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High morbidity and mortality due to COVID-19 were described in the pre-vaccination era in patients with chronic lymphocytic leukemia (CLL). To evaluate COVID-19 morbidity after the SARS-CoV-2 vaccine, we carried out a prospective study in 200 CLL patients. The median age of patients was 70 years; 35% showed IgG levels ≤ 550 mg/dL, 61% unmutated IGHV, and 34% showed TP53 disruption. Most patients, 83.5%, were previously treated, including 36% with ibrutinib and 37.5% with venetoclax. The serologic response rates to the second and third dose of the vaccine were 39% and 53%, respectively. With a median follow-up of 23.4 months, 41% of patients experienced COVID-19, 36.5% during the Omicron pandemic, and 10% had subsequent COVID-19 events. Severe COVID-19 requiring hospitalization was recorded in 26% of patients, and 4% died. Significant and independent factors associated with the response to the vaccine and vulnerability to COVID-19 were age (OR: 0.93; HR: 0.97) and less than 18 months between the start of targeted agents and vaccine (OR: 0.17; HR: 0.31). TP53 mutation and ≥two prior treatments also emerged as significant and independent factors associated with an increased risk of developing COVID-19 (HR: 1.85; HR: 2.08). No statistical difference in COVID-19 morbidity was found in patients with or without antibody response to the vaccine (47.5% vs. 52.5%; p = 0.21). Given the persistent risk of infection due to the continuous emergence of SARS-CoV-2 variants, our results support the importance of new vaccines and protective measures to prevent and mitigate COVID-19 in CLL patients.

Mastitis affects a high proportion of dairy cows and is still one of the greatest challenges faced by the dairy industry. Staphylococcal bacteria remain the most important cause of mastitis worldwide. We investigated how distinct staphylococcal species evade some critical host defense mechanisms, which may dictate the establishment, severity, and persistence of infection and the outcome of possible therapeutic and prevention interventions. Thus, the present study investigated variations among distinct bovine-associated staphylococci in their capability to resist phagocytosis and to trigger respiratory burst activity of blood and milk polymorphonuclear neutrophil leukocytes (PMNL) in dairy cows. To do so, PMNL of 6 primiparous and 6 multiparous dairy cows were used. A collection of 38 non-aureus staphylococci (NAS) and 12 Staphylococcus aureus were included. The phagocytosis and intracellular reactive oxygen species (ROS) production by blood and milk PMNL were analyzed by flow cytometry. Phagocytosis, by both blood and milk PMNL, did not differ between S. aureus and NAS as a group, although within-NAS species differences were observed. Staphylococcus chromogenes (a so-called milk-adapted NAS species) better resisted phagocytosis by blood PMNL than the so-called environmental (i.e., Staphylococcus fleurettii) and opportunistic (i.e., Staphylococcus haemolyticus) NAS species. Otherwise, S. haemolyticus was better phagocytosed by blood PMNL than S. aureus, S. fleurettii, and S. chromogenes. No influence of the origin of the isolates within the staphylococci species in the resistance to phagocytosis by blood and milk PMNL was found. Overall, both S. aureus and NAS did not inhibit intracellular ROS production in blood and milk PMNL. Non-aureus staphylococci induced fewer ROS by milk PMNL than S. aureus, which was not true for blood PMNL, although species-specific differences in the intensity of ROS production were observed. Staphylococcus chromogenes induced more blood PMNL ROS than S. fleurettii and S. haemolyticus, and as much as S. aureus. Conversely, S. chromogenes induced fewer milk PMNL ROS than S. aureus. The origin of the isolates within the staphylococci species did not affect the ROS production by blood and milk PMNL. In conclusion, our study showed differences in staphylococci species in evading phagocytosis and triggering ROS production, which may explain the ability of some staphylococci species (i.e., S. aureus and S. chromogenes) to cause persistent infection and induce inflammation.

