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Hepatic Changes Associated with Chronic Alcohol Exposure in an Alpha-1 Antitrypsin PiZ Mouse Model

Tue, 05/16/2017 - 4:45pm

The PiZ mutation in the alpha-1 antitrypsin (AAT) gene causes the PiZ mutant protein to be sequestered in the endoplasmic reticulum of hepatocytes, causing significant liver pathology in ~10% of PiZZ homozygous AAT disease patients. Current transgenic mouse models of the disease include the liver-specific over-expression of mutant PiZ protein. However, these animal models do not efficiently recapitulate the liver damage found in PiZZ homozygous patients. Since only a small percentage of patients develop liver disease and it is not reproducible in animal models of AATD, it suggests that there are other factors that participate in disease pathogenesis. Here, we propose that in the presence of alcohol, liver injury will be initiated and that the intensity of the disease will be exacerbated by the presence of accumulated PiZ mutant protein. To test this hypothesis, we have administered alcohol via the Lieber-DeCarli diet regimen to PiZ transgenic and control C57Bl/6 mice for 12 weeks. We found no difference in alcohol and non-alcohol fed mice in terms of elevations in liver enzymes (AST and ALT). We did find a difference in the degree of steatosis and inflammation in the livers of alcohol fed PiZ mice over those of control alcohol fed mice. These findings are consistent with a chronic low-level hepatic insult seen in chronic alcohol consumption. The difference between PiZ and control mice will allow us to test gene therapies that prevent the accumulation of PiZ aggregates within hepatocytes to determine if they will prevent the exacerbation of alcoholic liver disease.

Poly (GR) in C9ORF72-related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC- derived Motor Neurons

Tue, 05/16/2017 - 4:45pm

GGGGCC repeat expansions in C9ORF72 are the most common genetic cause of both ALS and FTD. To uncover underlying pathogenic mechanisms, we found that DNA damage was greater, in an age dependent manner, in motor neurons differentiated from iPSCs of multiple C9ORF72 patients than control neurons. Ectopic expression of the dipeptide repeat (DPR) protein (GR)80 in iPSC-derived control neurons increased DNA damage, suggesting poly(GR) contributes to DNA damage in aged C9ORF72neurons. Oxidative stress was also increased inC9ORF72 neurons in an age-dependent manner. Pharmacological or genetic reduction of oxidative stress partially rescued DNA damage in C9ORF72neurons and control neurons expressing (GR)80 or (GR)80-induced toxicity in flies. Moreover, interactome analysis revealed that (GR)80 preferentially bound to mitochondrial ribosomal proteins and caused mitochondrial dysfunction. Thus, poly(GR) in C9ORF72 neurons compromises mitochondrial function and causes DNA damage in part by increasing oxidative stress, revealing another pathogenic mechanism in C9ORF72-related ALS and FTD.

Emotional Eating is Associated with Intake of Energy-dense Foods in Latinos

Tue, 05/16/2017 - 4:45pm

Background: Latinos experience profound health disparities in diet-related chronic conditions. Emotional eating (EE) has been positively associated with such conditions, however, little is known about the relationship between EE and energy-dense food intake that may influence risk for developing these conditions.

Objective: To examine associations between EE and energy-dense food intake in Latino men and women.

Methods: Latino individuals were recruited from a community health center in Lawrence, MA. Participants completed standardized assessments. EE was measured with the Three Factor Eating Behavior Questionnaire R18-V2. Dietary intake was measured with a culturally tailored Food Frequency Questionnaire. Energy-dense food groups defined as food groups exceeding 225calories per 100 grams were identified. Covariates considered in this analysis included: age, sex, education, employment status and BMI. Statistical analysis consisted of multivariable logistic regression.

Results: A total of 201 participants were included in this analysis (53.7% female, 68.1% Dominicans). After adjusting for covariates, EE was significantly associated with high intake of sweet and/or fatty foods, namely dairy desserts (i.e., ice-cream, sherbet and frozen yogurt) (OR=1.55; 95%CI=1.08, 2.21; p=0.017), oleaginous fruits (i.e., nuts and seeds) (OR=1.44; 95%CI=1.01, 2.05; p=0.046) and baked goods (i.e., cakes, cookies, pies, doughnuts and muffins) (OR=1.54; 95%CI=1.07, 2.20; p=0.020).

