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Cognitive and Brain Reserve and the Risk of Postoperative Delirium in Older Patients

Wed, 05/13/2015 - 2:16pm

BACKGROUND: Cognitive and brain reserve theories suggest that aspects of neural architecture or cognitive processes modify the impact of neuropathological processes on cognitive outcomes. While frequently studied in the context of dementia, reserve in delirium is relatively understudied.

METHODS: We examined the association of three markers of brain reserve (head circumference, MRI-derived brain volume, and leisure time physical activity) and five markers of cognitive reserve (education, vocabulary, cognitive activities, cognitive demand of lifetime occupation, and interpersonal demand of lifetime occupation) and the risk of postoperative delirium in a prospective observational study of 566 older adults free of dementia undergoing scheduled surgery.

FINDINGS: Twenty four percent of patients (135/566) developed delirium during the postoperative hospitalization period. Of the reserve markers examined, only the Wechsler Test of Adult Reading (WTAR) was significantly associated with the risk of delirium. A one-half standard deviation better performance on the WTAR was associated with a 38% reduction in delirium risk (P = 0.01); adjusted relative risk of 0.62, 95% confidence interval 0.45-0.85.

INTERPRETATION: In this relatively large and well-designed study, most markers of reserve fail to predict delirium risk. The exception to this is the WTAR. Our findings suggest that the reserve markers that are important for delirium may be different from those considered to be important for dementia.

Rationales that providers and family members cited for the use of antipsychotic medications in nursing home residents with dementia

Wed, 05/13/2015 - 2:16pm

OBJECTIVES: To describe the rationales that providers and family members cite for the use of antipsychotic medications in people with dementia living in nursing homes (NHs).

DESIGN: Qualitative, descriptive study.

SETTING: Twenty-six medium-sized and large facilities in five Centers for Medicare and Medicaid Services regions.

PARTICIPANTS: Individuals diagnosed with dementia who received an antipsychotic medication.

MEASUREMENTS: Data were collected from medical record abstraction and interviews with prescribers, administrators, direct care providers, and family members. Textual data from medical record abstraction and responses to open-ended interview questions were analyzed using directed content analysis techniques. A coding scheme was developed, and coded reasons for antipsychotic prescribing were summarized across all sources.

RESULTS: Major categories of reasons for use of antipsychotic medications in the 204 NH residents in the study sample were behavioral (n = 171), psychiatric (n = 159), emotional states (n = 105), and cognitive diagnoses or symptoms (n = 114). The most common behavioral reasons identified were verbal (n = 91) and physical (n = 85) aggression. For the psychiatric category, psychosis (n = 95) was most frequently described. Anger (n = 93) and sadness (n = 20) were the most common emotional states cited.

CONCLUSION: The rationale for use of antipsychotic drug therapy frequently relates to a wide variety of indications for which these drugs are not approved and for which evidence of efficacy is lacking. These findings have implications for clinical practice and policy. Geriatrics Society.

Antidepressant Use and Cognitive Decline: The Health and Retirement Study

Wed, 05/13/2015 - 2:16pm

BACKGROUND: Depression is associated with cognitive impairment and dementia, but whether treatment for depression with antidepressants reduces the risk for cognitive decline is unclear. We assessed the association between antidepressant use and cognitive decline over 6 years.

METHODS: Participants were 3,714 adults aged 50 or older enrolled in the nationally-representative Health and Retirement Study (HRS) and with self-reported antidepressant use. Depressive symptoms were assessed using the 8-item Center for Epidemiologic Studies Depression Scale. Cognitive function was assessed at four time-points (2004, 2006, 2008, 2010) through using a validated 27-point scale. Change in cognitive function over the 6-year follow-up period was examined using linear growth models, adjusted for demographics, depressive symptoms, comorbidities, functional limitations and antidepressant anticholinergic activity load.

RESULTS: At baseline, cognitive function did not differ significantly between the 445 (12.1%) participants taking antidepressants and those not taking antidepressants (mean 14.9%, 95% CI: 14.3-15.4 vs. mean 15.1%, 95% CI: 14.9-15.3). During the 6-year follow up period, cognition declined in both users and nonusers of antidepressants, ranging from -1.4 change in mean score in those with high depressive symptoms and taking antidepressants to -.5 change in mean score in those with high depressive symptoms and not taking antidepressants. In adjusted models, people taking antidepressants declined at the same rate as those not taking antidepressants. Results remained consistent across different levels of baseline cognitive function, age, and duration of antidepressant use (prolonged versus short-term).