Leptospirosis causes abortion, premature birth, and stillbirth in cattle, but the mechanisms remain unclear. Infected cattle shed Leptospira intermittently and present a range of clinical symptoms, making diagnosis difficult. The primary route of Leptospira transmission in any animal is the colonization of the renal tubule and excretion by urine; however, Leptospira can also colonize the female reproductive tract of cows and can be transmitted by semen. Vaccination against Leptospira in the US is routine in cattle, but immunity is not guaranteed. The cell wall of Leptospira contains toll-like receptor agonists including peptidoglycan and lipopolysaccharide. The capacity of Leptospira to initiate an innate inflammatory response from uterine endometrial cells is unknown but may be a cause of reproductive failure. Using cell culture, we tested the capacity of bovine endometrial epithelial cells or human monocytes to elicit an inflammatory response to Leptospira borgpetersenii serovar Hardjo strain TC273. Cells were exposed to either heat-killed Leptospira, Leptospira outer membrane, Escherichia coli lipopolysaccharide, Pam3CSK4 or medium alone for 2 to 24 h. Exposure of bovine endometrial epithelial cells or human monocytes to heat-killed Leptospira or Leptospira outer membrane did not induce the expression of IL1A, IL1B, IL6, or CXCL8, while exposure to E. coli lipopolysaccharide or Pam3CSK4 increased the expression of IL1A, IL1B, IL6, and CXCL8 compared to control cells. This data suggest that Leptospira does not trigger a classical inflammatory response in endometrial cells. Understanding the interaction between Leptospira and the female reproductive tract is important in determining the mechanisms of Leptospirosis associated with reproductive failure. Lay summary Cows infected with the Leptospira have abortion and stillbirth. It is not known how Leptospira causes pregnancy failure in the cow. We tested if Leptospira causes inflammation in cells of the uterus which triggers pregnancy failure. We collected cells from the uterus of healthy cows at the abattoir and placed them into culture with Leptospira and measured the expression of genes associated with inflammation. To our surprise, cells of the uterus did not respond to Leptospira; however, the same cells did respond to other disease-causing bacteria found in the uterus. This suggests that cells of the uterus can recognize bacteria and produce an inflammatory reaction but not in response to Leptospira. This finding suggests the immune system of the uterus cannot detect Leptospira which may go on to cause reproductive failure in cows. Understanding how Leptospira interact with cells of the uterus will help reduce pregnancy failure of cows with leptospirosis.

Congenital factor XIII (FXIII) deficiency is a rare coagulation disorder characterized by muscular or mucocutaneous bleeding with life-threatening intracranial hemorrhages (ICHs), especially in cases with severe disease. The best treatment is the use of prophylactic plasma-derived or recombinant FXIII (rFXIII). Few data on the use of rFXIII in the real-world scenario are available. The main goal of this study was to assess the efficacy and safety of catridecacog (NovoThirteenWe collected and analyzed all pharmacokinetic and clinical data in our registry of the patients with congenital FXIII deficiency treated with rFXIII at eleven Italian hemophilia centers. Data were collected from January 2019 to December 2020.Overall, data on 20 patients with FXIII deficiency were collected, 16 of whom presented with severe disease. Pharmacokinetics was assessed in 18 cases before starting prophylaxis. Prophylaxis was subsequently started in these patients using a wide range of dosages (25.0-80.0 IU/kg; mean 33.8 IU/kg) and infusion intervals (3.0-8.0 weeks). During a mean follow up of 47 months, two minor bleeds and one ICH in a severe patient who had remained under on-demand treatment were reported.Efficacy and safety of rFXIII were proven in all patients. The dosage and infusion timing for the treated patients sometimes differed to those reported in the MENTOR pivotal studies, thus underlying the importance of tailored management in a real-world scenario.