Conclusion: EE was positively associated with consumption of energy-dense foods in this Latino sample. Future studies should examine longitudinal associations between EE, intake of energy-dense foods and risk of chronic health conditions. Understanding these associations can unveil potential intervention targets for Latinos at high risk of diet-related chronic health conditions.

A Novel Bromodomain and Extra-terminal Domain Inhibitors (BETi) that Reverses HIV-1 Latency

Tue, 05/16/2017 - 4:45pm

Although combinatory antiretroviral therapy (cART) is effective to reduce HIV-1 viremia, it does not eliminate HIV-1 infection. HIV-1 remains latent with the presence of cART, impeding the cure of AIDS. Recently, latency-reversing agents (LRAs) have been developed to purge latent HIV-1, providing an intriguing strategy for eradication of residual, latent viral reservoirs. Our earlier studies show that antagonism of HIV-1 competitive factor bromodomain containing 4 (BRD4) using bromodomain and extra-terminal domain inhibitor (BETi) JQ1 may facilitate the reversal of HIV-1 latency. BETis have recently emerged as a class of compounds that are promising for both the anticancer and HIV-1 latency-reversing uses. However, the current BETis, including JQ1, are modest to reverse HIV-1 latency as a single drug, which complicates the study of the underlining mechanisms. BETis, which are more potent and easier for synthesis, are currently under active development. UMB-32 is a novel BETi based on an imidazo[1,2-a]pyrazine scaffold. We screened 61 UMB-32 derivatives and identified that one BETi, UMB-136, reactivates HIV-1 in multiple cell models of HIV-1 latency with better efficiency than JQ1 and UMB-32. Furthermore, UMB-136 enhances the latency-reversing effect of PKC activators (Prostratin, Bryostatin) in CD8-depleted PBMCs containing HIV-1 latent reservoirs. Thus, our results illustrate that structurally improved BETis, such as UMB-136, could be use as promising LRAs for HIV-1 eradication.

Clot Characterization in Acute Ischemic Stroke

Tue, 05/16/2017 - 4:45pm

Background: In the treatment of acute ischemic stroke (AIS) with mechanical thrombectomy, revascularization depends upon integration of the thrombus into the retrieval device. The histologic and mechanical characteristics of thrombi are key determinants of effective thrombus-device interaction. Thrombi with greater calcium and fibrin content have been associated with more challenging thrombus retrievals.

Objective: To develop thrombus analogs with histologic and mechanical characteristics similar to those of challenging clinical thrombi for thrombectomy device testing.

Methods: Fifty thrombi were retrieved from twenty-nine patients with AIS. Clinical thrombi underwent histologic analysis to determine erythrocyte and fibrin content. Nine clinical thrombi underwent dynamic mechanical analysis to determine thrombus stiffness, which was defined as a function of stress variation at low and high strains. Results from the clinical thrombi were used to determine the key mechanical characteristics of the challenging thrombus analogs, the calcium apatite-rich and fibrin-rich thrombus analogs.

Results: Of the twenty-nine AIS cases, fifteen required multiple pass attempts. The average histologic composition of the challenging clinical thrombi was 26% erythrocyte, 54% fibrin, and 20% mixed. The average stiffness of the challenging clinical thrombi was found to be similar to that of the fibrin-rich thrombus analogs. Addition of calcium apatite increased the stiffness of the thrombus analogs at low strain approximately five-fold.

Conclusions: Thrombus analogs with mechanical characteristics similar to those of challenging clinical thrombi were successfully developed. The calcium apatite-rich thrombus analogs were found to be stiffer than the fibrin-rich red thrombus analogs.

Sex Differences in Neighborhood Perceptions and Physical Activity among Older Adults Living in Car-dependent Neighborhoods

Tue, 05/16/2017 - 4:45pm

INTRODUCTION: Older adults may have more physical limitations and no longer routinely travel outside their neighborhoods to work. Their daily living, health, and well-being may depend on neighborhood resources close to their homes. Therefore, access to resources critical for healthy aging may influence health in various aspects. In this study we investigated differences in neighborhood perceptions (NP) and their influences on physical activity (PA).

METHODS: Between 2012 and 2015, 111 men and 103 women aged 65 years and older living in car-dependent neighborhoods were queried on NP, use of neighborhood resources, and frequency and location of PA. Participants wore an accelerometer for 7 consecutive days.

