Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias

CD38 enzymatic activity regulates NAD+ and cADPR levels in mammalian tissues, and therefore has a prominent role in cellular metabolism and calcium homeostasis. Consequently, it is reasonable to hypothesize about its involvement in cardiovascular physiology as well as in heart related pathological conditions. Aim: To investigate the role of CD38 in cardiovascular performance, and its involvement in cardiac electrophysiology and calcium-handling. Methods and results: When submitted to a treadmill exhaustion test, a way of evaluating cardiovascular performance, adult male CD38KO mice showed better exercise capacity. This benefit was also obtained in genetically modified mice with catalytically inactive (CI) CD38 and in WT mice treated with antibody 68 (Ab68) which blocks CD38 activity. Hearts from these 3 groups (CD38KO, CD38CI and Ab68) showed increased NAD+ levels. When CD38KO mice were treated with FK866 which inhibits NAD+ biosynthesis, exercise capacity as well as NAD+ in heart tissue decreased to WT levels. Electrocardiograms of conscious unrestrained CD38KO and CD38CI mice showed lower basal heart rates and higher heart rate variability than WT mice. Although inactivation of CD38 in mice resulted in increased SERCA2a expression in the heart, the frequency of spontaneous calcium release from the sarcoplasmic reticulum under stressful conditions (high extracellular calcium concentration) was lower in CD38KO ventricular myocytes. When mice were challenged with caffeine-epinephrine, CD38KO mice had a lower incidence of bidirectional ventricular tachycardia when compared to WT ones. Conclusion: CD38 inhibition improves exercise performance by regulating NAD+ homeostasis. CD38 is involved in cardiovascular function since its genetic ablation decreases basal heart rate, increases heart rate variability and alters calcium handling in a way that protects mice from developing catecholamine induced ventricular arrhythmias.Fil: Agorrody, Guillermo. Universidad de la Republica. Facultad de Medicina; UruguayFil: Peclat, Thais R.. Mayo Clinic College Of Medicine; Estados UnidosFil: Peluso, Gonzalo. Universidad de la Republica. Facultad de Medicina; UruguayFil: Gonano, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Santos, Leonardo. Instituto Pasteur de Montevideo; UruguayFil: van Schooten, Wim. Teneobio; Estados UnidosFil: Chini, Claudia C. S.. Mayo Clinic College Of Medicine; Estados UnidosFil: Escande, Carlos. Instituto Pasteur de Montevideo; UruguayFil: Chini, Eduardo N.. Mayo Clinic College Of Medicine; Estados UnidosFil: Contreras, Paola. Universidad de la Republica. Facultad de Medicina; Urugua

Changes in body composition in early breast cancer patients treated with aromatase inhibitors

Purpose The aim of the study was to analyze the modification of total and regional body composition in early breast cancer patients treated with aromatase inhibitors (AIs).Methods This is a prospective, single-center, observational, longitudinal study. Four-hundred and twenty-eight patients treated with adjuvant aromatase inhibitors were enrolled at the Medical Oncology and Breast Unit of Spedali Civili Hospital in Brescia from September 2014 to June 2022. Several body composition parameters including total and regional fat and lean body mass were investigated with dual-energy X-ray absorptiometry (DXA) scan at baseline and after 18 months of treatment with aromatase inhibitors.Results A significant increase in fat body mass (mean + 7.2%, 95% confidence interval [CI]: 5.5;8.9%) and a reduction in lean body mass (mean -3.1%, 95% CI -3.9; -2.4) were documented in this population. The changes in fat and lean body mass varied considerably according to different body districts ranging between + 3.2% to + 10.9% and from-1.3% to -3.9%, respectively.Conclusion Aromatase inhibitor adjuvant therapy in early breast cancer is associated with changes in body composition, with a wide variability among different body districts, leading to a risk of sarcopenic obesity. Supervised physical exercise that focuses on single body parts that may display detrimental variations may be beneficial for AIs treated patients

Activation of RyR2 by class I kinase inhibitors

Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds.Centro de Investigaciones Cardiovasculare

The LOFAR Two-Metre Sky Survey (LoTSS): VI. Optical identifications for the second data release

The second data release of the LOFAR Two-Metre Sky Survey (LoTSS) covers 27% of the northern sky, with a total area of $\sim 5,700$ deg$^2$. The high angular resolution of LOFAR with Dutch baselines (6 arcsec) allows us to carry out optical identifications of a large fraction of the detected radio sources without further radio followup; however, the process is made more challenging by the many extended radio sources found in LOFAR images as a result of its excellent sensitivity to extended structure. In this paper we present source associations and identifications for sources in the second data release based on optical and near-infrared data, using a combination of a likelihood-ratio cross-match method developed for our first data release, our citizen science project Radio Galaxy Zoo: LOFAR, and new approaches to algorithmic optical identification, together with extensive visual inspection by astronomers. We also present spectroscopic or photometric redshifts for a large fraction of the optical identifications. In total 4,116,934 radio sources lie in the area with good optical data, of which 85% have an optical or infrared identification and 58% have a good redshift estimate. We demonstrate the quality of the dataset by comparing it with earlier optically identified radio surveys. This is by far the largest ever optically identified radio catalogue, and will permit robust statistical studies of star-forming and radio-loud active galaxies.Comment: 29 pages. Accepted by A&A; data products available at https://lofar-surveys.org/dr2_release.htm

