"Turning up the heat": role of neurotrophic batokines in the postnatal maturation and remodeling of brown adipose tissue in deer mice.

Activation of brown adipose tissue (BAT) thermogenesis impacts energy balance and must be tightly regulated. Several neurotrophic factors, expressed in BAT of adult laboratory rodents, have been implicated in remodeling the sympathetic neural network to enhance thermogenesis [e.g., nerve growth factor (NGF), neuregulin-4 (NRG4), and S100b]. Here, we compare, to our knowledge, for the first time, the relative roles of three neurotrophic "batokines" in establishing/remodeling innervation during postnatal development and adult cold stress. We used laboratory-reared Peromyscus maniculatus, which rely heavily on BAT-based thermogenesis for survival in the wild, beginning between postnatal days (P) 8 and 10. BAT sympathetic innervation was enhanced from P6 to P10, and exogenous NGF, NRG4, and S100b stimulated neurite outgrowth from P6 sympathetic neurons. Endogenous BAT protein stores and/or gene expression of NRG4, S100b, and calsyntenin-3ß (which may regulate S100b secretion) remained high and constant during development. However, endogenous NGF was low and ngf mRNA was undetectable. Conditioned media (CM) from cultured P10 BAT slices stimulated neurite outgrowth from sympathetic neurons in vitro, which was inhibited by antibodies against all three growth factors. P10 CM had significant amounts of secreted NRG4 and S100b protein, but not NGF. By contrast, BAT slices from cold-acclimated adults released significant amounts of all three factors relative to thermoneutral controls. These data suggest that although neurotrophic batokines regulate sympathetic innervation in vivo, their relative contributions differ depending on the life stage. They also provide novel insights into the regulation of BAT remodeling and BAT's secretory role, both of which are critical to our understanding of mammalian energy homeostasis.NEW & NOTEWORTHY In altricial Peromyscus mice, the developmental shift to endothermy accompanies the establishment of the brown adipose tissue sympathetic neural network. Cultured slices of neonatal BAT secreted high quantities of two predicted neurotrophic batokines: S100b and neuregulin-4, but surprisingly low levels of the classic neurotrophic factor, NGF. Despite low NGF, neonatal BAT-conditioned media was highly neurotrophic. Cold-exposed adults use all three factors to dramatically remodel BAT, suggesting that BAT-neuron communication is life-stage dependent.

Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity.

Interactions between the microbiota and distal gut are important for the maintenance of a healthy intestinal barrier; dysbiosis of intestinal microbial communities has emerged as a likely contributor to diseases that arise at the level of the mucosa. Intraepithelial lymphocytes (IELs) are positioned within the epithelial barrier, and in the small intestine they function to maintain epithelial homeostasis. We hypothesized that colon IELs promote epithelial barrier function through the expression of cytokines in response to interactions with commensal bacteria. Profiling of bacterial 16S ribosomal RNA revealed that candidate bacteria in the order Bacteroidales are sufficient to promote IEL presence in the colon that in turn produce interleukin-6 (IL-6) in a MyD88 (myeloid differentiation primary response 88)-dependent manner. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6-/- mice were noted to have increased paracellular permeability, decreased claudin-1 expression, and a thinner mucus gel layer, all of which were reversed by transfer of IL-6+/+ IELs, leading to protection of mice in response to Citrobacter rodentium infection. Therefore, we conclude that microbiota provide a homeostatic role for epithelial barrier function through regulation of IEL-derived IL-6.

Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection.