BACKGROUND: To highlight clinical practice among referral (Hub, HH) or satellite (Spoke, SH) hospitals Vascular Surgery Units (VSUs) in Lombardy, during the COVID-19 pandemic "phase 1" period (March 8 - May 3, 2020). METHODS: The Vascular Surgery Group of Regione Lombardia Register, a real-word, multicenter, retrospective register was interrogated. All patients admitted with vascular disease were included. Patients' data on demographics, COVID-19 positivity, comorbidities and outcomes were extrapolated. Two cohorts were obtained: patients admitted to HH or SH. Primary endpoint was 30- day mortality rate. Secondary outcomes were 30-day complications and amputation (in case of peripheral artery disease [PAD]) rates. Univariate and multivariate analysis were used to compare HH and SH groups and predictors of poor outcomes. RESULTS: During the study period, 659 vascular patients in 4 HH and 27 SH were analyzed. Among these, 321 (48.7%) were admitted to a HH. No difference in COVID-19 positive patients was described (21.7% in HH vs 15.9% in SH; p=.058). After 30 days from intervention, HH and SH experienced similar mortality and no-intervention-related complication rate (12.1% vs 10.0%; p=.427 and 10.3% vs 8.3%; p=.377, respectively). Conversely, in HH postoperative complications were higher (23.4% vs 16.9%, p=.038) and amputations in patients treated for PAD were lower (10.8% vs 26.8%; p

Acquired haemophilia A (AHA) is a rare bleeding disorder due to autoantibodies to coagulation factor VIII that may be secondary to autoimmune diseases, cancer, drugs, pregnancy, infections, or be idiopathic. Recurrent bleeding, often severe, mostly in muscles and soft tissues, and isolated prolonged activated partial thromboplastin time (aPTT), in the absence of personal and family history of bleeding, are typical features that should raise the suspicion of AHA. Poor awareness of the disease results in diagnostic delays and inappropriate treatment.The Italian Association of Haemophilia Centres (AICE) developed consensus recommendations in cooperation with the Italian Society on Thrombosis and Haemostasis (SISET). The document was shared with scientific societies of specialist physicians, laboratory professionals and pharmacists to spread knowledge about AHA and promote appropriate diagnosis/treatment.Ready availability of the aPTT mixing test is crucial, although diagnostic confirmation and optimal management require prompt referral of patients to specialised centres with rapidly available diagnostic and therapeutic facilities. If immediate referral is unfeasible, treatment must be undertaken early, under guidance of specialised centres or based on shared protocols. Recommendations about diagnosis, general management and, in bleeding patients, haemostatic therapy using bypassing agents or replacement treatment, including the recently available recombinant porcine factor VIII, are provided, considering the different clinical settings and laboratory facilities.This consensus document aims to improve the overall healthcare pathways for AHA, harmonise the management and therapeutic approaches to newly diagnosed patients and reduce the still relevant complications and mortality in this setting.

Study Design:Historically controlled clinical trial.Objectives:Patients presenting for correction of adolescent idiopathic scoliosis (AIS) by posterior spinal fusion may benefit from structured clinical pathways. We studied the effects of implementing a published clinical pathway for the perioperative care of patients with AIS that required intraoperative use of methadone at our institution.Methods:We performed a historically controlled clinical trial of patients undergoing posterior spinal fusion for AIS by comparing a retrospectively collected control group of 25 patients with a prospective experimental group of 14 patients receiving methadone, gabapentin, propofol, and remifentanil as part of a new clinical pathway.Results:Use of the pathway decreased average pain scores evaluated by the Numeric Rating Scale in the 24 hours following surgery (4.8 [4-6] to 3.4 [2-4], P = .03 [−2.6 to −0.2; t = −2.3]) and postoperative opioid consumption by 76% (41 [29-51] mg to 10 [4-17] mg, P < .001 [−45 to −15; Welch’s t = 4.9]) during the same period. Improved analgesia and reduced reliance on opioids facilitated other postoperative elements of the clinical pathway and shortened the average hospital length of stay by 1 day (4 [3-6] days to 3 [3-5] days, P = .001 [−2 to −1; U = 67, Z = −3.3]).Conclusions:Multimodal analgesia and a clinical pathway add value in the perioperative care of patients undergoing posterior spinal fusion for AIS by improving analgesia and shortening hospitalization. The prospective arm of the trial was registered at clinicaltrials.gov under NCT02481570.

The ceramic tile industry is a big consumer of feldspathic rocks and further raw materials able to act as flux during firing. This demand is currently fed with the recourse to a wide range of sources of igneous, sedimentary, metamorphic and metasomatic origin. The main geological features of flux deposits actually exploited by the ceramic industry are reviewed. The chemical and mineralogical composition is described to have a general picture of raw fluxes as well as average data and compositional perimeter for deposits of different origin. Overall beneficiation routes are drawn to trace the compositional path from deposit to commercial flux. The technological behavior in tile-making is shortly overviewed and new experimental data are provided on flux fusibility (by hot-stage microscopy). A chart is proposed to discriminate fluxes according to different fusibility.

