Low-complexity hardware design methodology for reliable and automated removal of ocular and muscular artifact from EEG.
EEG is a non-invasive tool for neuro-developmental disorder diagnosis and treatment. However, EEG signal is mixed with other biological signals including Ocular and Muscular artifacts making it difficult to extract the diagnostic features. Therefore, the contaminated EEG channels are often discarded by the medical practitioners which may result in less accurate diagnosis. Many existing methods require reference electrodes, which will create discomfort to the patient/children and cause hindrance to the diagnosis of the neuro-developmental disorder and Brain Computer Interface in the pervasive environment. Therefore, it would be ideal if these artifacts can be removed real time on the hardware platform in an automated fashion and then the denoised EEG can be used for online diagnosis in a pervasive personalized healthcare environment without the need of any reference electrode. In this paper we propose a reliable, robust and automated methodology to solve the aforementioned problem. The proposed methodology is based on the Haar function based Wavelet decompositions with simple threshold based wavelet domain denoising and artifacts removal schemes. Subsequently hardware implementation results are also presented. 100 EEG data from Physionet, Klinik für Epileptologie, Universität Bonn, Germany, Caltech EEG databases and 7 EEG data from 3 subjects from University of Southampton, UK have been studied and nine exhaustive case studies comprising of real and simulated data have been formulated and tested. The proposed methodology is prototyped and validated using FPGA platform. Like existing literature, the performance of the proposed methodology is also measured in terms of correlation, regression and R-square statistics and the respective values lie above 80%, 79% and 65% with the gain in hardware complexity of 64.28% and improvement in hardware delay of 53.58% compared to state-of-the art approaches. Hardware design based on the proposed methodology consumes 75 micro-Watt power. The automated methodology proposed in this paper, unlike the state of the art methods, can remove blink and muscular artifacts real time without the need of any extra electrode. Its reliability and robustness is also established after exhaustive simulation study and analysis on both simulated and real data. We believe the proposed methodology would be useful in next generation personalized pervasive healthcare for Brain Computer Interface and neuro-developmental disorder diagnosis and treatment.


Attenuating the Systemic Inflammatory Response to Adult Cardiopulmonary Bypass: A Critical Review of the Evidence Base.
A wide range of pharmacological, surgical, and mechanical pump approaches have been studied to attenuate the systemic inflammatory response to cardiopulmonary bypass, yet no systematically based review exists to cover the scope of anti-inflammatory interventions deployed. We therefore conducted an evidence-based review to capture "self-identified" anti-inflammatory interventions among adult cardiopulmonary bypass procedures. To be included, trials had to measure at least one inflammatory mediator and one clinical outcome, specified in the "Outcomes 2010" consensus statement. Ninety-eight papers satisfied inclusion criteria and formed the basis of the review. The review identified 33 different interventions and approaches to attenuate the systemic inflammatory response. However, only a minority of papers (35 of 98 [35.7%]) demonstrated any clinical improvement to one or more of the predefined outcome measures (most frequently myocardial protection or length of intensive care unit stay). No single intervention was supported by strong level A evidence (multiple randomized controlled trials [RCTs] or meta-analysis) for clinical benefit. Interventions at level A evidence included off-pump surgery, minimized circuits, biocompatible circuit coatings, leukocyte filtration, complement C5 inhibition, preoperative aspirin, and corticosteroid prophylaxis. Interventions at level B evidence (single RCT) for minimizing inflammation included nitric oxide donors, C1 esterase inhibition, neutrophil elastase inhibition, propofol, propionyl-L-carnitine, and intensive insulin therapy. A secondary analysis revealed that suppression of at least one inflammatory marker was necessary but not sufficient to confer clinical benefit. The most effective interventions were those that targeted multiple inflammatory pathways. These observations are consistent with a "multiple hit" hypothesis, whereby clinically effective suppression of the systemic inflammatory response requires hitting multiple inflammatory targets simultaneously. Further research is warranted to evaluate if combinations of interventions that target multiple inflammatory pathways are capable of synergistically reducing inflammation and improving outcomes after cardiopulmonary bypass.


Substance abuse and the duty to protect.
The Tarasoff case provided some legal guidance for handling the situation where a patient threatens deliberate violence against an identifiable individual. But what about the situation where a patient's substance abuse impairs safe driving of a large commercial vehicle such as an airplane, clearly endangering a class of individuals (passengers)? Some legal restrictions on confidentiality, if followed literally, would not even permit the therapist to take preventive measures advocated by the Tarasoff court when deliberate violence is threatened, let alone more specific measures to prevent a tragic accident with loss of many lives. Review of literature on the relationship between alcohol and operator safety leads to the conclusion that therapists must have some latitude in which to exercise judgment free of professional liability. The dilemma posed by contrasting duties to maintain confidentiality and to make preventive disclosures is too rigid to govern all situations, especially a worsening risk of substance-induced accidents by drivers of public carriers.


Cardiac Magnetic Resonance Myocardial Feature Tracking for Optimized Risk Assessment After Acute Myocardial Infarction in Patients With Type 2 Diabetes.
Type 2 diabetes predicts outcome following acute myocardial infarction (AMI). Since underlying mechanics are incompletely understood, we investigated left ventricular (LV) and left atrial (LA) pathophysiological changes and their prognostic implications using cardiovascular magnetic resonance (CMR). Consecutive patients (N = 1,147; n = 265 with diabetes, n = 882 without diabetes) underwent CMR 3 days after AMI. Analyses included LV ejection fraction (LVEF); global longitudinal strain (GLS) and circumferential and radial strains; LA reservoir, conduit, and booster pump strains; and infarct size, edema, and microvascular obstruction. Predefined end points were major adverse cardiovascular events (MACE) within 12 months. Patients with diabetes had impaired LA reservoir (19.8% vs. 21.2%, P < 0.01) and conduit (7.6% vs. 9.0%, P < 0.01) strains but not ventricular function or myocardial damage. They were at higher risk of MACE than patients without diabetes (10.2% vs. 5.8%, P < 0.01), with most MACE occurring in patients with LVEF ≥35%. While LVEF (P = 0.045) and atrial reservoir strain (P = 0.024) were independent predictors of MACE in patients without diabetes, GLS was in patients with diabetes (P = 0.010). Considering patients with diabetes and LVEF ≥35% (n = 237), GLS and LA reservoir strain below median were significantly associated with MACE. In conclusion, in patients with diabetes, LA and LV longitudinal strain permit optimized risk assessment early after reperfused AMI with incremental prognostic value over and above that of LVEF.


