Mutations in polycystin-1 (PC1) cause autosomal dominant polycystic kidney disease (ADPKD), a disorder that manifests with cardiac hypertrophy and dysfunction. We recently showed that cardiomyocyte-specific PC1 KO mice exhibit both systolic and diastolic dysfunction without signs of cardiac hypertrophy. The purpose of this study was to determine the effects of ADPKD-causing PC1 mutations on cardiac function using a mouse model for ADPKD harboring a mutation in PC1 R3277C (RC/RC). We used echocardiography to determine cardiac function and Western blot analysis to explore signaling pathways in WT and RC/RC mice (2-4 months of age).We observed a slight but significant decrease in ejection fraction (77.2±0.7 vs 86.2±2.4 %, N=5, 4, P=0.015) without signs of left ventricular hypertrophy (LV mass 78.4±5.5 vs 93.5±4.2 mg, N=5, 4, P>0.05) in RC/RC compared to WT mice. Western blot analysis from total heart lysates (WT and RC/RC; N=5) revealed no changes in protein levels of hypertrophic markers: beta myosin heavy chain (β-MHC) and regulator of calcineurin 1 (RCAN1). In addition, we studied multiple signaling pathways involved in cardiac hypertrophy by analyzing their phosphorylation status by Western blot (phosphorylated/total protein). We observed no changes in mTOR, S6K1 and S6 phosphorylation. However, a decrease in p-4EBP1 and p-eIF4B was observed in RC/RC compared to WT. Moreover, we observed a significant increase in p-ERK and p-CaMKII. Our data suggest that alterations in PC1 signaling promote cardiac dysfunction but do not promote hypertrophy in young mice (2-4 months of age). Published evidence (PMID: 32730856) suggest that RC/RC hearts become hypertrophic at 6 months of age. However, our data suggest there may be dysfunction prior to cardiac hypertrophy. This warrants further investigation into the more primary role of ADPKD-associated co-morbidities. More studies, with a larger animal cohort, are necessary to unveil the effects of mutant PC1 on cardiac function.

Early-career academic cardiologists, who many believe are an important component of the future of cardiovascular care, face myriad challenges. The Early Career Section Academic Working Group of the American College of Cardiology, with senior leadership support, assessed the progress of this cohort from 2013 to 2016 with a global perspective. Data consisted of accessing National Heart, Lung, and Blood Institute public information, data from the American Heart Association and international organizations, and a membership-wide survey. Although the National Heart, Lung, and Blood Institute increased funding of career development grants, only a small number of early-career American College of Cardiology members have benefited as funding of the entire cohort has decreased. Personal motivation, institutional support, and collaborators continued to be positive influential factors. Surprisingly, mentoring ceased to correlate positively with obtaining external grants. The totality of findings suggests that the status of early-career academic cardiologists remains challenging; therefore, the authors recommend a set of attainable solutions.

Ischemic injury to the kidneys is a prevalent clinical problem, contributing importantly to chronic kidney disease. Yet, underlying molecular mechanisms are elusive. To address the possible role of autophagy, we engineered a novel strain of mice harboring a ubiquitously expressed CAG-RFP-EGFP-LC3 transgene. Using this tool, we examined the post-ischemic kidney and detailed the dynamics of renal tubular epithelial autophagy. In addition, we defined the role of MTOR in the resolution of autophagy during epithelial survival and kidney repair.

