complication Rates Between Roux-en-Y Gastric Bypass and Longitudinal Sleeve Gastrectomy

Fri, 05/20/2016 - 3:30pm

Introduction: Sleeve Gastrectomy (SG) has surpassed Roux-en-Y Gastric Bypass (RYGB) as the most commonly performed bariatric operation. Though the beneficial effect of SG on Type 2 Diabetes Mellitus is less than that of RYGB, it is perceived to have a lower complication rate. The purpose of this study was to quantify the complication rates between of SG and RYGB in a severely obese diabetic population.

Methods: This was a retrospective cohort study that included all diabetic patients undergoing RYGB and SG at an academic medical center from January 1, 2011 to July 1, 2015. Patients were followed at 6 week, 6 month, 1 year, 2 year, and 3 year postoperatively. Outpatient and emergency visits were identified in the EMR system. Continuous data was analyzed using Student T tests and discrete data was analyzed using Fisher’s Exact Test. We defined early complications as those occurring within 30 days postoperatively, and late complications as those after 30 days.

Results: A total of 96 patients underwent RYGB and 89 underwent SG. The groups were concurrent and similar with regards to preoperative demographic factors such as age, gender, Hgb-A1c, HOMA2 parameters, excess body weight, BMI, and diabetic medication use. In terms of early complications, the rate of hemorrhage requiring transfusion was higher in the SG group compared to RYGB (10.1% vs. 3.1%, p=0.073). Postoperative length of stay was lower in the SG group (m=1.7 d vs. m=2 d, p=0.02), but the early readmission rate was also higher in the SG group (7.9% vs. 2.1%, p=0.09). For late postoperative complications, there were 4 anastomotic ulcer perforations and one case of internal hernia in the RYGB group. There were 6 late postoperative reoperations in the RYGB group (6% vs. 0%, p=0.03). In addition, 13 patients underwent 16 total upper endoscopies in the RYGB group (13.5% vs. 0%, p=0.0002). The cumulative rate of early and late interventions was higher in the RYGB group (20% vs. 3.4%, p=0.0005).

Conclusions: While the rate of early postoperative complication is similar between SG and RYGB, the need for late intervention is higher after RYGB. The cumulative need for reintervention (early and late) is higher after RYGB. This may explain the shift from Roux-en-Y Gastric Bypass to Sleeve Gastrectomy as the most commonly performed bariatric intervention.

Pre-exposure prophylaxis with OspA-specific human monoclonal antibodies protects mice against tick transmission of Lyme disease spirochetes

Fri, 05/20/2016 - 3:30pm

Background. Tick transmission of Borrelia spirochetes to humans results in significant morbidity from Lyme disease worldwide. Serum concentrations of antibodies against outer surface protein A (OspA) were shown to correlate with protection from infection with Borrelia burgdorferi, the primary cause of Lyme disease in the United States.

Methods. Mice transgenic for human immunoglobulin genes were immunized with OspA protein of B. burgdorferi to generate human monoclonal antibodies (HuMabs) against OspA. HuMabs were generated and tested in in vitro borreliacidal assays and animal protection assays.

Results. Nearly 100 unique OspA specific HuMabs were generated and four HuMabs (221-7, 857-2, 319-44, and 212-55) were selected as lead candidates based on borreliacidal activity. HuMab 319-44, 857-2 and 212-55 were borreliacidal against one or two Borrelia genospecies, whereas 221-7 was borreliacidal (IC50 < 1nM) against B. burgdorferi, B. afzelii and B. garinii, the three main genospecies endemic in the US, Europe and Asia. All four HuMabs completely protected mice from infection at 10 mg/kg in a murine model of tick-mediated transmission of B. burgdorferi.

Conclusions. Our study indicates that OspA-specific HuMabs can prevent the transmission of Borrelia and administration of these antibodies could be employed as pre-exposure prophylaxis for Lyme disease.

