Showing papers by "VA Palo Alto Healthcare System published in 2014"
TL;DR: Exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function, and structural and cognitive enhancements elicited by exposure are mediated by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus.
Abstract: As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.
823 citations
TL;DR: The results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.
Abstract: T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naive T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naive CD4 and CD8 T-cell repertoires of young adults. Naive repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini–Simpson index clonality score. In particular, large naive T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.
567 citations
TL;DR: Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of cITALopram may limit its practical application at the dosage of 30 mg per day.
Abstract: Importance Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. Objective The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. Design, Setting, and Participants The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. Interventions Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. Main Outcomes and Measures Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. Results Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 (95% CI, −1.80 to −0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (−1.05 points; 95% CI, −1.97 to −0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. Conclusions and Relevance Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. Trial Registration clinicaltrials.gov Identifier:NCT00898807
455 citations
TL;DR: This document challenges historical policy by acknowledging the need for more explicit and transparent assessment of the value of health care and suggesting a strategy to address this issue.
Abstract: Traditionally, resource utilization and value considerations have been explicitly excluded from practice guidelines and performance measures formulations, although they often are implicitly considered. This document challenges this historical policy. With accelerating healthcare costs and the desire to achieve the best value (health benefit for every dollar spent), there is growing recognition of the need for more explicit and transparent assessment of the value of health care. Thus, from a societal policy perspective, a critical healthcare …
432 citations
TL;DR: It is shown that H3K4me3 domains that spread more broadly over genes in a given cell type preferentially mark genes that are essential for the identity and function of that cell type.
388 citations
TL;DR: Among patients hospitalized with HF, patients with HFpEF and HFbEF had slightly lower mortality and higher all-cause readmission risk than patients with HFrEF, although the mortality differences did not persist after risk adjustment.
300 citations
TL;DR: In hospital-related settings, implementing C POE is associated with a greater than 50% decline in pADEs, although the studies used weak designs, which suggests that CPOE implementation, as subsidized under the HITECH Act, may benefit public health.
Abstract: The Health Information Technology for Economic and Clinical Health (HITECH) Act subsidizes implementation by hospitals of electronic health records with computerized provider order entry (CPOE), which may reduce patient injuries caused by medication errors (preventable adverse drug events, pADEs). Effects on pADEs have not been rigorously quantified, and effects on medication errors have been variable. The objectives of this analysis were to assess the effectiveness of CPOE at reducing pADEs in hospital-related settings, and examine reasons for heterogeneous effects on medication errors. Articles were identified using MEDLINE, Cochrane Library, Econlit, web-based databases, and bibliographies of previous systematic reviews (September 2013). Eligible studies compared CPOE with paper-order entry in acute care hospitals, and examined diverse pADEs or medication errors. Studies on children or with limited event-detection methods were excluded. Two investigators extracted data on events and factors potentially associated with effectiveness. We used random effects models to pool data. Sixteen studies addressing medication errors met pooling criteria; six also addressed pADEs. Thirteen studies used pre-post designs. Compared with paper-order entry, CPOE was associated with half as many pADEs (pooled risk ratio (RR) = 0.47, 95% CI 0.31 to 0.71) and medication errors (RR = 0.46, 95% CI 0.35 to 0.60). Regarding reasons for heterogeneous effects on medication errors, five intervention factors and two contextual factors were sufficiently reported to support subgroup analyses or meta-regression. Differences between commercial versus homegrown systems, presence and sophistication of clinical decision support, hospital-wide versus limited implementation, and US versus non-US studies were not significant, nor was timing of publication. Higher baseline rates of medication errors predicted greater reductions (P < 0.001). Other context and implementation variables were seldom reported. In hospital-related settings, implementing CPOE is associated with a greater than 50% decline in pADEs, although the studies used weak designs. Decreases in medication errors are similar and robust to variations in important aspects of intervention design and context. This suggests that CPOE implementation, as subsidized under the HITECH Act, may benefit public health. More detailed reporting of the context and process of implementation could shed light on factors associated with greater effectiveness.
281 citations
TL;DR: The evolution of materials used over time is reviewed in addition to the various advantages and pitfalls associated with each change to gain a better understanding of this procedure and how it has been adapted.
Abstract: Cranioplasty, one of the oldest surgical procedures used to repair cranial defects, has undergone many revolutions over time to find the ideal material to improve patient prognosis. Cranioplasty offers cosmetic and protective benefits for patients with cranial defects. The first primitive cranioplasty procedures date back to 7000 bc and used metal and gourds to repair cranial defects. Cranioplasty was first documented by Fallopius who described repair using gold plates; the first bone graft was documented by van Meekeren. The first significant improvement for this procedure began with experimentation involving bone grafts in the late 19th century as a more natural approach for repairing cranial defects. The next impetus for advancement came because of wartime injuries incurred during World Wars I and II and involved experimentation with synthetic materials to counter the common complications associated with bone grafts. Methyl methacrylate, hydroxyapatite, ceramics, and polyetheretherketone implants among...