RESULTS: Compared to women, men had a higher daily step count (mean (SD) 4385 (2122) men vs. 3671(1723) women, p=0.008). Men reported higher frequencies of any PA and moderate-to-vigorous PA, and a lower frequency of PA inside the home. Mean daily step counts and frequency of PA outside the home decreased progressively with age for both genders. Women had a sharper decline in frequencies of self-reported PA. Men had a significant decrease in utilitarian walking, which women did not (p=0.07). Among participants who reported any PA (n=190), more women indicated exercising indoors more often than outdoors (59% vs. 44%, p=0.04). Men perceived their neighborhoods more favorably than women. However, women perceived better accessibility to neighborhood resources. Higher NPs were associated with more frequent total PA and exercise outside the home. Association of NP with recreational walking was limited to men whereas association of NP with utilitarian walking was limited to women.

CONCLUSION: Older men and women differed in levels, types and location preferences of PA, NPs and their influences on PA. Consideration of these sex differences is necessary to improve the effectiveness of active living promotion programs among older adults, especially those targeting NPs.

Pharmacotherapy Use in Older Patients with Heart Failure and Reduced Ejection Fraction Living in Skilled Nursing Facilities

Tue, 05/16/2017 - 4:45pm

Background: Little is known about the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and β-blockers among older adults with heart failure and reduced ejection fraction (HFrEF) in skilled nursing facilities (SNFs).

Methods: Using national data Minimum Data Set 3.0 cross-linked with Medicare data (2011-2012), we studied 31,675 patients with HFrEF (ICD-9 codes: 428.2 or 428.4) aged ≥65 years admitted to 9,659 SNFs. We estimated the prevalence of a Part D claim for ACEIs/ARBs or β-blockers during 3 months before the SNF stay and used log-binomial models to evaluate correlates of use by estimating prevalence ratios (PR) and 95% confidence intervals (CI).

Results: The median age of the study population was 83 years, 60% were women, and 10% and 4% were African Americans and Hispanics, respectively. Approximately 46% had ≥3 important risk factors for HFrEF. Fifty-seven percent received an ACEI/ARB and 47% a β-blocker; 25% received neither. Older age was inversely associated with receipt of these therapies: adjusted PRs were 0.94 (95% CI: 0.91-0.96) for ACEIs/ARBs and 0.86 (95% CI: 0.84-0.89) for β-blockers for patients aged ≥85 years compared with those aged 65-74 years. Compared with Whites, use of these therapies was higher among African Americans (adjusted PRs were 1.07 [95% CI: 1.04-1.10] for ACEIs/ARBs and 1.11 [95% CI: 1.08-1.15] for β-blockers) and Hispanics (adjusted PRs were 1.13 [95% CI: 1.09-1.18] for ACEIs/ARBs and 1.12 [95% CI: 1.07-1.18] for β-blockers). The prevalence of ACEI/ARB use was greater in patients with ≥3 important risk factors than in those with ≤1 factor: adjusted PR was 1.16 (95% CI 1.13-1.19).

Conclusions: Use of guideline-directed medications may be suboptimal in older patients with HFrEF receiving SNF care. Whether this is a result of adverse drug events from prior use or insufficient evidence in vulnerable populations needs to be examined.

Acknowledgements: Lin Li has received funding from a National Institutes of Health Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant (5T32HL120823-02)

Combination Photodynamic Therapy and Chemotherapy for Temozolomide-Resistant Glioblastoma

Tue, 05/16/2017 - 4:45pm

Polymer based nanoparticles (NPs) are useful vehicles for drug therapy in treating glioblastoma because of their ideal characteristics such as small size, to cross the blood-brain barrier, and bind to overexpressed transferrin receptors via peptide conjugation and surface modification of NPs. The use of a photosensitizer drug such as verteporfin, or BPD, in combination with a repurposed drug, Cediranib (CED), prepared as a nanoparticle therapy will provide the medical field with new research on the possible ways to treat glioblastoma. BPD-CED-loaded NPs have the potential to induce cytotoxicity in glioblastoma cells by 1) remotely triggering BPD through photodynamic therapy by irradiating laser at 690 nm and subsequent production of reactive oxygen species and 2) anti-angiogenesis mechanisms which may allow for longer progression free survival in patients and fewer systemic side effects due to the nanoparticle drug delivery. The specific aims of this research were to synthesize, using nanoprecipitation, and characterize pegylated and transferrin-peptide conjugated PLGA-CED NPs, PLGA-BPD NPs, and PLGA-BPD-CED NPs which were less than 100 nm in size for enhanced permeation and retention effects. NPs were characterized using dynamic light scatter (DLS) to determine particle size, PDI, and zeta potential, while absorbance spectroscopy was used to find encapsulation efficiency of loaded drugs. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were used to obtain topographical and 3-D structural imaging of NPs. The cytotoxicity of the free drugs, targeted and non-targeted single and dual-drug-loaded NPs was evaluated using MTT assay in the U87-MG cell line. MTT assay results showed increased cell death by combination nanoparticles. The size, PDI, zeta potential and encapsulation efficiency of synthesized nanoparticles were acceptable. The major goal of this research was to investigate a new combination of photodynamic-chemotherapy drugs in NP formulation to provide for a more effective targeted cell therapy in glioblastoma patients.