Background Patients with type 1 (T1DM) and type 2 (T2DM) diabetes are at increased risk of vaccine-preventable diseases and their complications. The National Vaccinal Prevention Plan 2017-2019 includes specific recommendations for patients with diabetes, which in 2018 have been included in the standards of care of the Italian Diabetes Society (SID) and Italian Association of Clinical Diabetologists (AMD). Methods Adult diabetic patients attending the Diabetes clinic at the San Raffaele Hospital, a large teaching hospital in Milan, Italy, were surveyed with a questionnaire to investigate self-reported vaccinal history, knowledge, attitudes and practice on the recommended vaccinations, vaccinal hesitancy and information sources on the topic. Results Between May 16 and November 11, 2019 N = 222 T1DM and N = 57 T2DM patients were enrolled. 25.2% of T1DM and 26.3% of T2DM patients did get vaccinated annually against the flu in the past 3 year. 85.0% of T2DM patients were vaccinated at the General Practitioner's (GP) clinic, while 54.9% of T1DM patients were vaccinated by their GP and 24.4% from territorial vaccinal clinics. 54.5% of T1DM and 50.0% of T2DM patients chose not to be vaccinated because they didn't consider the vaccine useful, while the second most common reason was that they have not been advised by healthcare personnel. Conclusions We documented a low coverage and knowledge about influenza vaccination. Patients with diabetes trusted information and advice of diabetologists and GPs about vaccination and claimed that they would be more likely to vaccinate if vaccination were offered in the diabetes clinic. Implementing training programs for professionals and educational campaigns for patients with diabetes may improve vaccinal coverage. Key messages Vaccination coverage in T1DM and T2DM patients is low due to vaccination hesitancy. A strong action from care givers, in order to raise vaccination awareness in this at-risk population, is needed.

In 2016, a new recombinant B-domain deleted porcine FVIII (rpFVIII) was licensed in Italy for the treatment of acquired haemophilia A (AHA). But only a few cases of patients receiving this have been reported in the literature. Here we report the largest registry of the use of rpFVIII for the treatment of AHA. The objective of this retrospective study was to describe the efficacy and the safety of susoctocog-alfa for AHA.We studied a population of nine patients, recruited in five Italian haemophilia centres presenting AHA, and treated with ObizurIn our real world experience, susoctocog-alfa was proven to be an effective and safe therapeutic option for patients with AHA, also at a lower than recommended dosage. In our report, the appearance of low-titre inhibitors.

Up to forty percent of dairy cows can develop metritis or endometritis when bacteria infect the uterus after parturition. However, it is unclear why other cows exposed to similar pathogens do not develop uterine disease. We suggest that resilient dairy cows prevent the development of uterine disease using the three complimentary defensive strategies of avoiding, tolerating and resisting infection with pathogenic bacteria. Avoidance maintains health by limiting the exposure to pathogens. Avoidance includes intrinsic behaviors to prevent exposure to pathogens or infected animals, perhaps signaled by the fetid odor of uterine disease. Tolerance improves health by limiting the tissue damage caused by the pathogen burden. Tolerance depends on controlling the tissue damage that pathogens cause in the endometrium by neutralizing bacterial toxins, enhancing tissue repair, and inducing adaptive metabolic responses. Resistance improves health by limiting the pathogen burden. Resistance relies on the immune system generating an inflammatory response in the endometrium to eliminate pathogenic bacteria. People who manage dairy cows can also help prevent uterine disease by using extended lactations, avoiding trauma to the genital tract, maintaining hygiene, and supplying appropriate nutrition during the transition period and after parturition to counter the metabolic stress of lactation. Developing new ways to prevent uterine disease depends on increasing our understanding of the mechanisms of avoidance, tolerance and resistance to pathogens in the postpartum uterus.

