Osteopetrorickets due to Snx10 deficiency in mice results from both failed osteoclast activity and loss of gastric acid-dependent calcium absorption
Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some of them fatal. To study the disease pathogenesis, we investigated the expression of Snx10 and created mouse models in which Snx10 was knocked down globally or knocked out in osteoclasts. Endocytosis is severely defective in Snx10-deficient osteoclasts, as is extracellular acidification, ruffled border formation, and bone resorption. We also discovered that Snx10 is highly expressed in stomach epithelium, with mutations leading to high stomach pH and low calcium solubilization. Global Snx10-deficiency in mice results in a combined phenotype: osteopetrosis (due to osteoclast defect) and rickets (due to high stomach pH and low calcium availability, resulting in impaired bone mineralization). Osteopetrorickets, the paradoxical association of insufficient mineralization in the context of a positive total body calcium balance, is thought to occur due to the inability of the osteoclasts to maintain normal calcium-phosphorus homeostasis. However, osteoclast-specific Snx10 knockout had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Moreover, supplementation with calcium gluconate rescued mice from the rachitic phenotype and dramatically extended life span in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized. We conclude that tissue-specific effects of Snx10 mutation need to be considered in clinical approaches to this disease entity. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes fatal consequences. These studies established an essential role for Snx10 in bone homeostasis and underscore the importance of gastric acidification in calcium uptake.
Eukaryotic DNA is packaged in chromatin, whose repeating subunit, the nucleosome, consists of an octamer of histone proteins wrapped by about 147bp of DNA. This packaging affects the accessibility of DNA and hence any process that occurs on DNA, such as replication, repair, and transcription. An early observation from genome-wide nucleosome mapping in yeast was that genes had a surprisingly characteristic structure, which has motivated studies to understand what determines this architecture. Both sequence and trans acting factors are known to influence chromatin packaging, but the relative contributions of cis and trans determinants of nucleosome positioning is debated. Here we present data using genetic approaches to examine the contributions of cis and trans acting factors on nucleosome positioning in budding yeast.
We developed the use of yeast artificial chromosomes to exploit quantitative differences in the chromatin structures of different yeast species. This allows us to place approximately 150kb of sequence from any species into the S.cerevisiae cellular environment and compare the nucleosome positions on this same sequence in different environments to discover what features are variant and hence regulated by trans acting factors. This method allowed us to conclusively show that the great preponderance of nucleosomes are positioned by trans acting factors. We observe the maintenance of nucleosome depletion over some promoter sequences, but partial fill-in of NDRs in some of the YAC v promoters indicates that even this feature is regulated to varying extents by trans acting factors.
We are able to extend our use of evolutionary divergence in order to search for specific trans regulators whose effects vary between the species. We find that a subset of transcription factors can compete with histones to help generate some NDRs, with clear effects documented in a cbf1 deletion mutant. In addition, we find that Chd1p acts as a potential “molecular ruler” involved in defining the nucleosome repeat length differences between S.cerevisiae and K.lactis. The mechanism of this measurement is unclear as the alteration in activity is partially attributable to the N-terminal portion of the protein, for which there is no structural data. Our observations of a specialized chromatin structure at de novo transcriptional units along with results from nucleosome mapping in the absence of active transcription indicate that transcription plays a role in engineering genic nucleosome architecture. This work strongly supports the role of trans acting factors in setting up a dynamic, regulated chromatin structure that allows for robustness and fine-tuning of gene expression.