Selective Environmentally Benign Synthesis of Isotope Labeled Compounds: Introduction of Deuterium into Compounds of Medicinal Relevance

Tue, 05/16/2017 - 4:45pm

Deuterium (2H) is a less abundant isotope of hydrogen that possesses an additional neutron resulting in significant differences in the properties of a 1H-containing-molecule compared to its 2H homologues. Deuterium labeled organic compounds are valuable in medicinal chemistry as they offer widespread applications. For instance, in imaging deuteratium labeling can serve as biological tracers, thus, deuterated drugs can provide better understanding of the metabolic pathways; they can also help localize the metabolites of the drug and assess their toxicity. While metabolic enzymes easily transform drug molecules to metabolites that the body can excrete, the introduction of deuterium to drugs appears to strengthen the resistance of drugs toward metabolism. In fact, the carbon-deuterium bond is known to be six to ten times stronger than its C-1H counterpart. The higher the stability, the longer the drug remains intact, which allows lower dosage, potentially causing fewer side effects. Due to the carbon-deuterium bond strength, deuterated drugs can also prevent the formation of toxic metabolites observed with its hydrogen-containing homologue.

There are several known methods for the introduction of deuterium to organic compounds; most methods, however, do not conform to the recent expectations and standards of sustainable synthesis. Therefore, a green synthesis of deuterated organic compounds would be an important advance in producing these compounds in an environmentally sustainable way. Thus, we have turned our attention to the Al-H2O system that is commonly applied for hydrogenation reactions. Replacing the H2O with its deuterated version D2O in the system constitutes an easy, economic and safe source of deuterium. The application of either the commercially available Ni-Al alloy or Al in combination with Pd, a common hydrogenation catalyst, for the H-D exchange of compounds with reactive C-H bonds was performed, while yielding no harmful byproducts. The low reactivity of the aluminum metal was significantly enhanced by the application of ultrasonic irradiation prior to the reaction. The H-D exchange reaction was carried out under microwave irradiation and achieved good yields in no more than 1h. The success of the method was demonstrated by applying a broad variety of compounds from essential amino acids to actual drug compounds.

Health Applications of Network Science and Computational Social Science

Tue, 05/16/2017 - 4:45pm

Social network analysis has proliferated rapidly across the social and behavioral sciences, with increasingly apparent implications for human health. Shifting our focus from individuals to the patterns of social ties that connect them has enriched our understanding of a great variety of health-related phenomena, including the spread of STDs on contact networks, the spread of health care practices on practitioners’ professional networks, the dynamics of patient transfers on networks of clinics, and the spread of health behaviors on adolescent friendship networks. The advent of computational social science has augmented such contributions by introducing scalable methods of automatically monitoring and rigorously modeling these phenomena. Sample applications include analysis of electronic health records and other time-stamped communication traces among health care practitioners; streams of behavioral and biometric data from wearable sensors, location-aware devices, or electronic calendars; automated analysis of text in documents using natural language processing; and mapping networks of scientific collaboration by citations and co-authorships in clinical research literatures. Whereas much work in computational social science has offered new ways of empirically monitoring health behavior and health care behavior, a further contribution has been to directly model these social processes using system dynamics, microsimulation, discrete event simulation, and agent-based models. These approaches allow for computational ‘virtual’ experiments that assist in predicting, interpreting, and evaluating outcomes from health interventions. This poster will highlight some of my recent and pending work in this broad domain, aiming to identify potential collaborators in UMCCTS for projects that involve social networks or computational social science.

