eScholarship@UMMS

In animals, hearing loss resulting from cochlear mechanosensory cell damage can be mitigated by antioxidants such as d-methionine (d-met) and acetyl-l-carnitine (ALCAR). The systemic routes of administration of these compounds, that must of necessity transit trough the cochlear fluids, may affect the antioxidant levels in the cochlea and the resulting oto-protective effect. In this study, we analyzed the pharmacokinetics of [C]d-met in the cochlea and four other tissues after intratracheal (IT), intranasal (IN), and oral by gavage (OG) administration and compared it to intravenous administration (IV). We then analyzed the effect of these four routes on the antioxidant content of the cochlear fluids after d-met or ALCAR administration, by liquid chromatography/mass spectrometry. Our results showed that the concentration of methionine and ALCAR in cochlear fluids significantly increased after their respective systemic administration. Interestingly, d-met administration also contributed to an increase of ALCAR. Our results also showed that the delivery routes differently affected the bioavailability of administered [C]d-met as well as the concentrations of methionine, ALCAR and the ratio of oxidized to reduced glutathione. Overall, pulmonary delivery via IT administration achieved high concentrations of methionine, ALCAR, and oxidative-related metabolites in cochlear fluids, in some cases surpassing IV administration, while IN route appeared to be the least efficacious. To our knowledge, this is the first report of the direct measurements of antioxidant levels in cochlear fluids after their systemic administration. This report also demonstrates the validity of the pulmonary administration of antioxidants and highlights the different contributions of d-met and ALCAR allowing to further investigate their impact on oxidative stress in the cochlear microenvironment.

Inner ear sensory hair cells die following exposure to aminoglycoside antibiotics or chemotherapeutics like cisplatin, leading to permanent auditory and/or balance deficits in humans. Zebrafish (Danio rerio) are used to study drug-induced sensory hair cell death since their hair cells are similar in structure and function to those found in humans. We developed a cisplatin dose-response curve using a transgenic line of zebrafish that expresses membrane-targeted green fluorescent protein under the control of the Brn3c promoter/enhancer. Recently, several small molecule screens have been conducted using zebrafish to identify potential pharmacological agents that could be used to protect sensory hair cells in the presence of ototoxic drugs. Dimethyl sulfoxide (DMSO) is typically used as a solvent for many pharmacological agents in sensory hair cell cytotoxicity assays. Serendipitously, we found that DMSO potentiated the effects of cisplatin and killed more sensory hair cells than treatment with cisplatin alone. Yet, DMSO alone did not kill hair cells. We did not observe the synergistic effects of DMSO with the ototoxic aminoglycoside antibiotic neomycin. Cisplatin treatment with other commonly used organic solvents (i.e. ethanol, methanol, and polyethylene glycol 400) also did not result in increased cell death compared to cisplatin treatment alone. Thus, caution should be exercised when interpreting data generated from small molecule screens since many compounds are dissolved in DMSO.

Dietary composition has major effects on physiology. Here, we show that developmental rate, reproduction, and lifespan are altered in C. elegans fed Comamonas DA1877 relative to those fed a standard E. coli OP50 diet. We identify a set of genes that change in expression in response to this diet and use the promoter of one of these (acdh-1) as a dietary sensor. Remarkably, the effects on transcription and development occur even when Comamonas DA1877 is diluted with another diet, suggesting that Comamonas DA1877 generates a signal that is sensed by the nematode. Surprisingly, the developmental effect is independent from TOR and insulin signaling. Rather, Comamonas DA1877 affects cyclic gene expression during molting, likely through the nuclear hormone receptor NHR-23. Altogether, our findings indicate that different bacteria elicit various responses via distinct mechanisms, which has implications for diseases such as obesity and the interactions between the human microbiome and intestinal cells.

Gene expression is regulated at multiple levels, including transcription and translation, as well as mRNA and protein stability. Although systems-level functions of transcription factors and microRNAs are rapidly being characterized, few studies have focused on the posttranscriptional gene regulation by RNA binding proteins (RBPs). RBPs are important to many aspects of gene regulation. Thus, it is essential to know which genes encode RBPs, which RBPs regulate which gene(s), and how RBP genes are themselves regulated. Here we provide a comprehensive compendium of RBPs from the nematode Caenorhabditis elegans (wRBP1.0). We predict that as many as 887 (4.4%) of C. elegans genes may encode RBPs ~250 of which likely function in a gene-specific manner. In addition, we find that RBPs, and most notably gene-specific RBPs, are themselves enriched for binding and modification by regulatory proteins, indicating the potential for extensive regulation of RBPs at many different levels. wRBP1.0 will provide a significant contribution toward the comprehensive delineation of posttranscriptional regulatory networks and will provide a resource for further studies regulation by RBPs.