DNA double-strand break (DSB) repair is essential for maintenance of genome stability. However, the compaction of the eukaryotic genome into chromatin creates an inherent barrier to any DNA-mediated event, such as during DNA repair. This demands that there be mechanisms to modify the chromatin structure and thus access DNA. Recent work has implicated a host of chromatin regulators in the DNA damage response and several functional roles have been defined. Yet the mechanisms that control their recruitment to DNA lesions, and their relationship with concurrent histone modifications, remain unclear. We find that efficient DSB recruitment of many yeast chromatin regulators is cell-cycle dependent. Furthering this, we find recruitment of the INO80, SWR-C, NuA4, SWI/SNF, and RSC enzymes is inhibited by the non-homologous end joining machinery, and that their recruitment is controlled by early steps of homologous recombination. Strikingly, we find no significant role for H2A.X phosphorylation (γH2AX) in the recruitment of chromatin regulators, but rather that their recruitment coincides with reduced levels of γH2AX. We go on to determine the chromatin remodeling enzyme Fun30 functions in histone dynamics surround a DSB, but does not significantly affect γH2AX dynamics. Additionally, we describe a conserved functional interaction among the chromatin remodeling enzyme, SWI/SNF, the NuA4 and Gcn5 histone acetyltransferases, and phosphorylation of histone H2A.X. Specifically, we find that the NuA4 and Gcn5 enzymes are both required for the robust recruitment of SWI/SNF to a DSB, which in turn promotes the phosphorylation of H2A.X.
Language Proficiency, Citizenship, and Food Insecurity among Predominantly Immigrant Caribbean Latinos in Massachusetts: A Masters Thesis
BACKGROUND: Latinos report higher food insecurity than the national average, and food insecurity has been associated with adverse health outcomes wherein Latinos experience disparities. This study quantified the independent effects of language-speaking proficiency and citizenship on increased food insecurity among a predominantly immigrant Caribbean Latino sample in Lawrence, Massachusetts.
METHODS: The analytic sample comprised 574 participants aged 21-83 who visited a community health center in 2011-2013. Food insecurity was assessed via the 6-item US Household Food Security Survey. Multivariable logistic modeling (adjusted for self-reported age group, gender, education, and marital status) examined the independent associations between language proficiency and citizenship on increased food insecurity.
RESULTS: One-third of participants were classified as food insecure. Most respondents were citizens (59.5%), foreign-born (92.4%; 70.3% from the Dominican Republic), and spoke monolingual Spanish (72.8%). Monolingual Spanish-speakers had marginally increased odds of food insecurity (odds ratio (OR) = 1.50, 95% confidence interval (CI): 1.00 to 2.26), compared to bilingual participants; however after adjustment this relationship was attenuated (OR = 1.25, 95% CI: 0.79 to 2.00). Non-citizenship was not associated with increased odds of food insecurity (OR=1.18, 95% CI: 0.82 to 1.68).
CONCLUSION: Food insecurity in this predominantly immigrant Caribbean Latino sample was higher than the national average for Latinos. Future research on food insecurity among different Latino ethnicities is needed in order to inform targeted interventions that promote food security.
OBJECTIVE: To assess the following among women hospitalized antenatally due to high-risk pregnancies: (1) rates of depression symptoms and anxiety symptoms, (2) changes in depression symptoms and anxiety symptoms and, (3) rates of mental health treatment.
METHODS: Sixty-two participants hospitalized for high-risk obstetrical complications completed the Edinburgh Postnatal Depression Scale (EPDS), Generalized Anxiety Disorder 7-item scale (GAD-7) and Short-Form 12 weekly until delivery or discharge, and once postpartum.
RESULTS: Average length of total hospital stay was 8.3 +/- 7.6 days for women who completed an initial admission survey (n = 62) and 16.3 +/- 8.9 (n = 34), 25.4 +/- 10.2 (n = 17) and 35 +/- 10.9 days (n = 9) for those who completed 2, 3 and 4 surveys, respectively. EPDS was > /= 10 in 27% (n=17) and GAD-7 was > /= 10 in 13% (n = 8) of participants at initial survey. Mean anxiety (4.2 +/- 6.5 vs. 5.2 +/- 5.1, p = .011) and depression (4.4 +/- 5.6 vs. 6.9 +/- 4.8, p = .011) scores were lower postpartum compared to initial survey. Past mental health diagnosis predicted depression symptoms [odds ratio (OR) = 4.54; 95% confidence interval (CI) 1.91-7.17] and anxiety symptoms (OR = 5.95; 95% CI 3.04-8.86) at initial survey; however, 21% (n = 10) with no diagnostic history had EPDS > /= 10. Five percent (n = 3) received mental health treatment during pregnancy.