Targeted Combination Treatment for Glioblastoma Multiforme (GBM) Using Polymeric Nanoparticle

Fri, 05/20/2016 - 3:30pm

Glioblastoma Multiforme (GBM) is an aggressive cancer that originates from astrocytes and spreads to spinal cord and other parts of the brain. Increase in replication of glial cells leads to advantageous mutations in the tumor. In 2015 about 15,320 deaths were reported due to GBM. Five-year survival is less than 5% making GBM a dreadful cancer. Current treatment involves complex invasive surgery, followed by chemotherapy and radiation. There is a desperate unmet need for a targeted treatment of GBM with minimum damage to the surrounding normal tissue. Combination treatments are increasingly being used to target multiple hallmarks of cancer. The goal of this study is to develop a combination therapy to treat GBM using Poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulated with three different drugs namely gefitinib, temozolomide (TMZ) and GSK461364 each with a unique target. Nanoparticles facilitate combination of multiple drugs for simultaneous delivery to cancer cells in a single nano-sized platform. Gefitinib is a Tyrosine Kinase inhibitor, which competes for ATP-binding site of EGFR-TK. TMZ methylates DNA of tumor cells, resulting in apoptosis. GSK461364 is a Polo-like Kinase (PLK-1) inhibitor that blocks the G2/M transition in tumor cell cycle. These three distinct hydrophobic drugs are tested on U-87 MG (human malignant glioma) and MDA-MB-231 (triple negative breast cancer) cell lines. PLGA is attached to Polyethylene glycol (PEG), which is conjugated to transferrin receptor (TfR) binding peptide for targeting TfR overexpression, common in GBM. PEG is known to increase the circulation half-life in vivo and improves colloidal stability of nanoparticles. These transferrin peptides bind to TfR (or CD71) and enable the entry of PLGA across Blood Brain Barrier (BBB). Results of characterization, in vitro drug release profiles, stability at 37C and 4C, cytotoxicity assay, electron micrographs of nanoparticles containing drugs and fluorescent imaging will be presented.

Role of TSH and excess Heart Age in Predicting Atrial Fibrillation Recurrence Post-Ablation

Fri, 05/20/2016 - 3:30pm

Background: The association between atrial fibrillation (AF) and thyroid disease as defined by thyroid stimulating hormone (TSH) is established in literature. However, the relationship between TSH and recurrence of AF post ablation has not been established.

Methods: We studied 207 patients (60.54±9.39yrs, 35.7% female) with persistent or paroxysmal AF who underwent either Cryo or RFA ablation between April 2011 and Jan 2015 at our center. Patients were stratified into hypothyroid (TSH > >4.5 U/mL), euthyroid (TSH 0.5-4.5 U/mL) and hyperthyroid (TSH < 0.5 U/mL) based on pre procedure testing. Heart age was computed based on Framingham risk factors. Excess heart age was defined as the difference between actual age and heart age. Logistic regression and cox-proportional hazards model were implemented using R statistical software (v3.2.0).

Results: There was a statistically significant lower rate of AF recurrence among male patients (OR 2.92, p=0.003). In univariate analysis, there was no statistically significant relationship between TSH and incidence of AF recurrence (OR 1.05, p=0.74). Cox proportional hazards models did not show an association between recurrence and TSH states (HR 0.85, p=0.74 for hypothyroid and HR 0.75, p=0.56 for hyperthyroid).

Conclusions: This exploratory showed that TSH may not play a role in AF recurrence. While there is a tendency towards an association between TSH and AF recurrence, this was not statistically significant. We hypothesize that overt hyperthyroidism prior to ablation will not increase chance of recurrence. This was true after adjustment for Framingham risk factors. The limitation of this study was the small sample size of the patients with TSH in the hyperthyroid range. Further analysis using larger dataset is indicated.

Triad of Suffering: Pain, Depression, and Anxiety among Newly Admitted Nursing Homes Residents

Fri, 05/20/2016 - 3:30pm

Introduction: Depression and anxiety disorders are prevalent among older adults, as is pain. These conditions are independently associated with reduced functioning and quality of life. Despite the frequent co-occurrence of all three of these disorders, little is known about the epidemiology and treatment of these disorders in nursing homes. The objectives of this study were to: 1) describe the prevalence of depression, anxiety disorders, and pain among newly admitted nursing home residents; and 2) describe the treatment of these disorders.

