On entropy and information in gene interaction networks.

MOTIVATION: Modern biological experiments often produce candidate lists of genes presumably related to the studied phenotype. One can ask if the gene list as a whole makes sense in the context of existing knowledge: Are the genes in the list reasonably related to each other or do they look like a random assembly? There are also situations when one wants to know if two or more gene sets are closely related. Gene enrichment tests based on counting the number of genes two sets have in common are adequate if we presume that two genes are related only when they are in fact identical. If by related we mean well connected in the interaction network space, we need a new measure of relatedness for gene sets. RESULTS: We derive entropy, interaction information and mutual information for gene sets on interaction networks, starting from a simple phenomenological model of a living cell. Formally, the model describes a set of interacting linear harmonic oscillators in thermal equilibrium. Because the energy function is a quadratic form of the degrees of freedom, entropy and all other derived information quantities can be calculated exactly. We apply these concepts to estimate the probability that genes from several independent genome-wide association studies are not mutually informative; to estimate the probability that two disjoint canonical metabolic pathways are not mutually informative; and to infer relationships among human diseases based on their gene signatures. We show that the present approach is able to predict observationally validated relationships not detectable by gene enrichment methods. The converse is also true; the two methods are therefore complementary. AVAILABILITY AND IMPLEMENTATION: The functions defined in this paper are available in an R package, gsia, available for download at https://github.com/ucsd-ccbb/gsia.

Experimental Demonstration of the Stabilizing Effect of Dielectric Coatings on Magnetically Accelerated Imploding Metallic Liners.

Enhanced implosion stability has been experimentally demonstrated for magnetically accelerated liners that are coated with 70 µm of dielectric. The dielectric tamps liner-mass redistribution from electrothermal instabilities and also buffers coupling of the drive magnetic field to the magneto-Rayleigh-Taylor instability. A dielectric-coated and axially premagnetized beryllium liner was radiographed at a convergence ratio [CR=Rin,0/Rin(z,t)] of 20, which is the highest CR ever directly observed for a strengthless magnetically driven liner. The inner-wall radius Rin(z,t) displayed unprecedented uniformity, varying from 95 to 130 µm over the 4.0 mm axial height captured by the radiograph.

[Therapy of ANCA-associated vasculitis with severe renal manifestation under routine conditions]. / Therapie der ANCA-assoziierten Vaskulitis mit schwerer renaler Beteiligung unter Routinebedingungen.

INTRODUCTION: In the MEPEX trial the poor prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with severe renal manifestation (AAVr) could be significantly improved in the first year by plasmapheresis. How and to what extent is this knowledge of AAVr therapy implemented into routine practice and what effectiveness and adverse events resulted? METHODS: This was a retrospective cohort study in which all patients who received remission induction therapy for AAVr under routine clinical conditions (RCC) in this hospital from 2009 to 2014 after publication of the MEPEX trial (n = 22) were compared with those in the plasmapheresis arm of the MEPEX trial (n = 70). Endpoints were dialysis-dependent chronic kidney disease and mortality after 3 and 12 months and severe life-threatening adverse events during the first 12 months. RESULTS: All patients with AAVr were treated by plasmapheresis under RCC. The two groups showed no differences with respect to the rate of dialysis dependency (after 3 months RCC 14 % versus MEPEX 16 %, P = 1.00 and after 12 months RCC 23 % versus MEPEX 14 %, P = 0.55) or mortality (after 3 months RCC 18 % versus MEPEX 16 %, P = 0.75 and after 12 months RCC 18 % versus MEPEX 27 %, P = 0.57). The rate of severe life-threatening adverse events was similar under RCC and under controlled study conditions (64 % versus 69 %, P = 0.87). CONCLUSION: Under RCC there is a high quality of medical treatment for AAVr. All patients received plasmapheresis for remission induction with comparable effectiveness and safety compared to controlled study conditions.

Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial.

AIMS/HYPOTHESIS: Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes. METHODS: In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients. RESULTS: Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p < 0.001) but treatment differences in HbA(1c) levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HbA(1c) <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non-responders. CONCLUSIONS/INTERPRETATIONS: This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new-onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00378508 FUNDING: This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH.