CONCLUSION: Hospitalized high-risk obstetrical patients may commonly experience depression symptoms and/or anxiety symptoms and not receive treatment. A history of mental health treatment or diagnosis was associated with depression symptoms or anxiety symptoms in pregnancy. Of women with an EPDS > /= 10, > 50% did not report a past mental health diagnosis.
We examined mental health care use in relation to depressive symptoms (Patient Health Questionnaire (PHQ-9) >/=10) among a nationally representative sample of pregnant women using data from the National Health and Nutrition Examination Survey 2005-2012. Logistic regression models estimated crude and adjusted odds ratios for mental health care use in the past year in relation to depressive symptoms. While 8.2 % (95 % CI 4.6-11.8) of pregnant women were depressed, only 12 % (95 % CI 1.8-22.1) of these women reported mental health care use in the past year.
OBJECTIVE: We aimed to determine the effect of an open-label 8 week Vitamin D3 supplementation on manic symptoms, anterior cingulate cortex (ACC) glutamate, and γ-aminobutyric acid (GABA) in youth exhibiting symptoms of mania; that is, patients with bipolar spectrum disorders (BSD). We hypothesized that an 8 week Vitamin D3 supplementation would improve symptoms of mania, decrease ACC glutamate, and increase ACC GABA in BSD patients. Single time point metabolite levels were also evaluated in typically developing children (TD).
METHODS: The BSD group included patients not only diagnosed with BD but also those exhibiting bipolar symptomology, including BD not otherwise specified (BD-NOS) and subthreshold mood ratings (Young Mania Rating Scale [YMRS] ≥8 and Clinical Global Impressions - Severity [CGI-S] ≥3). Inclusion criteria were: male or female participants, 6-17 years old. Sixteen youth with BSD exhibiting manic symptoms and 19 TD were included. BSD patients were asked to a take daily dose (2000 IU) of Vitamin D3 (for 8 weeks) as a supplement. Neuroimaging data were acquired in both groups at baseline, and also for the BSD group at the end of 8 week Vitamin D3 supplementation.
RESULTS: Baseline ACC GABA/creatine (Cr) was lower in BSD than in TD (F[1,31]=8.91, p=0.007). Following an 8 week Vitamin D3 supplementation, in BSD patients, there was a significant decrease in YMRS scores (t=-3.66, p=0.002, df=15) and Children's Depression Rating Scale (CDRS) scores (t=-2.93, p=0.01, df=15); and a significant increase in ACC GABA (t=3.18, p=0.007, df=14).
CONCLUSIONS: Following an 8 week open label trial with Vitamin D3, BSD patients exhibited improvement in their mood symptoms in conjunction with their brain neurochemistry.
The George T. Harrell Health Sciences Library at Penn State Hershey initiated its participation in institutional research data management activities by coordinating and hosting a well-attended data management symposium. To maximize relevance to clinical and basic sciences researchers, a planning committee of faculty and administrators assisted in defining important topics for the event. This article describes the symposium development and outcomes. The goal is to share this information with librarians who are seeking ways to become more involved with data management in their institutions.
Objective: To understand how New England medical libraries are addressing scientific research data management and providing services to their communities.
Setting: The National Network of Libraries of Medicine, New England Region (NN/LM NER) contains 17 Resource Libraries. The University of Massachusetts Medical School serves as the New England Regional Medical Library (RML). Sixteen of the NER Resource Libraries completed this survey.
Methods: A 40-question online survey assessed libraries’ services and programs for providing research data management education and support. Libraries shared their current plans and institutional challenges associated with developing data services.
Results: This study shows few NER Resource Libraries currently integrate scientific research data management into their services and programs, and highlights the region’s use of resources provided by the NN/LM NER RML at the University of Massachusetts Medical School.
Conclusions: Understanding the types of data services being delivered at NER libraries helps to inform the NN/LM NER about the eScience learning needs of New England medical librarians and helps in the planning of professional development programs that foster effective biomedical research data services.