Early Detection of Preterm Intraventricular Hemorrhage From Clinical Electroencephalography.
Intraventricular hemorrhage is a common neurologic complication of extremely preterm birth and leads to lifelong neurodevelopmental disabilities. Early bedside detection of intraventricular hemorrhage is crucial to enabling timely interventions. We sought to detect early markers of brain activity that preempt the occurrence of intraventricular hemorrhage in extremely preterm infants during the first postnatal days. Cross-sectional study. Level III neonatal ICU. Twenty-five extremely preterm infants (22-28 wk gestational age). We quantitatively assessed electroencephalography in the first 72 hours of postnatal life, focusing on the electrical burst activity of the preterm. Cranial ultrasound was performed on day 1 (0-24 hr) and day 3 (48-72 hr). Outcomes were categorized into three classes: 1) no intraventricular hemorrhage (grade 0); 2) mild-moderate intraventricular hemorrhage (grades 1-2, i.e., germinal matrix hemorrhages or intraventricular hemorrhage without ventricular dilatation, respectively); and 3) severe intraventricular hemorrhage (grades 3-4, i.e., intraventricular hemorrhage with ventricular dilatation or intraparenchymal involvement). Quantitative assessment of electroencephalography burst shapes was used to preempt the occurrence and severity of intraventricular hemorrhage as detected by ultrasound. The shapes of electroencephalography bursts found in the intraventricular hemorrhage infants were significantly sharper (F = 13.78; p < 0.0001) and less symmetric (F = 6.91; p < 0.015) than in preterm infants without intraventricular hemorrhage. Diagnostic discrimination of intraventricular hemorrhage infants using measures of burst symmetry and sharpness yielded high true-positive rates (82% and 88%, respectively) and low false-positive rates (19% and 8%). Conventional electroencephalography measures of interburst intervals and burst counts were not significantly associated with intraventricular hemorrhage. Detection of intraventricular hemorrhage during the first postnatal days is possible from bedside measures of brain activity prior to ultrasound confirmation of intraventricular hemorrhage. Significantly, our novel automated assessment of electroencephalography preempts the occurrence of intraventricular hemorrhage in the extremely preterm. Early bedside detection of intraventricular hemorrhage holds promise for advancing individual care, targeted therapeutic trials, and understanding mechanisms of brain injury in neonates.


Community-based care for the management of type 2 diabetes: an evidence-based analysis.
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry's newly released Diabetes Strategy.After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,DIABETES STRATEGY EVIDENCE PLATFORM: Summary of Evidence-Based AnalysesContinuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based AnalysisBehavioural Interventions for Type 2 Diabetes: An Evidence-Based AnalysisBARIATRIC SURGERY FOR PEOPLE WITH DIABETES AND MORBID OBESITY: An Evidence-Based SummaryCommunity-Based Care for the Management of Type 2 Diabetes: An Evidence-Based AnalysisHome Telemonitoring for Type 2 Diabetes: An Evidence-Based AnalysisApplication of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario The objective of this report is to determine the efficacy of specialized multidisciplinary community care for the management of type 2 diabetes compared to usual care. TARGET POPULATION AND CONDITION Diabetes (i.e. diabetes mellitus) is a highly prevalent chronic metabolic disorder that interferes with the body's ability to produce or effectively use insulin. The majority (90%) of diabetes patients have type 2 diabetes. (1) Based on the United Kingdom Prospective Diabetes Study (UKPDS), intensive blood glucose and blood pressure control significantly reduce the risk of microvascular and macrovascular complications in type 2 diabetics. While many studies have documented that patients often do not meet the glycemic control targets specified by national and international guidelines, factors associated with glycemic control are less well studied, one of which is the provider(s) of care. Multidisciplinary approaches to care may be particularly important for diabetes management. According guidelines from the Canadian Diabetes Association (CDA), the diabetes health care team should be multi-and interdisciplinary. Presently in Ontario, the core diabetes health care team consists of at least a family physician and/or diabetes specialist, and diabetes educators (registered nurse and registered dietician). Increasing the role played by allied health care professionals in diabetes care and their collaboration with physicians may represent a more cost-effective option for diabetes management. Several systematic reviews and meta-analyses have examined multidisciplinary care programs, but these have either been limited to a specific component of multidisciplinary care (e.g. intensified education programs), or were conducted as part of a broader disease management program, of which not all were multidisciplinary in nature. Most reviews also do not clearly define the intervention(s) of interest, making the evaluation of such multidisciplinary community programs challenging. What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a registered nurse, registered dietician and physician (primary care and/or specialist) for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 1]What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a pharmacist and a primary care physician for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 2] English language full-reportsPublished between January 1, 2000 and September 28, 2008Randomized controlled trials (RCTs), systematic reviews and meta-analysesType 2 diabetic adult population (≥18 years of age)Total sample size ≥30Describe specialized multidisciplinary community care defined as ambulatory-based care provided by at least two health care disciplines (of which at least one must be a specialist in diabetes) with integrated communication between the care providers.Compared to usual care (defined as health care provision by non-specialist(s) in diabetes, such as primary care providers; may include referral to other health care professionals/services as necessary)≥6 months follow-up Studies where discrete results on diabetes cannot be abstractedPredominantly home-based interventionsInpatient-based interventions The primary outcomes for this review were glycosylated hemoglobin (rHbA1c) levels and systolic blood pressure (SBP). A literature search was performed on September 28, 2008 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and September 28, 2008. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology. Given the high clinical heterogeneity of the articles that met the inclusion criteria, specific models of specialized multidisciplinary community care were examined based on models of care that are currently being supported in Ontario, models of care that were commonly reported in the literature, as well as suggestions from an Expert Advisory Panel Meeting held on January 21, 2009. The initial search yielded 2,116 unique citations, from which 22 RCTs trials and nine systematic reviews published were identified as meeting the eligibility criteria. Of these, five studies focused on care provided by at least a nurse, dietician, and physician (primary care and/or specialist) model of care (Model 1; see Table ES 1), while three studies focused on care provided by at least a pharmacist and primary care physician (Model 2; see Table ES 2). Based on moderate quality evidence, specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in HbA1c of 1.0% compared with usual care. The effects of this model on SBP, however, are uncertain compared with usual care, based on very-low quality evidence. Specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in both HbA1c of 1.05% (based on high quality evidence) and SBP of 7.13 mm Hg (based on moderate quality evidence) compared to usual care. For both models, the evidence does not suggest a preferred setting of care delivery (i.e., primary care vs. hospital outpatient clinic vs. community clinic). Table ES1:Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 1OutcomeEstimate of effect(95% CI)Heterogeneity I(2)(p-value)GRADEGlycosylated Hemoglobin (HbA1c [%])-1.00 [-1.27, -0.73]4% (p=0.37)Moderate-quality Subgroup: Moderate-to-High Quality-0.91 [-1.19, -0.62]0% (p=0.74)Systolic Blood Pressure (mm Hg)-2.04 [-13.80, 9.72]89% (p=0.002)Very-low quality*Mean change from baseline to follow-up between intervention and control groupsTable ES2:Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 2OutcomeEstimate of effect(95% CI)Heterogeneity I(2)(p-value)GRADEGlycosylated Hemoglobin (HbA1c [%])-1.05 [-1.57, -0.52]0% (p=0.75)High-qualitySystolic Blood Pressure (mm Hg)-7.13 [-11.78, -2.48]46% (p=0.17)Moderate quality*Mean change from baseline to follow-up between intervention and control groups.


