Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator-activated receptor alpha (PPARα) for nuclear export via mono-ubiquitination. Since MuRF1−/− mice have an estimated fivefold increase in PPARα activity, we sought to determine how challenge with the PPARα agonist fenofibrate, a PPARα ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1 +/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle α-actin mRNA. In addition to pathological hypertrophy, MuRF1−/− mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1−/− genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <−4 log fold change; P≤.0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARα, cardiac hypertrophy, and hemostasis

Physiology of long pranayamic breathing: Neural respiratory elements may provide a mechanism that explains how slow deep breathing shifts the autonomic nervous system

Pranayamic breathing, defined as a manipulation of breath movement, has been shown to contribute to a physiologic response characterized by the presence of decreased oxygen consumption, decreased heart rate, and decreased blood pressure, as well as increased theta wave amplitude in EEG recordings, increased parasympathetic activity accompanied by the experience of alertness and reinvigoration. The mechanism of how pranayamic breathing interacts with the nervous system affecting metabolism and autonomic functions remains to be clearly understood. It is our hypothesis that voluntary slow deep breathing functionally resets the autonomic nervous system through stretchinduced inhibitory signals and hyperpolarization currents propagated through both neural and non-neural tissue which synchronizes neural elements in the heart, lungs, limbic system and cortex. During inspiration, stretching of lung tissue produces inhibitory signals by action of slowly adapting stretch receptors (SARs) and hyperpolarization current by action of fibroblasts. Both inhibitory impulses and hyperpolarization current are known to synchronize neural elements leading to the modulation of the nervous system and decreased metabolic activity indicative of the parasympathetic state. In this paper we propose pranayama’s physiologic mechanism through a cellular and systems level perspective,involving both neural and non-neural elements. This theoretical description describes a common physiological mechanism underlying pranayama and elucidate the role of the respiratory and cardiovascular system on modulating the autonomic nervous system. Along with facilitating the design of clinical breathing techniques for the treatment of autonomic nervous system and other disorders, this model will also validate pranayama as a topic requiring more research

Cerebellopontine epidermoid presenting with trigeminal neuralgia for 10 years: a case report

Trigeminal neuralgia, also called tic douloureux, is a common and potentially disabling pain syndrome, which affects the trigeminal or fifth cranial nerve. The precise pathophysiology of Trigeminal neuralgia remains obscure. The disorder causes extreme, sporadic, sudden burning or shock-like face pain that lasts from few seconds to minutes and can be physically and mentally incapacitating. More than one nerve branch can be affected by the disorder. A 55-year-old female presented with pain over the left side of face for 10 years uncontrolled with carbamazepine. On examination the positive findings were reduced sensation by 25% over the left side of face with House and Brackman grade II facial nerve palsy. The corneal reflex was absent on left side. Magnetic resonance imaging showed left cerebellopontine angle (CPA) mass suggestive of an epidermoid involving the Vth nerve and Gasserian ganglion and extending into the middle cranial fossa. She underwent left suboccipital craniectomy and near total excision of the tumor with decompression of the Vth nerve which was fully engulfed by the tumor. Postoperative the VII nerve palsy increased to grade III and she had 50% loss of sensation over left side. She had no further attacks of pain and hence tapered off the carbamazepine. TN caused by cerebellopontine angle epidermoids is uncommon and should be kept in view in all cases presenting with TN. The aim of surgery for epidermoids is to decompress the cranial nerves and brain stem and not total removal with its attendant morbidity and mortality

Fully-Automated Analysis of Body Composition from CT in Cancer Patients Using Convolutional Neural Networks

The amounts of muscle and fat in a person's body, known as body composition, are correlated with cancer risks, cancer survival, and cardiovascular risk. The current gold standard for measuring body composition requires time-consuming manual segmentation of CT images by an expert reader. In this work, we describe a two-step process to fully automate the analysis of CT body composition using a DenseNet to select the CT slice and U-Net to perform segmentation. We train and test our methods on independent cohorts. Our results show Dice scores (0.95-0.98) and correlation coefficients (R=0.99) that are favorable compared to human readers. These results suggest that fully automated body composition analysis is feasible, which could enable both clinical use and large-scale population studies

Medicare Bundled Payment Policy on Anemia Care, Major Adverse Cardiovascular Events, and Mortality among Adults Undergoing Hemodialysis