Dobrev, Christoph Maack, Lars S. Maier, Hermann-Josef Gröne, Hugo A. Katus, Eric N. Olson and Kohlhaas, Jan-Christian Reil, Kay Neumann, Michael D. Schneider, Joseph A. Hill, Dobromir Michael M. Kreusser, Lorenz H. Lehmann, Stanislav Keranov, Marc-Oskar Hoting, Michael Inhibit Calcineurin-Induced Myocardial Hypertrophy Contribute Redundantly to Adverse Remodeling but γ and δ The Cardiac CaMKII Genes Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2014 American Heart Association, Inc. All rights reserved. is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation published online August 14, 2014; Circulation. http://circ.ahajournals.org/content/early/2014/08/14/CIRCULATIONAHA.114.006185 World Wide Web at: The online version of this article, along with updated information and services, is located on the http://circ.ahajournals.org/content/suppl/2014/08/14/CIRCULATIONAHA.114.006185.DC1.html Data Supplement (unedited) at:

Despite recent scientific and technological advances, cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Autophagy, an evolutionarily ancient response to cellular stress, has been implicated in the pathogenesis of a wide range of heart pathologies. However, the precise role of autophagy in these contexts remains obscure owing to its multifarious actions. Here, we review recently derived insights regarding the role of autophagy in multiple manifestations of cardiac plasticity and disease.

ObjectiveThere is a greater incidence of reproductive-related disorders among underweight as well as obese females resulting in trouble getting pregnant naturally and with ART. Extremes in Body Mass Index (BMI) have been negatively associated with clinical outcomes (Fedorcsak et, al), but a causal relationship remains unclear. Hormonal disturbances, elevated LDL and steroid precursors related to the additional adipose tissue in overweight and obese patients may affect endometrial, oocyte, and embryo quality. To determine if IVF patients with an altered BMI have similar blastocyst development rates, implantation, FHB and SAB as patients with a normal BMI.DesignRetrospective analyses of patients (n=594).Materials and Methods1245 cycles, 594 were candidates. Good blastocyst development defined as an ICM and trophectoderm grades of better than 3 (Grade of 1 = distinct ICM, cohesive trophectoderm, 2 = present ICM, good trophectoderm, 3 = small ICM, trophectoderm with mooning or too few cells). Fisher's exact test (two tailed P value) was used for statistical analysis.ResultsTable 1BMI% BLASTPRFHBIRSAB<19.972/219 33%*19/38 50%15/65 23%*19/65 29%*4/38 11%*20-24.24.9527/1703 31%*141/260 54%131/430 30%*141/430 33%*10/260 4%25-29.9447/1197 37%*90/172 52%89/290 31%90/290 31%1/172 0.5%*>30329/789 42%*62/124 50%53/119 45%*62/119 52%*10/126 8%** = statistically significant.Increasing rates of miscarriage were associated with increasing BMI values. Open table in a new tab ConclusionMaternal obesity effects clinical outcome. Endometrial receptivity as evidenced by implantation and miscarriage rates is more adversely affected by BMI changes than embryo quality. Women with extremes of BMI either too thin or too heavy have significantly higher pregnancy loss rates than those with ideal body weights implying an altered endometrial environment in these women. ObjectiveThere is a greater incidence of reproductive-related disorders among underweight as well as obese females resulting in trouble getting pregnant naturally and with ART. Extremes in Body Mass Index (BMI) have been negatively associated with clinical outcomes (Fedorcsak et, al), but a causal relationship remains unclear. Hormonal disturbances, elevated LDL and steroid precursors related to the additional adipose tissue in overweight and obese patients may affect endometrial, oocyte, and embryo quality. To determine if IVF patients with an altered BMI have similar blastocyst development rates, implantation, FHB and SAB as patients with a normal BMI. There is a greater incidence of reproductive-related disorders among underweight as well as obese females resulting in trouble getting pregnant naturally and with ART. Extremes in Body Mass Index (BMI) have been negatively associated with clinical outcomes (Fedorcsak et, al), but a causal relationship remains unclear. Hormonal disturbances, elevated LDL and steroid precursors related to the additional adipose tissue in overweight and obese patients may affect endometrial, oocyte, and embryo quality. To determine if IVF patients with an altered BMI have similar blastocyst development rates, implantation, FHB and SAB as patients with a normal BMI. DesignRetrospective analyses of patients (n=594). Retrospective analyses of patients (n=594). Materials and Methods1245 cycles, 594 were candidates. Good blastocyst development defined as an ICM and trophectoderm grades of better than 3 (Grade of 1 = distinct ICM, cohesive trophectoderm, 2 = present ICM, good trophectoderm, 3 = small ICM, trophectoderm with mooning or too few cells). Fisher's exact test (two tailed P value) was used for statistical analysis. 1245 cycles, 594 were candidates. Good blastocyst development defined as an ICM and trophectoderm grades of better than 3 (Grade of 1 = distinct ICM, cohesive trophectoderm, 2 = present ICM, good trophectoderm, 3 = small ICM, trophectoderm with mooning or too few cells). Fisher's exact test (two tailed P value) was used for statistical analysis. ResultsTable 1BMI% BLASTPRFHBIRSAB<19.972/219 33%*19/38 50%15/65 23%*19/65 29%*4/38 11%*20-24.24.9527/1703 31%*141/260 54%131/430 30%*141/430 33%*10/260 4%25-29.9447/1197 37%*90/172 52%89/290 31%90/290 31%1/172 0.5%*>30329/789 42%*62/124 50%53/119 45%*62/119 52%*10/126 8%** = statistically significant.Increasing rates of miscarriage were associated with increasing BMI values. Open table in a new tab * = statistically significant. Increasing rates of miscarriage were associated with increasing BMI values. ConclusionMaternal obesity effects clinical outcome. Endometrial receptivity as evidenced by implantation and miscarriage rates is more adversely affected by BMI changes than embryo quality. Women with extremes of BMI either too thin or too heavy have significantly higher pregnancy loss rates than those with ideal body weights implying an altered endometrial environment in these women. Maternal obesity effects clinical outcome. Endometrial receptivity as evidenced by implantation and miscarriage rates is more adversely affected by BMI changes than embryo quality. Women with extremes of BMI either too thin or too heavy have significantly higher pregnancy loss rates than those with ideal body weights implying an altered endometrial environment in these women.