Potential effects of low molecular weight phthalate esters (C16H22O4 and C12H14O4) on the freshwater fish Cyprinus carpio.
The aim of the present study is to assess the toxic effect of dibutyl phthalate (DBP) and diethyl phthalate (DEP) on the freshwater fish Cyprinus carpio. The median lethal concentrations of DBP and DEP for 96 h are found to be 35 and 53 mg L-1, respectively. Fish were exposed to 3.5 mg L-1 (Treatment I) and 1.75 mg L-1 (Treatment II) of DBP and 5.3 mg L-1 (Treatment I) and 2.65 mg L-1 (Treatment II) of DEP for a period of 35 days. The DBP and DEP exposed fish show a concentration based toxic effect on the selected parameters of this study. The hematological parameters, such as hemoglobin (Hb), hematocrit (Hct) and erythrocyte (RBC), were found to decrease in the DBP and DEP treated fish, whereas their leucocyte (WBC) count increased compared to that of the control groups. A biphasic response is noted in the erythrocyte indices, such as mean cellular volume (MCV), mean cellular hemoglobin (MCH) and mean cellular hemoglobin concentration (MCHC), throughout the study period. Exposure to DBP and DEP caused a significant (p < 0.05) decrease in sodium (Na+), potassium (K+), and chloride (Cl-) levels in the gill and brain of the fish throughout the study period when compared to that of their respective controls. The plasma protein level decreased in all the treatments, whereas the plasma glucose level significantly increased in the DBP and DEP exposed fish. Maximum inhibition of Na+/K+-ATPase activity was noticed in the gill and brain of the fish exposed to DBP and DEP. The cholinesterase (ChE) activity in the brain of the fish significantly decreased throughout the study period. A significant (p < 0.05) increase in glutamate oxaloacetate transaminase (GOT) and glutamic pyruvate transaminase (GPT) activity was noted in the fish exposed to both toxicants. The antioxidant enzymatic parameters such as superoxide dismutase (SOD) and catalase (CAT) activities were found to decrease in the gill and liver of the DBP and DEP treated fish, whereas a significant (p < 0.05) increase in lipid peroxidation (LPO) was observed. The above mentioned parameters could be used as potential biomarkers in clinical trials for the assessment of plasticizers. This study provides indispensable information towards future research on the effect of plasticizers on non-target organisms including humans.


The Pheno- and Genotypic Characterization of Porcine Escherichia coli Isolates.
Escherichia (E.) coli is the main causative pathogen of neonatal and post-weaning diarrhea and edema disease in swine production. There is a significant health concern due to an increasing number of human infections associated with food and/or environmental-borne pathogenic and multidrug-resistant E. coli worldwide. Monitoring the presence of pathogenic and antimicrobial-resistant E. coli isolates is essential for sustainable disease management in livestock and human medicine. A total of 102 E. coli isolates of diseased pigs were characterized by antimicrobial and biocide susceptibility testing. Antimicrobial resistance genes, including mobile colistin resistance genes, were analyzed by PCR and DNA sequencing. The quinolone resistance-determining regions of gyrA and parC in ciprofloxacin-resistant isolates were analyzed. Clonal relatedness was investigated by two-locus sequence typing (CH clonotyping). Phylotyping was performed by the Clermont multiplex PCR method. Virulence determinants were analyzed by customized DNA-based microarray technology developed in this study for fast and economic molecular multiplex typing. Thirty-five isolates were selected for whole-genome sequence-based analysis. Most isolates were resistant to ampicillin and tetracycline. Twenty-one isolates displayed an ESBL phenotype and one isolate an AmpC β-lactamase-producing phenotype. Three isolates had elevated colistin minimal inhibitory concentrations and carried the mcr-1 gene. Thirty-seven isolates displayed a multi-drug resistance phenotype. The most predominant β-lactamase gene classes were blaTEM-1 (56%) and blaCTX-M-1 (13.71%). Mutations in QRDR were observed in 14 ciprofloxacin-resistant isolates. CH clonotyping divided all isolates into 51 CH clonotypes. The majority of isolates belonged to phylogroup A. Sixty-four isolates could be assigned to defined pathotypes wherefrom UPEC was predominant. WGS revealed that the most predominant sequence type was ST100, followed by ST10. ST131 was detected twice in our analysis. This study highlights the importance of monitoring antimicrobial resistance and virulence properties of porcine E. coli isolates. This can be achieved by applying reliable, fast, economic and easy to perform technologies such as DNA-based microarray typing. The presence of high-risk pathogenic multi-drug resistant zoonotic clones, as well as those that are resistant to critically important antibiotics for humans, can pose a risk to public health. Improved protocols may be developed in swine farms for preventing infections, as well as the maintenance and distribution of the causative isolates.


Hypothyroidism elicits electrophysiological noradrenergic subsensitivity in rat cerebellum.
discharge rats of Purkinje neurons were compared in control and hypothyroid adult rats. Purkinje neurons in hypothyroid rats fired significantly faster and were less sensitive to iontophoretically applied norepinephrine than those in control rats. The subsensitivity of the Purkinje neurons appeared to be primarily due to an alteration in the beta-receptor--adenylate cyclase complex, because the sensitivity of these cells to locally applied N6-monobutyryl adenosine 3'-5'-monophosphate (N6 cyclic AMP) did not change significantly. The sensitivity of the Purkinje neurons to norepinephrine could be restored in hypothyroid rats by administration of triiodothyronine.


