A software development environment utilizing PAMELA

Hardware capability and efficiency has increased dramatically since the invention of the computer, while software programmer productivity and efficiency has remained at a relatively low level. A user-friendly, adaptable, integrated software development environment is needed to alleviate this problem. The environment should be designed around the Ada language and a design methodology which takes advantage of the features of the Ada language as the Process Abstraction Method for Embedded Large Applications (PAMELA)

161. The Potential Role of Extensor Muscle Fatigue in the Onset of Intervertebral Disc Degeneration: A Novel In Vivo Model

BACKGROUND CONTEXT: Occupation is strongly correlated to low back pain (LBP). Specific occupational activities associated with low back pain include poor posture, whole body vibration, and repetitive lifting. These activities have a common link: they result in fatigue of the primary spinal extensor musculature. This fatigue may lead to increased intervertebral loading - a stimulus for disc degeneration. If true, this association could provide a vital connection between detrimental physical activities and LBP. However, the link between muscle fatigue and increased load across the disc space has never been quantified in vivo. PURPOSE: The purpose of this study was to develop and test a wireless multi-axial force-sensing implant and large animal model of primary extensor muscle fatigue. Combined, these tools allow measurement of in vivo spinal forces during muscle fatigue to quantify changes in spine loading

Cognitive Behavioral Therapy for Antenatal Depression in a Pilot Randomized Controlled Trial and Effects on Neurobiological, Behavioral and Cognitive Outcomes in Offspring 3-7 Years Postpartum:A Perspective Article on Study Findings, Limitations and Future Aims

Purpose of Article: In a previous pilot randomized controlled trial including 54 pregnant women with depression, maternal mood improved after Cognitive Behavioural Therapy (CBT) compared to treatment as usual (TAU), showing medium to large effect sizes. The effect persisted up to 9 months postpartum, with infant outcomes also showing medium to large effects favoring CBT in various child domains. This perspective article summarizes the results of a follow-up that was performed approximately 5 years later in the same cohort, assessing the effects of antenatal Cognitive Behavioural Therapy for depression and anxiety on child buccal cell DNA-methylation, brain morphology, behavior and cognition. Findings: Children from the CBT group had overall lower DNA-methylation compared to children from the TAU group. Mean DNA-methylation of all NR3C1 promoter-associated probes did not differ significantly between the CBT and TAU groups. Children from the CBT group had a thicker right lateral occipital cortex and lingual gyrus. In the CBT group, Voxel-Based-Morphometry analysis identified one cluster showing increased gray matter concentration in the right medial temporal lobe, and fixel-based analysis revealed reduced fiber-bundle-cross-section in the Fornix, the Optical Tract, and the Stria Terminalis. No differences were observed in full-scale IQ or Total Problems Score. When the total of hypotheses tests in this study was considered, differences in DNA-methylation and brain measurements were no longer significant. Summary: Our explorative findings suggest that antenatal depression treatment decreases overall child DNA-methylation, increases cortical thickness, and decreases white matter fiber-bundle cross-section in regions involved in cognitive function and the stress response. Nevertheless, larger studies are warranted to confirm our preliminary conclusion that CBT in pregnancy alters neurobiological outcomes in children. Clinical relevance remains unclear as we found no effects of antenatal CBT on child behavior or cognition (yet)

Micro-finance, women’s empowerment and fertility decline in Bangladesh: How important was women’s agency?

As Nobel Prize winner Amartya Sen has argued “[Bangladesh’s development achievements have] important lessons for other countries across the globe, [in particular a focus on] reducing gender inequality”. A major avenue through which this emphasis has been manifest lies, according to this narrative, in enhancements to women’s agency for instrumental and intrinsic reasons particularly through innovations in family planning and microfinance. The “Bangladesh paradox” of improved wellbeing despite low economic growth over the last four decades is claimed as a paradigmatic case of the spread of both modern family planning programmes and microfinance leading to women’s empowerment and fertility reduction. In this paper we show that the links between microfinance, empowerment and fertility reduction, are fraught with problems, and far from robust; hence the claimed causal links between microfinance and family planning via women’s empowerment needs to be further reconsidered