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children /=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >/=1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0.51-6.27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development. 01 januari 2020

Background: Children living at high altitude in San Antonio de los Cobres (SAC), Argentina, were shown to have lower high-density lipoprotein cholesterol (HDL-C) levels than Buenos Aires (BA) children. HDL antioxidant capacity is mainly attributed to paraoxonase1 (PON1). Objective: To compare PON1 activity in indigenous SAC vs. BA children. Methods: A cross-sectional study compared 158 SAC vs. 97 BA children (6–16 years). Anthropometric data and lipoprotein profile were measured. PON1 was evaluated employing paraoxon (PON) and phenylacetate (ARE) activity. Results: The prevalence of overweight/obesity was lower in SAC than in BA children (18.3 vs. 30.9%). Triglycerides (1.34 vs. 0.90 mmol/l), apo B (0.84 vs.0.72 g/l), apo A-I (1.33 vs. 1.27 g/l), and ARE activity (100 vs. 90 µmol/ml/min) were higher, while HDL-C (1.16 vs. 1.32 mmol/l) and PON activity (170 vs. 203 nmol/ml/min) were lower in SAC than in BA. Separate multiple linear regression analyses showed that SAC children had significantly higher triglyceride (Beta −0.38), apo B (Beta −0.34), and ARE (Beta −0.36) plus lower HDL-C (Beta 0.33) and PON (Beta 0.25) compared with BA; adjusted for age, gender, and BMI. Conclusion: SAC showed an unfavorable lipoprotein profile, lower PON and higher ARE activities compared with BA children, suggesting the presence of altered HDL metabolism and antioxidant capacity. Fil: Hirschler, V.. Universidad de Buenos Aires; Argentina Fil: Martin, Maximiliano Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Oestreicher, K.. Universidad de Buenos Aires; Argentina Fil: Molinari, C.. Universidad de Buenos Aires; Argentina Fil: Tetzlaff, Walter Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Botta, Eliana Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Boero, Laura Estela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Brites, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina

Background Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. Methods In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. Findings Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1.2-10.6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0.0-3.9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (

Semen induces post-coital inflammation of the endometrium in several species. Post-coital inflammation is proposed to alter the endometrial environment of early pregnancy, mediate embryonic development and modulate the maternal immune response to pregnancy. In cattle, it is common for pregnancies to occur in the absence of whole semen due to the high utilization of artificial insemination. Here, we have utilized a cell culture system to characterize semen-induced expression of inflammatory mediators in bovine endometrial cells and test the efficacy of transforming growth factor beta as the active agent in mediating any such change. We hypothesize that seminal plasma-derived transforming growth factor beta increases the expression of inflammatory mediators in bovine endometrial cells. Initially, we describe a heat-labile cytotoxic effect of seminal plasma on BEND cells, and a moderate increase in IL1B and IL6 expression. In addition, we show that transforming growth factor beta is present in bovine semen and can increase the expression of endometrial IL6, whereas blocking transforming growth factor beta in semen ameliorates this effect. However, intra-uterine infusion of seminal plasma, sperm or transforming growth factor beta did not alter the endometrial expression of inflammatory mediators. We conclude that bovine semen can modulate endometrial gene expression in vitro, which is partially due to the presence of transforming growth factor beta. It is likely that additional, unidentified, bioactive molecules in semen can alter the endometrial environment. Characterizing bioactive molecules in bovine semen may lead to the development of additives to improve artificial insemination in domestic species.