Oxycodone Ingestion Patterns in Acute Fracture Pain: a Pilot Study Using a Digital Pill

Tue, 05/16/2017 - 4:45pm

Background: Opioids are prescribed for acute pain as needed, but no data exists on how patients take opioids after discharge from the ED. This places the onus of dosing on the patient and contributes to variable prescribing by ED physicians. ED opioid prescriptions serve as a source for unintentional exposure and contribute to the opioid epidemic. We deployed a digital pill to measure opioid ingestion patterns in individuals discharged after acute fractures.

Methods: This pilot study involved individuals without chronic opioid use (i.e. prescribed opioids > 1 week) who were discharged from the ED following acute fracture. Participants were trained to use a digital pill system comprising a single pill (5 mg oxycodone tablet + radiofrequency emitter) and a hip mounted receiver. Upon contact with gastric contents, the digital pill transmitted a radio signal to the receiver, which relayed time of ingestion via cellular 3G signal in real-time to a cloud based server. Participants were instructed to take 1-2 oxycodone digital pills as needed every 8 hours for pain. Participants returned unused medication at orthopedic follow up or 1 week post discharge where any discrepancies between digital pill data and pill counts were reconciled.

Results: We enrolled 10 participants (mean age 42). 50% of fractures were managed operatively and 50% were managed nonoperatively. The system recorded ingestions with 85% accuracy. Participants ingested a mean 43 mg oxycodone during the 1 week study period with dose de-escalation occurring after 24 hours. Participants ingested a mean 75.8% of their 1 week total dose in the first 72 hours. 40% of participants stopped taking opioids by 96 hours. 40% of participants remained on opioids 1 week after injury; all required operative treatment.

Conclusions: This is the first study to determine opioid ingestion patterns in ED patients discharged with acute fracture pain. Participants self-tapered opioids after 24 hours, most ingestion occurred in the first 72 hours, and a substantial proportion (40%) stopped ingesting oxycodone by 96 hours. Our data shows individuals may require less opioid analgesics than previously considered for acute fracture pain. Additional studies should address ingestion patterns in other painful conditions and development of ED-based interventions to minimize outpatient opioid use while controlling pain.

Resident and Facility-level Correlations of Long-term Opioid Use in United States Nursing Homes

Tue, 05/16/2017 - 4:45pm

Background: There is limited information on the prevalence and multilevel risk factors of long-term opioid use in older nursing home residents despite their high burden of pain and vulnerability to adverse drug events.

Objectives: To estimate the prevalence and correlates of long-term opioid use in United States (US) nursing homes.

Methods: We used comprehensive administrative/claims data (Minimum Data Set 3.0; Medicare Part D) from 2012 to conduct a cross-sectional study of 369,180 long-stay nursing home residents who were Medicare beneficiaries, ≥65 years old, and had no cancer. Resident factors of interest included demographics and physical/cognitive impairment, and facility factors included US census region and structural characteristics (eg, bed size, ownership). Long-term opioid use was defined as ≥90 cumulative days of opioid use during a 120 day observation window - defined using fill dates and days’. Modified Poisson models were used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) between resident/ facility-level characteristics and long-term opioid use.

Results: Nearly one third of long-stay residents used any opioid, with 14.5% using opioids long-term. Among long-term users, 35.3% received a long-acting opioid, with 17.1% receiving high (≥90 mg/day oral morphine equivalents) daily doses. Hydrocodone (49.0%), tramadol (31.3%), and fentanyl (24.8%) were most commonly used. The prevalence of long-term use was higher in women (vs. men; aPR=1.20, 95% CI: 1.18-1.23) and those with no/mild cognitive impairment (vs. other; aPR=1.18, 95% CI: 1.16-1.20) or severe physical impairment (aPR=1.25; 95% CI: (1.22-1.27), and in government-owned nursing homes (vs. for-profit; aPR=1.10, 95% CI: 1.05-1.16). Long-term use varied by region (10.6% [Northeast] to 17.7% [Midwest]) and across facilities (median: 13.3% interquartile range: 6.7%-21.3%).

Conclusions: Long-term opioid use is substantially higher in nursing home residents than what has been previously reported in community-dwelling older adults. Further investigations of opioid safety in this frail population are needed.

