High serum osteopontin levels are associated with prevalent fractures and worse lipid profile in post-menopausal women with type 2 diabetes

Purpose: Patients with type 2 diabetes (T2DM) have increased fracture risk. Osteopontin (OPN) is a protein involved in bone remodeling and inflammation. The aim of this study was to evaluate the association of OPN with fracture prevalence and with metabolic parameters in post-menopausal women with T2DM. Methods: Sixty-four post-menopausal women with T2DM (age 67.0 ± 7.8 years, diabetes duration 8.9 ± 6.7 years), enrolled in a previous study, were followed up (3.6 ± 0.9 years). Previous fragility fractures were recorded. The FRAX score (without BMD) was calculated and biochemical parameters (plasma glucose, HbA1c, lipid profile and renal function) were assessed. Serum 25OH-vitamin D, calcium, PTH and OPN were evaluated at baseline. The association between OPN and fracture prevalence at baseline was evaluated by a logistic model. Results: OPN levels were higher in patients with previous fractures (n.25) than in patients without previous fractures at baseline (n.39) (p = 0.006). The odds of having fractures at baseline increased by 6.7 (1.9–31.4, 95% CI, p = 0.007) for each increase of 1 ng/ml in OPN levels, after adjustment for vitamin D and HbA1c levels. Fracture incidence was 4.7%. Higher OPN associated with a decrease in HDL-cholesterol (p = 0.048), after adjustment for age, basal HDL-cholesterol, basal and follow-up HbA1c and follow-up duration. 25OH-vitamin D associated with an increase in FRAX-estimated probability of hip fracture at follow-up (p = 0.029), after adjustment for age, 25OH-vitamin D and time. Conclusions: In post-menopausal women with T2DM, OPN might be a useful marker of fracture and worse lipid profile

Optimal settings for childbirth.

Many studies highlight how health is influenced by the settings in which people live, work, and receive health care. In particular, the setting in which childbirth takes place is highly influential. The physiological processes of women's labor and birth are enhanced in optimal ("salutogenic," or health promoting) environments. Settings can also make a difference in the way maternity staff practice. This paper focuses on how positive examples of Italian birth places incorporate principles of healthy settings. The "Margherita" Birth Center in Florence and the Maternity Home "Il Nido" in Bologna were purposively selected as cases where the physical-environmental setting seemed to reflect an embedded model of care that promotes health in the context of childbirth. Narrative accounts of the project design were collected from lead professional and direct inspections performed to elicit the key salutogenic components of the physical layout. Comparisons between cases with a standard hospital labor ward layout were performed. Cross-case similarities emerged. The physical characteristics mostly related to optimal settings were a result of collaborative design decisions with stakeholders and users, and the resulting local intention to maximize safe physiological birth, psychosocial wellbeing, facilitate movement and relaxation, prioritize space for privacy, intimacy, and favor human contact and relationships. The key elements identified in this paper have the potential to inform further investigations for the design or renovation of all birth places (including hospitals) in order to optimize the salutogenic component of any setting in any country

Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study.

Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4+ tumor, ≥7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS

Optimal outcomes and women's positive pregnancy experience: a comparison between the World Health Organization guideline and recommendations in European national antenatal care guidelines.

BACKGROUND: The publication of the World Health Organization (WHO) recommendations on antenatal care in 2016 introduced the perspective of women as a necessary component of clinical guidelines in maternity care. WHO highlights the crucial role played by evidence-based recommendations in promoting and supporting normal birth processes and a positive experience of pregnancy. This paper aims to explore and critically appraise recommendations of national antenatal care guidelines across European countries in comparison with the WHO guideline. METHODS: We collected guidelines from country partners of the EU COST Action IS1405. Components of the documents structure and main recommendations within and between them were compared and contrasted with the WHO guideline on antenatal care with a particular interest in exploring whether and how women's experience was included in the recommendations. RESULTS: Eight out of eleven countries had a single national guideline on antenatal care while three countries did not. National guidelines mostly focused on care of healthy women with a straightforward pregnancy. The level of concordance between the national and the WHO recommendations varied along a continuum from almost total concordance to almost total dissonance. Women's views and experiences were accounted for in some guidelines, but mostly not placed at the same level of importance as clinical items. CONCLUSIONS: Findings outline convergences and divergences with the WHO recommendations. They highlight the need for considering women's views more in the development of evidence-based recommendations and in practice for positive impacts on perinatal health at a global level, and on the experiences of each family

Molecular mechanism regulating myosin and cardiac functions by ELC

The essential myosin light chain (ELC) is involved in modulation of force generation of myosin motors and cardiac contraction, while its mechanism of action remains elusive. We hypothesized that ELC could modulate myosin stiffness which subsequently determines its force production and cardiac contraction. We therefore generated heterologous transgenic mouse (TgM) strains with cardiomyocyte-specific expression of ELC with human ventricular ELC (hVLC-1; TgM(hVLC-1)) or E56G-mutated hVLC-1 (hVLC-1(E56G); TgM(E56G)). hVLC-1 or hVLC-1(E56G) expression in TgM was around 39% and 41%, respectively of total VLC-1. Laser trap and in vitro motility assays showed that stiffness and actin sliding velocity of myosin with hVLC-1 prepared from TgM(hVLC-1) (1.67pN/nm and 2.3{my}m/s, respectively) were significantly higher than myosin with hVLC-1(E56G) prepared from TgM(E56G) (1.25pN/nm and 1.7{my}m/s, respectively) or myosin with mouse VLC-1 (mVLC-1) prepared from C57/BL6 (1.41 pN/nm and 1.5+-0.03 {my}m/s, respectively). Maximal left ventricular pressure development of isolated perfused hearts in vitro prepared from TgM(hVLC-1) (80.0mmHg) were significantly higher than hearts from TgM(E56G) (66.2mmHg) or C57/BL6 (59.3+-3.9 mmHg). These findings show that ELCs decreased myosin stiffness, in vitro motility, and thereby cardiac functions in the order hVLC-1 > hVLC-1(E56G) ≈ mVLC-1. They also suggest a molecular pathomechanism of cardiomyopathies caused by hVLC-1 mutations

Targeted DNA methylation by homology-directed repair in mammalian cells. Transcription reshapes methylation on the repaired gene.

We report that homology-directed repair of a DNA double-strand break within a single copy Green Fluorescent Protein (GFP) gene in HeLa cells alters the methylation pattern at the site of recombination. DNA methyl transferase (DNMT)1, DNMT3a and two proteins that regulate methylation, Np95 and GADD45A, are recruited to the site of repair and are responsible for selective methylation of the promoter-distal segment of the repaired DNA. The initial methylation pattern of the locus is modified in a transcription-dependent fashion during the 15\u201320 days following repair, at which time no further changes in the methylation pattern occur. The variation in DNA modification generates stable clones with wide ranges of GFP expression. Collectively, our data indicate that somatic DNA methylation follows homologous repair and is subjected to remodeling by local transcription in a discrete time window during and after the damage. We propose that DNA methylation of repaired genes represents a DNA damage code and is source of variation of gene expression

lba22negative hyper selection of ras wild type wt metastatic colorectal cancer mcrc patients randomized to first line folfox plus panitumumab pan followed by maintenance therapy with either 5fu lv plus pan or single agent pan translational analyses of the valentino study

n/

o 016first line folfox plus panitumumab followed by 5 fu lv plus panitumumab or single agent panitumumab as maintenance therapy in patients with ras wild type metastatic colorectal cancer mcrc the valentino study

n/