CONCLUSIONS: Antidepressant use did not modify the course of 6-year cognitive change in this nationally- representative sample.

Cognitive and Physical Demands of Activities of Daily Living in Older Adults: Validation of Expert Panel Ratings

Wed, 05/13/2015 - 2:16pm

BACKGROUND: Difficulties with performance of functional activities may result from cognitive and/or physical impairments. To date, there has not been a clear delineation of the physical and cognitive demands of activities of daily living.

OBJECTIVES: To quantify the relative physical and cognitive demands required to complete typical functional activities in older adults.

DESIGN: Expert panel survey.

SETTING: Web-based platform.

PARTICIPANTS: Eleven experts from 8 academic medical centers and 300 community-dwelling elderly adults age 70 and older scheduled for elective noncardiac surgery from 2 academic medical centers.

METHODS: Sum scores of expert ratings were calculated and then validated against objective data collected from a prospective longitudinal study.

MAIN OUTCOME MEASUREMENTS: Correlation between expert ratings and objective neuropsychologic tests (memory, language, complex attention) and physical measures (gait speed and grip strength) for performance-based tasks.

RESULTS: Managing money, self-administering medications, using the telephone, and preparing meals were rated as requiring significantly more cognitive demand, whereas walking and transferring, moderately strenuous activities, and climbing stairs were assessed as more physically demanding. Largely cognitive activities correlated with objective neuropsychologic performance (r = 0.13-0.23, P < .05) and largely physical activities correlated with physical performance (r = 0.15-0.46, P < .05).

CONCLUSIONS: Quantifying the degree of cognitive and/or physical demand for completing a specific task adds an additional dimension to standard measures of functional assessment. This additional information may significantly influence decisions about rehabilitation, postacute care needs, treatment plans, and caregiver education. Published by Elsevier Inc. All rights reserved.

Use of atypical antipsychotics in nursing homes and pharmaceutical marketing

Wed, 05/13/2015 - 2:16pm

OBJECTIVES: To describe the current extent and type of pharmaceutical marketing in nursing homes (NHs) in one state and to provide preliminary evidence for the potential influence of pharmaceutical marketing on the use of atypical antipsychotics in NHs.

DESIGN: Nested mixed-methods, cross-sectional study of NHs in a cluster randomized trial.

SETTING: Forty-one NHs in Connecticut.

PARTICIPANTS: NH administrators, directors of nursing, and medical directors (n = 93, response rate 75.6%).

MEASUREMENTS: Quantitative data, including prescription drug dispensing data (September 2009-August 2010) linked with Nursing Home Compare data (April 2011), were used to determine facility-level prevalence of atypical antipsychotic use, facility-level characteristics, NH staffing, and NH quality. Qualitative data, including semistructured interviews and surveys of NH leaders conducted in the first quarter of 2011, were used to determine encounters with pharmaceutical marketing.

RESULTS: Leadership at 46.3% of NHs (n = 19) reported pharmaceutical marketing encounters, consisting of educational training, written and Internet-based materials, and sponsored training. No association was detected between level of atypical antipsychotic prescribing and reports of any pharmaceutical marketing by at least one NH leader.

CONCLUSION: NH leaders frequently encounter pharmaceutical marketing through a variety of ways, although the impact on atypical antipsychotic prescribing is unclear. Geriatrics Society.

Incidence, in-hospital case-fatality rates, and management practices in Puerto Ricans hospitalized with acute myocardial infarction

Tue, 05/12/2015 - 10:32pm

OBJECTIVE: There are extremely limited data on minority populations, especially Hispanics, describing the clinical epidemiology of acute coronary disease. The aim of this study is to examine the incidence rate of acute myocardial infarction (AMI), in-hospital case-fatality rate (CFR), and management practices among residents of greater San Juan (Puerto Rico) who were hospitalized with an initial AMI.

METHODS: Our trained study staff reviewed and independently validated the medical records of patients who had been hospitalized with possible AMI at any of the twelve hospitals located in greater San Juan during calendar year 2007.

RESULTS: The incidence rate (# per 100,000 population) of 1,415 patients hospitalized with AMI increased with advancing age and were significantly higher for older patients for men (198) than they were for women (134). The average age of the study population was 64 years, and women comprised 45% of the study sample. Evidence-based cardiac therapies, e.g., aspirin, beta blockers, ACE inhibitors/angiotensin receptor blockers, and statins, were used with 60% of the hospitalized patients, and women were less likely than men to have received these therapies (59% vs. 65%) or to have undergone interventional cardiac procedures (47% vs. 59%) (p < 0.05). The in-hospital CFR increased with advancing age and were higher for women (8.6%) than they were for men (6.0%) (p < 0.05).