Gene families expand by gene duplication and resulting paralogs diverge through mutation. Functional diversification can include neo-functionalization as well as sub-functionalization of ancestral functions. In addition, redundancy in which multiple genes fulfill overlapping functions is often maintained. Here, we use the family of 40 Caenorhabditis elegans insulins to gain insight into the balance between specificity and redundancy. The insulin/insulin-like growth factor (IIS) pathway comprises a single receptor, DAF-2. To date, no single insulin-like peptide recapitulates all DAF-2-associated phenotypes, likely due to redundancy between insulin-like genes. To provide a first-level annotation of potential patterns of redundancy, we comprehensively delineate the spatiotemporal and conditional expression of all 40 insulins in living animals. We observe extensive dynamics in expression that can explain the lack of simple patterns of pair-wise redundancy. We propose a model in which gene families evolve to attain differential alliances in different tissues and in response to a range of environmental stresses.

Expression profiles are tailored according to dietary input. However, the networks that control dietary responses remain largely uncharacterized. Here, we combine forward and reverse genetic screens to delineate a network of 184 genes that affect the C. elegans dietary response to Comamonas DA1877 bacteria. We find that perturbation of a mitochondrial network composed of enzymes involved in amino acid metabolism and the TCA cycle affects the dietary response. In humans, mutations in the corresponding genes cause inborn diseases of amino acid metabolism, most of which are treated by dietary intervention. We identify several transcription factors (TFs) that mediate the changes in gene expression upon metabolic network perturbations. Altogether, our findings unveil a transcriptional response system that is poised to sense dietary cues and metabolic imbalances, illustrating extensive communication between metabolic networks in the mitochondria and gene regulatory networks in the nucleus.

Mammalian genomes encode genetic information in their linear sequence, but appropriate expression of their genes requires chromosomes to fold into complex three-dimensional structures. Transcriptional control involves the establishment of physical connections among genes and regulatory elements, both along and between chromosomes. Recent technological innovations in probing the folding of chromosomes are providing new insights into the spatial organization of genomes and its role in gene regulation. It is emerging that folding of large complex chromosomes involves a hierarchy of structures, from chromatin loops that connect genes and enhancers to larger chromosomal domains and nuclear compartments. The larger these structures are along this hierarchy, the more stable they are within cells, while becoming more stochastic between cells. Here, we review the experimental and theoretical data on this hierarchy of structures and propose a key role for the recently discovered topologically associating domains.

Objectives: (1) to identify common errors in data organization and metadata completeness that would preclude a “reader” from being able to interpret and re-use the data for a new purpose; and (2) to develop a set of best practices derived from these common errors that would guide researchers in creating more usable data products that could be readily shared, interpreted, and used.

Methods: We used directed qualitative content analysis to assess and categorize data and metadata errors identified by peer reviewers of data papers published in the Ecological Society of America’s (ESA) Ecological Archives. Descriptive statistics provided the relative frequency of the errors identified during the peer review process.

Results: There were seven overarching error categories: Collection & Organization, Assure, Description, Preserve, Discover, Integrate, and Analyze/Visualize. These categories represent errors researchers regularly make at each stage of the Data Life Cycle. Collection & Organization and Description errors were some of the most common errors, both of which occurred in over 90% of the papers.

Conclusions: Publishing data for sharing and reuse is error prone, and each stage of the Data Life Cycle presents opportunities for mistakes. The most common errors occurred when the researcher did not provide adequate metadata to enable others to interpret and potentially re-use the data. Fortunately, there are ways to minimize these mistakes through carefully recording all details about study context, data collection, QA/ QC, and analytical procedures from the beginning of a research project and then including this descriptive information in the metadata.

Background

The reduction in adrenergic activity and anxiety associated with meditation may be beneficial for patients with implantable cardioverter defibrillators. Purpose

This study aims to determine the feasibility of a phone-delivered mindfulness intervention in patients with defibrillators and to obtain preliminary indications of efficacy on mindfulness and anxiety. Methods

Clinically stable outpatients were randomized to a mindfulness intervention (eight weekly individual phone sessions) or to a scripted follow-up phone call. We used the Hospital Anxiety and Depression Scale and the Five Facets of Mindfulness to measure anxiety and mindfulness, and multivariate linear regression to estimate the intervention effect on pre-post-intervention changes in these variables. Results

We enrolled 45 patients (23 mindfulness and 22 control; age, 43–83; 30 % women). Retention was 93 %; attendance was 94 %. Mindfulness (beta = 3.31; p = 0.04) and anxiety (beta = −1.15; p = 0.059) improved in the mindfulness group. Conclusions

Mindfulness training can be effectively phone-delivered and may improve mindfulness and anxiety in cardiac defibrillator outpatients.