Collaborating to Cure the Most Common Parasites on the Planet

Tue, 05/16/2017 - 4:45pm

Soil-transmitted helminths (STHs), most notably, hookworms, whipworms, and Ascaris, are nematodes that infect more than 1.5 billion of the poorest people and are leading causes of morbidity worldwide. Only one class of de-worming drugs (anthelmintic) is commonly used in mass drug administrations. New anthelmintics are urgently needed to overcome emerging resistance and to produce higher cure rates. Crystal (Cry) proteins, in particular Cry5B, made by Bacillus thuringiensis (Bt) are promising new candidates. Cry5B has excellent anthelmintic properties against many free-living and parasitic nematodes, including in vivo efficacy against multiple STH infections in rodents (Heligomasmidoes polygyrus and Ancylostoma ceylanicum) and in pigs (Ascaris suum).

An enormous challenge for STHs, very different from most diseases worked on in the developing world, is the requirement that therapies be very cheap (the people infected are very poor and current drugs costs pennies a dose), massively scalable (over 4 billion people are at risk from infection), and have a long shelf life in harsh environments, that have high temperature and humidity and no cold chain.

Working together, we have made excellent progress in our development efforts to produce a deployable version of Cry5B that is cheap, safe, scalable, and stable. These efforts are focused on microbiology, bacterial engineering, expression, and formulation. In the process of this work, we have discovered a novel bacterial expression system that meets these key requirements. In addition, we will provide latest information about the broad spectrum of activity of Cry5B against key parasites that make this therapeutic a very attractive alternative from current treatments.

Emergency Department Super-utilizer Program Involvement: Pilot Data and Methods Challenges

Tue, 05/16/2017 - 4:45pm

Super-utilizers are patients who use extreme amounts of medical services, often due to comorbid medical, social, and mental health issues. The MyLink Evaluation Project (MEP) studies MyLink, a program that connects super-utilizers with community support workers (CSWs) to improve the patient experience and reduce costs. The MEP-eligible population is ≥18 years old with at least 5 Emergency Department (ED) visits within 12 months and no other exclusions (e.g., language barriers, living out-of-region). During MEP’s pilot, among 58 eligible patients, 28 consented to being referred to MyLink and followed up. Of these, 7 could not be located for follow-up, 8 refused enrollment, and the remaining 13 enrolled and “engaged” (had at least 3 face-to-face contacts and developed an initial plan). All 13 enrollees were followed at 6 months vs. 4 of the 8 not enrolled. Consequently, we expect about 50% of eligible patients to consent to the main randomized study, with the vast majority of the MyLink-assigned group becoming engaged and completing follow-up. Achieving this requires identifying patients in real-time at the ED, frequent communications between researchers and CSWs, cultivating rapport during patient referral, enrollment, and follow-up, coordinating with other care management programs serving our patients, and adhering to MEP protocols that are rapidly evolving to address and overcome barriers. Challenges include: increasingly heavy CSW case-loads that decrease “warm” handoffs during the ED visit; problematic patient contact information; and incomplete program and follow-up assessments due to patient withdrawal, relocation, or death. These challenges lead to missing quality-of-life and healthcare utilization data needed for program evaluation. To reduce incomplete assessments, we lengthened time windows and expanded outreach methods (e.g., in-person upon ED revisit, web and medical record searches for updated contact information). We hypothesize that MyLink will improve patient quality-of-life and reduce ED utilization and total costs of care for super-utilizers.

Theoretical and Experimental Analysis of the Antioxidant Features of Phenol and Aniline Model Compounds

Tue, 05/16/2017 - 4:45pm

Reactive oxygen and nitrogen species (ROS/RNS) have been implicated in the aging process and numerous diseases including cancer, cardiovascular diseases, neurodegenerative diseases and diabetes. Several natural products such and polyphenols including resveratrol have been investigated as potential antioxidants preventing and/or treating diseases related to oxidative stress. We intend to gain better insight into the mechanism of action of these bioactive molecules and ultimately develop new derivatives with improved antioxidant capacity. Our computational and experimental studies on resveratrol-inspired hydrazone derivatives have shown that an -NH group may act as a better radical scavenger than the phenolic-OH that is commonly found in natural polyphenols. To assess this idea, several simple phenol and aniline derivatives were selected as model compounds and basic structural, energetic and electronic features of these compounds were calculated by density functional theory (DFT) to determine the structural characteristics that has major effect on the radical scavenging activity. The structures were analyzed at the B3LYP/6-31G(d,p) level of theory using Gaussian09 to identify the ionization potential, N-H dissociation enthalpy, proton affinity, HOMO/LUMO energies, and the band gaps. This data was correlated with the experimental antioxidant activity determined in three assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzthiazoline6-sulphonic acid) (ABTS), and oxygen radical absorbance capacity (ORAC). The % radical scavenging has been analyzed as a function of the above determined structural parameters in order to identify the role of the structural, energetic and electronic features in determining the antioxidant activity.

