The low grade oral infection chronic periodontitis (CP) has been implicated in coronary artery disease risk, but the mechanisms are unclear. Here, a pathophysiological role for blood dendritic cells (DCs) in systemic dissemination of oral mucosal pathogens to atherosclerotic plaques was investigated in humans. The frequency and microbiome of CD19−BDCA-1+DC-SIGN+ blood myeloid DCs (mDCs) were analyzed in CP subjects with, or without existing acute coronary syndrome (ACS) and in healthy controls (CTL). FACS analysis revealed a significant increase in blood mDCs in the following order: CTL
blood dendritic cells; Porphyromonas gingivalis; atherosclerosis; chronic periodontitis; acute coronary syndrome
The Institute of Medicine (IOM) has called for a new health care paradigm that integrates patient values into discussions of the risks and benefits of treatment. Although CVD affects one-third of Americans, little is known about how adults regard the potential harms or complications of treatment.
We sought to determine the preferences of community dwelling adults for 15 potential harms or complications resulting from treatment of cardiovascular disease (CVD).
In a telephone survey, adults over 18 years of age residing on Long Island, New York were asked to score the preferences for 15 potential harms or complications of treatment of CVD on a scale from 0 to 100. All statistical analyses were based on non-parametric methods. Multivariable general linear model analyses were performed to identify demographic factors associated with the score assigned for each adverse outcome.
The 807 individuals surveyed generated 723 unique sequences of scores for the 15 outcomes. The ranking of scores from least to most acceptable was stroke, major myocardial infarction (MI), cognitive dysfunction, renal failure, death, prolonged ventilator support, heart failure, angina, sternal wound infection, major bleeding, re-operation, prolonged recovery in a nursing home, cardiac readmission, minor MI and percutaneous coronary intervention. Demographic factors accounted for less than 7% of the observed variation in the score attributed to each outcome.
Individual community-dwelling adults living on Long Island, New York assign unique values to their preferences for potential harms encountered following treatment of CVD. Thus, risk-benefit discussions and treatment decisions regarding CVD should be harmonized to the value system of each individual.
The KCNQ2 gene product, Kv7.2, is a subunit of the M-channel, a low-threshold voltage-gated K+ channel that regulates mammalian and human neuronal excitability. Spontaneous mutations one of the KCNQ2 genes cause disorders of neural excitability such as Benign Familial Neonatal Seizures. However there appear to be no reports in which both human KCNQ2 genes are mutated. We therefore asked what happens to M-channel function when both KCNQ2 genes are disrupted. We addressed this using sympathetic neurons isolated from mice in which the KCNQ2 gene was truncated at a position corresponding to the second transmembrane domain of the Kv7.2 protein. Since homozygote KCNQ2−/− mice die postnatally, experiments were largely restricted to neurons from late embryos. Quantitative PCR revealed an absence of KCNQ2 mRNA in ganglia from KCNQ2−/− embryos but 100–120% increase of KCNQ3 and KCNQ5 mRNAs; KCNQ2+/− ganglia showed ∼30% less KCNQ2 mRNA than wild-type (+/+) ganglia but 40–50% more KCNQ3 and KCNQ5 mRNA. Neurons from KCNQ2−/− embryos showed a complete absence of M-current, even after applying the Kv7 channel enhancer, retigabine. Neurons from heterozygote KCNQ2+/− embryos had ∼60% reduced M-current. In contrast, M-currents in neurons from adult KCNQ2+/− mice were no smaller than those in neurons from wild-type mice. Measurements of tetraethylammonium block did not indicate an increased expression of Kv7.5-containing subunits, implying a compensatory increase in Kv7.2 expression from the remaining KCNQ2 gene. We conclude that mouse embryonic M-channels have an absolute requirement for Kv7.2 subunits for functionality, that the reduced M-channel activity in heterozygote KCNQ2+/− mouse embryos results primarily from a gene-dosage effect, and that there is a compensatory increase in Kv7.2 expression in adult mice.