Hepatitis B in the United States: ongoing missed opportunities for hepatitis B vaccination, evidence from the Behavioral Risk Factor Surveillance Survey, 2007.

PURPOSE: In the USA, the burden of hepatitis B disproportionately affects high-risk adults who alone account for more than 75% of newly reported hepatitis B virus infections each year. Despite the localization of new infections in identifiable high-risk groups, vaccination rates in this subgroup, with the exception of health care workers, remain consistently low. The purpose of this study was to characterize those at risk for hepatitis B transmission and quantify the association between missed opportunities and hepatitis B vaccination. METHODS: Data from the 2007 Behavioral Risk Factor Surveillance Survey (BRFSS) of adults aged 18 years and older who were at high risk for hepatitis B infection (n = 15,432) were analyzed. Multivariate regression analysis was conducted to determine factors independently associated with vaccination. RESULTS: In a nationally representative sample, 51.4% of high-risk adults remained unvaccinated against hepatitis B and more than 50% had a missed opportunity for vaccination. High-risk adults who were vaccinated against pneumonia and influenza had a higher odds ratio of being vaccinated against hepatitis B than those not vaccinated against pneumonia and influenza (OR 2.27 and 1.67, respectively). Also, high-risk adults tested for human immunodeficiency virus (HIV) at a counseling and testing site or a drug treatment facility had a higher OR of being vaccinated than those who had not been tested for HIV (OR 1.78 and 1.73, respectively). The opposite relationship was true among individuals tested for HIV at a correctional facility (OR 0.60). CONCLUSIONS: The findings of this study underscore the inadequacy of vaccination coverage in high-risk adults and highlight advantageous opportunities to bridge gaps in vaccination coverage.

[Renal sonography]. / Nierensonographie.

Ultrasound is the most important non-invasive diagnostic tool for detecting morphological pathological alterations of the kidneys. With a low patient burden it permits rapid, potentially serial and highly reproducible bed-side diagnoses of postrenal acute kidney injury and chronic kidney disease. Within chronic kidney disease, polycystic kidney disease can reliably be detected and evidence can be obtained for ischemic nephropathy, diabetic nephropathy and chronic pyelonephritis by renal size and intrarenal morphological alterations. An additional domain of ultrasound is the differentiation of the dignity of solid and cystic renal lesions. Newly introduced contrast-enhanced ultrasound is of additional help as benign and malignant lesions display different perfusion patterns. Renal artery stenosis can reliably be identified and its hemodynamic effect can be assessed with a combination of direct and indirect criteria by Doppler and duplex ultrasound.

Arrhythmogenic right ventricular cardiomyopathy in Bulldogs: Evaluation of clinical and histopathologic features, progression, and outcome in 71 dogs (2004-2016).

OBJECTIVES: This study aimed to characterize the clinical and histopathological features of arrhythmogenic right ventricular cardiomyopathy (ARVC) in English Bulldogs, American Bulldogs, and Bulldog-type mixed breed dogs and assess affected Bulldogs for a striatin gene mutation previously reported in Boxers with ARVC. ANIMALS: Seventy-one Bulldogs fit the inclusion criteria. Genetic analysis was performed on five dogs. Cardiac post-mortem evaluations were performed on two dogs. METHODS: Medical records from a single veterinary cardiology group (CVCA) were retrospectively evaluated. Tissue and blood samples were submitted for histopathological analysis and genetic testing in select patients. RESULTS: Presenting complaints included syncope (38%), arrhythmia (81.7%), or murmur (34.2%) documented on examination. On presentation, congestive heart failure (CHF) was diagnosed in 22 (31%) dogs, and 58 (81.7%) had ventricular arrhythmias. On bivariable analyses, the two-dimensional (2D) left atrial-to-aortic root ratio (LA:Ao) was the only prognostic variable significantly associated with survival time. Dogs with 2D LA:Ao below the mean (1.41) had longer median survival to all-cause mortality (12 months; 95% confidence interval [CI] six-15 months) than those with 2D LA:Ao above the mean (four months; 95% CI two-six months; p=0.0384). Most dogs (54%) died from cardiac disease, with 42.1% experiencing sudden death. The median time from diagnosis to cardiac death was four months. CONCLUSIONS: Arrhythmogenic right ventricular cardiomyopathy affects Bulldogs with both arrhythmogenic and dilated-type phenotypes. Despite variable arrhythmia severity and predominantly right-sided involvement in many dogs, an increase in left atrial size was the only significant predictor of mortality in this sample of dogs.