CONCLUSION: Efforts are needed to reduce the magnitude of AMI, enhance the use of evidence-based cardiac therapies, reduce possible gender disparities, and improve the short-term prognoses of Puerto Rican patients hospitalized with an initial AMI.

Cement directed kyphoplasty reduces cement leakage as compared with vertebroplasty: results of a controlled, randomized trial

Tue, 05/12/2015 - 10:32pm

STUDY DESIGN: A novel randomized, controlled, unblinded clinical trial comparing 2 procedural interventions for painful osteoporotic vertebral compression fractures.

OBJECTIVE: The primary study objective was to evaluate cement leakage for a cement directed kyphoplasty system (CDKS) with anteriorly biased cement flow and vertebroplasty. The secondary study objective was to compare adjacent level fracture rates and vertebral body height for these 2 intervention methods.

SUMMARY OF BACKGROUND DATA: Cement leakage remains a significant clinical problem associated with vertebroplasty and kyphoplasty procedures. Uncontrolled cement flow in the posterior direction can result in leakage into the vertebral veins or spinal canal, leading to potentially serious clinical complications.

METHODS: Seventy-seven patients with painful osteoporotic vertebral compression fractures were enrolled. Patients were randomized 2:1 for treatment with CDKS (49 patients, 65 levels) or vertebroplasty (28 patients, 39 levels). Cement leakage was evaluated from radiographs and computed tomographic scans. Three- and 12-month follow-ups included additional radiographs and computed tomographic scans to assess changes in vertebral body height and the incidence of new fractures.

RESULTS: Treatment with CDKS significantly reduced the number of levels with leaks and the total number of leaks per level, as compared with vertebroplasty (P = 0.0132 and P = 0.0012, respectively). Significantly, fewer lateral cortical and spinal canal leaks (posterior leaks) occurred in the CDKS group (P = 0.0050, P = 0.02260, respectively). Three adjacent level fractures occurred in the vertebroplasty group, as compared with 2 in the CDKS group. Vertebral body height maintenance was equivalent.

CONCLUSION: Cement directed kyphoplasty effectively reduces posterior cement leakage, reducing the risk of leakage related complications.

LEVEL OF EVIDENCE: 2.

Multipronged CD4(+) T-cell effector and memory responses cooperate to provide potent immunity against respiratory virus

Tue, 05/12/2015 - 10:32pm

Over the last decade, the known spectrum of CD4(+) T-cell effector subsets has become much broader, and it has become clear that there are multiple dimensions by which subsets with a particular cytokine commitment can be further defined, including their stage of differentiation, their location, and, most importantly, their ability to carry out discrete functions. Here, we focus on our studies that highlight the synergy among discrete subsets, especially those defined by helper and cytotoxic function, in mediating viral protection, and on distinctions between CD4(+) T-cell effectors located in spleen, draining lymph node, and in tissue sites of infection. What emerges is a surprising multiplicity of CD4(+) T-cell functions that indicate a large arsenal of mechanisms by which CD4(+) T cells act to combat viruses.

Amyotrophic lateral sclerosis: Problems and prospects

Tue, 05/12/2015 - 10:32pm

Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disorder of motoneurons, which may occur concurrently with frontotemporal dementia. Genetic analyses of the approximately 10% of ALS cases that are dominantly inherited provide insight into ALS pathobiology. Two broad themes are evident. One, prompted by investigations of the SOD1 gene, is that conformational instability of proteins triggers downstream neurotoxic processes. The second, from studies of the TDP43, FUS, and C9orf72 genes, is that perturbations of RNA processing can be highly adverse in motoneurons. Several investigations support the concept that non-neuronal cells (microglia, astroglia, oligodendroglia) participate in the degenerative process in ALS. Recent data also emphasize the importance of molecular events in the axon and distal motoneuron terminals. Only 1 compound, riluzole, is approved by the US Food and Drug Administration for ALS; several therapies are in clinical trials, including 2 mesenchymal stem cell trials. The challenges and unmet needs in ALS emphasize the importance of new research directions: high-throughput sequencing of large DNA sets of familial and sporadic ALS, which will define scores of candidate ALS genes and pathways and facilitate studies of epistasis and epigenetics; infrastructures for candidate gene validation, including in vitro and in vivo modeling; valid biomarkers that elucidate causative molecular events and accelerate clinical trials; and in the long term, methods to identify environmental toxins. The unprecedented intensity of research in ALS and the advent of extraordinary technologies (rapid, inexpensive DNA sequencing; stem cell production from skin-derived fibroblasts; silencing of miscreant mutant genes) bode well for discovery of innovative ALS therapies.