259 citations
TL;DR: Evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors.
Abstract: While the relationship between increased physical activity and cognitive ability has been conjectured for centuries, only recently have the mechanisms underlying this relationship began to emerge. Convergent evidence suggests that physical activity offers an affordable and effective method to improve cognitive function in all ages, particularly the elderly who are most vulnerable to neurodegenerative disorders. In addition to improving cardiac and immune function, physical activity alters trophic factor signaling and, in turn, neuronal function and structure in areas critical for cognition. Sustained exercise plays a role in modulating anti-inflammatory effects and may play a role in preserving cognitive function in aging and neuropathological conditions. Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. Given the growing numbers of individuals with cognitive impairment in the US population, a better understanding of how these factors work in aggregate to contribute to cognition is imperative, and constitutes an important first step toward developing non-pharmacological therapeutic strategies to improve cognition in vulnerable populations.
242 citations
TL;DR: Results suggest that a comprehensive approach to treatment of posttraumatic stress disorder should include behavioral sleep medicine, and CBT-I was superior to the waitlist control condition in all sleep diary outcomes and in polysomnography-measured total sleep time.
Abstract: Study objectives Examine whether cognitive behavioral therapy for insomnia (CBT-I) improves sleep in posttraumatic stress disorder (PTSD) as well as nightmares, nonsleep PTSD symptoms, depression symptoms, and psychosocial functioning. Design RANDOMIZED CONTROLLED TRIAL WITH TWO ARMS: CBT-I and monitor-only waitlist control. Setting Department of Veterans Affairs (VA) Medical Center. Participants Forty-five adults (31 females: [mean age 37 y (22-59 y)] with PTSD meeting research diagnostic criteria for insomnia, randomly assigned to CBT-I (n = 29; 22 females) or monitor-only waitlist control (n = 16; nine females). Interventions Eight-session weekly individual CBT-I delivered by a licensed clinical psychologist or a board-certified psychiatrist. Measurements and results Measures included continuous monitoring of sleep with diary and actigraphy; prepolysomnography and postpolysomnography and Clinician-Administered PTSD Scale (CAPS); and pre, mid, and post self-report questionnaires, with follow-up of CBT-I participants 6 mo later. CBT-I was superior to the waitlist control condition in all sleep diary outcomes and in polysomnography-measured total sleep time. Compared to waitlist participants, CBT-I participants reported improved subjective sleep (41% full remission versus 0%), disruptive nocturnal behaviors (based on the Pittsburgh Sleep Quality Index-Addendum), and overall work and interpersonal functioning. These effects were maintained at 6-mo follow-up. Both CBT-I and waitlist control participants reported reductions in PTSD symptoms and CAPS-measured nightmares. Conclusions Cognitive behavioral therapy for insomnia (CBT-I) improved sleep in individuals with posttraumatic stress disorder, with durable gains at 6 mo. Overall psychosocial functioning improved following CBT-I. The initial evidence regarding CBT-I and nightmares is promising but further research is needed. Results suggest that a comprehensive approach to treatment of posttraumatic stress disorder should include behavioral sleep medicine. Clinical trial information TRIAL NAME: Cognitive Behavioral Treatment Of Insomnia In Posttraumatic Stress Disorder. URL: http://clinicaltrials.gov/ct2/show/NCT00881647. Registration number NCT00881647.
226 citations
TL;DR: It is indicated that medical cannabis users use and perceive cannabis to be beneficial for multiple conditions, some for which cannabis is not specifically prescribed or allowed at the state level; and report similar rates of disordered use as compared with population estimates among regular users.
Abstract: Objectives: Little research has investigated the demographic and symptom profile of medical cannabis users in states in the USA that have legalized cannabis use. Methods: In the present cross-secti...
University of Washington1, Università Campus Bio-Medico2, University of Pittsburgh3, University of Minnesota4, Johns Hopkins University5, University of California, San Francisco6, VA Palo Alto Healthcare System7, University of California, San Diego8, Oregon Health & Science University9, California Pacific Medical Center10
TL;DR: Men with diabetes who are using insulin have an increased risk of non-vertebral fracture for a given age and BMD.