Methods: We used national Minimum Data Set (MDS) version 3.0 data from 2011-2012. Federally-mandated for all residents living in Medicare/Medicaid-certified nursing facilities, the MDS is a comprehensive clinical assessment including > 400 items on sociodemographics, mood and behavior, symptoms, pain, clinical diagnoses, and treatments. We identified residents with MDS assessments performed at admission between 2011-2012 who were 65 years of age or older; were non-comatose; were not admitted to a swing bed provider; did not have mental retardation or developmental delays; & were able to complete a pain assessment (n = 783,826).

Results: At admission, 36% of residents (n = 283,050) had a documented active diagnosis of depression (other than bipolar disorder), anxiety disorder, or both. Having pain in the last 5 days was reported by 53% of residents. Rates of self-reported pain were similar across psychiatric disorders. 60-62% of residents reporting pain received a combination of pain management interventions. More than a third of residents did not receive any psychiatric treatment.

Conclusions: Many nursing home residents experience pain, depression, and anxiety at admission. Pain management is common. An improved understanding of the relationships between pain, mental health, and analgesic use is necessary since older adults, particularly those in nursing homes, are routinely excluded from clinical trials despite being at high risk for adverse effects of analgesics and other treatments.

Impact of multimorbidity on clinical outcomes in older adults with cardiovascular disease

Fri, 05/20/2016 - 3:30pm

Objective: To synthesize the current literature on the magnitude and impact of multiple chronic conditions on clinical outcomes, including total in-hospital and post discharge mortality and hospitalizations, in older patients with cardiovascular disease (CVD).

Methods: A systematic review was conducted. Four electronic databases and article bibliographies were searched for publications from 2005 to 2015 which assessed the impact of multimorbidity on clinical outcomes in the elderly with CVD. Identified studies were screened using pre-defined criteria for eligibility.

Results: Fifteen studies met our inclusion criteria. Multimorbidity was assessed by simple counting of morbidities and by the Charlson and Elixhauser indices. Case-fatality rates ranged from between 13% and 21% for patients with a myocardial infarction. Long-term mortality ranged from 28% to 73% among patients with heart failure, and 24% of patients with heart failure and presenting multimorbidities had at least one readmission during a follow-up period of 17 months. Most of the studies reported a significant association between number of multimorbidities or particular morbidities and the risk of dying, the most frequent morbidities examined were diabetes, chronic kidney disease, anemia, chronic pulmonary disease and dementia/cognitive impairment

Conclusions: There are limited data on the magnitude and impact of multimorbidities on clinical outcomes, and even less data on patient centered outcomes among elderly patients with CVD. There are also inconsistencies in the manner by which multimorbidities are assessed; very few studies have approached the “real” complexity of patients with CVD and multimorbidities and how best to manage these high risk patients.

Multiple Chronic Conditions and Psychosocial Limitations in a Contemporary Cohort of Patients Hospitalized with an Acute Coronary Syndrome

Fri, 05/20/2016 - 3:30pm

Background: As adults live longer, multiple chronic conditions have become more prevalent over the past several decades. We describe the prevalence of, and patient characteristics associated with, cardiac and non-cardiac-related multimorbidities in patients discharged from the hospital after an acute coronary syndrome (ACS).

Methods: We studied 2,174 patients discharged from the hospital after an ACS at 6 medical centers in Massachusetts and Georgia between April, 2011 and May, 2013. Hospital medical records yielded clinical information including presence of 8 cardiac-related and 8 non-cardiac-related morbidities on admission. We assessed multiple psychosocial characteristics during the index hospitalization using standardized in-person instruments.