The objective was to determine the association of four clinical risk scores and coronary plaque burden as detected by computed tomography (CT) with the outcome of acute coronary syndrome (ACS) in patients with acute chest pain. The hypothesis was that the combination of risk scores and plaque burden improved the discriminatory capacity for the diagnosis of ACS.
The study was a subanalysis of the Rule Out Myocardial Infarction Using Computer-Assisted Tomography (ROMICAT) trial—a prospective observational cohort study. The authors enrolled patients presenting to the emergency department (ED) with a chief complaint of acute chest pain, inconclusive initial evaluation (negative biomarkers, nondiagnostic electrocardiogram [ECG]), and no history of coronary artery disease (CAD). Patients underwent contrast-enhanced 64-multidetector-row cardiac CT and received standard clinical care (serial ECG, cardiac biomarkers, and subsequent diagnostic testing, such as exercise treadmill testing, nuclear stress perfusion imaging, and/or invasive coronary angiography), as deemed clinically appropriate. The clinical providers were blinded to CT results. The chest pain score was calculated and the results were dichotomized to ≥10 (high-risk) and <10 (low-risk). Three risk scores were calculated, Goldman, Sanchis, and Thrombolysis in Myocardial Infarction (TIMI), and each patient was assigned to a low-, intermediate-, or high-risk category. Because of the low number of subjects in the high-risk group, the intermediate- and high-risk groups were combined into one. CT images were evaluated for the presence of plaque in 17 coronary segments. Plaque burden was stratified into none, intermediate, and high (zero, one to four, and more than four segments with plaque). An outcome panel of two physicians (blinded to CT findings) established the primary outcome of ACS (defined as either an acute myocardial infarction or unstable angina) during the index hospitalization (from the presentation to the ED to the discharge from the hospital). Logistic regression modeling was performed to examine the association of risk scores and coronary plaque burden to the outcome of ACS. Unadjusted models were individually fitted for the coronary plaque burden and for Goldman, Sanchis, TIMI, and chest pain scores. In adjusted analyses, the authors tested whether the association between risk scores and ACS persisted after controlling for the coronary plaque burden. The prognostic discriminatory capacity of the risk scores and plaque burden for ACS was assessed using c-statistics. The differences in area under the receiver-operating characteristic curve (AUC) and c-statistics were tested by performing the −2 log likelihood ratio test of nested models. A p value <0.05 was considered statistically significant.
Among 368 subjects, 31 (8%) subjects were diagnosed with ACS. Goldman (AUC = 0.61), Sanchis (AUC = 0.71), and TIMI (AUC = 0.63) had modest discriminatory capacity for the diagnosis of ACS. Plaque burden was the strongest predictor of ACS (AUC = 0.86; p < 0.05 for all comparisons with individual risk scores). The combination of plaque burden and risk scores improved prediction of ACS (plaque + Goldman AUC = 0.88, plaque + Sanchis AUC = 0.90, plaque + TIMI AUC = 0.88; p < 0.01 for all comparisons with coronary plaque burden alone).
Risk scores (Goldman, Sanchis, TIMI) have modest discriminatory capacity and coronary plaque burden has good discriminatory capacity for the diagnosis of ACS in patients with acute chest pain. The combined information of risk scores and plaque burden significantly improves the discriminatory capacity for the diagnosis of ACS.
Cancer stem cells are responsible for tumor initiation and chemo-resistance. In ovarian cancer, the CD44+/MyD88+ ovarian cancer stem cells (OCSCs) are also able to repair the tumor and serve as tumor vascular progenitors. Targeting these cells is therefore necessary to improve treatment outcome and patient survival. The previous demonstration that the OCSCs are resistant to apoptotic cell death induced by conventional chemotherapy agents suggests that other forms of targeted therapy should be explored. We show in this study that targeting mitochondrial bioenergetics is a potent stimulus to induce caspase-independent cell death in a panel of OCSCs. Treatment of these cells with the novel isoflavone derivative, NV-128, significantly depressed mitochondrial function exhibited by decrease in ATP, Cox-I, and Cox-IV levels, and increase in mitochondrial superoxide and hydrogen peroxide. This promotes a state of “cellular starvation” that activates two independent pathways: 1) AMPKα1 pathway leading to mTOR inhibition; and 2) mitochondrial MEK/ERK pathway leading to loss of mitochondrial membrane potential. The demonstration that a compound can specifically target the mitochondria to induce cell death in this otherwise chemo-resistant cell population opens a new venue for treating ovarian cancer patients.