Perioperative treatment of several rats in our facility with ketoprofen (5 mg/kg SC) resulted in blood loss, peritonitis, and death within a day to a little more than a week after surgery that was not related to the gastrointestinal tract. Published reports have established the 5-mg/kg dose as safe and effective for rats. Because ketoprofen is a nonselective nonsteroidal antiinflammatory drug that can damage the gastrointestinal tract, the putative diagnosis for these morbidities and mortalities was gastrointestinal toxicity caused by ketoprofen (5 mg/kg). We conducted a prospective study evaluating the effect of this therapeutic dose of ketoprofen on the rat gastrointestinal tract within 24 h. Ketoprofen (5 mg/kg SC) was administered to one group of rats that then received gas anesthesia for 30 min and to another group without subsequent anesthesia. A third group was injected with saline followed by 30 min of gas anesthesia. Our primary hypothesis was that noteworthy gastrointestinal bleeding and lesions would occur in both groups treated with ketoprofen but not in rats that received saline and anesthesia. Our results showed marked gastrointestinal bleeding, erosions, and small intestinal ulcers in the ketoprofen-treated rats and minimal damages in the saline-treated group. The combination of ketoprofen and anesthesia resulted in worse clinical signs than did ketoprofen alone. We conclude that a single 5-mg/kg dose of ketoprofen causes acute mucosal damage to the rat small intestine.

STUDY OBJECTIVE: We describe the incidence and types of medical errors in emergency departments (EDs) and assess the validity of a survey instrument that identifies systems factors contributing to errors in EDs.

METHODS: We conducted the National Emergency Department Safety Study in 62 urban EDs across 20 US states. We reviewed 9,821 medical records of ED patients with one of 3 conditions (myocardial infarction, asthma exacerbation, and joint dislocation) to evaluate medical errors. We also obtained surveys from 3,562 staff randomly selected from each ED; survey data were used to calculate average safety climate scores for each ED.

RESULTS: We identified 402 adverse events (incidence rate 4.1 per 100 patient visits; 95% confidence interval [CI] 3.7 to 4.5) and 532 near misses (incidence rate 5.4 per 100 patient visits; 95% CI 5.0 to 5.9). We judged 37% of the adverse events, and all of the near misses, to be preventable (errors); 33% of the near misses were intercepted. In multivariable models, better ED safety climate was not associated with fewer preventable adverse events (incidence rate ratio per 0.2-point increase in ED safety score 0.82; 95% CI 0.57 to 1.16) but was associated with more intercepted near misses (incidence rate ratio 1.79; 95% CI 1.06 to 3.03). We found no association between safety climate and violations of national treatment guidelines.

CONCLUSION: Among the 3 ED conditions studied, medical errors are relatively common, and one third of adverse events are preventable. Improved ED safety climate may increase the likelihood that near misses are intercepted. Inc. All rights reserved.

We hypothesized that atomoxetine (ATMX) would produce similar brain effects in attention-deficit/hyperactivity disorder (ADHD) as those of methylphenidate (MPH). Eleven ADHD adults performed the Multi-Source Interference Task (MSIT) during functional magnetic resonance imaging (fMRI) at baseline and after 6 weeks of ATMX treatment. ATMX was associated with increased fMRI activation of dorsolateral prefrontal cortex, parietal cortex and cerebellum but not dorsal anterior midcingulate cortex (daMCC). These results suggest that ATMX and MPH have similar but not identical brain effects.

BACKGROUND: Previous studies examining characteristics of Internet health information seekers do not distinguish between those who only seek for themselves, and surrogate seekers who look for health information for family or friends. Identifying the unique characteristics of surrogate seekers would help in developing Internet interventions that better support these information seekers.

OBJECTIVE: To assess differences between self seekers versus those that act also as surrogate seekers.

METHODS: We analyzed data from the cross-sectional Pew Internet and American Life Project November/December 2008 health survey. Our dependent variable was self-report of type of health information seeking (surrogate versus self seeking). Independent variables included demographics, health status, and caregiving. After bivariate comparisons, we then developed multivariable models using logistic regression to assess characteristics associated with surrogate seeking.

