Testosterone deficiency independently predicts mortality in women with HFrEF: insights from the T.O.S.CA. registry.

AIMS: Testosterone deficiency (TD) is associated with increased morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). However, data in women are scanty. The aim of this study was to investigate the prognostic impact of TD on women with HFrEF. METHODS: Among 480 patients prospectively enrolled in the T.O.S.CA. (Terapia Ormonale Scompenso CArdiaco) registry, a prospective, multicentre, nationwide, observational study, 94 women were included in the current analysis. The TD was defined as serum testosterone levels lower than 25 ng/dl. Data regarding clinical status, echocardiography, exercise performance, cardiovascular hospitalization, and survival after an average follow-up of 36 months were analysed. RESULTS: Thirty patients (31.9%) displayed TD. TD was associated with lower tricuspid annular plane excursion (TAPSE) to pulmonary arterial systolic pressure PASP ratio (TAPSE/PASP) (P = 0.008), peak oxygen consumption (VO2 peak) (P = 0.03) and estimated glomerular filtration rate (P < 0.001). TD was an independent predictor of the combined endpoint of all-cause mortality/cardiovascular hospitalization (HR: 10.45; 95% CI: 3.54-17.01; P = 0.001), all-cause mortality (HR: 8.33; 95%: 5.36-15.11; P = 0.039), and cardiovascular hospitalization (HR: 2.41; 95% CI: 1.13-4.50; P = 0.02). CONCLUSIONS: One-third of women with HFrEF displays TD that impacts remarkably on their morbidity and mortality. TD is associated with a worse clinical profile including exercise capacity, right ventricular-pulmonary arterial coupling, and renal function. These findings lend support to an accurate profiling of women with HF, a problem often overlooked in clinical trials.

Calprotectin Levels and Neutrophil Count Are Prognostic Markers of Mortality in COVID-19 Patients.

Inflammation plays a crucial role in worsening coronavirus disease (COVID-19). Calprotectin is a pro-inflammatory molecule produced by monocytes and neutrophilic granulocytes. The aim of the study was to evaluate both the prognostic role of circulating calprotectin levels and neutrophil count toward fatal outcome in COVID-19 patients. We retrospectively collected and analyzed data on 195 COVID-19 adult patients, 156 hospitalized in the infectious disease unit and 39 in the intensive care unit (ICU). Calprotectin levels and neutrophil counts measured at the first hospitalization day were higher in the patients with a fatal outcome than in surviving ones. The association of high calprotectin levels and neutrophil count to patient death remain significant by logistic regression, independent of patient age. ROC curves analysis for calprotectin levels and neutrophil count revealed a good discriminatory power toward survival (area under the curve of 0.759 and 0.843, respectively) and identified the best cut-off (1.66 mg/L and 16.39 × 103/µL, respectively). Kaplan-Meier analysis confirmed the prognostic role of high calprotectin levels and neutrophil count in death prediction. In conclusion, this study highlights that calprotectin levels together with neutrophil count should be considered as biomarkers of mortality in COVID-19 patients.

Molecular Analysis of Prothrombotic Gene Variants in Patients with Acute Ischemic Stroke and with Transient Ischemic Attack.

Background and objectives: ischemic stroke (IS) is among the most frequent causes of death worldwide; thus, it is of paramount relevance to know predisposing factors that may help to identify and treat the high-risk subjects. Materials and Methods:we tested nine variants in genes involved in thrombotic pathway in 282 patients that experienced IS and 87 that had transient ischemic attacks (TIA) in comparison to 430 subjects from the general population (GP) of the same geographic area (southern Italy). We included cases of young and child IS to evaluate the eventual differences in the role of the analyzed variants. Results: we did not observe significant differences between TIA and the GP for any of the variants, while the allele frequencies of methylene-tetrahydrofolate reductase (MTHFR) C677T, beta-fibrinogen -455G>A and factor (FXIII) V34L were significantly higher in patients with IS than in the subjects from the GP. No significant interaction was observed with sex. Conclusions: the present data argue that some gene variants have a role in IS and this appears to be an interesting possibility to be pursued in large population studies to help design specific strategies for IS prevention.

B-Type Natriuretic Peptides and High-Sensitive Troponin I as COVID-19 Survival Factors: Which One Is the Best Performer?