ovarian cancer stem cells; mitochondria; caspase-independent cell death
Sensory substitution devices (SSDs) aim to compensate for the loss of a sensory modality, typically vision, by converting information from the lost modality into stimuli in a remaining modality. “The vOICe” is a visual-to-auditory SSD which encodes images taken by a camera worn by the user into “soundscapes” such that experienced users can extract information about their surroundings. Here we investigated how much detail was resolvable during the early induction stages by testing the acuity of blindfolded sighted, naïve vOICe users. Initial performance was well above chance. Participants who took the test twice as a form of minimal training showed a marked improvement on the second test. Acuity was slightly but not significantly impaired when participants wore a camera and judged letter orientations “live”. A positive correlation was found between participants' musical training and their acuity. The relationship between auditory expertise via musical training and the lack of a relationship with visual imagery, suggests that early use of a SSD draws primarily on the mechanisms of the sensory modality being used rather than the one being substituted. If vision is lost, audition represents the sensory channel of highest bandwidth of those remaining. The level of acuity found here, and the fact it was achieved with very little experience in sensory substitution by naïve users is promising.
sensory substitution; blindness; acuity; synthetic synesthesia; visual; auditory
Myocardial injury is common among patients with intracerebral hemorrhage (ICH). However, it is challenging for emergency physicians to recognize acute myocardial injury in this population, as electrocardiographic (ECG) abnormalities are common in this setting. Our objective is to examine whether ischemic-appearing ECG changes predict subsequent myocardial injury in the context of ICH.
Consecutive patients with primary ICH presenting to a single academic center were prospectively enrolled. Electrocardiograms were retrospectively reviewed by 3 independent readers. Anatomical areas of ischemia were defined as I and aVL; II, III, and aVF; V1 to V4; and V5 and V6. Medical record review identified myocardial injury, defined as troponin I or T elevation (cutoff 1.5 and 0.1 ng/mL, respectively), within 30 days.
Between 1998 and 2004, 218 patients presented directly to our emergency department and did not have a do-not-resuscitate/do-not-intubate order; arrival ECGs and troponin levels were available for 206 patients. Ischemic-appearing changes were noted in 41% of patients, and myocardial injury was noted in 12% of patients. Ischemic-appearing changes were more common in patients with subsequent injury (64% vs 37%; P = .02). After multivariable analysis controlling for age and cardiac risk factors, ischemic-appearing ECG changes independently predicted myocardial injury (odds ratio, 3.2; 95% confidence interval, 1.3-8.2). In an exploratory analysis, ischemic-appearing ECG changes in leads I and aVL as well as V5 and V6 were more specific for myocardial injury (P = .002 and P = .03, respectively).
In conclusion, although a range of ECG abnormalities can occur after ICH, the finding of ischemic-appearing changes in an anatomical distribution can help predict which patients are having true myocardial injury.
Airborne exposure to manganese (Mn) can result in neurologic effects. Stationary air sampling is the traditional technique to assess Mn exposure for communities, yet may not accurately reflect children’s personal exposure. The goal of the study was to characterize personal exposure to Mn and PM2.5 in a cohort of children ages 7–9 years residing near a ferromanganese refinery.
A subset of children living in non-smoking households ages 7–9 enrolled in the Marietta Community Actively Researching Exposure Study during March–June 2009 and 2010 were invited to participate. Blood and hair were collected and analyzed for Mn. Participants wore a PM2.5 sampler (Personal Modular Impactor) for 48 h. TWD was based on time spent at home and school and the distance of each from the refinery. Stationary outdoor air sampling was conducted 8 km from the refinery using a Harvard-type PM2.5 impactor. The relationship between personal Mn exposure and TWD was examined by multiple regression adjusting for stationary air Mn concentration, wind speed and direction, and precipitation.