Risk factors for lumbosacral plexus palsy related to pelvic fracture.
A retrospective study. We assessed risk factors for lumbosacral plexus palsy related to pelvic fracture that can be evaluated during the acute injury phase with diagnostics such as computed tomography (CT). Many patients with pelvic fracture are in vital shock, with polytrauma and loss of consciousness, making an accurate neurologic examination very difficult in the emergency room. This study included 22 patients who had AO classification type B or C pelvic fractures. The 22 patients had 27 posterior osteoligamentary lesions. The average injury severity score (ISS) was 27.5 (range, 16-50). Age, sex, ISS, suicidal jump, longitudinal displacement, sacral transverse fracture, pubic fracture, lumbar transverse process fracture, type of pelvic fracture (AO), and type of sacral fracture (Denis) were examined for a correlation with the lumbosacral plexus palsy. Using coronal reconstruction CT, we considered a 10 mm or greater displacement at the sacrum or sacroiliac joint to be a longitudinal displacement. Transverse sacral fracture was diagnosed by sagittal reconstruction CT. Of the 22 patients, 5 (22.7%) had lumbosacral plexus palsy (8 of 27 pelvic fractures) detected during treatment. The incidence of lumbosacral plexus palsy was not related to age, sex, ISS. Incidence of palsy was significantly higher when the patient's affected side had longitudinal displacement. Patients who had made a suicidal jump or had a sacral transverse fracture also had a significantly higher risk for lumbosacral plexus palsy. Palsy was not related to the type of pelvic fracture (AO) or sacral fracture (Denis). In this study, longitudinal displacement of the pelvis, transverse sacral fracture, and trauma from a suicidal jump were risk factors for lumbosacral plexus palsy. These risk factors were helpful in our examination of patients who had severe pelvic fracture with loss of consciousness.


Soluble receptor for advanced glycation endproducts is decreased in patients with juvenile idiopathic arthritis (ERA category) and inversely correlates with disease activity and S100A12 levels.
Membrane-bound receptor for advanced glycation endproducts (mRAGE) is overexpressed in response to increasing concentrations of its ligand (e.g., S100A12) and triggers an inflammatory immune response. In contrast, soluble RAGE (sRAGE) acts as a decoy receptor and downmodulates inflammation. Decreased sRAGE levels are associated with autoimmune diseases; however, limited data are available in juvenile idiopathic arthritis (JIA). We studied sRAGE levels in patients with JIA [enthesitis-related arthritis (ERA) category]. sRAGE levels were estimated in the serum of patients with ERA JIA (n = 101), systemic-onset JIA and polyarticular JIA (n = 10 each), and healthy controls (n = 45). Synovial fluid (SF) sRAGE was measured in patients with ERA, rheumatoid arthritis, reactive arthritis, and osteoarthritis (n = 10). Levels of S100A12 were also measured. Twenty-four patients with ERA were followed for 4 months. Disease activity was assessed by swollen joint count (SJC), tender joint count (TJC), and erythrocyte sedimentation rate (ESR). All levels are expressed as median (range). The serum sRAGE (pg/ml) level was significantly lower in patients compared to healthy controls [515 (64-1887) vs 1542 (627-3159); p < 0.0001]. In paired samples, SF had lower levels compared to corresponding plasma level [102 (51-799) vs 481 (134-1006); p < 0.0001]. The level of S100A12 (ng/ml) was higher in SF (1042; 573-1415) than serum (638; 208-779). Serum sRAGE correlated negatively with S100A12 levels (r = -0.474; p < 0.01.), ESR (r = -0.306; p < 0.01), and SJC (r = -0.237; p < 0.05), but not with TJC (r = -0.134; p = NS). The levels of sRAGE remained stable over time in patients with stable disease. Levels of sRAGE are reduced in patients with ERA and correlate negatively with disease activity and S100A12 levels. sRAGE may be a modulator of inflammation in these patients.


Case management in primary palliative care is associated more strongly with organisational than with patient characteristics: results from a cross-sectional prospective study.
Case managers have been introduced in Dutch primary palliative care; these are nurses with expertise in palliative care who offer support to patients and informal carers in addition to the care provided by the general practitioner and home care nurses. This study aims to describe support and investigate what characteristics of patients and the organizational setting are related to the number of contacts and to the number of times topics are discussed between the case manager and patients and/or informal carers. Prospective study following cancer patients (n = 662) receiving support from a palliative care case manager in Dutch primary care, using registration forms filled out by the case manager after contact with the patient and/or informal carer. In backward linear regression, the association was studied between patient or organizational characteristics and the number of contacts and the number of times conversation topics were discussed. Organizational characteristics add more to explained variability in data than patient characteristics. Case managers provide support in a flexible manner with regard to the number, mode, persons present, and duration of contacts. Support covered all domains of palliative care, with most attention given to physical complaints, life expectancy and psychological aspects. Support offered by the case managers is prompted by characteristics of the organization for which they work. This is contradictory to the idea of patient centered care highly valued in palliative care.


In vitro properties of surface-modified solid lipid microspheres containing an antimalarial drug: halofantrine.
To formulate and evaluate in vitro, surface-modified solid lipid microspheres containing halofantrine using lipid matrix formed from goat fat and a phospholipid (P90H). The model drug, halofantrine in an increasing concentration of 1%, 2%, 3%, 4% and 5% w/w was incorporated into surface-modified solid lipid microspheres formulated by hot homogenization. Effect of drug concentration on the encapsulation efficiency was studied. The dispersion was evaluated using particle size, particle morphology, pH and encapsulation efficiency. The drug formulation with highest encapsulation efficiency was selected and used for the release studies and compared with the release from a commercial dosage form (Halfan® 250 mg tablet, Glaxo-Smithkline, Mayenne France) using simulated gastric fluid (SGF pH 1.2), simulated intestinal fluid (SIF pH 7.2) and phosphate buffer (pH 6.8) as biorelevant media. Results were analyzed statistically and the level of significance was taken to be P < 0.05). Discrete and spherical solid lipid microspheres were produced. The particle size of the dispersion was low (32.48-33.87 μm) with minimal particle growth and high encapsulation efficiencies (86.8%-91.0%) after 3 months. The pH of the microspheres dispersion changed appreciably after 3 months. In vitro release result obtained revealed sustained and controlled drug release from the lipid microspheres compared with the tablet dosage form. Formulation of halofantrine as solid lipid microspheres presents a better alternative to the conventional tablet formulation as the in vitro dissolution of the highly lipophilic halofantrine was highly improved.