HIV-1-associated disruption of intestinal homeostasis is a major factor contributing to chronic immune activation and inflammation. Dendritic cells (DCs) are crucial in maintaining intestinal homeostasis, but the impact of HIV-1 infection on intestinal DC number and function has not been extensively studied. We compared the frequency and activation/maturation status of colonic myeloid DC (mDC) subsets (CD1c(+) and CD1c(neg)) and plasmacytoid DCs in untreated HIV-1-infected subjects with uninfected controls. Colonic mDCs in HIV-1-infected subjects had increased CD40 but decreased CD83 expression, and CD40 expression on CD1c(+) mDCs positively correlated with mucosal HIV-1 viral load, with mucosal and systemic cytokine production, and with frequencies of activated colon and blood T cells. Percentage of CD83(+)CD1c(+) mDCs negatively correlated with frequencies of interferon-γ-producing colon CD4(+) and CD8(+) T cells. CD40 expression on CD1c(+) mDCs positively associated with abundance of high prevalence mucosal Prevotella copri and Prevotella stercorea but negatively associated with a number of low prevalence mucosal species, including Rumminococcus bromii. CD1c(+) mDC cytokine production was greater in response to in vitro stimulation with Prevotella species relative to R. bromii. These findings suggest that, during HIV infection, colonic mDCs become activated upon exposure to mucosal pathobiont bacteria leading to mucosal and systemic immune activation.

Internal Jugular Vein Height and Inferior Vena Cava Diameter Measurement using Ultrasound to Determine Central Venous Pressure: A Correlation Study.

OBJECTIVE: To determine the correlation between central venous pressure (CVP) measured by conventional central venous access and ultrasonographic measurement of internal jugular vein (IJV) height and inferior vena cava (IVC) diameter. METHODS: A prospective, cross-sectional, convenience sampling observational study. RESULTS: 25 patients from the Emergency Department (ED) Universiti Kebangsaan Malaysia Medical Centre (UKMMC) were studied between 1st March and 30th April 2013. The median age was 63 years (95% CI 54-67). There was a significant correlation between IJV height and CVP using central venous access (r=0.64 p<0.001). Correlation between IVC diameter in end expiration and CVP was 0.74 (p<0.001). An IJV height measurement >8cm predicted a CVP >8cm H2O (sensitivity 71.4%, specificity of 83.3%). CONCLUSION: Measurement of IJV height and IVC diameter by ultrasonography correlates well with invasive CVP and is useful for the assessment of volume status in critically ill patients in the ED.

An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia.

Human immunodeficiency virus-1 (HIV-1) infection disrupts the intestinal immune system, leading to microbial translocation and systemic immune activation. We investigated the impact of HIV-1 infection on the intestinal microbiome and its association with mucosal T-cell and dendritic cell (DC) frequency and activation, as well as with levels of systemic T-cell activation, inflammation, and microbial translocation. Bacterial 16S ribosomal DNA sequencing was performed on colon biopsies and fecal samples from subjects with chronic, untreated HIV-1 infection and uninfected control subjects. Colon biopsies of HIV-1-infected subjects had increased abundances of Proteobacteria and decreased abundances of Firmicutes compared with uninfected donors. Furthermore at the genus level, a significant increase in Prevotella and decrease in Bacteroides was observed in HIV-1-infected subjects, indicating a disruption in the Bacteroidetes bacterial community structure. This HIV-1-associated increase in Prevotella abundance was associated with increased numbers of activated colonic T cells and myeloid DCs. Principal coordinates analysis demonstrated an HIV-1-related change in the microbiome that was associated with increased mucosal cellular immune activation, microbial translocation, and blood T-cell activation. These observations suggest that an important relationship exists between altered mucosal bacterial communities and intestinal inflammation during chronic HIV-1 infection.

Clinically suspected fibrocartilaginous embolism: clinical characteristics, treatments, and outcomes.