Bacterial infection of the uterus causes clinical endometritis in 15 to 20% of postpartum dairy cows and reduces fertility, even after the resolution of disease. However, it is difficult to disentangle the mechanisms linking reduced fertility with endometritis because cows have multiple confounding postpartum conditions. The aim of the present experiment was to develop an in vivo model of clinical endometritis in Holstein heifers using pathogenic Escherichia coli and Trueperella pyogenes. Estrous cycles of heifers were synchronized using a 5-d Co-Synch protocol, and subsequently received exogenous progesterone to elevate circulating progesterone at the time of uterine infusion. Endometrial scarification was performed before uterine infusion of live pathogenic Escherichia coli and Trueperella pyogenes, or sterile vehicle. Effects of infusion were evaluated by measuring rectal temperature, plasma haptoglobin, hematology, grading pus in the vaginal mucus, quantifying 16S rRNA in vaginal mucus, and transrectal ultrasonography. Bacterial infusion increased the median vaginal mucus to grade 2 by d 3 postinfusion, and to grade 3 from d 4 to 6 postinfusion. Control heifers maintained a median vaginal mucus grade ≤1 from d 1 to 6. Transrectal ultrasound revealed the accumulation of echogenic fluid in the uterus of heifers following bacterial infusion, which was absent in control heifers. Total 16S rRNA in vaginal mucus was elevated in bacteria-infused heifers compared with control heifers at d 5. Rectal temperature was increased in bacteria-infused heifers. Plasma haptoglobin, general health, and appetite did not differ between groups. As indicated by increased vaginal mucus grade after bacterial infusion and absence of systemic signs of illness, this model successfully induced symptoms resembling clinical endometritis in virgin Holstein heifers. The model allows the isolation of effects of uterine disease on fertility from confounding factors that can occur during the postpartum period in dairy cows.

Background and aim: The objective of this cross-sectional study was to evaluate the degree of glycaemic control and the frequency of diabetic complications in Italian people with diabetes who were treated with continuous subcutaneous insulin infusion (CSII). Methods and results: Questionnaires investigating the organisation of diabetes care centres, individuals’ clinical and metabolic features and pump technology and its management were sent to adult and paediatric diabetes centres that use CSII for treatment in Italy. Information on standard clinical variables, demographic data and acute and chronic diabetic complications was derived from local clinical management systems. The sample consisted of 6623 people with diabetes, which was obtained from 93 centres. Of them, 98.8% had type 1 diabetes mellitus, 57.2% were female, 64% used a conventional insulin pump and 36% used a sensor-augmented insulin pump. The median glycated haemoglobin (HbA1c) level was 60 mmol/mol (7.6%). The HbA1c target (i.e. 18 years) was achieved in 43.4% of paediatric and 23% of adult participants. Factors such as advanced pump functions, higher rate of sensor use, pregnancy in the year before the study and longer duration of diabetes were associated with lower HbA1c levels. The most common chronic complications occurring in diabetes were retinopathy, microalbuminuria and hypertension. In the year before the study, 5% of participants reported ≥1 episode of severe hypoglycaemic (SH) episodes (SH) and 2.6% reported ≥1 episode of ketoacidosis. Conclusions: Advanced personal skills and use of sensor-based pump are associated with better metabolic control outcomes in Italian people with diabetes who were treated with CSII. The reduction in SH episodes confirms the positive effect of CSII on hypoglycaemia. Clinical trial registration number: NCT 02620917 (ClinicalTrials.gov).

Acidic soils are distributed worldwide, predominantly in tropical and subtropical areas, reaching around 50% of the arable soil. This type of soil strongly reduces crop production, mainly because of the presence of aluminum, which has its solubility increased at low pH levels. A well-known physiological mechanism used by plants to cope with Al stress involves activation of membrane transporters responsible for organic acid anions secretion from the root apex to the rhizosphere, which chelate Al, preventing its absorption by roots. In sorghum, a membrane transporter gene belonging to multidrug and toxic compound extrusion (MATE) family was identified and characterized as an aluminum-activated citrate transporter gene responsible for Al tolerance in this crop. Setaria viridis is an emerging model for C4 species and it is an important model to validate some genes for further C4 crops transformation, such as sugarcane, maize, and wheat. In the present work, Setaria viridis was used as a model plant to overexpress a newly identified MATE gene from Brachypodium distachyon (BdMATE), closely related to SbMATE, for aluminum tolerance assays. Transgenic S. viridis plants overexpressing a BdMATE presented an improved Al tolerance phenotype, characterized by sustained root growth and exclusion of aluminum from the root apex in transgenic plants, as confirmed by hematoxylin assay. In addition, transgenic plants showed higher root citrate exudation into the rhizosphere, suggesting that Al tolerance improvement in these plants could be related to the chelation of the metal by the organic acid anion. These results suggest that BdMATE gene can be used to transform C4 crops of economic importance with improved aluminum tolerance.

