Repetitive Transcranial Magnetic Stimulation Delivered With an H-Coil to the Right Insula Reduces Functional Connectivity Between Insula and Medial Prefrontal Cortex.

OBJECTIVE: Insula neurocircuitry alterations are reported in a range of neuropsychiatric disorders holding promise for clinical interventions. We measured, in a pilot study, acute neuroplastic modulations resulting from high- and low-frequency stimulation with repetitive transcranial magnetic stimulation (rTMS) delivered via an H-coil that targeted the right insula and overlying prefrontal cortex. METHODS: Healthy, nonsmoking, adult participants (N = 28), in a within-participant, sham-controlled experiment, received a single rTMS session on four separate days. Participants received one session each of low- (1 Hz) and high (10 Hz)-frequency stimulation and two sessions of sham stimulation matched to each rTMS frequency. After each rTMS session, participants completed a functional magnetic resonance imaging (fMRI) scan while performing two cognitive tasks and a resting-state scan. The effect of rTMS was examined on task behavior as well as blood oxygenated level-dependent (BOLD) response during task performance and resting state. We expected low- and high-frequency stimulation to decrease and increase, respectively, insula and overlying cortical BOLD signal and network connectivity. RESULTS/CONCLUSIONS: There was no effect of rTMS, regardless of frequency, on task behavior or task-based BOLD response. There was an effect of rTMS compared to sham on rsFC between insula and medial prefrontal cortex, with connectivity reduced after rTMS compared to sham, regardless of frequency. Implications for using rTMS to the insula as a treatment for neuropsychiatric disorders are discussed in light of insula-medial prefrontal cortex connectivity.

Implementing a Just Culture: Perceptions of Nurse Managers of Required Knowledge, Skills and Attitudes.

BACKGROUND: Healthcare organizations have been challenged to create a just culture as part of their culture of safety. PURPOSE: To explore perceptions of nurse managers in developing personal competencies in order to enable them to effectively implement a just culture in their units. METHOD: Qualitative content analysis of semi-structured interviews with nine nurse managers identified themes. Data were independently analyzed by three members of the research team. FINDINGS: Analysis of interview transcripts identified the following four themes: need for education of managers and employees, need for a variety of new skills for nurse managers, need to change attitudes from the long-standing punitive culture and fault of individual and challenges in implementation because of time constraints. CONCLUSION: Implementing a just culture is complex. Education of nurse managers is crucial. A series of educational strategies is recommended. Findings support the need for new competencies to enable nurse managers to effectively implement a just culture in their units.

'Navy assignments test me to the limit'.

I am a specialist intensive care nurse, a specialist neurological trauma nurse and I have just completed my MSc in advanced practice neuroscience care.

[(76) Br]BMK-152, a nonpeptide analogue, with high affinity and low nonspecific binding for the corticotropin-releasing factor type 1 receptor.

Corticotropin-releasing factor (CRF), a neuropeptide, regulates endocrine and autonomic responses to stress through G-protein coupled receptors, CRF(1) or CRF(2) . A PET ligand able to monitor changes in CRF(1) receptor occupancy in vivo would aid in understanding the pathophysiology of stress-related diseases as well as in the clinical development of nonpeptide antagonists with therapeutic value. We have radiolabeled the CRF(1) receptor ligand, [8-(4-bromo-2,6-dimethoxyphenyl)-2,7-dimethylpyrazolo[1,5-α][1,3,5]triazin-4-yl]-N,N-bis-(2-methoxyethyl)amine (BMK-152) (ClogP = 2.6), at both the 3 and 4 position with [(76) Br]. Using in vitro autoradiography saturation studies the 4-[(76) Br]BMK-152 exhibited high affinity binding to both rat (K(d) = 0.23 ± 0.07 nM; n = 3) and monkey frontal cortex (K(d) = 0.31 ± 0.08 nM; n = 3) consistent with CRF(1) receptor regional distribution whereas with the 3-[(76) Br]BMK-152, the K(d) s could not be determined due to high nonspecific binding. In vitro autoradiography competition studies using [(125) I]Tyr(0) -o-CRF confirmed that 3-Br-BMK-152 (K(i) = 24.4 ± 4.9 nM; n = 3) had lower affinity (70-fold) than 4-Br-BMK-152 (K(i) = 0.35 ± 0.07 nM; n = 3) in monkey frontal cortex and similiar studies using [(125) I]Sauvagine confirmed CRF(1) receptor selectivity. In vivo studies with P-glycoprotein (PGP) knockout mice (KO) and their wild-type littermates (WT) showed that the brain uptake of 3-[(76) Br]BMK/4-[(76) Br]BMK was increased less than twofold in KO versus WT indicating that 3-[(76) Br]BMK-152/4-[(76) Br]BMK was not a Pgp substrate. Rat brain uptakes of 4-[(76) Br] BMK-152 from ex vivo autoradiography studies showed regional localization consistent with known published CRF(1) receptor distribution and potential as a PET ligand for in vivo imaging of CRF(1) receptors.