OBJECTIVE: To study the frequency, demographics, clinical characteristics, and outcomes of patients with an antemortem diagnosis of fibrocartilaginous embolism (FCE), a rare cause of spinal cord and cerebral infarction because of the presumed embolization of nucleus pulposus material into the vascular circulation. METHODS: We retrospectively reviewed the institutional experience of patients who received an antemortem diagnosis of FCE by their treating physician at the Mayo Clinic (Rochester, MN, USA) from 1997 to 2009. All patients underwent laboratory, radiological, and clinical exclusion of other possible and related diagnoses. RESULTS: Of 164 patients with acute spinal cord infarction seen during the study timeframe, 9 (5.5%; 95% CI 2.5, 10.2%) met inclusion criteria for high likelihood of FCE (6 men, 3 women; median age 46 years old, range 21-64). All patients were severely affected (median modified Rankin Scale 4, median Barthel index 45; mean time to evaluation 57 days). One patient (1/9) experienced concomitant cerebral infarction. No patients had noticeable improvement from steroid treatment. CONCLUSION: The diagnosis of FCE in life is common at this referral center, accounting for 5.5% of all cases of acute spinal cord infarction seen. Although FCE is a postmortem diagnosis, we propose clinical criteria for FCE in life to better characterize the relatively high number of patients with unexplained ischaemic myelopathy.

Therapeutic hypothermia in the emergency department following out-of-hospital cardiac arrest.

Out-of-hospital cardiac arrest (OHCA) is a leading cause of mortality and severe neurological disability. Recent literature suggests that mild therapeutic hypothermia (MTH) can improve survival and neurological outcome in some groups of comatose patients after cardiac arrest but uncertainty exists over the best way to implement this treatment. This review examines the evidence for the efficacy and mode of implementation of MTH after OHCA, particularly in the Emergency Department setting. A literature search was performed and all systematic reviews; human and animal randomised and non-randomised trials were screened for inclusion. Specific emphasis was placed on MTH being commenced in the prehospital and Emergency Department setting. Outcome measures were: time to reach target temperature, in-hospital mortality, neurological outcome at hospital discharge and complications of therapeutic hypothermia. Two systematic reviews found that MTH improved outcome after OHCA. Five human randomised controlled trials were identified. Two trials commenced cooling prehospital. One showed a favourable outcome but the other failed to show survival benefit. The other three trials only commenced cooling after the patient arrived in hospital and all showed improved survival for patients treated with MTH after OHCA. Evidence from animal and non-randomised studies suggests cooling should be commenced as early as possible after return of spontaneous circulation. Cold intravenous fluid was reported as a safe, effective means of cooling in the emergency setting. MTH improves patient outcome after OHCA. There is some evidence to suggest cooling should be commenced early. Cold intravenous crystalloid infusion may be the preferred cooling method in the Emergency Department.

Esophageal temperature after out-of-hospital cardiac arrest: an observational study.

INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) is a significant cause of death and severe neurological disability. The only post-return of spontaneous circulation (ROSC) therapy shown to increase survival is mild therapeutic hypothermia (MTH). The relationship between esophageal temperature post OHCA and outcome is still poorly defined. METHODS: Prospective observational study of all OHCA patients admitted to a single centre for a 14-month period (1/08/2008 to 31/09/2009). Esophageal temperature was measured in the Emergency Department and Intensive Care Unit (ICU). Selected patients had pre-hospital temperature monitoring. Time taken to reach target temperature after ROSC was recorded, together with time to admission to the Emergency Department and ICU. RESULTS: 164 OHCA patients were included in the study. 105 (64.0%) were pronounced dead in the Emergency Department. 59 (36.0%) were admitted to ICU for cooling; 40 (24.4%) died in ICU and 19 (11.6%) survived to hospital discharge. Patients who achieved ROSC and had esophageal temperature measured pre-hospital (n=29) had a mean pre-hospital temperature of 33.9 degrees C (95% CI 33.2-34.5). All patients arriving in the ED post OHCA had a relatively low esophageal temperature (34.3 degrees C, 95% CI 34.1-34.6). Patients surviving to hospital discharge were warmer on admission to ICU than patients who died in hospital (35.7 degrees C vs 34.3 degrees C, p<0.05). Patients surviving to hospital discharge also took longer to reach T(targ) than non-survivors (2h 48min vs 1h 32min, p<0.05). CONCLUSIONS: Following OHCA all patients have esophageal temperatures below normal in the pre-hospital phase and on arrival in the Emergency Department. Patients who achieve ROSC following OHCA and survive to hospital discharge are warmer on arrival in ICU and take longer to reach target MTH temperatures compared to patients who die in hospital. The mechanisms of action underlying esophageal temperature and survival from OHCA remain unclear and further research is warranted to clarify this relationship.