Baicalin Suppresses Hypoxia-Reoxygenation-Induced Arterial Endothelial Cell Apoptosis via Suppressing PKCδ/p53 Signaling.
BACKGROUND This study was aimed to investigate the protective role of baicalin on vascular endothelium exposed to ischemia reperfusion injury and the involved molecular mechanisms. MATERIAL AND METHODS Cultured human arterial endothelial cells (HAECs) were exposed to hypoxia/deoxygenation (H/R). Cells were also treated with baicalin at serially diluted concentrations. Cells were also treated with PKC activator PEP005 or specific siRNA against protein kinase Cδ (PKCδ). MTT assay was used to evaluate the cell viabilities. Flow cytometry was used to detect cell apoptosis. The protein phosphorylation and expression levels were determined by Western blotting. RESULTS PKCδ-siRNA transfection increased cell viabilities and reduced cell apoptosis in HAECs exposed to H/R. Baicalin treatment preserved cell viabilities and reduced apoptosis of H/R-exposed HAECs in a concentration- dependent manner. Baicalin treatment reduced phosphorylation levels of PKCδ and p53, as well as the expression levels of active caspase3 and bax in HAECs exposed to H/R. The treatment of PKC activator PEP005 impaired the protective effects of baicalin in increasing cell viabilities and reducing apoptosis in HAECs exposed to H/R. CONCLUSIONS Baicalin exerts vascular a protective effect on HAECs exposed to H/R by reducing cell apoptosis. The PKCδ/p53 apoptotic signaling pathway was the pharmacological target of baicalin.


Association of Early Interventions With Birth Outcomes and Child Linear Growth in Low-Income and Middle-Income Countries: Bayesian Network Meta-analyses of Randomized Clinical Trials.
The first 1000 days of life represent a critical window for child development. Pregnancy, exclusive breastfeeding (EBF) period (0-6 months), and complementary feeding (CF) period (6-24 months) have different growth requirements, so separate considerations for intervention strategies are needed. No synthesis to date has attempted to quantify the associations of interventions under multiple domains of micronutrient and balanced energy protein and food supplements, deworming, maternal education, water sanitation, and hygiene across these 3 life periods with birth and growth outcomes. To determine the magnitude of association of interventions with birth and growth outcomes based on randomized clinical trials (RCTs) conducted in low-income and middle-income countries (LMICs) using Bayesian network meta-analyses. MEDLINE, Embase, and Cochrane databases were searched from their inception up to August 14, 2018. Included were LMIC-based RCTs of interventions provided to pregnant women, infants (0-6 months), and children (6-24 months). Two independent reviewers used a standardized data extraction and quality assessment form. Random-effects network meta-analyses were performed for each life period. Effect sizes are reported as odds ratios (ORs) and mean differences (MeanDiffs) for dichotomous and continuous outcomes, with 95% credible intervals (CrIs). This study calculated probabilities of interventions being superior to standard of care by at least a minimal clinically important difference. The study compared ORs on preterm birth and MeanDiffs on birth weight for pregnancy, length for age (LAZ) for EBF, and height for age (HAZ) for CF. Among 302 061 participants in 169 randomized clinical trials, the network meta-analyses found several nutritional interventions that demonstrated greater association with improved birth and growth outcomes compared with standard of care. For instance, compared with standard of care, maternal supplements of multiple micronutrients showed reduced odds for preterm birth (OR, 0.54; 95% CrI, 0.27-0.97) and improved mean birth weight (MeanDiff, 0.08 kg; 95% CrI, 0.00-0.17 kg) but not LAZ during EBF (MeanDiff, -0.02; 95% CrI, -0.18 to 0.14). Supplementing infants and children with multiple micronutrients showed improved LAZ (MeanDiff, 0.20; 95% CrI, 0.03-0.35) and HAZ (MeanDiff, 0.14; 95% CrI, 0.02-0.25). The study found that pregnancy interventions generally had higher probabilities of a minimal clinically importance difference than the interventions for the EBF or CF in the first 1000 days of life. These analyses highlight the importance of intervening early for child development, during pregnancy if possible. Results of this study suggest that there is a need to combine interventions from multiple domains and test for their effectiveness as a package.


Ring finger protein20 regulates hepatic lipid metabolism through protein kinase A-dependent sterol regulatory element binding protein1c degradation.
Sterol regulatory element binding protein1c (SREBP1c) is a key transcription factor for de novo lipogenesis during the postprandial state. During nutritional deprivation, hepatic SREBP1c is rapidly suppressed by fasting signals to prevent lipogenic pathways. However, the molecular mechanisms that control SREBP1c turnover in response to fasting status are not thoroughly understood. To elucidate which factors are involved in the inactivation of SREBP1c, we attempted to identify SREBP1c-interacting proteins by mass spectrometry analysis. Since we observed that ring finger protein20 (RNF20) ubiquitin ligase was identified as one of SREBP1c-interacting proteins, we hypothesized that fasting signaling would promote SREBP1c degradation in an RNF20-dependent manner. In this work, we demonstrate that RNF20 physically interacts with SREBP1c, leading to degradation of SREBP1c via ubiquitination. In accordance with these findings, RNF20 represses the transcriptional activity of SREBP1c and turns off the expression of lipogenic genes that are targets of SREBP1c. In contrast, knockdown of RNF20 stimulates the expression of SREBP1c and lipogenic genes and induces lipogenic activity in primary hepatocytes. Furthermore, activation of protein kinase A (PKA) with glucagon or forskolin enhances the expression of RNF20 and potentiates the ubiquitination of SREBP1c via RNF20. In wild-type and db/db mice, adenoviral overexpression of RNF20 markedly suppresses FASN promoter activity and reduces the level of hepatic triglycerides, accompanied by a decrease in the hepatic lipogenic program. Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation. RNF20 acts as a negative regulator of hepatic fatty acid metabolism through degradation of SREBP1c upon PKA activation. Knowledge regarding this process enhances our understanding of how SREBP1c is able to turn off hepatic lipid metabolism during nutritional deprivation.


Catheter-directed embolectomy, fragmentation, and thrombolysis for the treatment of massive pulmonary embolism after failure of systemic thrombolysis.
The standard medical management for patients in extremis from massive pulmonary embolism (PE) is systemic thrombolysis, but the utility of this treatment relative to catheter-directed intervention (CDI) is unknown. We evaluated the effectiveness of CDI as part of a treatment algorithm for life-threatening PE. A retrospective review was performed on 70 consecutive patients with suspected acute PE over a 10-year period (from 1997 to 2006) who had been referred for pulmonary angiography and/or intervention. The criteria for study inclusion were patients who received CDI due to angiographically confirmed massive PE and hemodynamic shock (shock index, > or = 0.9). CDI involved suction embolectomy and fragmentation with or without catheter thrombolysis. Twelve patients were treated with CDI. There were seven men and five women (mean age, 56 years; age range, 21 to 80 years). Seven patients (58%) were referred for CDI after failing systemic infusion with 100 mg of tissue plasminogen activator, and five patients (42%) had contraindications to systemic thrombolysis. Catheter-directed fragmentation and embolectomy were performed in all patients (100%). Additionally, catheter-guided thrombolysis was performed in eight patients (67%). Technical success was achieved in 12 of 12 cases (100%). There were no major procedural complications (0%). Significant hemodynamic improvement (shock index, < 0.9) was observed in 10 of 12 cases (83%). The remaining two patients (17%) died secondary to cardiac arrest within 24 h. Ten of 12 patients (83%) survived and remained stable until hospital discharge (mean duration, 20 days; range, 3 to 51 days). In the setting of hemodynamic shock from massive PE, CDI is potentially a life-saving treatment for patients who have not responded to or cannot tolerate systemic thrombolysis.