The longitudinal outcome of canine (K9) myxomatous mitral valve disease (LOOK-Mitral) registry: Baseline treatment characteristics.

OBJECTIVES: To describe the medical treatment prescribed or modified by veterinary cardiologists at the enrollment visit in dogs included in the longitudinal outcome of canine (K9) myxomatous mitral valve disease (MMVD) registry (LOOK-mitral registry) and to evaluate the influence of the EPIC trial and other selected variables on cardiologist prescription habits. ANIMALS: The medical records of 6,102 dogs enrolled in the LOOK_mitral registry between 2015 and 2018 were retrospectively reviewed and 6,016 dogs were included. RESULTS: A medical treatment was prescribed by a cardiologist to 2,599 dogs (15% Stage-B1, 90% Stage-B2 and to all dogs in Stage-C). Angiotensin converting enzyme inhibitors (Ace-i) were the treatment most commonly prescribed for dogs in Stage-B1 (n = 352, 9%). The combination of pimobendan and an Ace-i was the most common treatment in Stage-B2 dogs (n = 367, 41%). Furosemide, an Ace-i, and pimobendan was the most common cardiac medical treatment prescribed for ACVIM Stage-C dogs (n = 704, 57%). Within each stage, dogs with larger left atrial and left ventricular dimensions were more likely to receive Ace-i, pimobendan or spironolactone. There was a four-fold increase in pimobendan prescription in Stage-B2 dogs after the publication of the EPIC trial. Moreover, a 15% reduction in Ace-i prescription and a 30% reduction in spironolactone prescription occurred after EPIC. In 974 dogs, a medical treatment was prescribed by the referring veterinarian. This was not changed (12%), modified (74%), or discontinued (14%) by the cardiologist. CONCLUSIONS: The EPIC trial and the echocardiographic assessment of left atrial and ventricular dimensions influence cardiologists' prescription habits.

The Longitudinal Outcome Of Canine (K9) myxomatous mitral valve disease (LOOK-Mitral registry): Baseline characteristics.

INTRODUCTION: The Longitudinal Outcome Of Canine (K9) myxomatous mitral valve disease (MMVD) registry (LOOK-Mitral registry) was established to describe the natural history and predictors of outcome in dogs affected by MMVD. This study was intended to describe the baseline characteristics of dogs in the LOOK-mitral registry. ANIMALS: Dogs with echocardiographic evidence of MMVD were prospectively enrolled by thirteen referral centers. RESULTS: A total of 6102 dogs with MMVD were included. The median age was 10 years (1-19 years), and mixed breed was the most common breed (n = 1,360, 22%). Concomitant diseases were reported in 2459 dogs with chronic respiratory diseases occurring most frequently (14%), followed by the presence of azotemia (6%) and orthopedic diseases (5%). Regarding disease severity, 65% of dogs were in ACVIM Stage-B1, 15% in Stage-B2, and 20% in Stage-C. Dogs in Stage-B1 were younger (p<0.001) than dogs in other stages. Murmur intensity, heart rate during physical examination, and radiographic vertebral heart score were positively associated with the stage. Dogs in Stage-C were more likely to have tachypnea (p<0.001), dyspnea (p<0.001), cough (p<0.001), syncopal episodes (p<0.001), and tachyarrhythmias (p<0.001) compared to dogs in Stage-B1 and B2. Echocardiographic indices of left atrial and ventricular size were positively correlated with the ACVIM stage. Interestingly, 4% of dogs that weighed <20 kg had an increased normalized end-systolic left ventricle internal diameter (>1.26). CONCLUSIONS: This study contributes to a better understanding of the clinical characteristics of dogs affected by MMVD and provides new findings that may be of clinical relevance.

Predictors of reoccurrence of congestive signs within 180 days after successful treatment of the first episode of congestive heart failure in dogs with myxomatous mitral valve disease.