Abstract: Aims/hypothesis
Diabetes mellitus is associated with increased fracture risk in women but few studies are available in men. To evaluate the relationship between diabetes and prospective non-vertebral fractures in elderly men, we used data from the Osteoporotic Fractures in Men (MrOS) study.
TL;DR: In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells.
Abstract: Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.
TL;DR: The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA‐associated inflammation.
Abstract: Objective
The co-occurrence of rheumatoid factor (RF) and anti–citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation.
Methods
In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti–cyclic citrullinated peptide [anti-CCP]−/RF−), anti-CCP+/RF−, anti-CCP−/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation.
Results
Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone).
Conclusion
The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.
TL;DR: It is discussed how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers.
TL;DR: The findings support the predominance of depressive symptoms compared with mood elevation/mixed symptoms in the course of bipolar illness, and thus an overall greater burden in terms of economic costs, functioning, caregiver burden, and suicide.
TL;DR: Increased rates of coping-oriented use of cannabis and greater frequency of cannabis use among medical users with high PTSD scores compared with low PTSD scores are found, and sleep improvement appears to be a primary motivator for coping- oriented use.
TL;DR: Topiramate can be a useful tool in the treatment of AUDs and its efficacy seems to be of somewhat greater magnitude than that of the most commonly prescribed medications for AUDs (naltrexone and acamprosate).
Abstract: Background
Influenced by several trials and reviews highlighting positive outcomes, topiramate is increasingly prescribed as a treatment for alcohol use disorders (AUDs). The only previously published meta-analysis of topiramate for AUDs was limited by a sample of only 3 randomized, placebo-controlled trials (RCTs).
TL;DR: How interactions among conditions result in clinical complexity and may affect quality of care is described, and how this comorbidity interrelatedness influences the value of existing quality guidelines and performance metrics is discussed.
Abstract: Multimorbidity—the presence of multiple chronic conditions in a patient—has a profound impact on health, health care utilization, and associated costs. Definitions of multimorbidity in clinical care and research have evolved over time, initially focusing on a patient’s number of comorbidities and the associated magnitude of required care processes, and later recognizing the potential influence of comorbidity characteristics on patient care and outcomes. In this article, we review the relationship between multimorbidity and quality of care, and discuss how this relationship may be mediated by the degree to which conditions interact with one another to generate clinical complexity (comorbidity interrelatedness). Drawing on established theoretical frameworks from cognitive engineering and biomedical informatics, we describe how interactions among conditions result in clinical complexity and may affect quality of care. We discuss how this comorbidity interrelatedness influences the value of existing quality guidelines and performance metrics, and describe opportunities to quantify this construct using data widely available through electronic health records. Incorporating comorbidity interrelatedness into conceptualizations of multimorbidity has the potential to enhance clinical and research efforts that aim to improve care for patients with multiple chronic conditions.
TL;DR: This review looks into various automated and semi-automated computer-aided grading systems and related retinal image analysis techniques for drusen, geographic atrophy and choroidal neovascularization detection and/or quantification for measurement of AMD severity using these imaging modalities.
TL;DR: A novel intragenic long noncoding RNA (lncRNA) is discovered within the IGF1R locus, named IRAIN, which is transcribed in an antisense direction from an intronic promoter and identified as a new imprinted lncRNA that is involved in long-range DNA interactions.
Abstract: Dysregulation of the insulin-like growth factor type I receptor (IGF1R) has been implicated in the progression and therapeutic resistance of malignancies. In acute myeloid leukemia (AML) cells, IGF1R is one of the most abundantly phosphorylated receptor tyrosine kinases, promoting cell growth through the PI3K/Akt signaling pathway. However, little is known regarding the molecular mechanisms underlying IGF1R gene dysregulation in cancer. We discovered a novel intragenic long noncoding RNA (lncRNA) within the IGF1R locus, named IRAIN, which is transcribed in an antisense direction from an intronic promoter. The IRAIN lncRNA was expressed exclusively from the paternal allele, with the maternal counterpart being silenced. Using both reverse transcription-associated trap and chromatin conformation capture assays, we demonstrate that this lncRNA interacts with chromatin DNA and is involved in the formation of an intrachromosomal enhancer/promoter loop. Knockdown of IRAIN lncRNA with shRNA abolishes this intrachromosomal interaction. In addition, IRAIN was downregulated both in leukemia cell lines and in blood obtained from high-risk AML patients. These data identify IRAIN as a new imprinted lncRNA that is involved in long-range DNA interactions.
TL;DR: Findings indicated that women exposed to more severe forms of sexual victimization were most likely to report these risk-taking behaviors and sexual functioning issues, and implications for sexual assault risk reduction programming and treatment are discussed.