Complete personal air sampling data were collected on 38 children. TWD ranged from 4.7 km to 28.5 km with a mean distance of 11.1 (4.7 sd) km. Mn concentration in personal air samples ranged from 1.5 ng/m3 to 54.5 ng/m3 (geometric mean, 8.1 ng/m3). TWD was a significant predictor of natural log personal air Mn concentration (lnMn) with an associated decrease of 0.075 lnMn for each km TWD (p<0.05, 95% CI −0.13 to −0.01). Personal Mn exposures were positively associated with stationary air Mn levels and inversely associated with wind speed. A child’s location (home and school) relative to the refinery is a significant predictor of personal Mn exposure. Wind speed is also an important contributor to personal Mn exposure.
Personal air sampling; Manganese; Particulate matter; Exposure; Air pollution; Children
IPEC-J2 cells are porcine intestinal columnar epithelial cells that were isolated from neonatal piglet mid-jejunum. This cell line forms polarized monolayers with high transepithelial electrical resistance when cultured on 0.4 μm pore-size filters. The cell line is unique in that it is derived from small intestinal tissue (compared to the common human colon-derived lines HT-29, T84, and Caco-2) and is not transformed (compared to the porcine small intestinal line, IPI-2I). Porcine intestinal epithelial cells more closely mimic human physiology than analogous rodent cell lines (e.g. IEC-6 or IEC-18), which is important in studies of zoonotic infections; in addition, they provide specificity to study porcine-derived infections. IPEC-J2 cells are increasingly being used in microbiological studies to examine the interactions of various animal and human pathogens, including Salmonella enterica and pathogenic Escherichia coli, with intestinal epithelial cells. The IPEC-J2 cell line has also been employed in some probiotic studies, in which the cells have been used as an initial screening tool for adhesiveness and anti-inflammatory properties of the potential probiotic microorganisms. The validity of these studies is not clear as follow-up studies to assess the efficacy of the probiotics in vivo have not been published to date. The aims of this review are to provide a comprehensive overview of the microbiological studies that have been conducted with IPEC-J2 cells and a reference guide of key cellular and immune markers that have been identified in this cell line that may prove to be useful in future studies.
IPEC-J2; porcine intestinal epithelial cell; cell line; Salmonella enterica; Escherichia coli
Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB2) receptors are expressed in the microglia in neurodegenerative disease models.
To explore the potential of CB2 agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB2-selective agonist, namely MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB2+/+ and CB2–/– mice. We hypothesize that the CB2 receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways.
We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB2-/- mice and was blocked by CB2 antagonists, suggesting that MDA7's action directly involves CB2 receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced Toll-like receptor and CB2 expression in the lumbar spinal cord, reduced levels of extracellular signal regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models.
Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae.
The biosynthesis of many vitamins and coenzymes has often proved difficult to elucidate due to a combination of low abundance and kinetic lability of the pathway intermediates. Through a serial reconstruction of the cobalamin (vitamin B12) pathway in E. coli, and by His-tagging the terminal enzyme in the reaction sequence, we have observed that many unstable intermediates can be isolated as tightly-bound enzyme-product complexes. Together, these approaches have been used to extract intermediates between precorrin-4 and hydrogenobyrinic acid in their free acid form and permitted the delineation of the overall reaction catalysed by CobL, including the formal elucidation of precorrin-7 as a metabolite. Furthermore, a substrate-carrier protein, CobE, has been identified, which can also be used to stabilize some of the transient metabolic intermediates and enhance their onward transformation. The tight association of pathway intermediates with enzymes provides evidence for a form of metabolite channeling.