A valuable study of the science behind the medicine, Muscle: Fundamental Biology and Mechanisms of Disease brings together key leaders in muscle biology. These experts provide state-of-the-art insights into the three forms of muscle - cardiac, skeletal, and smooth - from molecular anatomy, basic physiology, disease mechanisms, and targets of therapy. Commonalities and contrasts among these three tissue types are highlighted. This book focuses primarily on the biology of the myocyte. Individuals active in muscle investigation - as well as those new to the field--will find this work useful, as will students of muscle biology. In the case of the former, many wish to grasp issues at the margins of their own expertise (e.g. clinical matters at one end; molecular matters at the other), and this book is designed to assist them. Students, postdoctoral fellows, course directors and other faculty will find this book of interest. Beyond this, many clinicians in training (e.g. cardiology fellows) will benefit. It is the only resource to focus on science before the clinical work and therapeutics. Tiered approach to subject: discussion first of normal muscle function through pathological/disease state changes, and ending each section with therapeutic interventions. Coverage of topics ranging from basic physiology to newly discovered molecular mechanisms of muscle diseases for all three muscle types: cardiac, skeletal, and smooth.

Stress-induced hypertrophic growth of the myocardium is a pathogenetic milestone in the progression of heart failure. Some evidence suggests that suppression of pathological cardiac hypertrophy per se is a viable target for therapeutic intervention, and cardiomyocyte autophagy is an attractive mechanism for consideration as a means of controlling the hypertrophic response. However, although considerable insights have been gleaned in the molecular mechanisms governing cardiomyocyte autophagy, many details critical to rational targeting of the response remain unknown. Among them, mechanisms underlying the adaptive and maladaptive features of autophagy are obscure. With time and further study, it is possible that this near-ubiquitous cardiac response to stress will emerge as a target for therapeutic manipulation.