The LOFAR Two-Metre Sky Survey (LoTSS):VI. Optical identifications for the second data release

The second data release of the LOFAR Two-Metre Sky Survey (LoTSS) covers 27% of the northern sky, with a total area of $\sim 5,700$ deg$^2$. The high angular resolution of LOFAR with Dutch baselines (6 arcsec) allows us to carry out optical identifications of a large fraction of the detected radio sources without further radio followup; however, the process is made more challenging by the many extended radio sources found in LOFAR images as a result of its excellent sensitivity to extended structure. In this paper we present source associations and identifications for sources in the second data release based on optical and near-infrared data, using a combination of a likelihood-ratio cross-match method developed for our first data release, our citizen science project Radio Galaxy Zoo: LOFAR, and new approaches to algorithmic optical identification, together with extensive visual inspection by astronomers. We also present spectroscopic or photometric redshifts for a large fraction of the optical identifications. In total 4,116,934 radio sources lie in the area with good optical data, of which 85% have an optical or infrared identification and 58% have a good redshift estimate. We demonstrate the quality of the dataset by comparing it with earlier optically identified radio surveys. This is by far the largest ever optically identified radio catalogue, and will permit robust statistical studies of star-forming and radio-loud active galaxies

Prothrombin complex concentrate such as therapy and prophylaxis in factor X-deficient patient (Friuli Variant)

Background: Factor X (FX) deficiency is a serious, rare bleeding disorder, with 1 in 500 000 affected people. Hemorrhages, hematuria, epistaxis, and other bleeding complications are frequent. Case Report: Now, we report a case of a well-known 77-year-old FX-deficient patient (Friuli variant, level <1%, mutation Pro 343\u2192Ser, exon VIII) with hypertension, chronic obstructive pulmonary disease (COPD), and chronic gastritis, admitted many times to hospital due to surgical complications after aortic abdominal aneurysm (AAA) repair. Use of prothrombin complex concentrate (PCC) such as hemostatic therapy during surgeries and prophylaxis after discharge is shown in this article. Three consecutive surgeries were considered. First, endoleak postendoprosthesis; second, AAA breakage; and third, planned surgery, a new endovascular prosthesis positioning and femur-femoral bypass. No adverse events due to PCC were found by local physicians. Discussion: We discuss the methods commonly used in the treatment and prophylaxis of patients with FX deficiency to reduce hemorrhagic risk and to improve their quality of life. Conclusion: Waiting for specific therapeutic options for FX deficiency, currently, the best treatment is represented by PCC. Its correct use permits an improvement in life quality and a reduction in bleeding frequency in FX-deficient patients. \ua9 The Author(s) 2011

Increase of Serum a\ufa1-Acid Glycoprotein Despite the Decline of Liver Synthetic Function in Cirrhotics with Hepatocellular Carcinoma

\u3b1,-Acid glycoprotein, an acute phase reactant synthesised by the liver, has been reported to be increased in neoplastic conditions and reduced in chronic liver disease. We measured serum aracid glycoprotein by a nephelometric method in 186 subjects (112 males, 74 females): 55 had mild chronic liver disease (chronic hepatitis and steatofibrosis), 45 cirrhosis, 38 hepatocellular carcinoma, 15 extra-hepatic malignant disease; 33 healthy subjects were used as controls. Analysis of variance demonstrated a significant variability among groups (F = 17.08, P = 0.0000). Higher concentrations of \u3b11-acid glycoprotein were detected in malignant extra-hepatic disease than in all other groups (0.01); concentrations of \u3b11-acid glycoprotein were higher in hepatocellular carcinoma than in cirrhosis (0.01). Multiple regression analysis by groups (dependent variable = \u3b1\u3ca-acid glycoprotein; group 1 = mild chronic liver disease + cirrhosis; group 2 = hepatocellular carcinoma) showed a significant correlation for both group 1 (r = 0.6264, F = 8.005, P = 0.0000) and group 2 (r = 0.8947, F = 13.643, P = 0.0000). The significant standardised regression coefficients were: cholinesterase, C-reactive protein, \u3b3-glutamyltransferase and iron (negative) for regression upon group 1; C-reactive protein, \u3b1-antiproteinase, \u3b3-glutamyltransferase, iron (negative) for regression upon group 2. A difference between the 2 regression equation coefficients was detected (F = 5.209, P = 0.0002). In conclusion, a raised aracid glycoprotein concentration was found in patients with malignancies, both hepatic and extra-hepatic; however, patients with hepatocellular carcinoma had a lower \u3b11-acid glycoprotein concentration than patients with malignant extra-hepatic disease. In hepatocellular carcinoma, a good correlation existed between aracid glycoprotein and other serum indices of the acute phase response. In some patients with hepatocellular carcinoma, \u3b11-acid glycoprotein was increased, despite the decrease of liver function. \ua9 1993, Walter de Gruyter. All rights reserved