Shock outcome prediction before and after CPR: a comparative study of manual and automated active compression-decompression CPR.

We report on a study designed to compare the relative efficacy of manual CPR (M-CPR) and automated mechanical CPR (ACD-CPR) provided by an active compression-decompression (ACD) device. The ECG signals of out-of-hospital cardiac arrest patients of cardiac aetiology were analysed just prior to, and immediately after, cardiopulmonary resuscitation (CPR) to assess the likelihood of successful defibrillation at these time points. The cardioversion outcome prediction (COP) measure previously developed by our group was used to quantify the probability of return of spontaneous circulation (ROSC) after counter-shock and was used as a measure of the efficacy of CPR. An initial validation study using COP to predict shock outcome from the patient data set resulted in a performance of 60% specificity achieved at 100% sensitivity on a blind test of the data. This is comparable with previous studies and provided confidence in the robustness of the technique across hardware platforms. Significantly, the COP marker also displayed an ability to stratify according to outcomes: asystole, ventricular fibrillation (VF), pulseless electrical activity (PEA), normal sinus rhythm (NSR). We then used the validated COP marker to analyse the ECG data record just prior to and immediately after the chest compression segments. This was initially performed for 87 CPR segments where VF was both the pre- and post-CPR waveform. An increase in the mean COP values was found for both CPR types. A signed rank sum test found the increase due to manual CPR not to be significant (p>0.05) whereas the automated CPR was found to be significant (p<0.05). This increase was larger for the automated CPR (1.26, p=0.024) than for the manual CPR (0.99, p=0.124). These results indicate that the application of CPR does indeed provide beneficial preparation of the heart prior to defibrillation therapy whether manual or automated CPR is applied. The COP marker shows promise as a definitive, quantitative determinant of the immediate positive effect of both types of CPR regardless of the details of use. In work of a more exploratory nature we then used the validated COP marker to analyse the ECG pre- and post-CPR for all rhythm types (212 traces). We show a significant increase in the COP measure (p<0.001 in both cases) as indicated by a shift in the median COP marker distribution values. This increase was more pronounced for automated ACD-CPR than for manual CPR. However, a detailed statistical analysis carried out between the groups adjusted for pre-CPR value showed no significant difference between the two methods of CPR (p=0.20). Similarly, adjusting for length of CPR showed no significant difference between the groups. Secondary, subgroup analysis of the ECG according to the length of time for which CPR was performed showed that both types of CPR led to an increase in the likelihood of successful defibrillation after increasing durations of CPR, however results were less reliable after longer periods of continuous CPR.

Practical issues in the evaluation of methods for the prediction of shock outcome success in out-of-hospital cardiac arrest patients.

There is a need for robust, effective predictors of the outcome from shock for out-of-hospital cardiac arrest patients. Such technology would enable the emergency responder to provide a therapy tailored to the patient's needs. Here we report our most recent findings while dwelling intentionally on the rationale behind the decisions taken during system development. Specifically, we illustrate the need for sensible data selection, fully cross-validated results and the care necessary when evaluating system performance. We analyze 878 pre-shock ECG traces, all of at least 10 s duration from 110 patients with cardiac arrest of cardiac aetiology. The continuous wavelet transform was applied to preshock segments of ECG trace. Time-frequency markers are extracted from the transform and a linear threshold derived from a training set to provide high sensitivity prediction of successful defibrillation. These systems are then evaluated on a withheld test set. All experiments are cross-validated. When compared to popular Fourier-based techniques our wavelet transform method, COP (Cardioversion Outcome Predictor), provides a 10-20% improvement in performance with values of 66 +/- 4 specificity at 95 +/- 4 sensitivity, 61 +/- 4 specificity at 97 +/- 2 sensitivity and 56 +/- 1 specificity at 98 +/- 2 sensitivity achieved for datasets limited to 3, 6, and 9 shocks per patient, respectively. Thus, the assessment of the wavelet marker was associated with a high specificity value at or above 95% sensitivity in comparison to previously reported methods. Therefore, COP could provide an optimal index for the identification of patients for whom shocking would be futile, and for whom an alternative therapy could be considered.