Activation of nuclear factor kappa B in mammary epithelium promotes milk loss during mammary development and infection.
We investigated whether nuclear factor kappa B (NF-kappaB), which exhibits a regulated pattern of activity during murine mammary gland development, plays an important role during lactation and involution, when milk production ceases and the gland undergoes apoptosis and re-modeling. We generated a doxycycline inducible transgenic mouse model to activate NF-kappaB specifically in the mammary epithelium through expression of a constitutively active form of IKK2, the upstream kinase in the classical NF-kappaB signaling cascade. We found that activation of NF-kappaB during involution resulted in a more rapid reduction in milk levels and increased cleavage of caspase-3, an indicator of apoptosis. We also found that activation of NF-kappaB during lactation with no additional involution signals had a similar effect. The observation that NF-kappaB is a key regulator of milk production led us to investigate the role of NF-kappaB during mastitis, an infection of the mammary gland in which milk loss is observed. Mammary gland injection of E. coli LPS resulted in activation of NF-kappaB and milk loss during lactation. This milk loss was decreased by selective inhibition of NF-kappaB in mammary epithelium. Together, our data reveal that activation of NF-kappaB leads to milk clearance in the lactating mammary gland. Therefore, targeting of NF-kappaB signaling may prove therapeutic during mastitis in humans and could be beneficial for the dairy industry, where such infections have a major economic impact.


Aspergillus fumigatus-induced interleukin-8 synthesis by respiratory epithelial cells is controlled by the phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2 pathways and not by the toll-like receptor-MyD88 pathway.
Previous studies have established that phagocytes are key cells of the pulmonary innate immune defense against A. fumigatus, an opportunistic fungus responsible of invasive pulmonary aspergillosis. Macrophages detect A. fumigatus via Toll-like receptors 2 and 4 (TLR2 and -4) and respond by the MyD88-NF-kappaB-dependent synthesis of inflammatory mediators. In the present study, we demonstrate that respiratory epithelial cells also sense A. fumigatus and participate in the host defense. Thus, the interaction of respiratory epithelial cells with germinating but not resting conidia of A. fumigatus results in interleukin (IL)-8 synthesis that is controlled by phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2. Using MyD88-dominant negative transfected cells, we also show that IL-8 production is not dependent on the TLR-MyD88 pathway, although the MyD88 pathway is activated by A. fumigatus and leads to NF-kappaB activation. Thus, our results provide evidence for the existence of two independent signaling pathways activated in respiratory epithelial cells by A. fumigatus, one that is MyD88-dependent and another that is My88-independent and involved in IL-8 synthesis.


Density functional theory + U analysis of the electronic structure and defect chemistry of LSCF (La0.5Sr0.5Co0.25Fe0.75O3-δ).
Reducing operating temperatures is a key step in making solid oxide fuel cell (SOFC) technology viable. A promising strategy for accomplishing this goal is employing mixed ion-electron conducting (MIEC) cathodes. La1-xSrxCo1-yFeyO3-δ (LSCF) is the most widely employed MIEC cathode material; however, rational optimization of the composition of LSCF requires fundamental insight linking its electronic structure to its defect chemistry. To provide the necessary insight, density functional theory plus U (DFT+U) calculations are used to investigate the electronic structure of LSCF (xSr = 0.50, yCo = 0.25). The DFT+U calculations show that LSCF has a significantly different electronic structure than La1-xSrxFeO3 because of the addition of cobalt, but that minimal electronic structure differences exist between La0.5Sr0.5Co0.25Fe0.75O3 and La0.5Sr0.5Co0.5Fe0.5O3. The oxygen vacancy formation energy (ΔEf,vac) is calculated for residing in different local environments within La0.5Sr0.5Co0.25Fe0.75O3. These results show that configurations have the highest ΔEf,vac, while have the lowest ΔEf,vac and may act as traps for . We conclude that compositions with more Fe than Co are preferred because the additional sites would lead to higher overall ΔEf,vac (and lower concentrations), while the trapping strength of the sites is relatively weak (∼0.3 eV).


A new and improved strategy combining a dispersive-solid phase extraction-based multiclass method with ultra high pressure liquid chromatography for analysis of low molecular weight polyphenols in vegetables.
This paper reports on the development and optimization of a modified Quick, Easy, Cheap Effective, Rugged and Safe (QuEChERS) based extraction technique coupled with a clean-up dispersive-solid phase extraction (dSPE) as a new, reliable and powerful strategy to enhance the extraction efficiency of free low molecular-weight polyphenols in selected species of dietary vegetables. The process involves two simple steps. First, the homogenized samples are extracted and partitioned using an organic solvent and salt solution. Then, the supernatant is further extracted and cleaned using a dSPE technique. Final clear extracts of vegetables were concentrated under vacuum to near dryness and taken up into initial mobile phase (0.1% formic acid and 20% methanol). The separation and quantification of free low molecular weight polyphenols from the vegetable extracts was achieved by ultrahigh pressure liquid chromatography (UHPLC) equipped with a phodiode array (PDA) detection system and a Trifunctional High Strength Silica capillary analytical column (HSS T3), specially designed for polar compounds. The performance of the method was assessed by studying the selectivity, linear dynamic range, the limit of detection (LOD) and limit of quantification (LOQ), precision, trueness, and matrix effects. The validation parameters of the method showed satisfactory figures of merit. Good linearity (Rvalues2>0.954; (+)-catechin in carrot samples) was achieved at the studied concentration range. Reproducibility was better than 3%. Consistent recoveries of polyphenols ranging from 78.4 to 99.9% were observed when all target vegetable samples were spiked at two concentration levels, with relative standard deviations (RSDs, n=5) lower than 2.9%. The LODs and the LOQs ranged from 0.005 μg mL(-1) (trans-resveratrol, carrot) to 0.62 μg mL(-1) (syringic acid, garlic) and from 0.016 μg mL(-1) (trans-resveratrol, carrot) to 0.87 μg mL(-1) ((+)-catechin, carrot) depending on the compound. The method was applied for studying the occurrence of free low molecular weight polyphenols in eight selected dietary vegetables (broccoli, tomato, carrot, garlic, onion, red pepper, green pepper and beetroot), providing a valuable and promising tool for food quality evaluation.