Background and objectives In 2011, the Centers forMedicare & Medicaid Services implemented bundling of all services for patients receiving dialysis, including erythropoietin-stimulating agents use, and the Food and Drug Administration recommended conservative erythropoietin-stimulating agent dosing. Design, setting, participants, & measurements This retrospective cohort study investigated anemia care and clinical outcomes before and after the Centers for Medicare & Medicaid Services bundled payment and the revised Food and Drug Administration–recommended erythropoietin-stimulating agent labeling for Medicareinsured adults receiving hemodialysis using data from the United States Renal Data System from January 1, 2006 to December 31, 2016. Clinical outcomes included major adverse cardiovascular event (stroke, acute myocardial infarction, and all-cause mortality), cardiovascular mortality, and heart failure. Measurements were compared between prepolicy (2006–2010) and postpolicy (2012–2016) implementation using interrupted time series and Cox proportional hazards regression models. Results Of 481,564 patients, erythropoietin-stimulating agent use immediately decreased by 84.8 per 1000 persons (P11 g/dl decreased from 68% in January 2006 to 28% in December 2016, whereas those with hemoglobin >9 g/dl increased from 5% to 9%. Overall major adverse cardiovascular event (adjusted hazard ratio, 0.95; 95% confidence interval, 0.94 to 0.96), stroke (adjusted hazard ratio, 0.83; 95% confidence interval, 0.80 to 0.86), all-cause mortality (adjusted hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.89), cardiovascular mortality (adjusted hazard ratio, 0.81; 95% confidence interval, 0.79 to 0.83), and heart failure (adjusted hazard ratio, 0.86; 95% confidence interval, 0.84 to 0.88) risks were lower. Acute myocardial infarction risk (adjusted hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.06) was higher after policies changed. Conclusions The Medicare reimbursement policy and Food and Drug Administration–recommended erythropoietin-stimulating agent dosing changes were associated with lower erythropoietin-stimulating agent use and lower hemoglobin levels. These changes in anemia care were associated with lower risks of major adverse cardiovascular event, stroke, mortality, and heart failure but higher risk of acute myocardial infarction among adults receiving hemodialysis

Audit fees and book-tax differences

We investigate whether book-tax differences are associated with higher audit fees, a proxy for auditor risk assessments and auditor effort. Our evidence suggests that there is a significantly positive relation. Further, this association is larger for firms that appear to have managed earnings (i.e., have high accruals) relative to those that are tax avoiders (i.e., have low cash effective tax rates). Our evidence is consistent with large book-tax differences representing an observable proxy for earnings management that is associated with auditor decisions. Our study contributes to capital market research that examines audit fees, as well as other research that examines the usefulness of book-tax differences for market participants.Ernst & Young (Faculty Fellowship in Accounting

India and its diaspora: making sense of Hindu identity in South Africa.

Indian immigrants to South Africa in the late nineteenth century differed in terms of their origins, motivations, belief systems, customs, and practices from the indigenous African population as well as from the ruling white settler elite. It is within this context that this paper interrogates some of the ways in which several generations of (Indian) Hindus constructed and continue to (re)construct their religious identities in South Africa. Data for this study were achieved by administering face-to-face questionnaires to 66 individuals in the Metropolitan Area of Durban in KwaZulu-Natal, South Africa. The sample (selected through snowball sampling) comprised third to fifth generation Indians belonging to the four major language groups (Tamil, Telegu, Gujarati, and Hindi) residing in South Africa. Following the questionnaire responses, interviews were conducted with a selected number of respondents from the same sample. Quantitative data were analysed using SPSS while analysis of qualitative data followed a thematic model

Recall patterns and risk of primary liver cancer for subcentimeter ultrasound liver observations: a multicenter study

BACKGROUND: Patients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC). AIMS: The aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound. METHODS: We conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively. RESULTS: Of 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5-0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3-6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2-47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein \u3e10 ng/mL (HR: 4.01, 95% CI, 1.85-8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95-12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27-5.08). CONCLUSIONS: Recall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3-6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels

Ionized gas discs in elliptical and S0 galaxies at z < 1

We analyse the extended, ionized-gas emission of 24 early-type galaxies (ETGs) at 0 < z < 1 from the ESO Distant Cluster Survey (EDisCS). We discuss different possible sources of ionization and favour star formation as the main cause of the observed emission. 10 galaxies have disturbed gas kinematics, while 14 have rotating gas discs. In addition, 15 galaxies are in the field, while 9 are in the infall regions of clusters. This implies that, if the gas has an internal origin, this is likely stripped as the galaxies get closer to the cluster centre. If the gas instead comes from an external source, then our results suggest that this is more likely acquired outside the cluster environment, where galaxy–galaxy interactions more commonly take place. We analyse the Tully–Fisher relation of the ETGs with gas discs, and compare them to EDisCS spirals. Taking a matched range of redshifts, MB < −20, and excluding galaxies with large velocity uncertainties, we find that, at fixed rotational velocity, ETGs are 1.7 mag fainter in MB than spirals. At fixed stellar mass, we also find that ETGs have systematically lower specific star formation rates than spirals. This study constitutes an important step forward towards the understanding of the evolution of the complex ISM in ETGs by significantly extending the look-back-time baseline explored so far