RESULTS: Out of 1250 respondents who reported seeking health information online, 56% (N=705) reported being surrogate seekers. In multivariable models, compared with those who sought information for themselves only, surrogate seekers were more likely both married and a parent (OR=1.57, CI=1.08, 2.28), having good (OR=2.05, CI=1.34, 3.12) or excellent (OR=2.72, CI=1.70, 4.33) health status, being caregiver of an adult relative (OR=1.76, CI=1.34, 2.30), having someone close with a serious medical condition (OR=1.62, CI=1.21, 2.17) and having someone close to them facing a chronic illness (OR=1.55, CI=1.17, 2.04).

CONCLUSIONS: Our findings provide evidence that information needs of surrogate seekers are not being met, specifically of caregivers. Additional research is needed to develop new functions that support surrogate seekers.

Immigrants returning home to visit friends and relatives (VFR travelers) are at higher risk of travel-associated illness than other international travelers. We evaluated 3,707 VFR and 17,507 non-VFR travelers seen for pre-travel consultation in Global TravEpiNet during 2009-2011; all were traveling to resource-poor destinations. VFR travelers more commonly visited urban destinations than non-VFR travelers (42% versus 30%, P < 0.0001); 54% of VFR travelers were female, and 18% of VFR travelers were under 6 years old. VFR travelers sought health advice closer to their departure than non-VFR travelers (median days before departure was 17 versus 26, P < 0.0001). In multivariable analysis, being a VFR traveler was an independent predictor of declining a recommended vaccine. Missed opportunities for vaccination could be addressed by improving the timing of pre-travel health care and increasing the acceptance of vaccines. Making pre-travel health care available in primary care settings may be one step to this goal.

OBJECTIVES: The goal of this study was to assess the relationship of left ventricular (LV) trabeculae and papillary muscles (TPM) with clinical characteristics in a community-based, free-living adult cohort and to determine the effect of TPM on quantitative measures of LV volume, mass, and ejection fraction (EF).

BACKGROUND: Hypertrabeculation has been associated with adverse cardiovascular events, but the distribution and clinical correlates of the volume and mass of the TPM in a normal left ventricle have not been well characterized.

METHODS: Short-axis cine cardiac magnetic resonance images, obtained using a steady-state free precession sequence from 1,494 members of the Framingham Heart Study Offspring cohort, were analyzed with software that automatically segments TPM. Absolute TPM volume, TPM as a fraction of end-diastolic volume (EDV) (TPM/EDV), and TPM mass as a fraction of LV mass were determined in all offspring and in a referent group of offspring free of clinical cardiovascular disease and hypertension.

RESULTS: In the referent group (mean age 61 +/- 9 years; 262 men and 423 women), mean TPM was 23 +/- 3% of LV EDV in both sexes (p = 0.9). TPM/EDV decreased with age (p < 0.02) but was not associated with body mass index. TPM mass as a fraction of LV mass was inversely correlated with age (p < 0.0001), body mass index (p < 0.018), and systolic blood pressure (p < 0.0001). Among all 1,494 participants (699 men), LV volumes decreased 23%, LV mass increased 28%, and EF increased by 7.5 EF units (p < 0.0001) when TPM were considered myocardial mass rather than part of the LV blood pool.

CONCLUSIONS: Global cardiac magnetic resonance LV parameters were significantly affected by whether TPM was considered as part of the LV blood pool or as part of LV mass. Our cross-sectional data from a healthy referent group of adults free of clinical cardiovascular disease demonstrated that TPM/EDV decreases with increasing age in both sexes but is not related to hypertension or obesity. Elsevier Inc. All rights reserved.

INTRODUCTION: Identifying major bleeding is fundamental to assessing the outcomes of anticoagulation therapy. This drives the need for a credible implementation in automated data for the International Society of Thrombosis and Haemostasis (ISTH) definition of major bleeding.

MATERIALS AND METHODS: We studied 102,395 patients who received 158,511 person-years of warfarin treatment from the Veterans Health Administration (VA) between 10/1/06-9/30/08. We constructed a list of ICD-9-CM codes of "candidate" bleeding events. Each candidate event was identified as a major hemorrhage if it fulfilled one of four criteria: 1) associated with death within 30days; 2) bleeding in a critical anatomic site; 3) associated with a transfusion; or 4) was coded as the event that precipitated or was responsible for the majority of an inpatient hospitalization.

