The impact of vatinoxan on medetomidine-ketamine-midazolam immobilization in Patagonian maras (Dolichotis patagonum)

Objective To compare cardiovascular and ventilatory effects, immobilization quality and effects on tissue perfusion of a medetomidine-ketamine-midazolam combination with or without vatinoxan (MK-467), a peripherally acting alpha(2)-adrenoceptor antagonist. Study design Randomized, blinded, crossover study. Animals A group of nine healthy Patagonian maras (Dolichotis patagonum). Methods Maras were immobilized twice with: 1) medetomidine hydrochloride (0.1 mg kg(-1)) + ketamine (5 mg kg(-1)) + midazolam (0.1 mg kg(-1)) (MKM) + saline or 2) MKM + vatinoxan hydrochloride (0.8 mg kg(-1)), administered intramuscularly. Drugs were mixed in the same syringe. At 20, 30 and 40 minutes after injection, invasive blood pressure, heart rate, respiration rate, end-tidal CO2, haemoglobin oxygen saturation, and muscle oxygenation were measured, arteriovenous oxygen content difference was calculated. Muscle tone, jaw tone, spontaneous blinking and palpebral reflex were evaluated. Times to initial effect, recumbency, initial arousal and control of the head were recorded. Paired t test, Wilcoxon matched-pairs signed rank test and analysis of variance were used to compare protocols; (p 120 mmHg), whereas with 372 vatinoxan, four animals were hypotensive (MAP <60 mmHg). Muscle and jaw tone were significantly more frequently present with MKM (both p = 0.039). Other measurements did not significantly differ between protocols. Conclusions and clinical relevance In Patagonian maras, vatinoxan attenuated the increase in blood pressure induced by medetomidine. Muscle and jaw tone were more frequently present with MKM, indicating that quality of immobilization with vatinoxan was more profound.Peer reviewe

Effect of indomethacin on S. typhimurium and cholera toxin-induced fluid accumulation in pig jejunum

We have investigated the influence of prostaglandins (PGs) on the Salmonella typhimurium (St) and cholera toxin (CT)-induced fluid accumulation in jejunum of 9-10 weeks (18-20 kg) old female pigs. St (1010 colony forming units) and CT (56/ig) were instilled in separated tiedoff loops for 8 hours. Before instillation, and again after 4 hours, pigs were given an intravenous dose of the cyclooxygenase and prostaglandin synthesis inhibitor, indomethacin, or saline alone (control). In the St-loops indomethacin had no effect on the fluid accumulation, 9.1 ± 1.3 vs 8.2±0.5 mg fluid/mg loop dry weight, whereas in CT-Ioops, indomethacin reduced fluid accumulation significantly from 35±2 to 22±3 mg fluid/mg loop dry weight (P\u3c0.05). Our preliminary results indicate that PGs are not involved in St-induced fluid accumulation in pig jejunum, which is in contrast to the case in CT -induced fluid accumulation

Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 Oxidoreductase deficiency

Context: P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency. \ud \ud Objective: The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty. \ud \ud Design: Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted. \ud \ud Results: Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations. \ud \ud Conclusion: Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR

Study protocol for a randomized controlled trial of supportive parents – coping kids (SPARCK)—a transdiagnostic and personalized parent training intervention to prevent childhood mental health problems

Background: To meet the scientific and political call for effective prevention of child and youth mental health problems and associated long-term consequences, we have co-created, tested, and optimized a transdiagnostic preventive parent-training intervention, Supportive parents – coping kids (SPARCK), together with and for the municipal preventive frontline services. The target group of SPARCK is parents of children between 4 and 12 years who display symptoms of anxiety, depression, and/or behavioral problems, that is, indicated prevention. The intervention consists of components from various empirically supported interventions representing different theorical models on parent–child interactions and child behavior and psychopathology (i.e., behavioral management interventions, attachment theory, emotion socialization theory, cognitive-behavioral therapy, and family accommodation intervention). The content and target strategies of SPARCK are tailored to the needs of the families and children, and the manual suggests how the target strategies may be personalized and combined throughout the maximum 12 sessions of the intervention. The aim of this project is to investigate the effectiveness of SPARCK on child symptoms, parenting practices, and parent and child stress hormone levels, in addition to later use of specialized services compared with usual care (UC; eg. active comparison group). Methods: We describe a randomized controlled effectiveness trial in the frontline services of child welfare, health, school health and school psychological counselling services in 24 Norwegian municipalities. It is a two-armed parallel group randomized controlled effectiveness and superiority trial with 252 families randomly allocated to SPARCK or UC. Assessment of key variables will be conducted at pre-, post-, and six-month follow-up. Discussion: The current study will contribute with knowledge on potential effects of a preventive transdiagnostic parent-training intervention when compared with UC. Our primary objective is to innovate frontline services with a usable, flexible, and effective intervention for prevention of childhood mental health problems to promote equity in access to care for families and children across a heterogeneous service landscape characterized by variations in available resources, personnel, and end user symptomatology. Trial registration: ClinicalTrials.gov ID: NTCT0580052

Prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) in cytosols and pellet extracts derived from 892 breast cancer patients

To evaluate the clinical relevance of urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) measured by a recently developed enzyme-linked immunosorbent assay (ELISA), we analysed both components in samples derived from 892 patients with primary breast cancer (median follow-up 99 months). The assays were performed in cytosolic extracts as well as in corresponding detergent extracts of pellets obtained after ultracentrifugation, which was carried out when preparing the cytosolic fractions for routine steroid hormone receptor determination. Statistically significant correlations were found between the cytosolic levels and those determined in the pellet extracts (Spearman correlation coefficient rs = 0.60, P < 0.0001 for uPA and rs = 0.65, P < 0.0001 for PAI-1). Furthermore, strong correlations were found between the levels of both uPA (rs = 0.85, P < 0.0001) and PAI-1 (rs = 0.90, P < 0.0001) in the cytosols and their levels previously measured with ELISAs based on commercial reagents. In both Cox univariate and multivariate analysis, high cytosolic levels of uPA or PAI-1 were significantly associated with increased rates of relapse and death. The levels of uPA and PAI-1 in the pellet extracts also provided prognostic information, although to a lesser extent compared with the cytosolic extracts. The prediction of prognosis on the basis of uPA and PAI-1 assessed by an alternative ELISA once again emphasizes the established prognostic role and usefulness of these parameters in selection of breast cancer patients at high or low risk of recurrence. © 1999 Cancer Research Campaig

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes.Systematic review and meta-analysis.We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE.Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to 'low quality' due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence).This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable increased risk in non-serious adverse events. The analyses may overestimate the intervention benefit due bias

Perceptions of quality across the maternal care continuum in the context of a health financing intervention: Evidence from a mixed methods study in rural Malawi

Background: In 2013, Malawi with its development partners introduced a Results-Based Financing for Maternal and Newborn Health (RBF4MNH) intervention to improve the quality of maternal and newborn health-care services. Financial incentives are awarded to health facilities conditional on their performance and to women for delivering in the health facility. We assessed the effect of the RBF4MNH on quality of care from women’s perspectives. Methods: We used a mixed-method prospective sequential controlled pre- and post-test design. We conducted 3060 structured client exit interviews, 36 in-depth interviews and 29 focus group discussions (FGDs) with women and 24 in-depth interviews with health service providers between 2013 and 2015. We used difference-in-differences regression models to measure the effect of the RBF4MNH on experiences and perceived quality of care. We used qualitative data to explore the matter more in depth. Results: We did not observe a statistically significant effect of the intervention on women’s perceptions of technical care, quality of amenities and interpersonal relations. However, in the qualitative interviews, most women reported improved health service provision as a result of the intervention. RBF4MNH increased the proportion of women reporting to have received medications/treatment during childbirth. Participants in interviews expressed that drugs, equipment and supplies were readily available due to the RBF4MNH. However, women also reported instances of neglect, disrespect and verbal abuse during the process of care. Providers attributed these negative instances to an increased workload resulting from an increased number of women seeking services at RBF4MNH facilities. Conclusion: Our qualitative findings suggest improvements in the availability of drugs and supplies due to RBF4MNH. Despite the intervention, challenges in the provision of quality care persisted, especially with regard to interpersonal relations. RBF interventions may need to consider including indicators that specifically target the provision of respectful maternity care as a means to foster providers’ positive attitudes towards women in labour. In parallel, governments should consider enhancing staff and infrastructural capacity before implementing RBF

Expression of uPAR in tumor-associated stromal cells is associated with colorectal cancer patient prognosis: a TMA study

BACKGROUND: The receptor for urokinase-type plasminogen activator (uPAR) is associated with cancer development and progression. Within the tumor microenvironment uPAR is expressed by malignant cells as well as tumor-associated stromal cells. However, the contribution of uPAR expression in these stromal cells to malignancy and patient survival in colorectal cancer is still unclear. This study compares the association of uPAR expression in both colorectal tumor-associated stromal cells and neoplastic cells with clinico-pathological characteristics and patient survival using tissue micro arrays (TMA). METHODS: Immunohistochemical staining of uPAR expression was performed on tumor tissue from 262 colorectal cancer patients. Kaplan-Meier, log rank, and uni- and multivariate Cox’s regression analyses were used to calculate associations between uPAR expression and patient survival. RESULTS: In the colorectal tumor-associated stromal microenvironment, uPAR is expressed in macrophages, (neoangiogenic) endothelial cells and myofibroblasts. uPAR expression in tumor-associated stromal cells and neoplastic cells (and both combined) were negatively associated with overall survival (OS) and Disease Free Survival (DFS). Uni- and multivariate Cox’s regression analysis for combined uPAR expression in tumor-associated stromal and neoplastic cells showed significant and independent negative associations with OS and DFS. Only uPAR expression in tumor-associated stromal cells showed independent significance in the uni- and multivariate analysis for DFS. CONCLUSION: This study demonstrates a significant independent negative association between colorectal cancer patient survival and uPAR expression in especially tumor-associated stromal cells