It is known that mumps virus (MuV) strains may vary in their neurovirulent capacity, and certain MuV strains may be highly neurotropic. In animal models and epidemiological studies, mutations at specific amino acids (aa) have been proposed to be associated with neurovirulence. To assess whether these genetic variations can be observed in clinical samples from patients and if they correlate with neurovirulence as determined by clinical symptoms, 39 mumps patients with or without neurological symptoms were investigated.
Respiratory samples, oral fluids, throat swabs, and neurological and cerebrospinal fluid samples were tested by RT-PCR and products sequenced. Sequences of the entire small hydrophobic (SH) gene and the partial hemagglutinin-neuraminidase (HN) gene were compared.
The results showed there was no significant difference between the samples of the two groups of patients at the aa sites in either the HN protein or the SH protein, which have previously been hypothesized to be associated with neurovirulence or antigenicity. The occurrence of neurological symptoms of mumps does not appear to be due to a single point mutation in either the HN or SH gene.
Skin keratinocytes fulfil important signalling and protective functions. Immunocytochemical experiments revealed the unexpected presence of immunoreactivity for the M-type potassium channel subunit Kv7.2 in the keratinocyte layer of intact rat paw skin and in keratinocytes isolated from the skin of 1-day-old rats and cultured in vitro for 3–10 days. Application of the M-channel enhancer retigabine (3–10 μM) to isolated cultured rat keratinocytes: (a) increased outward membrane currents recorded under voltage clamp, (b) produced ~3 mV hyperpolarization at rest, (c) enhanced ~3-fold the release of ATP induced by the TRPV3 agonist carvacrol (1 mM) and (d) increased the amplitude of the carvacrol-induced intracellular Ca2+ transient measured with Fura-2. The effect of retigabine on ATP release was prevented by the M-channel blocking agent XE991. We conclude that rat skin keratinocytes possess M-channels that, when activated, can modify their physiological properties, with potential significance for their sensory and other biological functions.
Electronic supplementary material
The online version of this article (doi:10.1007/s00424-013-1276-2) contains supplementary material, which is available to authorized users.
Potassium channels; Keratinocytes; ATP release; Immunocytochemistry; Membrane currents; Calcium
To gain insights into individual variations in acute inflammation and physiology.
Large-animal study combined with mathematical modeling.
Academic large-animal and computational laboratories.
Outbred juvenile swine.
Four swine were instrumented and subjected to endotoxemia (100 μg/kg), followed by serial plasma sampling.
Measurements and Main Results
Swine exhibited various degrees of inflammation and acute lung injury (ALI), including one death with severe ALI (P/F ratio <200 and static compliance <10 L/cmH2O). Plasma interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, high mobility group box-1 (HMGB1), and NO2−/NO3−,, were significantly (p <0.05) elevated over the course of the experiment. Principal Component Analysis (PCA) was used to suggest principal drivers of inflammation. Based in part on PCA, an Ordinary Differential Equation (ODE) model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces TNF-αin monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of HMGB1, which in turn stimulates the release of IL-1βfrom resident macrophages. The ODE model also included blood pressure, PaO2, and FiO2, and a damage variable that summarizes the health of the animal. This ODE model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the Oxygen Index in 3 of the 4 swine.
The approach described herein may aid in predicting inflammation and physiological dysfunction in small cohorts of subjects with diverse phenotypes and outcomes.
Endotoxemia; Sepsis; Swine; Inflammation; Models; Theoretical; Systems Biology
BACKGROUND AND PURPOSE
Organized systems of care have the potential to improve acute stroke care delivery. The current report describes the experience of implementing a countywide system of spoke-and-hub Stroke Neurology Receiving Centers (SNRC) that incorporated several comprehensive stroke center recommendations.
Observational study of patients with suspected stroke <5 hours duration transported by Emergency Medical System personnel to an SNRC during the first year of this system.