Food Selectivity, Mealtime Behavior Problems, Spousal Stress, and Family Food Choices in Children with and without Autism Spectrum Disorder
Mealtime behavior problems and family stress occur frequently among families of children with autism spectrum disorder (ASD). However, it is unknown whether food selectivity is an associated factor. The associations of high food selectivity with mealtime behavior problems, spousal stress, and influence on family members were assessed among 53 children with ASD and 58 typically developing (TD) children ages 3-11 years. Compared to TD children, children with ASD were more likely to have high food selectivity, and their parents reported more mealtime behavior problems, higher spousal stress, and influence on what other family members ate. High food selectivity was associated with mealtime behavior problems in both groups. Interventions to reduce food selectivity may lead to decreases in mealtime behavior problems.
Including Youth with Intellectual Disabilities in Health Promotion Research: Development and Reliability of a Structured Interview to Assess the Correlates of Physical Activity among Youth
BACKGROUND: The input of youth with intellectual disabilities in health promotion and health disparities research is essential for understanding their needs and preferences. Regular physical activity (PA) is vital for health and well-being, but levels are low in youth generally, including those with intellectual disabilities. Understanding the perceptions of and barriers to PA as reported by youth with intellectual disabilities themselves is important for designing effective interventions.
MATERIALS AND METHODS: We developed a structured interview that queried youth with intellectual disabilities and typically developing youth (ages 13-21 years) about their enjoyment, preferences and perceived barriers to PA. We describe the development of this interview and present its test-retest reliability on 15 youth with intellectual disabilities and 20 typically developing youth.
RESULTS: Twenty-three of 33 questions were reliable in both groups. The results suggest that youth with intellectual disabilities can reliably report activities that they do or do not enjoy, as well as their beliefs and perceived benefits of PA.
CONCLUSIONS: Self-reported information on the experiences, preferences, beliefs and perceptions about among youth with intellectual disabilities is key for research efforts in health promotion and health disparities.
Functional analysis of problem behavior: A systematic approach for identifying idiosyncratic variables
When inconclusive functional analysis (FA) outcomes occur, a number of modifications have been made to enhance the putative establishing operation or consequence associated with behavioral maintenance. However, a systematic method for identifying relevant events to test during modified FAs has not been evaluated. The purpose of this study was to develop and evaluate a technology for systematically identifying events to test in a modified FA after an initial FA led to inconclusive outcomes. Six individuals, whose initial FA showed little or no responding or high levels only in the control condition, participated. An indirect assessment (IA) questionnaire developed for identifying idiosyncratic variables was administered, and a descriptive analysis (DA) was conducted. Results from the IA only or a combination of the IA and DA were used to inform modified FA test and control conditions. Conclusive FA outcomes were obtained with 5 of the 6 participants during the modified FA phase.
A hallmark of applied behavior analysis is the development of function-based interventions for problem behavior. A widely recommended function-based intervention is differential reinforcement of alternative behavior (DRA), in which reinforcement is contingent upon socially acceptable alternatives to problem behavior (e.g., teaching communication skills). Typically, DRA is introduced under rich schedules of reinforcement. Although effective for initiating behavior change, rich schedules are often impractical in the natural setting. In this study, we evaluated the extent to which a stimulus fading program could be employed to elaborate alternative behavior (mands) in two individuals diagnosed with an Autism Spectrum Disorder. For both participants, problem behavior was reduced substantially upon implementation of the DRA procedure. Further, problem behavior rates remained low and mand rates decreased to more practical levels as the DRA behavioral requirements increased during the fading program. The fading approach demonstrated in this paper may be a useful component of intervention packages for clinicians.
Our previous study using a go/no-go procedure with compound stimuli taught pigeons to peck at two-component compounds A1B1, A2B2, B1C1, B2C2 and refrain from pecking at A1B2, A2B1, B1C2, B2C1. Subjects showed training-consistent responding in tests presenting compounds rotated 180 degrees (BA and CB relations) but not recombined (AC and CA relations). It is unclear whether the responses to BA and CB stimuli were controlled by the relation between the components (conditional discrimination) or by the compounds functioning as a unitary stimulus (simple discrimination). The present study assessed whether the four pigeons from our previous study would show maintained discrimination when the positions of the components of each compound were changed relative to the training stimuli. Training components were rotated 90 degrees to the right and left (Tests 1 and 2, respectively), presented with a 1cm separation (Test 3), and presented with a 1cm separation and rotated 180 degrees (Test 4). Subject P11 maintained discriminations in all tests. Maintained discriminations were only observed in Tests 1 and 2 for P21, 1-3 for P10, and 1, 2, and 4 for P9. Results indicate that pigeons may not maintain discrimination when stimulus elements are presented further apart and/or rotated 180 degrees relative to training.
