Resting‐state networks show dynamic functional connectivity in awake humans and anesthetized macaques

Characterization of large‐scale brain networks using blood‐oxygenation‐level‐dependent functional magnetic resonance imaging is typically based on the assumption of network stationarity across the duration of scan. Recent studies in humans have questioned this assumption by showing that within‐network functional connectivity fluctuates on the order of seconds to minutes. Time‐varying profiles of resting‐state networks (RSNs) may relate to spontaneously shifting, electrophysiological network states and are thus mechanistically of particular importance. However, because these studies acquired data from awake subjects, the fluctuating connectivity could reflect various forms of conscious brain processing such as passive mind wandering, active monitoring, memory formation, or changes in attention and arousal during image acquisition. Here, we characterize RSN dynamics of anesthetized macaques that control for these accounts, and compare them to awake human subjects. We find that functional connectivity among nodes comprising the “oculomotor (OCM) network” strongly fluctuated over time during awake as well as anaesthetized states. For time dependent analysis with short windows (<60 s), periods of positive functional correlations alternated with prominent anticorrelations that were missed when assessed with longer time windows. Similarly, the analysis identified network nodes that transiently link to the OCM network and did not emerge in average RSN analysis. Furthermore, time‐dependent analysis reliably revealed transient states of large‐scale synchronization that spanned all seeds. The results illustrate that resting‐state functional connectivity is not static and that RSNs can exhibit nonstationary, spontaneous relationships irrespective of conscious, cognitive processing. The findings imply that mechanistically important network information can be missed when using average functional connectivity as the single network measure. Hum Brain Mapp 34:2154–2177, 2013. © 2011 Wiley Periodicals, Inc.     

Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson's disease

Cervical dystonia (CD) is a movement disorder that involves involuntary turning and twisting of the neck caused by abnormal muscle contraction. Deep brain stimulation (DBS) in the globus pallidus internus (GPi) is used to treat both CD and the motor symptoms of Parkinson's disease (PD). It has been suggested that the differing motor symptoms in CD and PD may arise from a decreased GPi output in CD and elevation of output in PD. To test this hypothesis, extracellular recordings of GPi neuronal activity were obtained during stereotactic surgery for the implantation of DBS electrodes in seven idiopathic CD and 14 PD patients. The mean GPi neuronal firing rate recorded from CD patients was lower than that in PD patients (P < 0.001; means +/- SE: 71.4 +/- 2.2 and 91.7 +/- 3.0 Hz, respectively). Furthermore, GPi neurons fired in a more irregular pattern consisting of more frequent and longer pauses in CD compared with PD patients. When comparisons were done based on locations of recordings, these differences in firing rates and patterns were limited to the ventral portion of the GPi. In contrast, no difference in firing rate or pattern was observed in the globus pallidus externus between the two groups. These findings suggest that alterations in both firing rate and firing pattern may underlie the differing motor symptoms associated with these two movement disorders.     

Developing leaders at every level: accountability and empowerment actualized through shared governance

The shortage of frontline nursing staff and their managers in acute care organizations necessitates strategies to both use and recognize the unique knowledge and skills of these individuals. The authors describe one organization's successful implementation of a shared decision-making structure that promotes an empowering work environment in which professional fulfillment and personal satisfaction can flourish. With support and opportunity, leaders are developed across all levels of nursing.     

Season-related changes in circulating androgen,brain aromatase,and perch-calling in male ring doves

The perch-call of ring doves (Streptopelia risoria) is related to territorial defence and mate attraction. Perch-calls are sexually dimorphic and individually different in structure. The expression of perch-call is androgen-dependent and is controlled by the action of testosterone on the preoptic-hypothalamic areas. However, it is not known whether the acoustic features of the call vary with the reproductive condition. We studied plasma androgen levels, brain steroid metabolism, and perch-calling of male ring doves kept in winter-like (low temperature, short days) or spring-like (mild temperature, long day) conditions. Circulating levels of androgen were higher in males kept on spring-like condition. Spring males spent more time in perch-calling than winter males. However, a detailed analysis of the call structure revealed no difference for any time or frequency parameter between groups. This work shows that in ring doves season-dependent variations in the circulating levels of androgen are correlated with differences in the amount of time males spend in perch-calling. In addition, the study suggests that in adult males the acoustic structure of the perch-calls is not influenced by season-related changes in androgen levels.     