Abstract: The purpose of the present study was to examine the relationship between college women’s sexual victimization experiences, health risk behaviors, and sexual functioning. A sample of 309 college women at a mid-sized Midwestern university completed measures assessing sexual victimization, sexual risk taking, substance use behaviors, sexual desire, sexual functioning, prior sexual experiences, and social desirability. Severity of sexual victimization was measured using a multi-item, behaviorally specific, gender-neutral measure, which was divided into four categories based on severity (none, sexual contact, sexual coercion, rape). Within the sample, 72.8% (n = 225) of women reported at least one experience of sexual victimization since age 16. Results from MANCOVAs and a multinomial logistic regression, controlling for social desirability and prior sexual experience, revealed that sexual victimization among female students was related to increased drug use, problematic drinking behaviors, sexual risk taking, sexual dysfunction,
TL;DR: A mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device, and a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury are developed.
Abstract: Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all TBIs. The consequences of repetitive mTBI have become of particular concern for individuals engaged in certain sports or in military operations. Many mTBI patients suffer long-lasting neurobehavioral impairments. In order to expedite pre-clinical research and therapy development, there is a need for animal models that reflect the long-term cognitive and pathological features seen in patients. In the present study, we developed and characterized a mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device. Using GFAP-luciferase bioluminescence reporter mice that provide a readout of astrocyte activation, we observed an increase in bioluminescence relative to the force delivered by the impactor after single impact and cumulative effects of repetitive mTBI. Using the injury parameters established in the reporter mice, we induced a repetitive mTBI in wild-type C57BL/6J mice and characterized the long-term outcome. Animals received repetitive mTBI showed a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury. A robust astrogliosis and increased p-Tau immunoreactivity was observed upon post-mortem pathological examinations. These findings are consistent with the deficits and pathology associated with mTBI in humans and support the use of this model to evaluate potential therapeutic approaches.
TL;DR: The hypotheses that CRPS involves activation of the innate immune system, with keratinocyte and mast cell activation and proliferation, inflammatory mediator release, and pain are supported.
TL;DR: It is shown that influenza vaccination induces the recall of memory B cells that express antibodies that previously underwent affinity maturation against prior years' seasonal influenza, suggesting that ' original antigenic sin' shapes the antibody response to influenza vaccination.
TL;DR: Results show that the antiatherogenic activity of BET inhibitor, RVX-208, occurs via a combination of lipid changes and anti-inflammatory activities.
TL;DR: It is shown that satellite cells, the stem cells resident in skeletal muscle, have a compromised myogenic potential in the mdx mouse model of Duchenne muscular dystrophy, and pharmacological inhibition of the TGFβ pathway in vivo reduced the fibrogenic characteristics of satellite cells.
Abstract: We have previously observed that Wnt signaling activates a fibrogenic program in adult muscle stem cells, called satellite cells, during aging. We genetically labeled satellite cells in a mouse model of Duchenne muscular dystrophy to follow their fate during the progression of the disease. We observed that a fraction of satellite cells had a reduced myogenic potential and showed enhanced expression of profibrotic genes compared to age-matched controls. By combining in vitro and in vivo results, we found that expression of transforming growth factor-β2 (TGFβ2) was induced in response to elevated canonical Wnt signaling in dystrophic muscles and that the resulting increase in TGFβ activity affected the behavior of satellite cells in an autocrine or paracrine fashion. Indeed, pharmacological inhibition of the TGFβ pathway in vivo reduced the fibrogenic characteristics of satellite cells. These studies shed new light on the cellular and molecular mechanisms responsible for stem cell dysfunction in dystrophic muscle and may contribute to the development of more effective and specific therapeutic approaches for the prevention of muscle fibrosis.
TL;DR: The association between women's prepregnancy BMI and risk of spontaneous preterm birth is complex and is influenced by race/ethnicity, gestational age, and parity.
Abstract: Background
Findings from studies examining risk of preterm birth associated with elevated prepregnancy body mass index (BMI) have been inconsistent.
Methods
Within a large population-based cohort, we explored associations between prepregnancy BMI and spontaneous preterm birth across a spectrum of BMI, gestational age, and racial/ethnic categories. We analysed data for 989 687 singleton births in California, 2007–09. Preterm birth was grouped as 20–23, 24–27, 28–31, or 32–36 weeks gestation (compared with 37–41 weeks). BMI was categorised as <18.5 (underweight); 18.5–24.9 (normal); 25.0–29.9 (overweight); 30.0–34.9 (obese I); 35.0–39.9 (obese II); and ≥40.0 (obese III). We assessed associations between BMI and spontaneous preterm birth of varying severity among non-Hispanic White, Hispanic, and non-Hispanic Black women.