Pleural Sepsis Associated with High Mortality in Orthotopic Liver Transplantation Recipients

Tue, 05/16/2017 - 4:45pm

Background: Orthotopic liver transplantation (OLT) is currently the only definitive treatment for patients with acute liver failure and end-stage liver cirrhosis. Pulmonary complications are a leading cause of post-operative morbidity and mortality. Post-transplant pleural effusions have been reported in the immediate post-operative period reported in about 32 – 47 % of effusion.

Methods: From a database of 1517 patients who presented at our medical center with pleural effusions from 2010 – 2015, we identified 21 patients who had liver transplants using ICD code 50.59. We performed chart reviews to assess the occurrence of the pleural effusion in relation to their liver transplant and determined the impact this had on survival.

Results: Mean age was 60 years (± 7), 71 % were men, and the mean MELD score was 21 (± 8). There were 5 patients who developed pleural effusions after OLT resulting in an incidence rate of 23.8%. Four out of the 5 patients had a positive pleural fluid culture. The most common isolate was Pseudomonas aeruginosa (3 patients) while the other two had Klebsiella pneumonia and Candida glabarata respectively.

Mortality rate in the 5 year period was 42.9 %; and was higher in patients with sepsis (71 vs. 28.5 %, p= 0.06). In multivariate cox regression analysis, pleural sepsis was the strongest predictor of mortality (HR 9.2 95 % CI 1.2-66, p 0.03).

Conclusions: Pleural effusions are a common post-operative complication in OLT patients with an increased mortality associated with pleural space infections. OLT patients who present with pleural effusions must therefore undergo pleural aspiration with a view to diagnose and treat these infections promptly in order to improve survival. Our study is limited by a small sample size and retrospective design selecting for patients who may have had a higher risk of mortality in the first instance.

Video Capsule Endoscopy in Patients with Muir-Torre Syndrome

Tue, 05/16/2017 - 4:45pm

Introduction: Muir-Torre Syndrome (MTS) is a rare, primarily autosomal dominant disorder that is distinguished by having sebaceous skin malignancies in addition to visceral malignancies. The most common form of MTS is a variant of HNPCC. Our aim is to demonstrate the utilization of VCE in patients with MTS as the first line screening method.

Methods: Single center, retrospective chart review study of outpatients with MTS who underwent a video capsule endoscopy study between January 2006 and January 2016.

Results: Four patients, all women and mean age of 57 years old, with MTS underwent a video capsule endoscopy at our institution. In 75% of the patients, VCE detected polyps at a point in the small bowel which upper endoscopy and colonoscopy did not visualize. Two patients had large jejunal polyps, approximately 20mm in diameter. One patient had multiple 3-20mm sessile polyps from the duodenum to the ileum. On endoscopy, only one of the patients had a polyp detected and it was a 10mm polyp in the stomach which was positive for GIST. With regards to colonoscopy, 2 of the patients had critical findings of colonic mucosa with focal adenomatous changes and cryptitis (high grade dysplasia) and T1 poorly differentiated signet cell carcinoma respectively. Both of these patients underwent total colectomies. Cumulatively, all four of these patients have undergone 17 endoscopies/colonoscopies.

Conclusion: MTS is a disorder that needs to be monitored closely as patients have a high propensity of developing gastrointestinal malignancies. Current recommendations are colonoscopies annually starting at ages 20-25 and endoscopies with gastric antrum biopsies starting at ages 30-35. 75% of the patients had lesions in the small bowel that were only picked up by VCE. Failure to detect asymptomatic advanced lesions in the small bowel may have serious consequences. We therefore recommend pan-endoscopy in this rare syndrome.

The Home Matters: Adolescents Drink More SSBs When Available at Home

Tue, 05/16/2017 - 4:45pm

Objective: Sugar sweetened beverage (SSB) consumption has increased by 300% in the past three decades and the largest source of both added sugar and calories in the diets of US adolescents. It has been argued that the increased intake of SSBs has contributed to the rising prevalence of obesity. The availability and accessibility of foods/drinks in multiple levels of an adolescent’s environment can influence one’s choices and impact consumption. The aim of this study is to examine the association between adolescent self-report of the availability of SSBs in their home and SSB consumption and whether neighborhood and school SSB availability modifies the association between availability of SSBs in the home and adolescent SSB consumption.