Genomic and epigenomic evolution of acquired resistance to combination therapy in esophageal squamous cell carcinoma.
BACKGROUNDTargeted arterial infusion of verapamil combined with chemotherapy (TVCC) is an effective clinical interventional therapy for esophageal squamous cell carcinoma (ESCC), but multidrug resistance (MDR) remains the major cause of relapse or poor prognosis, and the underlying molecular mechanisms of MDR, temporal intratumoral heterogeneity, and clonal evolutionary processes of resistance have not been determined.METHODSTo elucidate the roles of genetic and epigenetic alterations in the evolution of acquired resistance during therapies, we performed whole-exome sequencing on 16 serial specimens from 7 patients with ESCC at every cycle of therapeutic intervention from 3 groups, complete response, partial response, and progressive disease, and we performed whole-genome bisulfite sequencing for 3 of these 7 patients, 1 patient from each group.RESULTSPatients with progressive disease exhibited a substantially higher genomic and epigenomic temporal heterogeneity. Subclonal expansions driven by the beneficial new mutations were observed during combined therapies, which explained the emergence of MDR. Notably, SLC7A8 was identified as a potentially novel MDR gene, and functional assays demonstrated that mutant SLC7A8 promoted the resistance phenotypes of ESCC cell lines. Promoter methylation dynamics during treatments revealed 8 drug resistance protein-coding genes characterized by hypomethylation in promoter regions. Intriguingly, promoter hypomethylation of SLC8A3 and mutant SLC7A8 were enriched in an identical pathway, protein digestion and absorption, indicating a potentially novel MDR mechanism during treatments.CONCLUSIONOur integrated multiomics investigations revealed the dynamics of temporal genetic and epigenetic inter- and intratumoral heterogeneity, clonal evolutionary processes, and epigenomic changes, providing potential MDR therapeutic targets in treatment-resistant patients with ESCC during combined therapies.FUNDINGNational Natural Science Foundation of China, Science Foundation of Peking University Cancer Hospital, CAMS Innovation Fund for Medical Sciences, Major Program of Shenzhen Bay Laboratory, Guangdong Basic and Applied Basic Research Foundation, and the third round of public welfare development and reform pilot projects of Beijing Municipal Medical Research Institutes.


IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans.
IL-23 and Th17 cells play important roles in host defense against systemic infections with extracellular bacteria and fungi, although their roles in immunity against localized skin infections are less well defined. Here, the contributions of IL-23 and Th17 cytokines in host defense against cutaneous Candida albicans infection were evaluated. Mice deficient in IL-23 or IL-17A demonstrated delayed healing and decreased IL-17A production after skin infection with C. albicans compared with wild-type mice or mice deficient in IL-12 or IL-22. Histologic examination revealed epidermal hyperplasia overlying infected dermis four days postinoculation in wild-type mice. In IL-23-deficient mice, fungal burden was greater in skin, neither IL-17A nor IL-22 mRNAs were expressed postinfection, and these mice demonstrated only minimal epidermal hyperplasia. Exogenous recombinant IL-17A injected at the site of skin infection promoted more rapid healing of candidiasis in both wild-type mice and mice deficient in IL-23 and IL-12. Taken together, these results demonstrate that IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal host defense against cutaneous candidiasis. In addition, recombinant IL-17A may serve as a potential therapy to enhance healing in individuals with chronic cutaneous candidiasis.


Improved phase retrieval method of dual-wavelength interferometry based on a shorter synthetic-wavelength.
In dual-wavelength interferometry (DWI), by combing the advantage of the shorter synthetic-wavelength and the immune algorithm of phase ambiguity, we propose an improved phase retrieval method with both high accuracy and large measurement range, which is a pair of contradiction in the reported DWI method. First, we calculate the height of measured object at longer synthetic-wavelength through using the wrapped phases of two single-wavelengths. Second, by combining the immune algorithm of phase ambiguity and the height of measured object at longer synthetic-wavelength, we can perform the phase unwrapping of the larger one of the two single-wavelengths, then achieve accurate height at single-wavelength named as the transition height. Finally, we perform phase unwrapping of shorter synthetic-wavelength through using the immune algorithm of phase ambiguity and the transition height, and then the height at shorter synthetic-wavelength can be achieved. Compared with the reported method, in addition to maintaining the advantage of high accuracy, the proposed method does not need the additional wavelength, so the corresponding measurement procedures is greatly simplified. Simulation and experimental results demonstrate the performance of proposed method.


Endovascular treatment of acute aortic syndrome.
The term acute aortic syndrome (AAS) encompasses a range of conditions that have a risk of imminent aortic rupture and where delays in treatment result in increased mortality. Endovascular treatment offers an attractive alternative to open surgery but little is known about the durability of the repair and the factors that predict mortality. Prospective data were collected for a cohort of 110 consecutive patients with endovascular treatment for AAS. Patient and procedural characteristics were related to short- and midterm outcome using multivariate logistic regression analysis. There were 75 men and 35 women with a median age of 68 (range 57-76) years. The pathologies treated were acute dissection (35), symptomatic aneurysm (32), infected aneurysm (18), transection (12), chronic dissection (9), penetrating ulcer (3), and intramural hematoma (1). Thirty-day mortality was 12.7% and this was associated with hypotension (odds ratio [OR], 5.25), use of general anesthetic (OR, 5.23), long procedure duration (OR, 2.03), and increasing age (OR, 1.07). The causes of death were aortic rupture (4), myocardial infarction (4), stroke (3), and multisystem organ failure (3). The stroke and paraplegia rates were 7.3% and 6.4%, respectively. The 1-year survival was 81% and the 5-year survival 63%. Secondary procedures were required in 13 (11.8%) patients. Factors associated with death at 1 year were presence of an aortic fistula (OR, 9.78), perioperative stroke (OR, 5.87), and use of general anesthetic (OR, 3.76); and at 5 years were aortic fistula (OR, 12.31) and increasing age (OR, 1.06). Acute aortic syndrome carries significant early and late mortality. Emergency endovascular repair offers a minimally invasive treatment option associated with acceptable short and midterm results. Continued surveillance is important as secondary procedures and aortic-related deaths continue to occur throughout the follow-up period.