INTRODUCTION: Myxomatous mitral valve disease (MMVD) is the most common cause of left-sided congestive heart failure in dogs. We sought to identify predictors of first reoccurrence of congestive signs (CS) within 180 days in dogs with MMVD and clinically stable heart failure. ANIMALS: A total of 445 dogs affected by stable American College of Veterinary Internal Medicine (ACVIM)-Stage-C MMVD were included, 106 in the reoccurrence group (RG) and 339 in no reoccurrence group (NRG). Patients were considered "stable" if medical treatment had been unchanged for at least 4 weeks since the first identification of CS. METHODS: Medical records of dogs with stable ACVIM-Stage-C MMVD included in a registry of dogs affected by MMVD were reviewed. Follow-up was required for inclusion in this investigation. Logistic regression was used to identify clinical and echocardiographic variables that independently predict first reoccurrence of CS. RESULTS: Baseline left atrial-aortic ratio (p=0.022, OR: 1.89, 90% CI: 1.20-2.98), left ventricular internal diameter at end-diastole (LVIDd_N) (p=0.014, OR: 2.84, 90% CI: 1.41-5.77), peak velocity of early diastolic transmitral flow (p=0.049, OR: 1.81, 90% CI: 1.10-3.00) and furosemide daily dosage (p=0.039, OR: 1.19, 90% CI: 1.04-1.37) were associated with reoccurrence of CS in univariable analyses. The LVIDd_N (p=0.014) remained significant in the multivariable analysis, but the area under the receiver operator characteristic curve was 0.57. CONCLUSION: This study failed to identify accurate predictors of reoccurrence of CS. However, dogs with larger value of LVIDd_N are more likely to have reoccurrence of CS within 180 days.

How does late nephrological co-management impact chronic kidney disease? - an observational study.

AIMS: To assess the impact of late referral (LR) for nephrological co-management compared with early referral (ER) on morbidity and mortality in chronic kidney disease (CKD) and to identify individual factors associated with higher mortality in LR, correcting for lead-time and immortal time bias. PATIENTS AND METHODS: Retrospective observational study comparing 46 LR patients with 103 ER patients. The quality of CKD management was assessed by measures to prevent CKD progression and to modify CKD complications and cardiovascular risk factors according to current guidelines. One-year mortality of LR and ER was compared and factors associated with mortality were identified. Analysis was performed with equivalent GFR (glomerular filtration rate) of ER and LR at baseline to correct for lead-time and immortal time bias. RESULTS: Late referral was associated with inferior control of most risk factors for CKD progression, CKD complications and cardiovascular risk factors. In particular, glycaemic control, the use of angiotensin converting enzyme inhibitors and angiotensin-2-receptor blockers in diabetic nephropathy or proteinuria, the control of nutritional and volume status were inferior in LR. One-year mortality was significantly higher in LR (RR 5.9 (95% CI 1.5-19.6); p < 0.01). Inadequate control of blood pressure, anaemia, volume status, malnutrition and emergency initial dialysis, but not LR itself were independently associated with mortality. CONCLUSIONS: Late referral was associated with a substantially lower survival after correction for lead-time and immortal time bias and with inferior control of most risk factors for CKD progression, complications and cardiovascular risk factors. CKD patients may particularly profit from adequate control of blood pressure, anaemia, nutritional and volume status, and avoidance of emergency initial dialysis as these factors may predominately contribute to survival.

Intent to accept and acceptance of herpes testing in adolescents and young adults.

OBJECTIVES: Understanding the intention-behaviour association with HSV-2 testing is important because it can inform interventions that might be needed to support an effective HSV-2 control programme. This study aims to understand attitudinal, symptomatic and historical precursors to intent to accept, and acceptance of, HSV-2 testing. METHODS: The sample included 900 individuals recruited from four sites located in two US cities. Participants completed self-report questionnaires. Expressed intent to accept HSV-2 testing was assessed with an item that asked about acceptance of a test with the same characteristics as the test offered later. The health behaviour outcome was acceptance of the HSV-2 test when it was offered. Predictors examined were STI history, genital symptoms, anxiety and STI-related stigma. RESULTS: Expressed intent significantly predicted test acceptance. However, a number of participants made testing decisions which were at odds with their stated intent. Genital symptoms and STI history significantly predicted both greater intent and test acceptance. STI stigma only predicted lower intent, whereas anxiety only predicted greater acceptance. Intent fully mediated the relationship between genital symptoms and test acceptance, but did not mediate the relationship between STI history and test acceptance. CONCLUSIONS: This study suggests that intent does not always predict behaviour, even when the two are measured within close temporal proximity. There are factors that may predict intent only or behaviour only, or may predict behaviour, but solely through influencing intent. Understanding how these various relationships work may be important to efforts designed to maximise acceptance of HSV-2 testing.