A total of 1,360 patients with suspected stroke were evaluated at 9 hub SNRCs, of which 553 (40.7%) had a discharge diagnosis of ischemic stroke. Of these 553, intravenous (IV) tPA was given to 110 patients (19.9% of ischemic strokes). Care at the 6 neurointerventional-ready SNRC was a major focus, where 25.1% (99/395) of the patients with ischemic stroke received acute IV or intraarterial reperfusion therapy, and where provision of such therapies was less common with milder stroke, higher age, and Hispanic origin. The door-to-needle time for IV tPA met the <60 minute target in only 25% of patients and was 37% longer (p=0.0001) when SNRCs were neurointerventional-ready.
A stroke system that incorporates features of comprehensive stroke centers can be effectively implemented, and with substantial rates of acute reperfusion therapy administration. Experiences potentially useful to broader implementation of comprehensive stroke centers are considered.
Acute Care; Stroke Centers; pre-hospital systems
The scientific review of the application leading to the approval, in the European Union, of cabazitaxel for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen is summarized.
After completing this course, the reader will be able to:
Summarize the efficacy outcomes of cabazitaxel pivotal trials in the treatment of hormone-refractory metastatic prostate cancer.Describe the safety profile and most common adverse effects of cabazitaxel in patients with hormone-refractory metastatic prostate cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
On March 17, 2011 the European Commission issued a marketing authorization valid throughout the European Union for Jevtana® (Sanofi-Aventis, Paris, France) for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.
The active substance of Jevtana® is cabazitaxel acetone solvate, an antineoplastic agent that acts by disrupting the microtubular network in cells. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour i.v. infusion every 3 weeks in combination with oral prednisone or prednisolone, 10 mg, administered daily throughout treatment.
In the main study submitted for this application, a 2.4-month longer median overall survival time and a 30% lower risk for death were observed for cabazitaxel, compared with mitoxantrone. The most common side effects with cabazitaxel were anemia, leukopenia, neutropenia, thrombocytopenia, and diarrhea.
This paper summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency Web site (http://www.ema.europa.eu).
Cabazitaxel; Jevtana; Hormone-refractory metastatic prostate cancer; EMA; European Medicines Agency
More than 500,000 deaths are attributed to rotavirus gastroenteritis annually worldwide, with the highest mortality in India. Two successive, naturally occurring rotavirus infections have been shown to confer complete protection against moderate or severe gastroenteritis during subsequent infections in a birth cohort in Mexico. We studied the protective effect of rotavirus infection on subsequent infection and disease in a birth cohort in India (where the efficacy of oral vaccines in general has been lower than expected).
We recruited children at birth in urban slums in Vellore; they were followed for 3 years after birth, with home visits twice weekly. Stool samples were collected every 2 weeks, as well as on alternate days during diarrheal episodes, and were tested by means of enzyme-linked immunosorbent assay and polymerase-chain-reaction assay. Serum samples were obtained every 6 months and evaluated for seroconversion, defined as an increase in the IgG antibody level by a factor of 4 or in the IgA antibody level by a factor of 3.
Of 452 recruited children, 373 completed 3 years of follow-up. Rotavirus infection generally occurred early in life, with 56% of children infected by 6 months of age. Levels of reinfection were high, with only approximately 30% of all infections identified being primary. Protection against moderate or severe disease increased with the order of infection but was only 79% after three infections. With G1P, the most common viral strain, there was no evidence of homotypic protection.
Early infection and frequent reinfection in a locale with high viral diversity resulted in lower protection than has been reported elsewhere, providing a possible explanation why rotavirus vaccines have had lower-than-expected efficacy in Asia and Africa. (Funded by the Wellcome Trust.)
The American College of Emergency Physicians (ACEP) Task Force on Boarding described high-impact initiatives to decrease crowding. Furthermore, some emergency departments (EDs) have implemented a novel initiative we term “vertical patient flow,” i.e. segmenting patients who can be safely evaluated, managed, admitted or discharged without occupying a traditional ED room. We sought to determine the degree that ACEP-identified high-impact initiatives for ED crowding and vertical patient flow have been implemented in academic EDs in the United States (U.S.).