Estrogen induces premature luteal regression in rhesus monkeys during spontaneous menstrual cycles, but not in cycles driven by exogenous gonadotropin-releasing hormone

Administration of exogenous estradiol during the mid- to late luteal phase of the menstrual cycle results in premature regression of the corpus luteum. The present study was initiated to identify the site of action of estrogen as well as to determine why administration of estrogen during the early luteal phase of the menstrual cycle does not result in luteolysis. Based upon extant literature, we hypothesized that estrogen and progesterone synergize to promote premature luteal regression. We tested this hypothesis in intact, spontaneously cycling rhesus monkeys by inserting estradiol, progesterone, or estrogen plus progesterone capsules on days 2 through 6 of the luteal phase. Insertion of estrogen or progesterone capsules alone did not advance luteolysis compared with the effect of control empty implants (n = 3). In contrast, insertion of estrogen plus progesterone implants on days 2 through 6 of the luteal phase resulted in a significant lowering of serum progesterone concentrations, and menses was advanced 5-6 days compared with control cycles. On the basis of these findings in spontaneously cycling monkeys, we speculated that estrogen treatment causes luteal regression only in the presence of a progesterone-mediated decrease in LH pulse frequency. To test this hypothesis, we used rhesus monkeys whose endogenous gonadotropin secretion was abolished by either placement of radiofrequency lesions in the mediobasal hypothalamus or transection of the hypothalamic-pituitary stalk. Ovulatory menstrual cycles were restored by pulsatile administration of exogenous synthetic GnRH. Insertion of estradiol capsules during the luteal phase into animals whose gonadotropin pulse frequency was set at either one pulse per h or one pulse per 8 h failed to cause premature luteal regression (n = 4). These findings indicate that whereas estrogen promotes luteal regression in intact, spontaneous cycling rhesus monkeys, it does not do so in animals whose gonadotropin secretion is controlled by exogenous GnRH. On the basis of these observations, we conclude that the hypothalamus is a major site of action of estrogen in the initiation of luteal regression in macaques.     

Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation

This report describes the effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production and platelet function in humans. Subjects with advanced solid tumors received PEG-rHuMGDF daily for up to 10 days. There was no increase in circulating platelet count at doses of 0.03 or 0.1 microgram/kg/d by day 12 of study. At doses of 0.3 and 1.0 microgram/kg/d there was a threefold median increase (maximum 10-fold) in platelet count by day 16. The platelets produced in vivo in response to PEG-rHuMGDF showed unchanged aggregation and adenosine triphosphate (ATP)-release responses in in vitro assays. Tests included aggregation and release of ATP in response to adenosine diphosphate (ADP) (10, 5, 2.5, and 1.25 mumol/L), collagen (2 micrograms/mL), thrombin-receptor agonist peptide (TRAP, 10 mumol/L) and ristocetin (1.5 mg/mL). Administration of aspirin to an individual with platelet count of 1,771 x 10(3)/L resulted in the typical aspirin-induced ablation of the normal aggregation and ATP-release response to stimulation with arachidonic acid (0.5 mg/mL), collagen, and ADP (2.5 and 1.25 mumol/L). There was no change in the expression of the platelet-surface activation marker CD62P (P-selectin) nor induction of the fibrinogen binding site on glycoprotein IIb/IIIa as reported by the monoclonal antibody, D3GP3. An elevation of reticulated platelets was evident after 3 days of treatment with PEG-rHuMGDF and preceded the increase in circulating platelet count by 5 to 8 days; this reflected the production of new platelets in response to PEG-rHuMGDF. At later time points, the mean platelet volume (MPV) decreased in a manner inversely proportional to the platelet count. Levels of plasma glycocalicin, a measure of platelet turnover, rose 3 days after the initial increase in the peripheral platelet count. The level of plasma glycocalicin was proportional to the total platelet mass, suggesting that platelets generated in response to PEG-rHuMGDF were not more actively destroyed. Thus, the administration of PEG-rHuMGDF, to humans, increased the circulating platelet count and resulted in fully functional platelets, which showed no detectable increase in reactivity nor alteration in activation status.     

Development of an orthopedic surgery trauma patient handover checklist

Background

In surgery, preoperative handover of surgical trauma patients is a process that must be made as safe as possible. We sought to determine vital clinical information to be transferred between patient care teams and to develop a standardized handover checklist.