An audit of clinical practice in the management of head injured patients following the introduction of the Scottish Intercollegiate Guidelines Network (SIGN) recommendations.

A prospective study was conducted by the Scottish Trauma Audit Group (STAG) in A&E of Edinburgh Royal Infirmary to examine clinical practices in the management of head injured patients pre- and post-inception of the SIGN guidelines published in August 2000.1607 patients attended the department in two separate one month periods at equal intervals pre- and post-guidelines publication. The majority of patients with a SIGN indication for admission were admitted (93% pre- and 92% post-guidelines). For skull x ray (SXR) requests, in the pre-guidelines group, 92% of admitted patients with a SIGN indication for x ray had a SXR: this figure dropped to 79% post-guidelines. 36% of patients with a SIGN indication for CT actually had a scan pre-guidelines: this figure increased to 64% post-guidelines.57% of patients pre-guidelines and 44% of patients post-guidelines were discharged from A&E in accordance with the SIGN recommendations. Of patients admitted for neurological observations, this increased from 50% pre- to 88% post-guidelines. Of patients who were discharged "inappropriately", only one re-presented and was subsequently admitted but required no neurosurgical intervention. Despite publication of the SIGN guidelines and positive reinforcement in A&E and at ward level, practice has not changed significantly. Where our practice did not adhere to SIGN recommendations, there was no untoward sequelae. For published national guidelines to be effective, a formal audit structure with regular feedback is necessary to ensure a continued change in clinical practices.

Prospective audit of 106 consecutive human bite injuries: the importance of history taking.

OBJECTIVES: Some patients attempt to conceal human bites with factitious mechanisms of injury. Follow up questioning allows patients to modify their histories. This practice was prospectively audited. METHODS: Patients with cutaneous wounds who did not present with a history of human bite were asked a follow up question. Those who then gave a history of human bite were noted. RESULTS: Certain groups of patients with human bites were significantly more likely to provide a factitious history and/or delay presentation. CONCLUSION: Follow up questioning dramatically increased the case-detection rate, prompting specific management.

Thrombolysis and its implications in the management of stroke in the accident and emergency department.

OBJECTIVES: Examination of initial management of stroke patients in the emergency setting to assess feasibility of thrombolysis for acute ischaemic stroke. METHODS: Retrospective analysis of all patients presenting with a clinical diagnosis of stroke over a two month period. Exclusion criteria for thrombolysis were applied to assess the number of patients that would potentially have been eligible for thrombolysis. RESULTS: Of 94 patients identified with clinical stroke, only 57 (60.6%) had a CT scan; 23 (24.4%) were confirmed as having had an acute ischaemic stroke. Mean delay in scanning was 2.2 days (range 0-15 days). Even if all patients had presented and been scanned within three hours (as required for thrombolysis), only six (6.4%) patients would have been eligible for thrombolysis. CONCLUSIONS: The great majority of patients presenting with clinical stroke do not fulfill the criteria for thrombolysis. Current practice involves significant delays in CT scanning, which has implications for resource structuring should thrombolysis become widely available.

Paramedic activities, drug administration and survival from out of hospital cardiac arrest.