Flowering is an important trait in major crops like soybean due to its direct relation to grain production. The circadian clock mediates the perception of seasonal changes in day length and temperature to modulate flowering time. The circadian clock gene EARLY FLOWERING 4 (ELF4) was identified in Arabidopsis thaliana and is believed to play a key role in the integration of photoperiod, circadian regulation, and flowering. The molecular circuitry that comprises the circadian clock and flowering control in soybeans is just beginning to be understood. To date, insufficient information regarding the soybean negative flowering regulators exist, and the biological function of the soybean ELF4 (GmELF4) remains unknown. Here, we investigate the ELF4 family members in soybean and functionally characterize a GmELF4 homologous gene. The constitutive overexpression of GmELF4 delayed flowering in Arabidopsis, showing the ELF4 functional conservation among plants as part of the flowering control machinery. We also show that GmELF4 alters the expression of Arabidopsis key flowering time genes (AtCO and AtFT), and this down-regulation is the likely cause of flowering delay phenotypes. Furthermore, we identified the GmELF4 network genes to infer the participation of GmELF4 in soybeans. The data generated in this study provide original insights for comprehending the role of the soybean circadian clock ELF4 gene as a negative flowering controller.

Cette etude explore les relations qui se tissent entre les langues francaise et anglaise au Quebec. Apres un excursus historique, dont le but est de presenter les etapes qui ont amene a la situation actuelle, nous allons reflechir a l’action de francisation menee par l’Office Quebecois de la Langue Francaise et par Radio Canada. Il nous semble en effet que le projet visant a reduire l’influence exercee par l’anglais se traduit dans une reflexion sur le francais, tant et si bien que l’anglais peut etre considere en tant qu’outil propulseur de l’enrichissement de la langue francaise. C’est dans cette perspective que seront examines les projets de l’Office Quebecois de la Langue Francaise et de Radio Canada : la correction des anglicismes sur les plans lexical, morphologique et syntaxique manifeste non seulement une visee didactique mais contribue aussi a ameliorer la qualite du francais quebecois. Peut-on donc parler effectivement d’un francais de qualite ?

We conducted a pilot study to evaluate the effectiveness of resveratrol absorbed orally, conveyed through a new patented technology that increases the absorption through the oral mucosa in treatment of hot flushes (HF) during menopause.This is a randomized controlled double-blind study with crossover design. From October 2012 to July 2014 we considered the first 50 patients enrolled at the Center for Menopause Maggiore Hospital of Charity of Novara, with diagnosis of physiological or surgical menopause. Each woman received a diary in which she indicated the weekly number of HF and the perceived intensity, in a 0-10 Scale (Visual Analogue Scale, VAS).Reduction of the monthly number of vasomotor episodes. Resveratrol 16/28 (57.1%); P2/22 placebo (9.1%)0.001. The resveratrol group gets a positive result 6.28 times more compared to the placebo arm (95% CI: 1.61-24.49). Improvement of the intensity of symptoms and improving quality of life: resveratrol 22/28 (78.6%); placebo 4/22 P (18.2%)0.001. Resveratrol group obtained a positive result 4:32 times more than the placebo arm (95% CI: 1.74-10.71).Resveratrol is effective in reducing the number of episodes vasomotor and the intensity of HF, with the transition from moderate/severe to mild symptoms in 78.6% of patients. Resveratrol has the characteristics to be an alternative therapy in the treatment of HF in menopause.

Skeletal Muscle Biopsy is a minor surgical procedure for the diagnosis of different neuromuscular pathological conditions and has recently gained popularity also in the research field of age-related muscular modifications and sarcopenia. Few studies focused on the application of mini-invasive muscular biopsy in both normal and pathological conditions. The aim of our study was to describe a mini invasive ultrasound-guided skeletal muscular biopsy technique in complete spinal cord injured (SCI) patients and healthy controls with a tri-axial end-cut needle.Skeletal muscle biopsies were collected from 6 chronic SCI patients and 3 healthy controls vastus lateralis muscle with a tri-axial end cut needle (Biopince© - Angiotech). Muscle samples were stained for ATPase to determine fibers composition, moreover, gene expression of cyclooxygenase-1 (COX-1) and prostaglandin E2 receptor has been analyzed by Real Time RT-PCR.All the procedures were perfomed easily without failures and complications. Control tissue was macroscopically thicker than SCI one. Control specimen displayed an equal distribution of type I and type II fibers, while SCI sample displayed a prevalence of type II fibers SCI specimen displayed a significant reduction in COX-1 gene expression. This mini-invasive approach was easy, accurate and with low complication rate in performing skeletal muscle biopsy in both SCI patients and controls.This technique could be useful in conditions in which the overall quantity of specimen required is small like for molecular biology analysis. For histological diagnostic purposes and/or conditions in which the original tissue is already pathologically modified, this technique should be integrated with more invasive techniques.