Methods

We conducted standardized small-group interviews about trauma patient handover. Based on this information, we created a questionnaire to gather perspectives from all Canadian Orthopaedic Association (COA) members about which topics they felt would be most important on a handover checklist. We analyzed the responses to develop a standardized handover checklist.

Results

Of the 1106 COA members, 247 responded to the questionnaire. The top 7 topics felt to be most important for achieving patient safety in the handover were comorbidities, diagnosis, readiness for the operating room, stability, associated injuries, history/mechanism of injury and outstanding issues. The expert recommendations were to have handover completed the same way every day, all appropriate radiographs available, adequate time, all appropriate laboratory work and more time to spend with patients with more severe illness.

Conclusion

Our main recommendations for safe handover are to use standardized checklists specific to the patient and site needs. We provide an example of a standardized checklist that should be used for preoperative handovers. To our knowledge, this is the first checklist for handover developed by a group of experts in orthopedic surgery, which is both manageable in length and simple to use.     

Concordance of the SHEA-IDSA severity classification for Clostridium difficile infection and the ATLAS bedside scoring system in hospitalized adult patients

Purpose

The Society for Healthcare Epidemiology of America and Infectious Diseases Society of America (SHEA-IDSA) guidelines for the treatment of Clostridium difficile infection (CDI) recommend initial treatment of CDI based on disease severity. This severity definition has not been validated or evaluated based on clinical outcomes. The ATLAS scoring system is a validated tool useful in predicting treatment response and mortality in CDI. The main purpose of this study is to evaluate the concordance of the ATLAS scoring system and the SHEA-IDSA staging for CDI severity.

Methods

This was a retrospective study which included hospitalized patients with confirmed CDI. Bivariate analyses compared baseline demographics and clinical information between patients with nonsevere and severe CDI based on the SHEA-IDSA criteria for CDI severity. Kappa scores were calculated to compare the concordance of the two scoring systems in defining CDI severity. Sensitivity and specificity of the ATLAS scoring system to determine CDI severity were calculated using the SHEA-IDSA criteria as the reference standard.

Results

Sixty-four patients met inclusion criteria. Of those, 62.5 % were classified as mild to moderate CDI, 25 % were severe, uncomplicated, and 12.5 % were severe, complicated based on SHEA-IDSA criteria. In the bivariate analyses, ATLAS score breakpoints of ≥4, ≥5, and ≥6 revealed moderate agreement with the SHEA-IDSA classification for severity. The sensitivities and specificities for ATLAS scores in predicting CDI severity ranged from 58.3 to 87.5, and 67.5–87.5 %, respectively.

Conclusion

The ATLAS score may be useful in evaluating CDI severity and determining drug therapy selection.     

Cannabinoids and the Microbiota–Gut–Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders

The endocannabinoid system (ECS) has emerged in recent years as a potential treatment target for alcohol use disorders (AUD). In particular, the nonpsychoactive cannabinoid cannabidiol (CBD) has shown preclinical promise in ameliorating numerous clinical symptoms of AUD. There are several proposed mechanism(s) through which cannabinoids (and CBD in particular) may confer beneficial effects in the context of AUD. First, CBD may directly impact specific brain mechanisms underlying AUD to influence alcohol consumption and the clinical features of AUD. Second, CBD may influence AUD symptoms through its actions across the digestive, immune, and central nervous systems, collectively known as the microbiota–gut–brain axis (MGBA). Notably, emerging work suggests that alcohol and cannabinoids exert opposing effects on the MGBA. Alcohol is linked to immune dysfunction (e.g., chronic systemic inflammation in the brain and periphery) as well as disturbances in gut microbial species (microbiota) and increased intestinal permeability. These MGBA disruptions have been associated with AUD symptoms such as craving and impaired cognitive control. Conversely, existing preclinical data suggest that cannabinoids may confer beneficial effects on the gastrointestinal and immune system, such as reducing intestinal permeability, regulating gut bacteria, and reducing inflammation. Thus, cannabinoids may exert AUD harm-reduction effects, at least in part, through their beneficial actions across the MGBA. This review will provide a brief introduction to the ECS and the MGBA, discuss the effects of cannabinoids (particularly CBD) and alcohol in the brain, gut, and immune system (i.e., across the MGBA), and put forth a theoretical framework to inform future research questions.