OBJECTIVE: To examine the impact of administration of cardioactive drugs on the outcome from out of hospital cardiac arrest. DESIGN: Longitudinal observational cohort study with historical controls before and after the introduction of drug use in cardiac arrest by paramedics. SUBJECTS: Adult patients who had sustained an out of hospital cardiac arrest of cardiac aetiology and were treated by paramedics. SETTING: Edinburgh, Scotland. OUTCOME MEASURES: Return of spontaneous circulation, admission to and discharge from hospital. RESULTS: There was no significant difference in the demographics between Period 1 (prior to drug administration) and Period 2 (after). There was no difference in outcome between Period 1 and Period 2 for all three parameters, return of spontaneous output 30.1 versus 35%, admission to hospital 18.9 versus 24.5% and discharge 5.8 versus 6.5%. If the presenting rhythm of VF/pulseless VT alone was considered survival to hospital discharge was 12.1% in Period 1 and 10.3% in Period 2. CONCLUSION: The addition of cardioactive drug administration to the treatment of out of hospital cardiac arrest does not improve survival.

A novel wavelet transform based analysis reveals hidden structure in ventricular fibrillation.

We report a new method of interrogating the surface ECG signal using techniques developed in the field of wavelet transform analysis. Previously unreported structure within the ECG during ventricular fibrillation (VF) is found using a high-resolution decomposition of the signal employing the continuous wavelet transform. We believe that wavelet transform methods could lead to the development of powerful tools for use in the resuscitation of patients with cardiac arrest.

Initial serum ferritin levels in patients with multiple trauma and the subsequent development of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) represents a catastrophic form of inflammatory lung injury that occurs unpredictably in some, but not all, at-risk patients. In this study, we investigated serum ferritin as a marker for ARDS development in a homogenous group of patients at-risk because of multiple trauma. We hypothesized that since ferritin synthesis is increased by proinflammatory cytokines, which are increased and implicated in ARDS, that ferritin levels would increase and that ferritin increases would correlate with the degree of inflammation and therefore the development of ARDS. We studied 42 patients (25 male, 17 female) who as a consequence of multiple trauma became at-risk for developing ARDS. Using the European/American Consensus definition for ARDS, 16 (38%) patients subsequently developed ARDS (11 male and five female). We found that initial serum ferritin levels correlated with the subsequent development of both ARDS (progression to ARDS, median = 638 ng/ml; (range, 70 to 4,500) versus nonprogression to ARDS = 185 ng/ml; range, 12 to 2,850) (p = 0.02, r = -0.27) and multiple organ failure (p < 0.05, r = 0.39). Using our previously established cutoff points for serum ferritin, the positive predictive value was 62% for men and 75% for women. Initial serum ferritin levels also correlated with a measurement of the degree of initial trauma injury, i.e., the injury severity score (ISS) (p < 0.05, r = 0.37). However, there was no correlation between serum ferritin levels and other markers of clinical injury, namely, lowest PaO2/FIO2 ratio (p = 0.67), days requiring ventilation (p = 0.09), or mortality (p = 0.42). A significant association existed between serum ferritin levels and products of endothelial activation, i.e., sE-selectin (p < 0.04, r = 0.37) and sICAM-1 (p < 0.01, r = 0.21). In the future, with the development of novel anti-inflammatory therapies, early identification of specific high-risk patients would allow the institution of these therapies and thereby increase the chances of reducing ARDS morbidity and mortality.

Advanced life support for out-of-hospital cardiac arrest--the changing role of a hospital-based flying squad.

The success of hospital-based flying squads in the management of out-of-hospital cardiac arrest has been well documented, but since the introduction of ambulance paramedics the need for such teams to deal with cardiac arrests has been questioned. We performed a 3-year retrospective study of non-traumatic arrests attended by Medic 1, the flying squad based at the Royal Infirmary of Edinburgh. There were 99 males and 46 females, mean age 57.6 years (range 17-86 years). Seventy-eight (53.9%) patients were pronounced dead at scene, 47 patients (32.4%) were admitted to hospital and 20 (13.7%) survived to hospital discharge. All but two of the survivors had return of spontaneous circulation prior to the arrival of Medic 1. Accident flying squads operating as a secondary response unit to victims of non-traumatic cardiac arrest are unlikely to have a significant effect upon overall survival.