We surveyed the physician leadership of all U.S. academic EDs from March to May 2010 using a 2-minute online survey. Academic ED was defined by the primary site of an emergency residency program.
We had a response rate of 73% (106/145) and a completion rate of 71% (103/145). The most prevalent hospital-based initiative was inpatient discharge coordination (46% [47/103] of respondents) while the least fully initiated was surgical schedule smoothing (11% [11/103]). The most prevalent ED-based initiative was fast track (79% [81/103]) while the least initiated was physician triage (12% [12/103]). Vertical patient flow had been implemented in 29% (30/103) of responding EDs while an additional 41% (42/103) reported partial/in progress implementation.
We found great variability in the extent academic EDs have implemented ACEP’s established high-impact ED crowding initiatives, yet most (70%) have adopted to some extent the novel initiative vertical patient flow. Future studies should examine barriers to implementing these crowding initiatives and how they affect outcomes such as patient safety, ED throughput and patient/provider satisfaction.
The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1−/−) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1−/− mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1−/− mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.
Many patients with childhood-onset growth hormone (GH) deficiency do not fulfill diagnostic criteria for GH deficiency (GHD) after attainment of adult height and may not require long-term GH treatment. Patients with history of idiopathic GHD (IGHD) pose the greatest management dilemma, as data regarding factors predictive of persistent GHD in this group are lacking.
The objective of this study was to assess potential predictors of persistent GHD in a US patient cohort during transition from childhood to adulthood, particularly in patients with history of IGHD.
We studied 73 US patients with history of childhood-onset GHD screened at 21 US pediatric endocrine centers for a randomized clinical trial of GH replacement after attainment of adult height. The cohort comprised 42 boys/men and 31 girls/women aged14–22 years, who had received ≥1 year of GH treatment and had completed linear growth. The main outcome measures were sensitivity, specificity, positive and negative predictive values (PPV, NPV) of clinical and hormonal factors for persistent GHD (defined a priori in this study as peak GH < 5 μg/L).
For the cohort as a whole, the best predictors of persistent GHD (100% PPV) were history of organic hypothalamic-pituitary disorder or ≥2 additional pituitary hormone deficiencies (PHD). Best predictors of persistent GHD in patients with childhood history of IGHD were standard deviation scores (SDS) for serum insulin-like growth factor binding protein-3 (IGFBP-3) below -2.0, and for insulin-like growth factor-I (IGF-I) below -5.3 (measured ≥6 weeks after completion of GH treatment; PPV 100% for both), and age <4 years at original diagnosis (PPV 89%). IGF-I above -1.6 SDS had 100% NPV.
US patients with an organic cause of childhood-onset GHD or ≥2 additional PHDs may not require GH stimulation testing to reconfirm GHD after completion of childhood treatment. In contrast, patients with idiopathic childhood-onset GHD almost invariably require retesting, as GHD persists in only a minority (those who were very young at initial diagnosis and those who have subnormal IGFBP-3 or extremely low IGF-I after completion of childhood treatment). Subnormal posttreatment IGF-I (<-2.0 SDS) lacked predictive power for persistent GHD, whereas IGF-I > -1.6 SDS was 100% predictive of GH sufficiency.
Transition; Growth hormone deficiency; Hypopituitarism; Predictive value of tests; Child; Adolescent; Adult; Idiopathic
High serum levels of macrophage inhibitory cytokine 1 (MIC-1) are strongly associated with metastatic prostate cancer, suggesting MIC-1 is a biomarker for prostate cancer prognosis.
We conducted a prospective cohort study of 1,442 Swedish men with a pathologically verified diagnosis of prostate cancer between 2001 and 2003. Blood was drawn either pretreatment (n = 431) or posttreatment (n = 1,011) and cases were followed for a mean time of 4.9 years (range, 0.1–6.8 years).