Impact of COPD on the mortality and treatment of patients hospitalized with acute decompensated heart failure: the Worcester Heart Failure Study
BACKGROUND: COPD is a common comorbidity in patients with heart failure, yet little is known about the impact of this condition in patients with acute decompensated heart failure (ADHF), especially from a more generalizable, community-based perspective. The primary objective of this study was to describe the in-hospital and postdischarge mortality and treatment of patients hospitalized with ADHF according to COPD status.
METHODS: The study population consisted of patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during four study years: 1995, 2000, 2002, and 2004. Patients were followed through 2010 for determination of their vital status.
RESULTS: Of the 9,748 patients hospitalized with ADHF during the years under study, 35.9% had a history of COPD. The average age of this population was 76.1 years, 43.9% were men, and 93.3% were white. At the time of hospital discharge, patients with COPD were less likely to have received evidence-based heart failure medications, including beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, than patients without COPD. Multivariable, adjusted in-hospital death rates were similar for patients with and without COPD. However, among patients who survived to hospital discharge, patients with COPD had a significantly higher risk of dying at 1 year (adjusted relative risk [RR], 1.10; 95% CI, 1.06-1.14) and 5 years (adjusted RR, 1.40; 95% CI, 1.28-1.52) after hospital discharge than patients who were not previously diagnosed with COPD.
CONCLUSIONS: COPD is a common comorbidity in patients hospitalized with ADHF and is associated with a worse long-term prognosis. Further research is required to understand the complex interactions of these diseases and ensure that patients with ADHF and COPD receive optimal treatment modalities.
IMPORTANCE: Advanced dementia is characterized by severe cognitive impairment and complete functional dependence. Patients' goals of care should guide the prescribing of medication during such terminal illness. Medications that do not promote the primary goal of care should be minimized.
OBJECTIVES: To estimate the prevalence of medications with questionable benefit used by nursing home residents with advanced dementia, identify resident- and facility-level characteristics associated with such use, and estimate associated medication expenditures.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of medication use by nursing home residents with advanced dementia using a nationwide long-term care pharmacy database linked to the Minimum Data Set (460 facilities) between October 1, 2009, and September 30, 2010. MAIN
OUTCOMES AND MEASURES: Use of medication deemed of questionable benefit in advanced dementia based on previously published criteria and mean 90-day expenditures attributable to these medications per resident. Generalized estimating equations using the logit link function were used to identify resident- and facility-related factors independently associated with the likelihood of receiving medications of questionable benefit after accounting for clustering within nursing homes.
RESULTS: Of 5406 nursing home residents with advanced dementia, 2911 (53.9%) received at least 1 medication with questionable benefit (range, 44.7% in the Mid-Atlantic census region to 65.0% in the West South Central census region). Cholinesterase inhibitors (36.4%), memantine hydrochloride (25.2%), and lipid-lowering agents (22.4%) were the most commonly prescribed. In adjusted analyses, having eating problems (adjusted odds ratio [AOR], 0.68; 95% CI, 0.59-0.78), a feeding tube (AOR, 0.58; 95% CI, 0.48-0.70), or a do-not-resuscitate order (AOR, 0.65; 95% CI, 0.57-0.75), and enrolling in hospice (AOR, 0.69; 95% CI, 0.58-0.82) lowered the likelihood of receiving these medications. High facility-level use of feeding tubes increased the likelihood of receiving these medications (AOR, 1.45; 95% CI, 1.12-1.87). The mean (SD) 90-day expenditure for medications with questionable benefit was $816 ($553), accounting for 35.2% of the total average 90-day medication expenditures for residents with advanced dementia who were prescribed these medications.