Purpose of reviewDespite maximum medical and mechanical support therapy, heart failure remains a relentlessly progressive disorder with substantial morbidity and mortality. Autophagy, an evolutionarily conserved process of cellular cannibalization, has been implicated in virtually all forms of cardiovascular disease. Indeed, its role is context dependent, antagonizing or promoting disease depending on the circumstance. Here, we review current understanding of the role of autophagy in the pathogenesis of heart failure and explore this pathway as a target of therapeutic intervention.Recent findingsIn preclinical models of heart disease, cardiomyocyte autophagic flux is activated; indeed, its role in disease pathogenesis is the subject of intense investigation to define mechanism. Similarly, in failing human heart of a variety of etiologies, cardiomyocyte autophagic activity is upregulated, and therapy, such as with mechanical support systems, elicits declines in autophagy activity. However, when suppression of autophagy is complete, rapid and catastrophic cell death occurs, consistent with a model in which basal autophagic flux is required for proteostasis. Thus, a narrow zone of 'optimal' autophagy seems to exist. The challenge moving forward is to tune the stress-triggered autophagic response within that 'sweet spot' range for therapeutic benefit.SummaryWhereas we have known for some years of the participation of lysosomal mechanisms in heart disease, it is only recently that upstream mechanisms (autophagy) are being explored. The challenge for the future is to dissect the underlying circuitry and titrate the response into an optimal, proteostasis-promoting range in hopes of mitigating the ever-expanding epidemic of heart failure.

Background: Mechanical unloading of the diseased ventricle has emerged as an important treatment strategy in advanced heart failure. In rare instances, dramatic improvements in ventricular performance are seen, yet little is known regarding underlying mechanisms. Histone deacetylases (HDACs) are implicated in the control of cell growth and remodeling. Recent studies have demonstrated that HDAC inhibition (HDACi) suppresses pathological cardiac hypertrophy and attenuates re-induction of the fetal gene program. We hypothesized that HDACi would accelerate unloading-induced cardiac atrophy. Methods: Mechanical unloading of murine hearts was accomplished by heterotopic transplantation into the abdomen of same-strain recipients (7 days). Two days prior to surgery, mice were randomized to daily sq injections of either trichostatin A (TSA, 1 mg/kg) or vehicle. Left ventricular (LV) cardiomyocyte area was measured from H&E sections (100 myocytes/heart), and LV transcript abundance was measured by quantitative real-time RT-PCR. Native hearts from recipient mice served as controls. Results: Consistent with a role for HDACs in cardiac atrophy, the protein abundance of HDAC-1 (54%; p<0.05), -2 (52%; p<0.01) and -3 (40%; p<0.05) were significantly increased in untreated donor hearts. Unloading-induced cardiomyocyte atrophy was accelerated in hearts transplanted into TSA-treated mice (25±4% atrophy, TSA vs 13±1% atrophy, vehicle; p<0.05). Remarkably, TSA treatment did not blunt (p=NS) the dramatic (72-fold, p<0.05) up-regulation of fetal β MHC seen in vehicle-treated hearts, despite significant increases in the rate of atrophy development. The cyclin dependent kinase inhibitors (CDKIs) p21(Cip1/Waf1) and p27(Kip1), which are known to negatively regulate cardiac hypertrophy, were each increased (p21, 45%, p<0.1; p27, 31%, p<0.1) in TSA-treated hearts relative to control. Conclusions: HDAC inhibition elicits a bona fide cardiomyocyte atrophy response during ventricular unloading in association with up-regulation of CDKI transcript expression. HDAC inhibition, however, does not blunt re-activation of the fetal gene program. These findings may have important implications for heart failure patients undergoing LV assist device support. This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).

Calibration of the relative response of the individual channels of the barrel electromagnetic calorimeter of the CMS detector was accomplished, before installation, with cosmic ray muons and test beams. One fourth of the calorimeter was exposed to a beam of high energy electrons and the relative calibration of the channels, the intercalibration, was found to be reproducible to a precision of about 0.3%. Additionally, data were collected with cosmic rays for the entire ECAL barrel during the commissioning phase. By comparing the intercalibration constants obtained with the electron beam data with those from the cosmic ray data, it is demonstrated that the latter provide an intercalibration precision of 1.5% over most of the barrel ECAL. The best intercalibration precision is expected to come from the analysis of events collected in situ during the LHC operation. Using data collected with both electrons and pion beams, several aspects of the intercalibration procedures based on electrons or neutral pions were investigated.