Results
Analyses of mothers without hypertension and diabetes, adjusted for age, education, height, and prenatal care initiation, showed obesity categories I–III to be associated with increased risk of spontaneous preterm birth at 20–23 and 24–27 weeks among those of parity 1 in each race/ethnic group. Relative risks for obese III and preterm birth at 20–23 weeks were 6.29 [95% confidence interval (CI) 3.06, 12.9], 4.34 [95% CI 2.30, 8.16], and 4.45 [95% CI 2.53, 7.82] for non-Hispanic Whites, non-Hispanic Blacks, and Hispanics, respectively. A similar, but lower risk, pattern was observed for women of parity ≥2 and preterm birth at 20–23 weeks. Underweight was associated with modest risks for preterm birth at ≥24 weeks among women in each racial/ethnic group regardless of parity.
Conclusions
The association between women's prepregnancy BMI and risk of spontaneous preterm birth is complex and is influenced by race/ethnicity, gestational age, and parity.
TL;DR: Patients with multiple chronic conditions account for a disproportionate share of VA healthcare expenditures and interventions that aim to optimize care and contain costs for multimorbid patients need to incorporate strategies specific to the most prevalent and the most costly combinations of conditions.
Abstract: Background: Multimorbidity (the presence of multiple chronic conditions) is associated with high levels of healthcare utilization and associated costs. We investigated the association between number of chronic conditions and costs of care for nonelderly and elderly Veterans Affairs (VA) patients, and estimated mean VA healthcare costs for the most prevalent and most costly combinations of 3 conditions (triads). Methods: We identified a cohort of 5,233,994 patients who received care within the VA system in fiscal year 2010. We estimated the costs of VA care for each patient using established methods and aggregated costs for inpatient care, outpatient care, prescription drugs, and contract care. Using ICD-9 diagnosis fields from all inpatient and outpatient records, we determined the prevalence of 28 chronic conditions and all condition triads. We then compared the condition-cost gradient, most prevalent triads, and most costly triads among nonelderly (below 65y) and elderly (65y and above) patients. Results: Almost one third of nonelderly and slightly more than a third of elderly VA patients had Z3 conditions, but these patients accounted for 65% and 67% of total VA healthcare costs, respectively. The most common triad of chronic conditions for both nonelderly and elderly patients was diabetes, hyperlipidemia, and hypertension (24% and 29%, respectively). Conditions that were present in the most costly triads included spinal cord injury, heart failure, renal failure, ischemic heart disease, peripheral vascular disease, stroke, and depression. Although patients with the most costly triads had average costs that were 3 times higher than average costs among patients with Z3 conditions, the prevalence of these costly triads was extremely low (0.1%‐0.4%). Conclusions: Patients with multiple chronic conditions account for a disproportionate share of VA healthcare expenditures. Interventions that aim to optimize care and contain costs for multimorbid patients need to incorporate strategies specific to the most prevalent and the most costly combinations of conditions.
TL;DR: It is found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of m TORC1 with rapamycin, which represents a potential therapeutic target in neurogenic muscle atrophy.
Abstract: Skeletal muscle mass and function are regulated by motor innervation, and denervation results in muscle atrophy. The activity of mammalian target of rapamycin complex 1 (mTORC1) is substantially increased in denervated muscle, but its regulatory role in denervation-induced atrophy remains unclear. At early stages after denervation of skeletal muscle, a pathway involving class II histone deacetylases and the transcription factor myogenin mediates denervation-induced muscle atrophy. We found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of mTORC1 with rapamycin. Activation of mTORC1 through genetic deletion of its inhibitor TSC1 (tuberous sclerosis complex 1) sensitized mice to denervation-induced muscle atrophy and suppressed the kinase activity of Akt, leading to activation of FoxO transcription factors and increasing the expression of genes encoding E3 ubiquitin ligases atrogin [also known as MAFbx (muscle atrophy F-box protein)] and MuRF1 (muscle-specific ring finger 1). Rapamycin treatment of mice restored Akt activity, suggesting that the denervation-induced increase in mTORC1 activity was producing feedback inhibition of Akt. Genetic deletion of the three FoxO isoforms in skeletal muscle induced muscle hypertrophy and abolished the late-stage induction of E3 ubiquitin ligases after denervation, thereby preventing denervation-induced atrophy. These data revealed that mTORC1, which is generally considered to be an important component of anabolism, is central to muscle catabolism and atrophy after denervation. This mTORC1-FoxO axis represents a potential therapeutic target in neurogenic muscle atrophy.