Primary endpoints of the biventricular pacing after cardiac surgery trial

Tue, 05/12/2015 - 10:32pm

BACKGROUND: This study sought to determine whether optimized biventricular pacing increases cardiac index in patients at risk of left ventricular dysfunction after cardiopulmonary bypass. Procedures included coronary artery bypass, aortic or mitral surgery and combinations. This trial was approved by the Columbia University Institutional Review Board and was conducted under an Investigational Device Exemption.

METHODS: Screening of 6,346 patients yielded 47 endpoints. With informed consent, 61 patients were randomized to pacing or control groups. Atrioventricular and interventricular delays were optimized 1 (phase I), 2 (phase II), and 12 to 24 hours (phase III) after bypass in all patients. Cardiac index was measured by thermal dilution in triplicate. A 2-sample t test assessed differences between groups and subgroups.

RESULTS: Cardiac index was 12% higher (2.83+/-0.16 [standard error of the mean] vs 2.52+/-0.13 liters/minute/square meter) in the paced group, less than predicted and not statistically significant (p = 0.14). However, when aortic and aortic-mitral surgery groups were combined, cardiac index increased 29% in the paced group (2.90+/-0.19, n = 14) versus controls (2.24+/-0.15, n = 11) (p = 0.0138). Using a linear mixed effects model, t-test revealed that mean arterial pressure increased with pacing versus no pacing at all optimization points (phase I 79.2+/-1.7 vs 74.5+/-1.6 mm Hg, p = 0.008; phase II 75.9+/-1.5 vs 73.6+/-1.8, p = 0.006; phase III 81.9+/-2.8 vs 79.5+/-2.7, p = 0.002).

CONCLUSIONS: Cardiac index did not increase significantly overall but increased 29% after aortic valve surgery. Mean arterial pressure increased with pacing at 3 time points. Additional studies are needed to distinguish rate from resynchronization effects, emphasize atrioventricular delay optimization, and examine clinical benefits of temporary postoperative pacing. All rights reserved.

Evolution of faculty affairs and faculty development offices in U.S. medical schools: a 10-year follow-up survey

Tue, 05/12/2015 - 10:32pm

PURPOSE: To determine how U.S. MD-granting medical schools manage, fund, and evaluate faculty affairs/development functions and to determine the evolution of these offices between 2000 and 2010.

METHOD: In December 2010, the authors invited faculty affairs designees at 131 U.S. MD-granting medical schools to complete a questionnaire developed by the Association of American Medical Colleges Group on Faculty Affairs, based on a 2000 survey. Schools were asked about core functions, budget, staffing, and performance metrics. The authors analyzed the data using descriptive statistics.

RESULTS: A total of 111 schools (84.7%) responded. Fifty percent of the offices were established since 2000. Seventy-eight percent reported their top core function as administrative support for appointments, promotions, and tenure, as in 2000. Faculty policies, appointments, databases, governance support, grievance proceedings, management issues, and annual trend analyses continued as major functions. All 11 core functions identified in 2000 remain predominantly provided by central offices of faculty affairs, except support of major leadership searches. Web site communication emerged as a new core function. Similar to 2000, several other offices were responsible for some faculty development functions. Office size and budget correlated positively with size of the faculty and age of the office (P < .05 for all). Thirty-five schools (31.5%) reported formally evaluating their faculty affairs office.

CONCLUSIONS: The number of faculty affairs offices and their responsibilities have substantially increased since 2000. Most major core functions have not changed. These offices are now an established part of the central administration of most medical schools.

Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1beta response and host resistance to Trypanosoma cruzi infection

Tue, 05/12/2015 - 10:32pm

The innate immune response to Trypanosoma cruzi infection comprises several pattern recognition receptors (PRRs), including TLR-2, -4, -7, and -9, as well as the cytosolic receptor Nod1. However, there are additional PRRs that account for the host immune responses to T. cruzi. In this context, the nucleotide-binding oligomerization domain-like receptors (NLRs) that activate the inflammasomes are candidate receptors that deserve renewed investigation. Following pathogen infection, NLRs form large molecular platforms, termed inflammasomes, which activate caspase-1 and induce the production of active IL-1beta and IL-18. In this study, we evaluated the involvement of inflammasomes in T. cruzi infection and demonstrated that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) inflammasomes, including NLR family, pyrin domain-containing 3 (NLRP3), but not NLR family, caspase recruitment domain-containing 4 or NLR family, pyrin domain-containing 6, are required for triggering the activation of caspase-1 and the secretion of IL-1beta. The mechanism by which T. cruzi mediates the activation of the ASC/NLRP3 pathway involves K(+) efflux, lysosomal acidification, reactive oxygen species generation, and lysosomal damage. We also demonstrate that despite normal IFN-gamma production in the heart, ASC(-)/(-) and caspase-1(-)/(-) infected mice exhibit a higher incidence of mortality, cardiac parasitism, and heart inflammation. These data suggest that ASC inflammasomes are critical determinants of host resistance to infection with T. cruzi.

Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics

Tue, 05/12/2015 - 10:32pm

RATIONALE: Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear.

OBJECTIVE: To determine how mitochondria impact endothelial cell function.

METHODS AND RESULTS: We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochondrial uncoupling protein 2 (UCP2). Analysis in silico indicated increased UCP2 expression is common in highly proliferative cell types, including cancer cells. Upregulation of UCP2 was critical for controlling mitochondrial membrane potential (Deltapsi) and superoxide production. In the absence of UCP2, endothelial growth stimulation provoked mitochondrial network fragmentation and premature senescence via a mechanism involving superoxide-mediated p53 activation. Mitochondrial network fragmentation was both necessary and sufficient for the impact of UCP2 on endothelial cell phenotype.

CONCLUSIONS: These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2.

Cochlear implant electrode failure secondary to silicone touch-up during device manufacturing

Tue, 05/12/2015 - 10:32pm

STUDY DESIGN: Retrospective case report.

SETTING: Tertiary referral cochlear implant center.

PATIENT: A 21-year-old woman was implanted with Advanced Bionics HiFocus Clarion device without complication. Five years later, the patient presented with dizziness, fluctuating implant performance, and facial pain.

INTERVENTION: Surgical exploration revealed a torn electrode silicon casing in conjunction with scar contraction bending the electrode against bony facial nerve canal at the facial recess. Suspension of the electrode such that the damaged portion was not in contact with mastoid cavity led to temporary resolution of symptoms. Explantation and reimplantation procedures were carried out 2 months later.

RESULTS: Postexplantation device analysis by the manufacturer demonstrated silicone touch-up at the site of failure. Six years since reimplantation, the patient has remained symptom-free. It is very likely that the touch-up silicon weakened the electrode and, in conjunction with chronic scar contraction, led to the tear on the silicon casing.

CONCLUSION: Isolated cochlear implant electrode failure is a rare but possible long-term complication in older generation devices. The author reports 1 case of implant device failure partly because of silicon touch-up that was applied at the location of electrode failure during its manufacturing process.

Expression of inhibitory markers is increased on effector memory T cells during hepatitis C virus/HIV coinfection as compared to hepatitis C virus or HIV monoinfection

Tue, 05/12/2015 - 10:32pm

OBJECTIVE: Hepatitis C virus (HCV)/HIV coinfection is associated with rapid progression of hepatic fibrosis and liver disease. T-cell response has been implicated in the pathophysiological outcome of the disease.

DESIGN: This study sought to evaluate the role of memory T-cell exhaustion in enhancing immune dysfunction during coinfection.

METHODS: Sixty-four patients were included in the study; HCV monoinfected (n = 21), HIV monoinfected (n = 23), HCV/HIV coinfected (n = 20), and healthy controls (n = 20). Peripheral blood mononuclear cells (PBMCs) were isolated; immunophenotyped and functional assays were performed.

RESULTS: A significant increase in the naive T cells and central memory T cells and a marked reduction in effector memory T cells (TEM) were observed with coinfection as compared to monoinfection. Inhibitory markers programmed death 1 (PD-1) and T-cell immunoglobulin and mucin domain containing molecule 3 (TIM3) were highly upregulated on TEM in coinfection and functionally, these TEM cells displayed lowered proliferation. Increased expression of PD-1 and TIM3 correlated with decreased levels of CD8+CD107a+ TEM cells in coinfection. Pro-inflammatory cytokines interferon-gamma and interleukin-2 (IL-2) secretion by TEM cells were also reduced during chronic viral infection. Secretion of IL-10, a human cytokine synthesis inhibitory factor, was significantly upregulated in CD4 TEM with HCV/HIV coinfection in comparison to HCV monoinfection.

