A critical role for the chromatin remodeller CHD7 in anterior mesoderm during cardiovascular development

CHARGE syndrome is caused by spontaneous loss-of-function mutations to the ATP-dependant chromatin remodeller chromodomain-helicase-DNA-binding protein 7 (CHD7). It is characterised by a distinct pattern of congenital anomalies, including cardiovascular malformations. Disruption to the neural crest lineage has previously been emphasised in the aetiology of this developmental disorder. We present evidence for an additional requirement for CHD7 activity in the Mesp1-expressing anterior mesoderm during heart development. Conditional ablation of Chd7 in this lineage results in major structural cardiovascular defects akin to those seen in CHARGE patients, as well as a striking loss of cardiac innervation and embryonic lethality. Genome-wide transcriptional analysis identified aberrant expression of key components of the Class 3 Semaphorin and Slit-Robo signalling pathways in Chd7(fl/fl);Mesp1-Cre mutant hearts. CHD7 localises at the Sema3c promoter in vivo, with alteration of the local chromatin structure seen following Chd7 ablation, suggestive of direct transcriptional regulation. Furthermore, we uncover a novel role for CHD7 activity upstream of critical calcium handling genes, and demonstrate an associated functional defect in the ability of cardiomyocytes to undergo excitation-contraction coupling. This work therefore reveals the importance of CHD7 in the cardiogenic mesoderm for multiple processes during cardiovascular development

Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol

Adult onset neuronal lipofuscinosis (ANCL) is a human neurodegenerative disorder characterized by progressive neuronal dysfunction and premature death. Recently, the mutations that cause ANCL were mapped to the DNAJC5 gene, which encodes cysteine string protein alpha. We show here that mutating dnj-14, the Caenorhabditis elegans orthologue of DNAJC5, results in shortened lifespan and a small impairment of locomotion and neurotransmission. Mutant dnj-14 worms also exhibited age-dependent neurodegeneration of sensory neurons, which was preceded by severe progressive chemosensory defects. A focussed chemical screen revealed that resveratrol could ameliorate dnj-14 mutant phenotypes, an effect mimicked by the cAMP phosphodiesterase inhibitor, rolipram. In contrast to other worm neurodegeneration models, activation of the Sirtuin, SIR-2.1, was not required, as sir-2.1; dnj-14 double mutants showed full lifespan rescue by resveratrol. The Sirtuin-independent neuroprotective action of resveratrol revealed here suggests potential therapeutic applications for ANCL and possibly other human neurodegenerative diseases

Defining care products to finance health care in the Netherlands

A case-mix project started in the Netherlands with the primary goal to define a complete set of health care products for hospitals. The definition of the product structure was completed 4 years later. The results are currently being used for billing purposes. This paper focuses on the methodology and techniques that were developed and applied in order to define the casemix product structure. The central research question was how to develop a manageable product structure, i.e., a limited set of hospital products, with acceptable cost homogeneity. For this purpose, a data warehouse with approximately 1.5 million patient records from 27 hospitals was build up over a period of 3 years. The data associated with each patient consist of a large number of a priori independent parameters describing the resource utilization in different stages of the treatment process, e.g., activities in the operating theatre, the lab and the radiology department. Because of the complexity of the database, it was necessary to apply advanced data analysis techniques. The full analyses process that starts from the database and ends up with a product definition consists of four basic analyses steps. Each of these steps has revealed interesting insights. This paper describes each step in some detail and presents the major results of each step. The result consists of 687 product groups for 24 medical specialties used for billing purposes

Capacity management of nursing staff as a vehicle for organizational improvement

<p>Abstract</p> <p>Background</p> <p>Capacity management systems create insight into required resources like staff and equipment. For inpatient hospital care, capacity management requires information on beds and nursing staff capacity, on a daily as well as annual basis. This paper presents a comprehensive capacity model that gives insight into required nursing staff capacity and opportunities to improve capacity utilization on a ward level.</p> <p>Methods</p> <p>A capacity model was developed to calculate required nursing staff capacity. The model used historical bed utilization, nurse-patient ratios, and parameters concerning contract hours to calculate beds and nursing staff needed per shift and the number of nurses needed on an annual basis in a ward. The model was applied to three different capacity management problems on three separate groups of hospital wards. The problems entailed operational, tactical, and strategic management issues: optimizing working processes on pediatric wards, predicting the consequences of reducing length of stay on nursing staff required on a cardiology ward, and calculating the nursing staff consequences of merging two internal medicine wards.</p> <p>Results</p> <p>It was possible to build a model based on easily available data that calculate the nursing staff capacity needed daily and annually and that accommodate organizational improvements. Organizational improvement processes were initiated in three different groups of wards. For two pediatric wards, the most important improvements were found to be improving working processes so that the agreed nurse-patient ratios could be attained. In the second case, for a cardiology ward, what-if analyses with the model showed that workload could be substantially lowered by reducing length of stay. The third case demonstrated the possible savings in capacity that could be achieved by merging two small internal medicine wards.</p> <p>Conclusion</p> <p>A comprehensive capacity model was developed and successfully applied to support capacity decisions on operational, tactical, and strategic levels. It appeared to be a useful tool for supporting discussions between wards and hospital management by giving objective and quantitative insight into staff and bed requirements. Moreover, the model was applied to initiate organizational improvements, which resulted in more efficient capacity utilization.</p

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

DnaC Inactivation in Escherichia coli K-12 Induces the SOS Response and Expression of Nucleotide Biosynthesis Genes