Bromocriptine administration reduces hyperphagia and adiposity and differentially affects dopamine D2 receptor and transporter binding in leptin-receptor-deficient Zucker rats and rats with diet-induced obesity.

BACKGROUND: The dopamine (DA) D(2) receptor (D2R) agonist bromocriptine (BC) decreases body fat in animal and human models and increases lean muscle mass, improves glucose intolerance and insulin resistance, and reduces triglycerides and free fatty acids. We have previously shown a negative correlation between D2R and body weight in obese individuals and in rodents, and that chronic food restriction increases D2R binding in genetically obese rats. The purpose of this study was to assess whether the antiobesity and metabolic effects of BC are related to changes in midbrain DA and D2R activity by measuring D2R and DA transporter (DAT) binding in a genetic (leptin-receptor-deficient) and environmental (diet-induced) rodent obesity model. METHODS: Obese (fa/fa) (leptin-receptor-deficient), lean (FA/FA) Zucker rats and rats with diet-induced obesity (DIO) were treated with 10 mg/kg BC for 4 weeks. Body weight, food intake, locomotor activity and blood glucose levels were measured along with D2R- and DAT-binding levels using in vitro receptor autoradiography. RESULTS: BC decreased food intake and body fat and increased locomotor activity in both the (fa/fa) and DIO rats. Furthermore, BC increased D2R binding in (fa/fa) but not in DIO rats. Finally, BC increased DAT binding in DIO rats but not in the (fa/fa) rats. CONCLUSION: These observations are all consistent with the existence of unique leptin-DA interactions and the hypothesis that there is hyposensitivity of the DA system in obesity.

Bromocriptine reduces steatosis in obese rodent models.

BACKGROUND/AIMS: Obesity is a risk factor for glucose intolerance, steatosis, and oxidative stress, characteristics of nonalcoholic fatty liver disease. Bromocriptine may have anti-obesity, insulin-sensitizing, lipolytic, and antioxidant properties. We, therefore, hypothesized that bromocriptine would improve markers of nonalcoholic fatty liver disease in obese rodent models. METHODS: We performed a randomized, controlled experiment in genetically obese fatty Zucker rats and diet-induced obese rats to assess for behavioral and peripheral anti-obesity actions of bromocriptine (10mg/kg) that would improve nonalcoholic fatty liver disease. RESULTS: Behaviorally, food intake decreased and locomotor activity increased in bromocriptine-treated fatty Zucker and dietary-induced obese rats. Peripherally, liver triglycerides were significantly reduced and hepatic manganese superoxide dismutase significantly increased in bromocriptine-treated fatty Zucker and diet-induced obese rats compared to controls. Blood glucose was significantly lower in bromocriptine-treated Zucker rats compared to fatty controls and was no different than that of lean controls. CONCLUSIONS: Improvements in obesigenic behaviors, glucose tolerance, hepatic lipid accumulation, and mitochondrial oxidative stress observed in genetically obese and diet-induced obese rodents indicate that bromocriptine may be promising as a broad-based therapy for nonalcoholic fatty liver disease.

Chlorhexidine-containing mucoadhesive polymeric compacts designed for use in the oral cavity: an examination of their physical properties, in vitro/in vivo drug release properties and clinical acceptability.

This study describes the formulation, physicochemical and mucoadhesive properties and in in vitro/in vivo release of chlorhexidine from mucoadhesive, polymeric compacts, designed for application within the oral cavity. Compacts were prepared by direct compression of mixtures containing 100 mg sodium carboxymethylcellulose (NaCMC), 25 mg hydroxyethylcellulose (HEC)/75 mg polyacrylic acid (PAA) and 75 mg HEC/25 mg PAA. The mechanical and mucoadhesive properties of the drug-loaded compacts were examined using a texture analyzer in compression and tension modes, respectively. Evaluation of mucoadhesion was performed using a mucin-coated gauze substrate. In vitro release of chlorhexidine was performed under sink conditions (phosphate buffered saline, pH 7.0, 37 degrees C) using a Caleva 7ST dissolution apparatus. Salivary chlorhexidine levels were determined following intra-oral placement of drug-containing formulations. Quantification of the mass of chlorhexidine released both in vitro and in vivo was performed using HPLC with ultraviolet detection. Furthermore, the in vivo acceptability of the various polymeric compacts was assessed in volunteers using standard questionnaires. Compacts composed of HEC/PAA exhibited greater in vivo retention than those composed of NaCMC. Compacts composed of 25 mg PAA and 75 mg HEC displayed greatest patient acceptability. Introduction of chlorhexidine into these compacts did not significantly compromise either the work required for compact fracture or the in vitro mucoadhesion. Controlled release of chlorhexidine from these compacts was observed both in vitro and in vivo, the concentration of chlorhexidine in saliva exceeding the minimum inhibitory concentration of the common oral pathogens over the study period. In light of the patient acceptability and in vivo performance, it is suggested that the compact composed of 25 mg PAA/75 mg HEC containing 10 mg chlorhexidine offers considerable promise for use as an antimicrobial agent in the oral cavity.