Increased concentrations of B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin I (HsTnI) in COVID-19 patients have already been reported. The aim of this study is to evaluate which of these common markers of cardiac disease is the most useful predictor of fatal outcome in COVID-19 patients. One hundred and seventy-four patients affected with COVID-19 were recruited, and markers of cardiac disease and the clinical history of the patients were collected at admission in the infectious disease unit or intensive care unit. NT-proBNP, BNP and HsTnI values were higher in in-hospital non-surviving patients. Receiver operating characteristic (ROC) curve analysis of NT-proBNP, BNP and HsTnI was performed, with NT-proBNP (AUC = 0.951) and HsTnI (AUC = 0.947) being better performers (p = 0.01) than BNP (AUC = 0.777). Logistic regression was performed assessing the relation of HsTnI and NT-proBNP to fatal outcome adjusting for age and gender, with only NT-proBNP being significant. The population was then divided into two groups, one with higher NT-proBNP values at admission than the cut-off resulted from the ROC curve (511 ng/L) and a second one with lower values. The Kaplan-Meier analysis showed an absence of fatal outcome in the group of patients with NT-proBNP values lower than the cut-off (p < 0.001). NT-proBNP proved to be the best prognostic tool for fatal outcome among markers of cardiac disease in COVID-19 patients.

Oxidative Stress in Non-alcoholic Fatty Liver Disease. An Updated Mini Review.

Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it remains still orphan of an adequate therapeutic strategy. Herein we focus on the interplay between oxidative stress (OS) and the other causal pathogenetic factors. Different reactive oxygen species (ROS) generators contribute to NAFLD inflammatory and fibrotic progression, which is quite strictly linked to the lipotoxic liver injury from fatty acids and/or a wide variety of their biologically active metabolites in the context of either a two-hit or a (more recent) multiple parallel hits theory. An antioxidant defense system is usually able to protect hepatic cells from damaging effects caused by ROS, including those produced into the gastrointestinal tract, i.e., by-products generated by usual cellular metabolic processes, normal or dysbiotic microbiota, and/or diet through an enhanced gut-liver axis. Oxidative stress originating from the imbalance between ROS generation and antioxidant defenses is under the influence of individual genetic and epigenetic factors as well. Healthy diet and physical activity have been shown to be effective on NAFLD also with antioxidant mechanisms, but compliance to these lifestyles is very low. Among several considered antioxidants, vitamin E has been particularly studied; however, data are still contradictory. Some studies with natural polyphenols proposed for NAFLD prevention and treatment are encouraging. Probiotics, prebiotics, diet, or fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors will likely assist in further selecting the treatment that could work best for a specific patient.

Coffee prevents fatty liver disease induced by a high-fat diet by modulating pathways of the gut-liver axis.

Coffee consumption is inversely associated with the risk of non-alcoholic fatty liver disease (NAFLD). A gap in the literature still exists concerning the intestinal mechanisms that are involved in the protective effect of coffee consumption towards NAFLD. In this study, twenty-four C57BL/6J mice were divided into three groups each receiving a standard diet, a high-fat diet (HFD) or an HFD plus decaffeinated coffee (HFD+COFFEE) for 12 weeks. Coffee supplementation reduced HFD-induced liver macrovesicular steatosis (P < 0·01) and serum cholesterol (P < 0·001), alanine aminotransferase and glucose (P < 0·05). Accordingly, liver PPAR- α (P < 0·05) and acyl-CoA oxidase-1 (P < 0·05) as well as duodenal ATP-binding cassette (ABC) subfamily A1 (ABCA1) and subfamily G1 (ABCG1) (P < 0·05) mRNA expressions increased with coffee consumption. Compared with HFD animals, HFD+COFFEE mice had more undigested lipids in the caecal content and higher free fatty acid receptor-1 mRNA expression in the duodenum and colon. Furthermore, they showed an up-regulation of duodenal and colonic zonulin-1 (P < 0·05), duodenal claudin (P < 0·05) and duodenal peptide YY (P < 0·05) mRNA as well as a higher abundance of Alcaligenaceae in the faeces (P < 0·05). HFD+COFFEE mice had an energy intake comparable with HFD-fed mice but starting from the eighth intervention week they gained significantly less weight over time. Data altogether showed that coffee supplementation prevented HFD-induced NAFLD in mice by reducing hepatic fat deposition and metabolic derangement through modification of pathways underpinning liver fat oxidation, intestinal cholesterol efflux, energy metabolism and gut permeability. The hepatic and metabolic benefits induced by coffee were accompanied by changes in the gut microbiota.

