Transcriptional activation of the human brain-derived neurotrophic factor gene promoter III by dopamine signaling in NT2/N neurons

We have identified a functional cAMP-response element (CRE) in the human brain-derived neurotrophic factor (BDNF) gene promoter III and established that it participated in the modulation of BDNF expression in NT2/N neurons via downstream signaling from the D1 class of dopamine (DA) receptors. The up-regulation of BDNF expression, in turn, produced neuroprotective signals through receptor tyrosine kinase B (TrkB) and promoted cell survival under the conditions of oxygen and glucose deprivation. To our knowledge this is the first evidence showing the presence of a functional CRE in the human BDNF gene and the role of DA signaling in establishing transcriptional competence of CRE in post-mitotic NT2/N neurons. This ability of DA to regulate the expression of the BDNF survival factor has a profound significance for the nigrostriatal pathway, because it indicates the existence of a feedback loop between the neutrophin, which promotes both the maturation and survival of dopaminergic neurons, and the neurotransmitter, which the mature neurons ultimately produce and release

Screening of entomopathogenic fungi against citrus mealybug, Plannococcus citri (Hemiptera: Pseudococcidae)

Planococcus citri (citrus mealybug) is a common and damaging citrus crop pest which has proven difficult to control using conventional methods, such as chemical pesticides and insect growth regulators, particularly late in the citrus growing season. The virulence of two entomopathogenic fungal species was studied in laboratory bioassays against the crawlers and adults of P. citri. Isolates of Metarhizium anisopliae and Beauveria bassiana, collected from citrus orchards in the Eastern Cape Province in South Africa, were verified using and molecular techniques. Mealybug bioassays were performed in 24-well plates. Beauveria bassiana (GAR 17 B3) and M. anisopliae (FCM AR 23 B3) isolates both resulted in 67.5 % mortality of mealybug crawlers and B. bassiana (GB AR 23 13 3) resulted in 64 % crawler mortality with concentrations of 1 x 107 conidia/ml. These three isolates were further tested in multipledose bioassays to determine the median lethal concentration (LC50), which were 5.29 x 105conidia/ml for the M. anisopliae isolate (FCM AR 23 B3), 4.25 x 106 conidia/ml for B. bassiana (GAR 17 B3), and 6.65 x 107 conidia/ml B. bassiana (GB AR 23 13 3) for crawlers, respectively. The results of this study suggested that two isolates (M. anisopliae FCM AR 23 B3 and B. bassiana GAR 17 B3) showed potential for further development as biological control agents against citrus mealybug. Further research would be required to determine their ability to perform under field conditions

Type 2 diabetes and risk of hospital admission or death for chronic liver diseases

Background & aims: the impact of type 2 diabetes (T2DM) on hospital admissions and deaths due to common chronic liver diseases (CLDs) is uncertain. Our aim was to investigate associations between T2DM and CLDs in a national retrospective cohort study and to investigate the role of sex and socio-economic status (SES).Methods: we used International Classification of Disease codes to identify incident alcoholic liver disease (ALD), autoimmune liver disease, haemochromatosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and viral liver disease from linked diabetes, hospital, cancer and death records for people of 40–89 years of age in Scotland 2004–2013. We used quasi Poisson regression to estimate rate ratios (RR).Results: there were 6667 and 33624 first mentions of CLD in hospital, cancer and death records over ?1.8 and 24 million person-years in people with and without T2DM, respectively. The most common liver disease was ALD among people without diabetes and was NAFLD among people with T2DM. Age-adjusted RR for T2DM compared to the non-diabetic population (95% confidence intervals) varied between 1.27 (1.04–1.55) for autoimmune liver disease and 5.36 (4.41–6.51) for NAFLD. RRs were lower for men than women and for more compared to less deprived populations for both ALD and NAFLD.Conclusions: T2DM is associated with increased risk of hospital admission or death for all common CLDs and the strength of the association varies by type of CLD, sex and SES. Increasing prevalence of T2DM is likely to result in increasing burden of all CLD

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Vivre en français pendant la petite enfance et apprendre à l’école française, y a-t-il un lien ?

Plusieurs études récentes démontrent que l’accès aux expériences langagières appropriées et de haute qualité accroît le développement du jeune enfant, et que ce vécu préscolaire a une incidence sur ses compétences académiques et sociales ultérieures. L’objectif de l’étude est de parfaire notre compréhension de l’incidence de la langue utilisée au préscolaire sur le développement de l’enfant en maternelle ainsi que sur sa réussite scolaire et son comportement en 3e année à l’école française dans le contexte anglo-dominant manitobain. Les données ont été recueillies auprès de 217 enfants à l’âge préscolaire, à l’entrée à l’école et en 3e année. En ce qui a trait au vocabulaire réceptif en maternelle, les enfants issus d’un environnement préscolaire où ils parlaient en français ont des scores nettement plus élevés (56,7) que ceux des enfants provenant d’un milieu où ils parlaient les deux langues à parts égales (46,6) ou l’anglais (18,7). Les scores en matière de développement langagier sont significativement plus élevés pour les enfants qui étaient exposés aux activités de littératie en français (9,21) que ceux qui participaient à ces activités dans les deux langues à parts égales (7,89) ou en anglais (6,23). En 3e année, les enfants qui parlaient français au foyer au préscolaire ont 5,79 plus de chance de répondre aux exigences scolaires en compréhension de lecture que ceux qui parlaient anglais, et 2,18 plus de chance que ceux qui parlaient les deux langues à parts égales. Cette étude confirme un lien important entre « vivre en français à la petite enfance » et « apprendre à l’école française ».Elle constitue un excellent moteur pour entamer des discussions sur l’importance et l’urgence de renforcer les services existants en français pour les enfants d’âge préscolaire et leur famille pour le maintien et la croissance de la communauté francophone minoritaire.Several recent studies have shown that access to appropriate and high-quality language experiences enhance the development of young children and that these pre-scholastic experiences have an effect on academic and social competencies later on. The objective of the study was to refine our understanding of the effects that the language spoken at home during a child’s early years has on that child’s development in kindergarten, first of all, then on his or her scholastic achievement and behaviour in grade 3 of French School in the context of the Anglo-dominant Manitoban school system. Data were gathered among 217 preschool-aged children when they entered school in kindergarten, then again in grade 3. Focusing on receptive vocabulary in kindergarten, children from a pre-scholastic environment in which they spoke French achieve markedly higher scores (56.7) than those of children from families in which two languages were spoken in equal proportions (46.6) or in which only English was spoken (18.7). Scores pertaining to language development were significantly higher for children who were exposed to literacy activities in French (9.21) than for children who took part in such activities in both languages inequal proportions (7.89) or in English only (6.23). In grade 3, children who spoke French at home before they started school were 5.79 times more likely to meet scholastic requirements in reading comprehension than were children who spoke English only and 2.18 times more likely than children who spoke both languages in equal portions. This study confirms a significant link between “living in French during early childhood“ and “learning in French school.“ It constitutes an excellent impetus for engaging dialogue on the importance and the urgency of reinforcing existing services in French for preschool-aged children and their families in order to maintain and expand the minority francophone community