Background: Initiation of chromosome replication in E. coli requires the DnaA and DnaC proteins and conditionally-lethal dnaA and dnaC mutants are often used to synchronize cell populations. Methodology/Principal Findings: DNA microarrays were used to measure mRNA steady-state levels in initiation-deficient dnaA46 and dnaC2 bacteria at permissive and non-permissive temperatures and their expression profiles were compared to MG1655 wildtype cells. For both mutants there was altered expression of genes involved in nucleotide biosynthesis at the non-permissive temperature. Transcription of the dnaA and dnaC genes was increased at the non-permissive temperature in the respective mutant strains indicating auto-regulation of both genes. Induction of the SOS regulon was observed in dnaC2 cells at 38uC and 42uC. Flow cytometric analysis revealed that dnaC2 mutant cells at non-permissive temperature had completed the early stages of chromosome replication initiation. Conclusion/Significance: We suggest that in dnaC2 cells the SOS response is triggered by persistent open-complex formation at oriC and/or by arrested forks that require DnaC for replication restart

Integral strategy to supportive care in breast cancer survivors through occupational therapy and a m-health system: design of a randomized clinical trial

Background: Technological support using e-health mobile applications (m-health) is a promising strategy to improve the adherence to healthy lifestyles in breast cancer survivors (excess in energy intake or low physical activity are determinants of the risk of recurrence, second cancers and cancer mortality). Moreover, cancer rehabilitation programs supervised by health professionals are needed due to the inherent characteristics of these breast cancer patients. Our main objective is to compare the clinical efficacy of a m-health lifestyle intervention system alone versus an integral strategy to improve Quality of Life in breast cancer survivors. Methods: This therapeutic superiority study will use a two-arm, assessor blinded parallel RCT design. Women will be eligible if: they are diagnosed of stage I, II or III-A breast cancer; are between 25 and 75 years old; have a Body Mass Index > 25 kg/m2; they have basic ability to use mobile apps; they had completed adjuvant therapy except for hormone therapy; and they have some functional shoulder limitations. Participants will be randomized to one of the following groups: integral group will use a mobile application (BENECA APP) and will receive a face-to-face rehabilitation (8-weeks); m-health group will use the BENECA app for 2-months and will received usual care information. Study endpoints will be assessed after 8 weeks and 6 months. The primary outcome will be Quality of Life measured by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core and breast module. The secondary outcomes: body composition; upper-body functionality (handgrip, Disability of the Arm, Shoulder and Hand questionnaire, goniometry); cognitive function (Wechsler Adult Intelligence Scale, Trail Making Test); anxiety and depression (Hospital Anxiety and Depression Scale); physical fitness (Short version of the Minnesota Leisure Time Physical Activity Questionnaire, Self-Efficacy Scale for Physical Activity); accelerometry and lymphedema. Discussion: This study has been designed to seek to address the new needs for support and treatment of breast cancer survivors, reflecting the emerging need to merge new low cost treatment options with much-needed involvement of health professionals in this type of patients. Trial registration: ClinicalTrials.gov Identifier: NCT02817724 (date of registration: 22/06/2016).The study was funded by the Spanish Ministry of Economy and Competitiveness (Plan Estatal de I + D + I 2013-2016), Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI14/01627), Fondos Estructurales de la Unión Europea (FEDER) and by the Spanish Ministry of Education (FPU14/01069). This is part of a Ph.D. Thesis conducted in the Clinical Medicine and Public Health Doctoral Studies of the University of Granada, Spain

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer

Published first January 24, 2022.Purpose: DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. Experimental Design: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). Results: Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucosederived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. Conclusions: Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK–mediated aggressive disease phenotypes.Emanuela Dylgjeri, Vishal Kothari, Ayesha A. Shafi, Galina Semenova, Peter T. Gallagher, Yi F. Guan, Angel Pang, Jonathan F. Goodwin, Swati Irani, Jennifer J. McCann, Amy C. Mandigo, Saswati Chand, Christopher M. McNair, Irina Vasilevskaya, MatthewJ. Schiewer, Costas D. Lallas, Peter A. McCue, Leonard G. Gomella, Erin L. Seifert, Jason S. Carroll, Lisa M. Butler, Jeff Holst, William K. Kelly, and Karen E. Knudse

Factor structure of the Hospital Anxiety and Depression Scale in Japanese psychiatric outpatient and student populations

<p>Abstract</p> <p>Background</p> <p>The Hospital Anxiety and Depression Scale (HADS) is a common screening instrument excluding somatic symptoms of depression and anxiety, but previous studies have reported inconsistencies of its factor structure. The construct validity of the Japanese version of the HADS has yet to be reported. To examine the factor structure of the HADS in a Japanese population is needed.</p> <p>Methods</p> <p>Exploratory and confirmatory factor analyses were conducted in the combined data of 408 psychiatric outpatients and 1069 undergraduate students. The data pool was randomly split in half for a cross validation. An exploratory factor analysis was performed on one half of the data, and the fitness of the plausible model was examined in the other half of the data using a confirmatory factor analysis. Simultaneous multi-group analyses between the subgroups (outpatients vs. students, and men vs. women) were subsequently conducted.</p> <p>Results</p> <p>A two-factor model where items 6 and 7 had dual loadings was supported. These factors were interpreted as reflecting anxiety and depression. Item 10 showed low contributions to both of the factors. Simultaneous multi-group analyses indicated a factor pattern stability across the subgroups.</p> <p>Conclusion</p> <p>The Japanese version of HADS indicated good factorial validity in our samples. However, ambiguous wording of item 7 should be clarified in future revisions.</p