Validation of Calculated Globulin (CG) as a Screening Test for Antibody Deficiency in an Italian University Hospital.

BACKGROUND: Morbidity and mortality of primary and secondary antibody deficiencies (AD) are frequently associated with diagnostic delays. These could be avoided by a combination of factors including a widespread and effective development in screening tests. METHODS: Calculated globulin (CG), derived from the difference between serum total protein and albumin levels, reflects immunoglobulin serum levels and has shown to have a predictive value in the early diagnosis of antibody deficiencies. This study investigated the possibility to use low levels of CG to detect antibody deficiency in an Italian University Hospital. RESULTS: First, we conducted an analysis of anonymized adult samples collected at our biochemistry laboratory with a range of calculated globulin levels from 15 to 22 g/l. A CG cut-off of 19 g/l detected subjects with IgG lower than 600 mg/dl with a sensitivity of 70% and a specificity of 75%. To further verify the clinical usefulness of CG, we retrospectively evaluated the relationship between CG values and serum IgG levels in 38 patients diagnosed with CVID at our Institution. Using a CG cut-off of 19 g/l, we detected antibody deficiency in 97.3% (37/38) of the subjects present in our cohort. CONCLUSION: Finally, we chose a CG value of 19 g/l as the cut-off for a prospective AD screening program. The results of this study show that a screening CG test can be used as a tool to reduce diagnostic delays, improve long-term prognosis and reduce the healthcare costs of antibody deficiency.

Celiac disease-related hepatic injury: Insights into associated conditions and underlying pathomechanisms.

BACKGROUND: Celiac disease (CD) is the most common autoimmune enteropathy. Clinical manifestations may range from a typical malabsorption syndrome to several apparently unrelated extra-intestinal symptoms. AIM: Here we specifically focus on the spectrum of CD-related liver disorders and the underlying pathomechanisms. METHODS: A computer-based search up to August 2015 was completed using appropriate keywords. References from selected papers were also reviewed and used if relevant. RESULTS: An unexplained hypertransaminasemia with nonspecific histologic hepatic changes is the most common hepatic presentation. CD however can coexist with a number of liver disorders such as Autoimmune Hepatitis, Autoimmune Cholangitis, Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis requiring a specific treatment in addition to gluten-free diet. CD has also been associated with Viral Hepatitis, Fatty Liver, Non-Alcoholic Steatohepatitis and some severe cryptogenic hepatopaties in the liver transplantation list. Pathomechanisms underlying hepatic injury in CD are multiple, appear still not completely defined and may probably co-occur. CONCLUSIONS: An ever-increasing number of CD-related liver injuries exist, probably representing a continuum of a same disorder where genetic predisposition, timing, and duration of previous gluten exposure might influence the reversibility of liver damage. Evidences, although not conclusive, support therefore testing for CD also in cryptogenic hepatobiliary conditions where the relationship with CD has not yet been fully investigated.

Calcium and vitamin D intakes in children: a randomized controlled trial.

BACKGROUND: Calcium (Ca(2+)) and vitamin D (VitD) play an important role in child health. We evaluated the daily intake of Ca(2+) and VitD in healthy children. Moreover, we demonstrate the efficacy of Ca(2+) and VitD supplementation. METHODS: Daily Ca(2+) and VitD intake was evaluated in consecutive healthy children through a validated questionnaire. Subjects with <70% of dietary reference intakes (DRIs) of Ca(2+) and VitD were invited to participate in a prospective randomized trial with 2 groups of nutritional intervention: Group 1, dietary counseling aiming to optimize daily Ca(2+) and VitD intake plus administration of a commercially available Ca(2+) and VitD supplementation product; Group 2, dietary counseling alone. At the enrollment (T0) and after 4 months (T1) serum 25(OH) Vitamin D levels were assessed. RESULTS: We evaluated 150 healthy children (male 50%, mean age 10 years); at baseline a low VitD intake was observed in all subjects (median 0.79 µg/die, IQR 1.78; range 0.01-5.02); this condition was associated with Ca(2+) intake <70% of the DRIs in 82 subjects (55%). At baseline serum 25(OH)D levels were low (<30 ng/ml) in all study subjects and after 4 months of nutritional intervention, a normalization of serum 25(OH)D levels (≥30 ng/ml) was observed in all children in Group 1 and in only one subject in Group 2 [Group 1: T1 33.8 ng/ml (IQR 2.5) vs Group 2: T1 24.5 ng/ml (IQR 5.2), p <0.001]. CONCLUSIONS: Adequate Ca(2+) and VitD intakes are difficult to obtain through dietary counseling alone in pediatric subjects. Oral supplementation with of Ca(2+) and VitD is a reliable strategy to prevent this condition. TRIAL REGISTRATION: The study was registered in Clinical Trials Protocol Registration System (ID number: NCT01638494).

