Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

Mindfulness and psychoeducation to manage stress in amnestic mild cognitive impairment: A pilot study

Objectives: Amnestic mild cognitive impairment (aMCI) often corresponds to the prodromal stage of Alzheimer disease (AD). The aMCI stage represents a crucial time window to apply preventive interventions in an attempt to delay cognitive decline. Stress, one of AD’s modifiable risk factors frequently co-occurring with aMCI, stands out as a key intervention target. The goal of this study was to assess the impacts of two non-pharmacological interventions, mindfulness and psychoeducation, on stress at the psychological and physiological levels among aMCI older adults.

Methods: Forty-eight aMCI participants were randomized between a mindfulness-based intervention (MBI) and a psychoeducation-based intervention (PBI) for eight weekly sessions. Anxiety symptoms, perceived stress levels, cortisol awakening response (CAR), and coping strategies were assessed pre- and post-intervention. Mindfulness attitudes and time dedicated to at-home meditative practices were evaluated in the MBI group.

Results: The main results revealed a slight reduction of the CAR among MBI participants who practiced meditation at home the most and a decrease in perceived stress levels in the PBI group. Both interventions enhanced problem-focused coping strategies.

Conclusion: In sum, this pilot study supports the potential of MBI and PBI to reduce stress at the physiological and psychological level, respectively, and increase coping strategies in older adults at risk for AD.     

Steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia

Objective To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of piperacillin/tazobactam (P/T) administered to critically ill patients with severe bacterial pneumonia.Design Prospective, open-label study.Setting An intensive care unit and research ward in a university hospital.Patients Ten adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation.Interventions All subjects received a 30-min intravenous infusion of P/T 4 g/0.5 g every 8 h. The steady-state plasma and ELF concentrations of P/T were determined by high-performance liquid chromatography.Measurements and main results The mean±SD steady-state plasma trough, peak, and intermediate concentrations were 8.5±4.6 µg/ml, 55.9±21.6 µg/ml, and 24.0±13.8 µg/ml for piperacillin, and 2.1±1.0 µg/ml, 4.8±2.1 µg/ml, and 2.4±1.2 µg/ml for tazobactam, respectively. The mean±SD steady-state intermediate ELF concentrations were 13.6±9.4 µg/ml for piperacillin and 2.1±1.1 µg/ml for tazobactam, respectively, showing a mean percentage penetration of piperacillin and tazobactam into ELF of 56.8% and 91.3 %, respectively, with a P/T ratio of 6.5:1.Conclusion Our results show that during the treatment of severe nosocomial pneumonia, a regimen of P/T 4 g/0.5 g every 8 h might provide insufficient concentrations into lung tissue to exceed the MIC of many causative pathogens. This suggests that higher doses of P/T should be administered in order to maximize the antibiotic concentration at the site of infection, or that a second antimicrobial agent should be used in association.     

Reproducibility of protected specimen brush and bronchoalveolar lavage conserved at 4 degrees C for 48 hours

OBJECTIVE: Protected specimen brush (PSB) and bronchoalveolar lavage (BAL) are proposed in combination to optimize antimicrobial treatment. Nevertheless, they are only validated for immediate laboratory processing. This study was therefore conducted to determine whether 48 h conservation at a mere 4 degrees C enables good culture reproducibility for both PSB and BAL. DESIGN AND SETTING: Prospective study, evaluation of a conservation procedure for PSB and BAL, from February 1994 to February 1995, in the 12 bed ICU of a general hospital (938 beds). SAMPLES: Ninety-nine PSB and 86 BAL samples, obtained from 100 bronchoscopic procedures, were analyzed. Thresholds were 10(3) and 10(4) cfu/ml for PSB and BAL, respectively. MEASUREMENTS AND RESULTS: Qualitative comparison between the immediate and 48 h procedures were, for PSB, specificity 100%, sensitivity 78%, positive predictive value 100%, negative predictive value 84% and overall accuracy 90%; and for BAL: 100%, 89%, 100%, 89% and 94%. Lowered 10(2) and 10(3) cfu/ml thresholds at the 48 h procedure for PSB and BAL reduce the false negatives from 10 to 3 and 5 to 1, respectively. Microorganism results were comparable for PSB and BAL ( r = 0.63 and 0.67), especially for the most resistant strains: Staphylococcus, Enterobacteriaceae and Pseudomonas. However, there was a decrease in the Neisseria and Haemophilus group ( p < 0.01). CONCLUSION: There is a good culture reproducibility for both PSB and BAL after 48 h conservation at 4 degrees C, especially with lowered thresholds; this technique is therefore appropriate for routine use.     

When nightclub security agents assault clients

In 2006, a medico-legal consultation service devoted to adult victims of interpersonal violence was set up at the Lausanne University Hospital Centre, Switzerland: the Violence Medical Unit. Most patients are referred to the consultation by the Emergency Department. They are received by forensic nurses for support, forensic examination (in order to establish medical report) and community orientation. Between 2007 and 2009, among community violence, aggressions by security agents of nightclubs on clients have increased from 6% to 10%. Most of the victims are young men who had drunk alcohol before the assault. 25.7% presented one or several fractures, all of them in the head area. These findings raise questions about the ability of security agents of nightclubs to deal adequately with obviously risky situations and ensure client security.