Uridine adenosine tetraphosphate acts as an autocrine hormone affecting glomerular filtration rate.

Recently, uridine adenosine tetraphosphate (Up(4)A) was described as a strong vasoconstrictor released from endothelial cells after stimulation with mechanical stress. In this study, we isolated and identified Up(4)A from kidney tissue, and we characterized the essential varying effects of Up(4)A on the afferent and efferent arterioles. Porcine and human kidney tissue was fractionated by size exclusion chromatography, affinity chromatography, anion exchange chromatography and reverse phase chromatography. In fractions purified to homogeneity, Up(4)A was identified by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS), MALDI-LIFT fragment mass spectrometry (MALDI-TOF/TOF MS), retention-time comparison and enzymatic cleavage analysis. We analysed the release of Up(4)A from cultivated renal proximal tubule cells after stimulation of protein kinase C with oleoyl-2-acetyl-sn-glycerol (OAG). Up(4)A was identified in renal tissue, and the effect of Up(4)A on the vascular tone of isolated perfused afferent and efferent arterioles was tested. Stimulation of tubule cells with OAG increased the release rate of Up(4)A from tubule cells about tenfold. Up(4)A acts as a strong vasoconstrictive mediator on afferent arterioles, but has no significant effect on the tone of efferent arterioles, suggesting a functional role of Up(4)A as an autocrine hormone for glomerular perfusion. Because of the predominant effect of the Up(4)A on afferent arterioles, we assume that Up(4)A may decrease glomerular perfusion, intra-glomerular pressure and, hence, glomerular filtration rate. The release of Up(4)A from renal tubular cells may be an additional mechanism whereby tubular cells could affect renal perfusion. Up(4)A release may further contribute to renal vascular autoregulation mechanisms. In conclusion, as Up(4)A occurs in renal tissue and has marked effects on afferent but not efferent arterioles, Up(4)A may play a role in renal hemodynamics and possibly blood pressure regulation.

Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium.

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

Transformation of a tungsten wire to the plasma state by nanosecond electrical explosion in vacuum.

Experiment demonstrates the first direct transformation of a tungsten wire core to the plasma state by Joule heating during nanosecond electrical explosion in vacuum. Energy of approximately 130 eV/atom was deposited into the 12 microm W wire coated by 2 microm polyimide during the first approximately 10 ns. All the metal rapidly transformed to highly ionized plasma, while the surrounding polyimide coating remained primarily in a gaseous state. This coating totally suppressed corona formation. The expansion velocity of the wire was approximately 12-18 km/s, the average wire ionization at 50 ns reached approximately 67% with corresponding LTE temperature of approximately 1.2 eV . Explosion of bare W wire demonstrated earlier termination of the wire core heating due to shunting corona generation. Magnetohydrodynamic (MHD) simulation reproduces the main features of coated and uncoated W wire explosion.

Advance provision of emergency contraception to young men: An exploratory study in a clinic setting.

PURPOSE: To explore the acceptability of advance provision of emergency contraceptive pills (ECPs) to young men seeking health care. METHODS: For this exploratory study in a clinic setting, we approached young men aged 16-35 to participate in a survey eliciting socio-demographics, sexual and contraceptive history, and knowledge about ECPs. We offered young men advance provision of ECPs and compared characteristics of 126 young men who did and did not accept the ECPs. RESULTS: Most (76%) of the participants accepted advance provision and left with an ECP pack, with even higher proportions among males whose sexual histories were suggestive of increased risk of involvement in an unintended pregnancy. CONCLUSIONS: This study holds promise to inform scale up of advance provision of ECPs among young men.

Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study.