Characterization of red cell membrane proteins as a function of red cell density: annexin VII in different forms of hereditary spherocytosis.

Fresh human blood samples were collected from healthy controls and splenectomized and unsplenectomized patients with hereditary spherocytosis due to band 3 or ankyrin and spectrin deficiency. The erythrocytes were separated into age-related fractions using self-forming Percoll density gradients. Membrane proteins were analysed by 2D electrophoresis and identified by mass spectrometry. Annexin VII was present in reticulocytes but was then lost as the cells matured. A different pattern was found in band 3-deficient samples: annexin VII was in fact present in both mature and immature red cell membranes. Cytoskeletal anomalies may then influence the turn-over of annexin VII during erythrocyte maturation.

Vitamin E treatment in pediatric obesity-related liver disease: a randomized study.

OBJECTIVE: A beneficial role of antioxidants in hepatopathic obese individuals has hitherto been inferred only from uncontrolled pilot studies. The authors compared the effect of vitamin E and weight loss on transaminase values and on ultrasonographic bright liver in a controlled group of children with obesity-related liver dysfunction. METHODS: Twenty-eight children with obesity-related hypertransaminasemia and bright liver were randomly allocated to two single-blind groups: group 1 (n = 14) treated with a low-calorie diet associated with oral placebo for 5 months, and group 2 (n = 14) treated with a low-calorie diet associated with oral vitamin E (400 mg/d x 2 months, 100 mg/d x 3 months). Transaminase values and ultrasonographic liver brightness along with weight loss and vitamin E levels were monitored. RESULTS: Variations in transaminase levels and percentage of patients with normalized transaminase values were comparable in the two groups. The disappearance of bright liver was observed only in patients who lost weight and was twice as common in patients from group 1. Two subgroups of patients with complete normalization of transaminase values emerged as a consequence of controlled adherence to diet alone (n = 6; significant decrease of percent overweight: P = 0.0019 ) and to vitamin E alone (n = 7; unmodified percent overweight and significant increase of vitamin E/cholesterol ratio: P < 0.0001). Changes in treatment-induced alanine aminotransferase levels in these two subgroups were comparable at month 2, whereas values at month 5 were significantly lower in the subgroup adherent to diet alone (P = 0.04). In the subgroup adherent to vitamin E alone, after 2 months washout, transaminase remained stable in 5 patients and increased in 2; bright liver persisted in all. CONCLUSIONS: Oral vitamin E warrants consideration in obesity-related liver dysfunction for children unable to adhere to low-calorie diets.

Serum oxidative and antioxidant parameters in a group of Italian patients with age-related maculopathy.

OBJECTIVES: The purpose of this study was to measure the oxidative and antioxidant biochemical parameters in the serum of Italian patients with age-related maculopathy (ARM) and in a similar age control group from the same area, in order to determine the weight of oxidative status as risk factor in the early stage of macular degeneration onwards. DESIGN AND METHODS: Forty-eight ARM patients (19 early and 29 late form) and 46 normal subjects, similar for age, sex and life-style, were studied. A series of serum and/or plasma antioxidants (vitamins C, E, A, total and individual carotenoids, zinc, total plasma antioxidant capacity--TRAP) and oxidative parameters (reactive oxygen metabolites--ROM, oxidized-low-density lipoprotein antibodies-anti-Ox-LDL) were evaluated in both groups, also with regard to age and disease stage. RESULTS: Levels of vitamins C, E, total carotenoids and beta-cryptoxanthine were lower in late ARM than in early ARM (p<0.05). Of the serum carotenoids investigated, only lycopene was lower in the two ARM forms than in controls (p<0.05). The main biochemical parameters, TRAP, zinc, anti-Ox-LDL and ROM were similar in the two groups. CONCLUSIONS: A deficit of antioxidants (vitamins C, E and carotenoids) seems to be associated with ARM in Italian patients, particularly the advanced form, it is also suggested that in ARM patients macular susceptibility to oxidative damage is not related with age.