An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes

Cancers are characterized by non-random chromosome copy number alterations that presumably contain oncogenes and tumor-suppressor genes (TSGs). The affected loci are often large, making it difficult to pinpoint which genes are driving the cancer. Here we report a cross-species in vivo screen of 84 candidate oncogenes and 39 candidate TSGs, located within 28 recurrent chromosomal alterations in ependymoma. Through a series of mouse models, we validate eight new ependymoma oncogenes and ten new ependymoma TSGs that converge on a small number of cell functions, including vesicle trafficking, DNA modification and cholesterol biosynthesis, identifying these as potential new therapeutic targets.We are grateful to F.B. Gertler (Massachusetts Institute of Technology) and S. Gupton (University of North Carolina) for the generous gift of the VAMP7-phlorin construct and the staffs of the Hartwell Center for Bioinformatics and Biotechnology, the Small Animal Imaging Center, the Animal Resources Center, the Cell and Tissue Imaging Center, and the Flow Cytometry and Cell Sorting Shared Resource at St. Jude Children's Research Hospital for technical assistance. This work was supported by grants from the US National Institutes of Health (R01CA129541, P01CA96832 and P30CA021765, R.J.G.), by the Collaborative Ependymoma Research Network (CERN) and by the American Lebanese Syrian Associated Charities (ALSAC)

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy

Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients

RNA Polymerase II Pausing Downstream of Core Histone Genes Is Different from Genes Producing Polyadenylated Transcripts

Recent genome-wide chromatin immunoprecipitation coupled high throughput sequencing (ChIP-seq) analyses performed in various eukaryotic organisms, analysed RNA Polymerase II (Pol II) pausing around the transcription start sites of genes. In this study we have further investigated genome-wide binding of Pol II downstream of the 3′ end of the annotated genes (EAGs) by ChIP-seq in human cells. At almost all expressed genes we observed Pol II occupancy downstream of the EAGs suggesting that Pol II pausing 3′ from the transcription units is a rather common phenomenon. Downstream of EAGs Pol II transcripts can also be detected by global run-on and sequencing, suggesting the presence of functionally active Pol II. Based on Pol II occupancy downstream of EAGs we could distinguish distinct clusters of Pol II pause patterns. On core histone genes, coding for non-polyadenylated transcripts, Pol II occupancy is quickly dropping after the EAG. In contrast, on genes, whose transcripts undergo polyA tail addition [poly(A)+], Pol II occupancy downstream of the EAGs can be detected up to 4–6 kb. Inhibition of polyadenylation significantly increased Pol II occupancy downstream of EAGs at poly(A)+ genes, but not at the EAGs of core histone genes. The differential genome-wide Pol II occupancy profiles 3′ of the EAGs have also been confirmed in mouse embryonic stem (mES) cells, indicating that Pol II pauses genome-wide downstream of the EAGs in mammalian cells. Moreover, in mES cells the sharp drop of Pol II signal at the EAG of core histone genes seems to be independent of the phosphorylation status of the C-terminal domain of the large subunit of Pol II. Thus, our study uncovers a potential link between different mRNA 3′ end processing mechanisms and consequent Pol II transcription termination processes

Promotoras as Mental Health Practitioners in Primary Care: A Multi-Method Study of an Intervention to Address Contextual Sources of Depression

We assessed the role of promotoras—briefly trained community health workers—in depression care at community health centers. The intervention focused on four contextual sources of depression in underserved, low-income communities: underemployment, inadequate housing, food insecurity, and violence. A multi-method design included quantitative and ethnographic techniques to study predictors of depression and the intervention’s impact. After a structured training program, primary care practitioners (PCPs) and promotoras collaboratively followed a clinical algorithm in which PCPs prescribed medications and/or arranged consultations by mental health professionals and promotoras addressed the contextual sources of depression. Based on an intake interview with 464 randomly recruited patients, 120 patients with depression were randomized to enhanced care plus the promotora contextual intervention, or to enhanced care alone. All four contextual problems emerged as strong predictors of depression (chi square, p < .05); logistic regression revealed housing and food insecurity as the most important predictors (odds ratios both 2.40, p < .05). Unexpected challenges arose in the intervention’s implementation, involving infrastructure at the health centers, boundaries of the promotoras’ roles, and “turf” issues with medical assistants. In the quantitative assessment, the intervention did not lead to statistically significant improvements in depression (odds ratio 4.33, confidence interval overlapping 1). Ethnographic research demonstrated a predominantly positive response to the intervention among stakeholders, including patients, promotoras, PCPs, non-professional staff workers, administrators, and community advisory board members. Due to continuing unmet mental health needs, we favor further assessment of innovative roles for community health workers