MIC-1 serum levels independently predicted poor cancer-specific survival with an almost 3-fold higher cancer death rate in patients with serum levels in the highest quartile compared with men with serum levels in the lowest quartile (adjusted hazard ratio, 2.98; 95% confidence interval, 1.82–4.68). Pretreatment MIC-1 levels revealed an even stronger association with disease outcome with an 8-fold higher death rate in the highest compared with the lowest category (adjusted hazard ratio, 7.98; 95% confidence interval, 1.73–36.86). Among patients considered to have localized disease, MIC-1 significantly increased the discriminative capacity between indolent and lethal prostate cancer compared with the established prognostic markers clinical stage, pathologic grade, and prostate-specific antigen level (P = 0.016). A sequence variant in the MIC-1 gene was associated with decreased MIC-1 serum levels (P = 0.002) and decreased prostate cancer mortality (P = 0.003), suggesting a causative role of MIC-1 in prostate cancer prognosis.
Serum MIC-1 concentration is a novel biomarker capable of predicting prostate cancer prognosis.
All Kv7 potassium channels require membrane phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) for their normal function and hence can be physiologically regulated by neurotransmitters and hormones that stimulate phosphoinositide hydrolysis. Recent mutational analysis indicates that a cluster of basic residues in the proximal C-terminus (K354/K358/R360/K362) is crucial for PI(4,5)P2 activation of cardiac Kv7.1 channels. Since this cluster is largely conserved in all Kv7 subunits, we tested whether homologous residues are also required for activation of Kv7.2 (a subunit of neuronal M-channels). We found that the mutation Kv7.2 (R325A) (corresponding to R360 in Kv7.1) reduced Kv7.2 current amplitude by ∼60 % (P < 0.02) without change in voltage sensitivity and reduced the sensitivity of Kv7.2 channels to dioctanoyl-phosphatidylinositol-4,5-bisphosphate by ∼eightfold (P < 0.001). Taking into account previous experiments (Zhang et al., Neuron 37:963–75, 2003) implicating Kv7.2 (H328), and since R325 and H328 are conserved in homologous positions in all other Kv7 channels, we suggest that this proximal C-terminal domain adjacent to the last transmembrane domain that contains R325 and H328 (in Kv7.2) might play a major role in the activation of all members of the Kv7 channel family by PI(4,5)P2.
Potassium channels; Phosphatidylinositol-4,5-bisphosphate (PIP2); Membrane currents
Severe spinal cord injuries above mid-thoracic levels can lead to a potentially life-threatening hypertensive condition termed autonomic dysreflexia that is often triggered by painful distension of pelvic viscera (bladder or bowel) and consequent sensory fiber activation, including nociceptive C-fibers. Interruption of tonically active medullo-spinal pathways after injury causes disinhibition of thoracolumbar sympathetic preganglionic neurons, and intraspinal sprouting of nerve growth factor (NGF)-responsive primary afferent fibers is thought to contribute to their hyperactivity. We investigated spinal levels that are critical for eliciting autonomic dysreflexia using a model of noxious colorectal distension (CRD) after complete spinal transection at the 4th thoracic segment in rats. Post-traumatic sprouting of calcitonin gene-related peptide (CGRP)-immunoreactive primary afferent fibers was selectively altered at specific spinal levels caudal to the injury with bilateral microinjections of adenovirus encoding the growth-promoting NGF or growth-inhibitory semaphorin 3A (Sema3a) compared to control green fluorescent protein (GFP). Two weeks later, cardio-physiological responses to CRD were assessed among treatment groups prior to histological analysis of afferent fiber density at the injection sites. Dysreflexic hypertension was significantly higher with NGF over-expression in lumboscral segments compared to GFP, whereas similar over-expression of Sema3a significantly reduced noxious CRD-evoked hypertension. Quantitative analysis of CGRP immunostaining in the spinal dorsal horns showed a significant correlation between the extent of fiber sprouting into the spinal segments injected and the severity of autonomic dysreflexia. These results demonstrate that site-directed genetic manipulation of axon guidance molecules after complete spinal cord injury can alter endogenous circuitry in order to modulate plasticity-induced autonomic pathophysiology.
nerve growth factor; semaphorin 3A; sprouting; sympathetic; neurotrophin