CONCLUSIONS AND RELEVANCE: Most nursing home residents with advanced dementia receive medications with questionable benefit that incur substantial associated costs.
Predictors of psychological distress and interest in mental health services in individuals with cancer
Identifying risk factors for psychological distress in patients with cancer may help providers more efficiently screen, identify, and manage distress. This article presents predictors of psychological distress in a large heterogeneous sample of cancer patients. In total, 836 patients were enrolled in a large randomized control trial and completed computerized psychosocial assessments Mental Health Assessment and Dynamic Referral for Oncology. Multivariate regressions examined predictors of distress and interest in mental health services. Final models suggest that psychological distress was related to six variables, and interest in mental health services was related to previous history of mental health counseling, total number of cancer-related symptoms, and race/ethnicity. Results may be used to identify high-risk patients who may benefit from proactive psychosocial interventions.
The comparative experiences of women in control: diabetes self-management education in a virtual world
The purpose was to characterize participants' experiences of a diabetes self-management (DSM) education program delivered via a virtual world (VW) versus a face-to-face (F2F) format. Participants included a randomly selected sample of participants who completed the Women in Control study. Four focus groups were conducted with 32 participants. Four researchers coded the data and conducted a qualitative thematic analysis. Four overarching themes were identified. Three domains apply to both VW and F2F formats, including (1) the value of DSM knowledge gained, (2) cultivating DSM attitudes and skills, and (3) the value of peer-derived social support. The fourth domain is labeled positive technological development for DSM (VW condition only). VW and F2F groups both reported mastery of DSM knowledge, attitudes, and skills, and there were no differences in peer-derived social support between groups. The technological aspects of VW participation afforded VW participants a unique sense of personal agency and diabetes self-efficacy not reported by F2F participants. DSM education in a VW is feasible and educational outcomes are similar to a F2F classroom experience. Furthermore, learning DSM skills in a VW offers unique advantages in supporting personal agency for health behavior change. Further research is warranted.
OBJECTIVE: To describe diagnostic and psychotropic medication prescription characteristics among college students referred by college counseling centers for psychopharmacologic evaluation.
PARTICIPANTS: Participants were 540 college students referred by 6 college counseling centers in Massachusetts between November 2005 and May 2011.
METHODS: Students completed self-report measures of depression, anxiety, suicidal ideation and attempts, and substance use. Information regarding DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) diagnosis, previous history of medication prescription, and current psychotropic medication(s) prescribed by the consulting psychiatrist was obtained from medical records. RESULTS: Depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD) were the most common psychiatric problems identified in students. Half of these students had been prescribed mediation prior to evaluation. Antidepressant medication was the most frequently prescribed medication. A large proportion of students reported previous thoughts of suicide, and 12% had made at least 1 suicide attempt. CONCLUSIONS: Depression, anxiety, and ADHD are common among students referred by college counseling centers for medication evaluation and treatment.
Promoting tobacco cessation utilizing pre-health professional students as research associates in the emergency department
OBJECTIVE: The objective of this study was to investigate the extent to which volunteer research associates (RAs) can be utilized to screen emergency department patients and their visitors for tobacco use and effectively refer tobacco users requesting help to state Tobacco Quitlines.
METHODS: A sample of 19,149 individuals in 10 emergency departments around the country was enrolled into a prospective, interventional study on tobacco cessation by pre-health professional RAs. Participants who screened positive for tobacco use were provided a brief description of Tobacco Quitline programs and then offered a faxed referral to their respective state Quitline.
RESULTS: A total of 10,303 (54%) participants reported tobacco use for more than one month during their lives, with 3861 (20%) currently using every day and an additional 1340 using on some days (7%). Most importantly, 2151 participants requested a faxed Tobacco Quitline referral (36% of individuals who used tobacco in the past month).
DISCUSSION: Pre-health professional RAs were shown to be an effective and cost-efficient resource for providing a strongly recommended service in the emergency department. Patient care (and the care of their visitors) was supplemented, emergency department personnel were not provided with additional burden, and RAs were provided with valuable experience for their futures in the health professions.