BACKGROUND: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. OBJECTIVES: To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF. ANIMALS: Three hundred and fifty-four dogs with MMVD and cardiomegaly. MATERIALS AND METHODS: Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4-0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored. RESULTS: At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN -0.06 (IQR: -0.15 to +0.02), P < 0.0001, and LA:Ao -0.08 (IQR: -0.23 to +0.03), P < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in ΔLVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in ΔLA:Ao was 1.14, P = 0.0002. At onset of CHF, groups were similar. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo.

Exogenous growth hormone inhibits growth hormone-releasing factor-induced growth hormone secretion in normal men.

Previous studies from this laboratory and by others in rats, monkeys, and humans support the concept that growth hormone (GH) can regulate its own secretion through an autofeedback mechanism. With the availability of human growth hormone-releasing factor (GRF), the possible existence of such a mechanism was reexplored by examining the effect of exogenous GH on the GH response induced by GRF-44-NH2 in six normal men (mean age, 32.4 yr). In all subjects the plasma GH response evoked by GRF-44-NH2 (1 microgram/kg i.v. bolus) was studied before and after 5 d of placebo (1 ml normal saline i.m. every 12 h), and then before and 12 h after 5 d of biosynthetic methionyl human GH (5 U i.m. every 12 h). The GH response to GRF (maximal increment over time 0 value) was significantly inhibited after GH treatment (0-1.3 vs. 2.3-11.2 ng/ml before treatment, P = 0.05), but was not significantly affected by placebo. This impaired pituitary response to GRF persisted for at least 24 h following exogenous GH treatment in two subjects who underwent further study. Serum somatomedin-C concentrations were significantly increased after 5 d of GH treatment (2.66-5.00 vs. 0.92-1.91 U/ml before treatment, P = less than 0.01). The impaired pituitary response to GRF may be mediated indirectly through somatomedin, somatostatin, by a direct effect of GH on the pituitary somatotropes, or by all of these mechanisms. These data suggest that after GH treatment, the blunted GH response to synthetic GRF is not solely a consequence of the inhibition of hypothalamic GRF secretion.

Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II.

Muscle is an important target tissue for insulin-like growth factor (IGF) action. The presence of specific, high affinity IGF receptors, as well as the expression of IGF peptides and binding proteins by muscle suggest that a significant component of IGF action in this tissue is mediated through autocrine and/or paracrine mechanisms. To explore autocrine/paracrine action of IGFs in muscle, we studied the regulation of the IGF-I receptor and the expression of IGF peptides during differentiation of the mouse BC3H-1 muscle cell line. Differentiation from myoblasts to myocytes was associated with a 60% decrease in IGF-I receptor sites determined by Scatchard analysis. Analysis of mRNA abundance and protein labeling studies indicated that the decrease in IGF-I receptor sites was associated with similar reductions in IGF-I receptor gene expression and receptor biosynthesis. IGF-II peptide gene expression was detected in myoblasts and increased 15-fold with differentiation; the increase in IGF-II gene expression preceded the decrease in IGF-I receptor gene expression. In contrast, IGF-I peptide gene expression was low in myoblasts and decreased slightly with differentiation. To explore the potential role of endogenous IGF-II in the differentiation-associated decrease in IGF-I receptor expression, we investigated the effects of IGF-II treatment in myoblasts. The addition of IGF-II to undifferentiated myoblasts resulted in downregulation of the IGF-I receptor which was associated with decreased IGF-I receptor biosynthesis and decreased IGF-I receptor mRNA abundance. These studies suggest, therefore, that IGF-I receptor expression during muscle cell differentiation may be regulated, at least in part, through autocrine production of IGF-II.

Thermodynamical calculation of metal heating in nanosecond exploding wire and foil experiments.

A method of thermodynamical calculation of thin metal wire heating during its electrical explosion is discussed. The technique is based on a calculation of Joule energy deposition taking into account the current wave form and the temperature dependence of the resistivity and heat capacity of the metal. Comparing the calculation to a set of exploding tungsten wire experiments demonstrates good agreement up to the time of melting. Good agreement is also demonstrated with resistive magnetohydrodynamics simulation. A similar thermodynamical calculation for Mo, Ti, Ni, Fe, Al, and Cu shows good agreement with experimental data. The thermodynamical technique is useful for verification of the voltage measurements in exploding wire experiments. This technique also shows good agreement with an exploding W foil experiment.