Results: The mean age of the study sample was 61 years, 67% were men, and 81% were non-Hispanic whites. The most common cardiac-related morbidities were hypertension, hyperlipidemia, and diabetes (76%, 69%, and 31%, respectively). Arthritis, chronic pulmonary disease, and depression (20%, 18%, and 13%, respectively) were the most common non-cardiac morbidities. Patients with ≥4 morbidities (37% of the population) were slightly older and more frequently female than those with 0-1 morbidity; they were also heavier and more likely to be cognitively impaired (26% vs. 12%), have symptoms of moderate/severe depression (31% vs. 15%), high perceived stress (48% vs. 32%), a limited social network (22% vs. 15%), low health literacy (42% vs. 31%), and low health numeracy (54% vs. 42%).

Conclusions: Multimorbidity, highly prevalent in patients hospitalized with an ACS, is strongly associated with indices of psychosocial deprivation. This emphasizes the challenge of caring for these patients, which extends well beyond ACS management.

Reprogramming of mTOR Signaling by Perinatal Exposure to Brominated Flame Retardant

Fri, 05/20/2016 - 3:30pm

Mammalian target of rapamycin (mTOR), also known as mechanistic target of rapamycin, is a known metabolic master-switch. In conditions of starvation, mTOR suppresses biosynthetic programs and increases the recycling of proteins and organelles. Upon stimulation by nutrients and growth factors, however, mTOR causes activation of biosynthesis and suppression of autophagy. The mTOR-centered molecular pathway is a major pathway of growth regulation and metabolism, linked to aging and the development of cancer, obesity, type 2 diabetes, neurodevelopmental and neurodegenerative diseases. Currently, the role of environmental factors in the modulation of the mTOR pathway remains largely unknown. The present study suggests that perinatal exposure to environmentally-relevant doses of polybrominated diphenyl ethers (PBDEs), a group of ubiquitous flame-retardants, results in long-lasting reprogramming of the mTOR pathway in mouse liver. This reprogramming includes suppression of mTORC1 and mTORC2 activity, accompanied by coordinated up-regulation of protein synthesis machinery and increased concentrations of circulating IGF-1. Further, experiments with MCF-7 breast cancer cells demonstrate that exposure to PBDEs results in fast induction of the REDD1/DDIT4 gene – a potent suppressor of mTORC1. This data indicates that the response of liver tissue to PBDE exposure during this critical developmental window is a dynamic process, and is likely triggered via a REDD1-dependent mechanism, ultimately resulting in long-lasting changes in the metabolic profile of the tissue. This study suggests that environmental exposures to brominated flame retardants may have profound and long-term effects on the central regulation hub of metabolic health, and may be implicated in the pathogenesis of the most relevant diseases of modern society.

Microengineering Approaches for Regenerative Medicine

Fri, 05/20/2016 - 3:30pm

Stem cells, especially human pluripotent stem cells (hPSCs), hold significant promise for modeling developmental and disease processes, drug and toxicology screening, and cell-based regenerative medicine. Most hPSC studies have so far focused on identifying extrinsic soluble factors, intracellular signaling pathways, and transcriptional regulatory networks involved in regulating hPSC behaviors. We focus on the development and applications of some novel synthetic micromechanical systems to understand the mechano-sensitive and -responsive properties of hPSCs and their functional regulation of self-renewal, directed differentiation, and survival of hPSCs. First, we have demonstrated that rigid PDMS micropost arrays (PMAs) support the maintenance of pluripotency of hPSCs. Blocking cytoskeleton contractility by blebbistatin and inhibiting E-cadherin functions by DECMA-1 antibody both impair mechanoresponsive self-renewal of hPSCs on rigid substrates. We have further achieved efficient neuroepithelial induction, caudalization, and motor neuron differentiation from hPSCs combining soft PMAs (Eeff < 5kPa) with dual Smad inhibition. The purity and yield of functional motor neurons derived from hPSCs within 23 days of culture using soft PMAs were improved four- and twelve-fold, respectively, compared to coverslips or rigid PMAs. Our mechanistic work has helped reveal for the first time that biomechanical cues, including intracellular contractile forces and cell shape, converge and reinforce signal integration of TGF-β, Wnt, Hippo/YAP, Rho GTPase, and the actomyosin cytoskeleton to regulate the neural plate specification. We also developed a novel acoustic tweezing cytometry (ATC) utilizing ultrasound pulses to actuate functionalized lipid-encapsulated microbubbles (MBs) targeted to cell surface integrin receptors to exert subcellular mechanical forces in the pN - nN range. ATC can robustly induce cell traction force changes through acoustic radiation forces and bubble cavitation induced shear stresses. Importantly, ATC stimulations increased the survival rate and cloning efficiency of hESCs by 3-fold, suggesting its potential application in large-scale expansion of hPSCs.

