Objective: Systemic sclerosis (SSc) is characterized by the fibrosis of various organs, vascular hyperreactivity, and immunologic dysregulation. Since Notch signaling is known to affect fibroblast homeostasis, angiogenesis, and lymphocyte development, we undertook this study to investigate the role of the Notch pathway in human and murine SSc.Methods: SSc was induced in BALB/c mice by subcutaneous injections of HOCl every day for 6 weeks. Notch activation was analyzed in tissues from mice with SSc and from patients with scleroderma. Mice with SSc were either treated or not treated with the γ‐secretase inhibitor DAPT, a specific inhibitor of the Notch pathway, and the severity of the disease was evaluated.Results: As previously described, mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti–DNA topoisomerase I antibodies. The Notch pathway was hyperactivated in the skin, lung, fibroblasts, and splenocytes of diseased mice and in skin biopsy samples from patients with scleroderma. ADAM‐17, a proteinase involved in Notch activation, was overexpressed in the skin of mice and patients in response to the local production of reactive oxygen species. In HOCl‐injected mice, DAPT significantly reduced the development of skin and lung fibrosis, decreased skin fibroblast proliferation and ex vivo serum‐induced endothelial H₂O₂ production, and abrogated the production of anti–DNA topoisomerase I antibodies.Conclusion: Our results show the pivotal role of the ADAM‐17/Notch pathway in SSc following activation by reactive oxygen species. The inhibition of this pathway may represent a new treatment of this life‐threatening disease.

The need for bone and joint prostheses is currently growing due to population aging, leading to an increase in prosthetic joint infection cases. Biofilms represent an adaptive and quite common bacterial response to several stress factors which confer an important protection to bacteria. Biofilm formation starts with bacterial adhesion on a surface, such as an orthopedic prosthesis, further reinforced by matrix synthesis. The biofilm formation and structure depend on the immediate environment of the bacteria. In the case of infection, the periprosthetic joint environment represents a particular interface between bacteria, host cells, and the implant, favoring biofilm initiation and maturation. Treating such an infection represents a huge challenge because of the biofilm-specific high tolerance to antibiotics and its ability to evade the immune system. It is crucial to understand these mechanisms in order to find new and adapted strategies to prevent and eradicate implant-associated infections. Therefore, adapted models mimicking the infectious site are of utmost importance to recreate a relevant environment in order to test potential antibiofilm molecules. In periprosthetic joint infections, Staphylococcus aureus is mainly involved because of its high adaptation to the human physiology. The current review deals with the mechanisms involved in the antibiotic resistance and tolerance of Staphylococcus aureus in the particular periprosthetic joint infection context, and exposes different strategies to manage these infections.

Type 2 diabetes mellitus (T2D) is responsible for an important premature mortality. Pharmacists involved in community-based pharmaceutical care services could help patients with diabetes through education and management as they participate in their regular and long-term care. This meta-analysis aimed to evaluate the association between interventions led by pharmacists in the primary care setting and mean change in HbA1c levels. Randomized controlled trials and quasi-experimental studies with a control group were included. Standardized mean differences (SMD) and their 95% confidence intervals (95% CI) were calculated to compare the mean change in HbA1c values between baseline and end of the intervention in each group. Subgroup analyses were performed to explore heterogeneity. Twelve articles were included. The results showed that pharmacist’s interventions significantly reduced HbA1c compared to usual care with an overall SMD of −0.67 (95% CI = [−0.87; −0.48], p < 0.0001). Even if no significant difference between subgroups were found, the reduction of HbA1c seemed more important when baseline HbA1c was ≥8.5%, the intervention occurred monthly, in a primary care center and in countries with a lower human development index. Our results suggest that pharmacists-led interventions in the primary care setting can improve glycemic control for adults with T2D.

Staphylococcus aureus Biofilms and their Impact on the Medical Field | InTechOpen, Published on: 2017-03-08. Authors: Fany Reffuveille, Jérôme Josse, Quentin Vallé, et

Pharmaceutical care activities at hospital admission have a significant impact on patient safety. The objective of this study was to identify predictive factors for clinically significant pharmacist interventions (PIs) performed during medication reconciliation and medication review at patient hospital admission. A 4-week prospective study was conducted in 4 medicine wards. At hospital admission, medication reconciliation and medication review were conducted and PIs were performed by the pharmaceutical team. The clinical impact of PIs was determined using the clinical economic and organizational (CLEO) tool. Clinical characteristics, laboratory results, and medication data for each patient were collected and analyzed as potential predictive factors of clinically significant PIs. Univariate and multivariate binary logistic regression were subsequently used to identify independent predictive factors for clinically relevant PIs. Among 265 patients admitted, 150 patients were included. Among 170 PIs performed at hospital admission, 71 were related to unintentional discrepancies (41.8%) during medication reconciliation, and 99 were related to drug-related problems (DRPs) (58.8%) during medication review. Overall, 115 PIs (67.7%) were considered to have a clinical impact. By multivariate analysis, number of medications ≥5 (P = .01) based on the best possible medication history, and Charlson comorbidity index score ≥2 (P < .01) were found to be independent predictive factors of clinically significant PIs at hospital admission. Identifying predictive factors of clinically significant PIs is valuable to optimize clinical pharmacist practices at hospital admission during both medication reconciliation and medication review. These 2 steps of the pharmaceutical care process improve medication safety at hospital admission.

A random mutagenesis technique was used to predict the evolutionary potential of β-lactamase CTX-M-9 toward the acquisition of improved catalytic activity against ceftazidime. Thirty CTX-M mutants were obtained during three rounds of mutagenesis. These mutants conferred 1- to 128-fold-higher MICs of ceftazidime than the parental enzyme CTX-M-9. The CTX-M mutants contained one to six amino acid substitutions. Mutants harbored the substitutions Asp240Gly and Pro167Ser, which were previously observed in clinical CTX-M enzymes. Additional substitutions, notably Arg164His, Asp179Gly, and Arg276Ser, were observed near the active site. The kinetic constants of the three most active mutants revealed two distinct ways of improving catalytic efficiency against ceftazidime. One enzyme had a 17-fold-higher k _cat value than CTX-M-9 against ceftazidime. The other two had 75- to 300-fold-lower K _m values than CTX-M-9 against ceftazidime. The current emergence of CTX-M β-lactamases with improved activity against ceftazidime may therefore be the beginning of an evolutionary process which might subsequently generate a great diversity of CTX-M-type ceftazidimases.