The energy resolution of the barrel part of the CMS Electromagnetic Calorimeter has been studied using electrons of 20 to 250 GeV in a test beam. The incident electron's energy was reconstructed by summing the energy measured in arrays of 3 x 3 or 5 x 5 channels. There was no significant amount of correlated noise observed within these arrays. For electrons incident at the centre of the studied 3 x 3 arrays of crystals, the mean stochastic term was measured to be 2.8% and the mean constant term to be 0.3%. The amount of the incident electrons' energy which is contained within the array depends on its position of incidence. The variation of the containment with position is corrected for using the distribution of the measured energy within the array. For uniform illumination of a crystal with 120 GeV electrons a resolution of 0.5% was achieved. The energy resolution meets the design goal for the detector.

The amplitude of the signal collected from the PbWO4 crystals of the CMS electromagnetic calorimeter is reconstructed by a digital filtering technique. The amplitude reconstruction has been studied with test beam data recorded from a fully equipped barrel supermodule. Issues specific to data taken in the test beam are investigated, and the implementation of the method for CMS data taking is discussed.

BACKGROUND: Women with recurrent pregnancy loss (RPL) and T-helper (Th)1-type immunity to trophoblast antigens have an increased frequency of the IL1B-511*1 promoter variant. Since CD46 gene products also regulate maternal immune responses including Th1 immunity, we investigated whether CD46 gene polymorphisms are also associated with RPL in women with and without Th1 immunity to trophoblast, and the possibility of a synergistic effect with the IL1B-511*1 promoter variant. METHODS: A case-controlled study was performed to document HindIII site polymorphism in intron 1 of the CD46 gene in 131 women with RPL and 72 fertile controls. Clinical information, Th1-type immune responsiveness to trophoblast in women with RPL history, and IL1B promoter allelotypes for this cohort were documented in a previous study. RESULTS: The frequency of the CD46H*2 allele and CD46H*2 homozygosity were significantly increased in women with RPL compared with fertile controls (P < 0.028 and P < 0.011). CD46H*2 homozygosity was highly associated with RPL-Th1(+) (32.4 versus 9.7% in fertile controls, P < 0.0045). Logistic regression analysis revealed that women homozygous for both the IL1B-511*1 and CD46H*2 alleles had an extremely high risk of RPL-Th1(+) [exponential coefficients (EC) = 24]. Among women with RPL, homozygosity at both alleles, but not each alone, significantly increased the risk of Th1 immunity to trophoblast antigens (EC = 16), suggesting a possible genetic interaction between these two alleles in the development of Th1 immunity. CONCLUSIONS: The combination of homozygosity for both IL1B-511*1 and CD46H*2 alleles is a high risk factor for RPL-Th1(+).

We conducted a prospective observational study among a cohort of 40 term parturients undergoing spinal anaesthesia for elective Caesarean section, to determine the concentration of beta-trace protein in cerebrospinal fluid (CSF) and serum. Serum and CSF samples, taken at the time of dural puncture, were assayed by nephelometry. The mean serum beta-trace protein concentration was 0.39 mg.l(-1) and the mean CSF concentration was 27.9 mg.l(-1), giving a mean ratio of CSF to serum concentration of 76. This ratio is higher than that published for non-pregnant females and for males because of both a higher mean CSF and a lower mean serum beta-trace protein concentration. The concentration correlated positively with both serum creatinine and gestational age. If these concentrations are used to estimate the normal range, we propose that the nephelometric measurement of beta-trace protein might prove a useful diagnostic test for cerebrospinal fluid-cutaneous fistula in parturients.