Can Physician Champions Improve Kangaroo Care? Trends over 5 Years in Rural Western India

Fri, 05/20/2016 - 3:30pm

Introduction: In 2013, approximately 2.8 million children worldwide died within the neonatal period. India is at the epicenter of this tragedy, accounting for one-third of all neonatal mortalities. Prematurity and/or with low birth weight are the leading cause of neonatal mortality and India has the highest number of neonates born preterm and weighing less than 2,500 grams worldwide. It is estimated that Kangaroo Care can avert up to 48% of all neonatal deaths among premature babies by 2025. However, the promise of Kangaroo Care as a low-cost, safe, and efficacious intervention to reduce neonatal mortality in India has not been realized due to suboptimal implementation. Physician champions can improve Kangaroo Care implementation, but the magnitude of their impact is unknown.

Methods: A retrospective cohort study of 648 infants identified using clinical data from a NICU located in rural western India. Physicians who led Kangaroo Care training sessions with neonates and coached peer healthcare professionals were considered champions. Two Kangaroo Care champions were on staff full-time from January 2010 through June 2011, part-time from July 2011 through June 2012, and absent thereafter. We examined the effect of the withdrawal of physician champions on overall use using logistic regression, time to initiation using competing risk cox regression, and intensity using linear regression models of the two main components of Kangaroo Care, skin-to-skin care and breastfeeding, separately.

Findings: In comparison to when Kangaroo Care champions were present, their absence was associated with a 45% decrease in the odds of receiving skin-to-skin care (95% CI): 64% to 17%), 38% decrease in the rate of initiation of skin-to-skin care (95% CI: 53% to 82%), and on average, 1.47 less hours of skin-to-skin care (95% CI: -2.07 to -0.86). Breastfeeding practices were similar across different champion environments.

Interpretation: Withdrawal of Kangaroo Care champions from neonatal intensive care unit in rural western India is associated with diminished administration, delayed initiation, and shorter duration of skin-to-skin care, but did not impact breastfeeding practices. Training healthcare workers and community stakeholders to become champions could help in scaling up and maintaining Kangaroo Care practices.

Funding: This research was supported by TL1-TR001454 (to A.S.) from National Center for Advancing Translational Sciences, and P60-MD006912-05 (to J.A.) from National Institute on Minority Health and Disparities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Interrogating Plant Cell Culture Library for Novel Antimicrobial Agents

Fri, 05/20/2016 - 3:30pm

The Plant Cell Culture Library (PCCL) at UMass Amherst contains more than 2,200 live plant cell cultures, representing diverse plant species from around the world. The availability of this collection offers a rich resource for us to discover bioactive phytochemicals and uncover their mechanisms of action. Using data-mining surveys of bioactive plant extracts, I have organized subsets of PCCL cell lines that are likely to possess antifungal, antibacterial, antiviral, anthelmintic, anti-trypanosomal, or anticancer properties, which prove to be useful when deciding which species to screen first against a specific pathogen. Another distinct advantage of using the live plant cells in this research is the ability to stimulate the biosynthesis of pathogen-specific phytochemicals upon simulation of an attack (elicitation) by the microorganism in question. This could be accomplished by pathogen homogenates or plant hormones responsible for mounting defenses to infection.

Over the past six months, I have been working to optimize elicitation, lysis, and extraction conditions for obtaining high-throughput screening materials to be used against variable pathogens. Equipped with crude extracts from appropriately elicited cells, I am collaborating with a multidisciplinary team of UMass scientists to develop and implement high-throughput screening protocols for profiling a large number of plant-derived materials against various pathogens. Recently, I have screened a small pool (40) of extracts derived from cell lines with predicted anti-fungal properties against the highly resistant strain of fungus Fusarium oxysporum, one of the causal agents of an opportunistic infection often seen in immunocompromised patients known as fusariosis. Gratifyingly, I have found several plant species that produced specialized metabolites with better antifungal activity than the leading antibiotic against F. oxysporum, Amphotericin B, validating this line of antimicrobial research. We are also actively reaching out to other academic labs partners to form partnerships in diverse antimicrobial research venues.