Methods: The Family Life, Activity, Sun, Health and Eating (FLASHE) was used to conduct a cross sectional analysis of 1,484 parent-adolescent dyads. Each dyad completed four online surveys about dietary and activity health behaviors. Ordinal logistic regression analyses were conducted to determine the association between the measures of SSB availability in the home and teen SSB consumption behaviors. The potential moderators, school SSB availability and neighborhood SSB availability, were tested separately using stratified ordinal logistic regression analyses.

Results: The greater frequency of availability of SSB’s in the home had a positive association with teen SSB consumption. This association remained present despite the availability of SSB’s in other locations. There was no moderation effect present in either school SSB availability and neighborhood SSB availability.

Conclusion: Understanding the impact of the availability of SSB’s in multiple environments on consumption is important for obesity prevention efforts. This study found that parents can be important factors in reducing adolescent SSB consumption by influencing the home environment. Despite the availability of SSB’s in other environments, the home remains important for impacting consumption.

A Randomized Controlled Trial of Community Health Workers Using Patient Stories to Support Hypertension Management: Preliminary Results

Tue, 05/16/2017 - 4:45pm

Background: Uncontrolled hypertension is a significant public health problem in the U.S. with about one half of people able to keep blood pressure under control. Furthermore, the social and economic costs of poor hypertension control are staggering. Community Health Worker (CHW) interventions are a low-cost, culturally tailored approach to improve chronic disease outcomes.

Methods: This randomized trial conducted at two Community Health Centers (CHCs) in Massachusetts assessed the effect of CHWs assisting patients with hypertension. CHWs, trained in motivational interviewing, used video narratives from patients who have worked to control their BP through diet, exercise, and better medication adherence. Participants enrolled in the study were randomly assigned to immediate intervention or a delayed intervention (DI) (4 to 6 months later). Each participant received a DVD and met with a CHW 5 times (twice in person and three times telephonically) over six months.

Results: One hundred seventy-one patients were randomly assigned to one of two treatment conditions. Participants ranged in age from 25 to 79 years old (mean = 56 years old). Seventy-three percent of participants were Hispanic and reported speaking Spanish at home. The intervention group experienced a significant reduction in BP over the 6 month period of time they were receiving the intervention. At 6 months, the average systolic BP declined from 141 at baseline to 136 (p <.0001); while the average diastolic declined from 91 to 86 (p<.0001). During this same period of time, the control group did not experience a significant reduction in BP. The control group's average systolic BP declined from 141 to 138 (p=0.2076) and average diastolic BP declined from 87 to 83 (p=0.2325).

Discussion: Having culturally appropriate tools, such as narrative videos and CHWs trained in motivational interviewing, can be an important, cost effective aid to educate, support, and encourage people to manage hypertension.

Evolution of the Alpha-1 Antitrypsin Muscle Gene Therapy: Translation from Clinical Trial to Benchtop and Back Again

Tue, 05/16/2017 - 4:45pm

Alpha-one antitrypsin (AAT) deficiency is a genetic disease affecting the lungs due to inadequate anti-protease activity in the pulmonary interstitium. On-going human trials use intra-muscular delivery of adeno-associated virus (rAAV1), allowing expressing myofibers to secrete normal (M)AAT protein. In the Phase IIa trial, patients in the highest dose cohort (6x1012vg/kg) were given 100 intra-muscular (IM) injections of undiluted vector, with serum AAT levels still substantially below target levels. Previous work has shown that delivering rAAV vector to the musculature via limb perfusion leads to widespread gene expression in myofibers. We hypothesize that widespread delivery would result in an overall increase in serum AAT levels with the same dose of AAV gene therapy vector and allow for increased volume and thereby dose of vector. In macaques, similar serum myc-tagged rhAAT was produced using regional venous infusion when compared to direct IM delivery at the same total vg dose with either rAAV1 or rAAV8, while not being limited to a small volume as with IM injection. These data prove the concept that a 30-fold expanded volume of rAAV-AAT could be delivered to myofibers using limb perfusion without loss of potency on a per vg basis, thereby enabling potential achievement of therapeutic AAT levels in patients. This will allow us to proceed to a phase IIb clinical trial in AAT patients employing venous limb perfusion.