CONCLUSION: TEM cells play an important role during viral infection and enhanced expression of inhibitory markers is associated with decreased proliferation and cytotoxicity and increased IL-10 production, which was pronounced in HCV/HIV coinfection. Thus, decreased TEM functionality contributes to diminished host immune responses during HCV/HIV coinfection as compared to HCV or HIV monoinfection.

Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

Tue, 05/12/2015 - 10:32pm

Intestinal stem cells (ISCs) in the Drosophila adult midgut are essential for maintaining tissue homeostasis, and their proliferation and differentiation speed up in order to meet the demand for replenishing the lost cells in response to injury. Several signaling pathways including JAK-STAT, EGFR and Hippo (Hpo) pathways have been implicated in damage-induced ISC proliferation, but the mechanisms that integrate these pathways have remained elusive. Here, we demonstrate that the Drosophila homolog of the oncoprotein Myc (dMyc) functions downstream of these signaling pathways to mediate their effects on ISC proliferation. dMyc expression in precursor cells is stimulated in response to tissue damage, and dMyc is essential for accelerated ISC proliferation and midgut regeneration. We show that tissue damage caused by dextran sulfate sodium feeding stimulates dMyc expression via the Hpo pathway, whereas bleomycin feeding activates dMyc through the JAK-STAT and EGFR pathways. We provide evidence that dMyc expression is transcriptionally upregulated by multiple signaling pathways, which is required for optimal ISC proliferation in response to tissue damage. We have also obtained evidence that tissue damage can upregulate dMyc expression post-transcriptionally. Finally, we show that a basal level of dMyc expression is required for ISC maintenance, proliferation and lineage differentiation during normal tissue homeostasis.

Relationship of left ventricular hypertrophy and diastolic function with cardiovascular and renal outcomes in African Americans with hypertensive chronic kidney disease

Tue, 05/12/2015 - 10:32pm

African Americans with hypertension are at high risk for adverse outcomes from cardiovascular and renal disease. Patients with stage 3 or greater chronic kidney disease have a high prevalence of left ventricular (LV) hypertrophy and diastolic dysfunction. Our goal was to study prospectively the relationships of LV mass and diastolic function with subsequent cardiovascular and renal outcomes in the African American Study of Kidney Disease and Hypertension cohort study. Of 691 patients enrolled in the cohort, 578 had interpretable echocardiograms and complete relevant clinical data. Exposures were LV hypertrophy and diastolic parameters. Outcomes were cardiovascular events requiring hospitalization or causing death; a renal composite outcome of doubling of serum creatinine or end-stage renal disease (censoring death); and heart failure. We found strong independent relationships between LV hypertrophy and subsequent cardiovascular (hazard ratio, 1.16; 95% confidence interval, 1.05-1.27) events, but not renal outcomes. After adjustment for LV mass and clinical variables, lower systolic tissue Doppler velocities and diastolic parameters reflecting a less compliant LV (shorter deceleration time and abnormal E/A ratio) were significantly (P < 0.05) associated with future heart failure events. This is the first study to show a strong relationship among LV hypertrophy, diastolic parameters, and adverse cardiac outcomes in African Americans with hypertension and chronic kidney disease. These echocardiographic risk factors may help identify high-risk patients with chronic kidney disease for aggressive therapeutic intervention.

Nucleosome dynamics as modular systems that integrate DNA damage and repair

Tue, 05/12/2015 - 10:32pm

By some estimates, a eukaryotic cell must repair up to 10,000 DNA lesions per cell cycle to counteract endogenous sources of DNA damage. Exposure to environmental toxins, UV sources, or other radiations only increases this enormous number. Failure to repair such lesions can lead to a deleterious mutation rate, genomic instability, or cell death. The timely and efficient repair of eukaryotic DNA damage is further complicated by the realization that DNA lesions must be detected and repaired in the context of chromatin with its complex organization within the nucleus. Numerous studies have shown that chromatin packaging can inhibit nearly all repair pathways, and recent work has defined specific mechanisms that facilitate DNA repair within the chromatin context. In this review, we provide a broad overview of chromatin regulatory mechanisms, mainly at the nucleosomal level, and then focus on recent work that elucidates the role of chromatin structure in regulating the timely and efficient repair of DNA double-strand breaks (DSBs).