Sedentary Behavior and Cardiovascular Disease Risk Factors among Latino Adults

Fri, 05/20/2016 - 3:30pm

Background: Compared to other racial/ethnic subgroups in the U.S., Latinos experience increased rates of cardiovascular disease (CVD) and CVD risk factors such as hypertension, inactivity, and diabetes. Sedentary behavior has also been defined as an additional risk factor for CVD, independent of physical activity participation. However, while sedentary behavior has been associated with increased risk for CVD among primarily White samples, previous studies in Latinos have shown mixed results.

Purpose: To explore the relationships between sedentary behavior and CVD risk factors, including BMI, waist circumference, blood pressure, physical activity, dyslipidemia, and diabetes, among a sample of Latino adults.

Methods: Cross-sectional secondary analysis of the Latino Health and Well-Being Study. Latino adults were recruited from the Greater Lawrence Family Health Center (N= 602). Surveys of sedentary behavior and physical activity were verbally administered. Anthropometric measurements included weight, height, waist circumference and blood pressure. Medical record data for diabetes and dyslipidemia were obtained.

Results: This study showed that individuals in older age strata, females, and individuals with a less than high school education were more sedentary than their younger, male, and more educated counter parts. Sedentary behavior was positively associated with BMI (β = .164, p < .001) and waist circumference (β = .162, p < .001). There were no associations between sedentary behavior and blood pressure, high cholesterol, diabetes, or physical activity.

Conclusions: There is growing evidence that sedentary behavior may have its own unique set of metabolic consequences. However, the consequences of sedentary behavior may not be uniform across subgroups. Evaluating the relationship between sedentary behavior and CVD risk is critical in identifying behaviors, like sedentariness, that contribute to the development of CVD.

A Pilot Study to Assess the Feasibility, Safety and Acceptability of Soy-based Diet for Pregnant Women at High Risk for Gestational Diabetes Mellitus

Fri, 05/20/2016 - 3:30pm

Background: Diet plays an important role in the prevention and management of gestational diabetes mellitus (GDM). Previous studies suggest that soy protein and isoflavones may have beneficial effects on lipid and glucose metabolism. Little is known regarding the cardiometabolic effects of soy intake during pregnancy. This pilot study assessed the feasibility, safety and acceptability of daily consumption of soy foods during pregnancy in women at high risk for GDM, and participant adherence to their assigned treatment.

Methods: A randomized controlled trial (RCT) was conducted among pregnant women at high risk for GDM. The Soy group were counseled to consume a combination of foods designed to contain ~25 grams of soy protein and 60-75 mg of isoflavones daily from 14 weeks until birth. They were provided with recipes and contents of different soy foods. The Control group maintained their regular diet while minimizing intake of soy containing foods. Assessments, conducted at 14 and 28 weeks of pregnancy, and 6 week postpartum, included physical measurement, questionnaire, and fasting blood samples for lipid, glucose and isoflavone metabolism biomarkers. Monthly follow-up calls were conducted to assess safety and encourage adherence.

Results: Twenty-nine subjects were recruited over a 10 month period. Both Soy and Control groups demonstrated high adherence (80-90%), defined as ≥ 15 days consuming soy foods in the past four weeks for soy group and ≤ 5 days for controls. Only five adverse events were reported possibly associated with soy intake, including nausea, vomiting, diarrhea, and itchy mouth. They were all transient and resolved without sequelae.

Conclusion: Although adherence can be challenging in such a trial, this study used a variety of approaches such as recommended recipes, dietician consultation, and monthly follow-up calls to enhance feasibility and compliance. Results indicated feasibility and adherence to treatment assignment, including the soy-based diet intervention.