Background: The clinical benefits of prophylaxis in patients with hemophilia are well-established and include the following: reduced bleeding episodes, prevention of joint damage, decreased inhibitor development, and improved health-related quality of life. However, the cost-effectiveness of prophylaxis is still not clear. Procedures: We reviewed the published hemophilia prophylaxis economic models focusing on utility assumptions. Results: We found six cost-utility studies that compared prophylaxis and on-demand regimens. These studies reported remarkably different results, using utility values based on different assumptions and data sources. Conclusions: We suggest that cooperation among key stakeholders (clinicians, patient organizations and health-care decision makers) as a means of collecting evidence-based and experiential data to represent both the utility and the quality of life changes for patients with Hemophilia A who are treated with prophylaxis or receive on-demand treatments may represent a winning strategy with which to resolve the outstanding issues related to health technology assessments in the care of patients with hemophilia. Pediatr Blood Cancer 2015;62:1826-1831.

Although current treatment guidelines recommend prophylaxis in paediatric patients with haemophilia, specific indications for and barriers to the prescription of prophylaxis in the paediatric haemophiliac population have not been established. The aim of this web-based survey of clinicians at Haemophilia Treatment Centres in Italy was to identify factors for and against the initiation of prophylactic coagulation factor replacement therapy in paediatric patients with haemophilia.A literature search was conducted to identify factors to include in the survey. Seventeen clinicians from Italian Haemophilia Centres were invited to complete the web-based survey and to rank factors in favour of and those that acted as barriers to prophylaxis in terms of "importance" and "influence" on a numerical scale (0=not important to 100=very important). Any factors for which there was a large discrepancy in results from the survey were further "ranked" by clinicians at an interactive question and answer session at a symposium.A total of 13 web surveys were returned; the most highly scored factors favouring prophylaxis were "bleeding frequency", "bleeding severity" and "presence of target joints", and the most highly scored barriers were "parents' acceptance", "venous access" and "compliance to therapy". Other important factors favouring prophylaxis were "severity of coagulation defect" and "orthopaedic score".This survey gives helpful clinician-derived information for people treating haemophiliacs in Italy, to help the treatment-providers orient themselves better regarding the prescription of prophylaxis for paediatric patients.

The most important adverse effect of BoNT-A is the systemic diffusion of the toxin. There is some evidence that the administration of high doses can increase the risk of systemic diffusion and the development of clinically evident adverse effects, however an international consensus does not exist about its maximum dose.The aim of this study was to evaluate changes in autonomic heart drive induced by high doses (higher than 600 units) of incobotulinumtoxinA injection in spastic stroke patients. Moreover, the treatment safety by monitoring adverse events occurrence was assessed.Case control study.Eleven stroke survivors with spastic hemiplegia.Patients were treated with intramuscular focal injections of IncobotulinumtoxinA (NT 201; Xeomin®, Merz Pharmaceuticals GmbH, Frankfurt, Germany). Doses were below 12 units/Kg. Each patient underwent an ECG recording before injection and 10 days after treatment. Linear and non-linear Heart Rate variability (HRV) measures were derived from ECGs with a dedicated software.None of the variable considered showed statistically significant changes after BoNT-A injection.The use of incobotulinumtoxinA in adult patients at doses up to 12 units/kg seems to be safe regarding autonomic heart drive.The use of IncobotulinumtoxinA up to 600 units could be a safe therapeutic option in spastic hemiplegic stroke survivors.