RESULTS: This definition classified 11,240 (15.8%) of 71, 338 candidate events as major hemorrhage. Typically, events more likely to be severe were retained at higher rates than those less likely to be severe. For example, Diverticula of Colon with Hemorrhage (562.12) and Hematuria (599.7) were retained 46% and 4% of the time, respectively. Major, intracranial, and fatal hemorrhage were identified at rates comparable to those found in randomized clinical trials however, higher than those reported in observational studies: 4.73, 1.29, and 0.41 per 100 patient years, respectively.

CONCLUSIONS: We describe here a workable definition for identifying major hemorrhagic events from large automated datasets. This method of identifying major bleeding may have applications for quality measurement, quality improvement, and comparative effectiveness research.

Coinfection with Plasmodium falciparum malaria and Epstein-Barr virus (EBV) is a major risk factor for endemic Burkitt lymphoma (eBL), still one of the most prevalent pediatric cancers in equatorial Africa. Although malaria infection has been associated with immunosuppression, the precise mechanisms that contribute to EBV-associated lymphomagenesis remain unclear. In this study, we used polychromatic flow cytometry to characterize CD8(+) T-cell subsets specific for EBV-derived lytic (BMFL1 and BRLF1) and latent (LMP1, LMP2, and EBNA3C) antigens in individuals with divergent malaria exposure. No malaria-associated differences in EBV-specific CD8(+) T-cell frequencies were observed. However, based on a multidimensional analysis of CD45RO, CD27, CCR7, CD127, CD57, and PD-1 expression, we found that individuals living in regions with intense and perennial (holoendemic) malaria transmission harbored more differentiated EBV-specific CD8(+) T-cell populations that contained fewer central memory cells than individuals living in regions with little or no (hypoendemic) malaria. This profile shift was most marked for EBV-specific CD8(+) T-cell populations that targeted latent antigens. Importantly, malaria exposure did not skew the phenotypic properties of either cytomegalovirus (CMV)-specific CD8(+) T cells or the global CD8(+) memory T-cell pool. These observations define a malaria-associated aberration localized to the EBV-specific CD8(+) T-cell compartment that illuminates the etiology of eBL.

BACKGROUND: Among patients receiving oral anticoagulation, a gap of andgt; 56 days between international normalized ratio tests suggests loss to follow-up that could lead to poor anticoagulation control and serious adverse events.

METHODS: We studied long-term oral anticoagulation care for 56,490 patients aged 65 years and older at 100 sites of care in the Veterans Health Administration. We used the rate of gaps in monitoring per patient-year to predict percentage time in therapeutic range (TTR) at the 100 sites.

RESULTS: Many patients (45%) had at least one gap in monitoring during an average of 1.6 years of observation; 5% had two or more gaps per year. The median gap duration was 74 days (interquartile range, 62-107). The average TTR for patients with two or more gaps per year was 10 percentage points lower than for patients without gaps (P andlt; .001). Patient-level predictors of gaps included nonwhite race, area poverty, greater distance from care, dementia, and major depression. Site-level gaps per patient-year varied from 0.19 to 1.78; each one-unit increase was associated with a 9.2 percentage point decrease in site-level TTR (P andlt; .001).

CONCLUSIONS: Site-level gap rates varied widely within an integrated care system. Sites with more gaps per patient-year had worse anticoagulation control. Strategies to address and reduce gaps in monitoring may improve anticoagulation control.

Older adults with multiple chronic conditions (MCCs) require considerable health services and complex care. Because the persistence and progression of diseases and courses of treatments affect health status in multiple dimensions, well-validated universal outcome measures across diseases are needed for research, clinical care, and administrative purposes. An expert panel meeting held by the National Institute on Aging in September 2011 recommends that older persons with MCCs complete a brief initial composite measure that includes general health; pain; fatigue; and physical health, mental health, and social role function, along with gait speed measurement. Suitable composite measures include the Medical Outcomes Study 8 (SF-8) and 36 (SF-36) -item Short-Form Survey and the Patient Reported Outcomes Measurement Information System 29-item Health Profile. Based on responses to items in the initial measure, short follow-on measures should be selectively targeted to symptom burden, depression, anxiety, and daily activities. Persons unable to walk a short distance to assess gait speed should be assessed using a physical function scale. Remaining gaps to be considered for measure development include disease burden, cognitive function, and caregiver burden. Routine outcome assessment of individuals with MCCs could facilitate system-based care improvement and clinical effectiveness research. Geriatrics Society. Conditions