Cross-Tissue Exploration of Genetic and Epigenetic Effects on Brain Gray Matter in Schizophrenia.
Closely linking genetics and environment factors, epigenetics has been of increasing interest in psychiatric disease studies. In this work, we integrated single nucleotide polymorphisms (SNPs), DNA methylation of blood and saliva, and brain gray matter (GM) measures to explore the role of genetic and epigenetic variation to the brain structure changes in schizophrenia (SZ). By focusing on the reported SZ genetic risk regions, we applied a multi-stage multivariate analysis to a discovery dataset (92 SZ patients and 110 controls, blood) and an independent replication dataset (93 SZ patients and 99 controls, saliva). Two pairs of SNP-methylation components were significantly correlated (r = .48 and .35) in blood DNA, and replicated (r = .46 and .29) in saliva DNA, reflecting cross-tissue SNP cis-effects. In the discovery data, both SNP-related methylation components were also associated with one GM component primarily located in cerebellum, caudate, and thalamus. Additionally, another methylation component in NOSIP gene with significant SZ patient differences (P = .009), was associated with 8 GM components (7 with patient differences) including superior, middle, and inferior frontal gyri, superior, middle, and inferior temporal gyri, cerebellum, insula, cuneus, and lingual gyrus. Of these, 5 methylation-GM associations were replicated (P < .05). In contrast, no pairwise significant associations were observed between SNP and GM components. This study strongly supports that compared to genetic variation, epigenetics show broader and more significant associations with brain structure as well as diagnosis, which can be cross-tissue, and the potential in explaining the mechanism of genetic risks in SZ.


Stroke associated with cocaine use.
We describe eight patients in whom cocaine use was related to stroke and review 39 cases from the literature. Among these 47 patients the mean (+/- SD) age was 32.5 +/- 12.1 years; 76% (34/45) were men. Stroke followed cocaine use by inhalation, intranasal, intravenous, and intramuscular routes. Intracranial aneurysms or arteriovenous malformations were present in 17 of 32 patients studied angiographically or at autopsy; cerebral vasculitis was present in two patients. Cerebral infarction occurred in 10 patients (22%), intracerebral hemorrhage in 22 (49%), and subarachnoid hemorrhage in 13 (29%). These data indicate that (1) the apparent incidence of stroke related to cocaine use is increasing; (2) cocaine-associated stroke occurs primarily in young adults; (3) stroke may follow any route of cocaine administration; (4) stroke after cocaine use is frequently associated with intracranial aneurysms and arteriovenous malformations; and (5) in cocaine-associated stroke, the frequency of intracranial hemorrhage exceeds that of cerebral infarction.


Case report: persistently seronegative neuroborreliosis in an immunocompromised patient.
Infection with Borrelia burgdorferi sensu lato complex (B. b. sl) spirochetes can cause Lyme borreliosis, manifesting as localized infection (e.g. erythema migrans) or disseminated disease (e.g. Lyme neuroborreliosis). Generally, patients with disseminated Lyme borreliosis will produce an antibody response several weeks post-infection. So far, no case of neuroborreliosis has been described with persistently negative serology one month after infection. We present a patient with a history of Mantle cell lymphoma and treatment with R-CHOP (rituximab, doxorubicine, vincristine, cyclofosfamide, prednisone), with a meningo-encephalitis, who was treated for a suspected lymphoma relapse. However, no malignant cells or other signs of malignancy were found, and microbial tests did not reveal any clues, including Borrelia serology. He did not recall being bitten by ticks, and a Borrelia PCR on CSF was negative. After spontaneous improvement of symptoms, he was discharged without definite diagnosis. Several weeks later, he was readmitted with a relapse of symptoms of meningo-encephalitis. This time however, a Borrelia PCR on CSF was positive, confirmed by two independent laboratories, and the patient received ceftriaxone upon which he partially recovered. Interestingly, during the diagnostic process of this exceptionally difficult case, a variety of different serological assays for Borrelia antibodies remained negative. Only P41 (flagellin) IgG was detected by blot and the Liaison IgG became equivocal 2 months after initial testing. To the best of our knowledge this is the first case of neuroborreliosis that is seronegative on repeated sera and multiple test modalities. This unique case demonstrates the difficulty to diagnose neuroborreliosis in severely immunocompromised patients. In this case, a delay in diagnosis was caused by broad differential diagnosis, an absent known history of tick bites, negative serology and the low sensitivity of PCR on CSF. Therefore, awareness of the diagnostic limitations to detect Borrelia infection in this specific patient category is warranted.


Mercury exposure in an endangered seabird: long-term changes and relationships with trophic ecology and breeding success.
Mercury (Hg) is an environmental contaminant which, at high concentrations, can negatively influence avian physiology and demography. Albatrosses (Diomedeidae) have higher Hg burdens than all other avian families. Here, we measure total Hg (THg) concentrations of body feathers from adult grey-headed albatrosses (Thalassarche chrysostoma) at South Georgia. Specifically, we (i) analyse temporal trends at South Georgia (1989-2013) and make comparisons with other breeding populations; (ii) identify factors driving variation in THg concentrations and (iii) examine relationships with breeding success. Mean ± s.d. feather THg concentrations were 13.0 ± 8.0 µg g-1 dw, which represents a threefold increase over the past 25 years at South Georgia and is the highest recorded in the Thalassarche genus. Foraging habitat, inferred from stable isotope ratios of carbon (δ13C), significantly influenced THg concentrations-feathers moulted in Antarctic waters had far lower THg concentrations than those moulted in subantarctic or subtropical waters. THg concentrations also increased with trophic level (δ15N), reflecting the biomagnification process. There was limited support for the influence of sex, age and previous breeding outcome on feather THg concentrations. However, in males, Hg exposure was correlated with breeding outcome-failed birds had significantly higher feather THg concentrations than successful birds. These results provide key insights into the drivers and consequences of Hg exposure in this globally important albatross population.


Spectral reading of optical resonance-encoded cells in microfluidics.
The ability to label individual cells is useful for single-cell-level studies of complex cellular interactions and heterogeneity. Optically readable cell labeling is attractive as it can be investigated non-invasively and repeatedly at high speeds. Here, we demonstrate the feasibility of large-scale cell barcoding and identification using fluorescent polystyrene microbeads loaded into cells. Intracellular beads with different diameters in a range of 5 to 12 μm generate spectrally distinguished features or barcodes. A microfluidic chip was used to measure fluorescence resonance peaks emitted from individual cells. An algorithm comparing the peak wavelengths to a reference barcode library allowed barcode identification with high accuracy. This work provides a guideline to increase the number of unique identifiers and reduce various false-positive and false-negative errors.


Formulation, physicochemical characterization and stability study of lithium-loaded microemulsion system.
Lithium biocompatible microemulsion based on Peceol(®), lecithin, ethanol and water was studied in attempt to identify the optimal compositions in term of drug content, physicochemical properties and stability. Lithium solubilization in microemulsion was found to be compatible with a drug-surfactant binding model. Lithium ions were predominantly solubilized within lecithin head group altering significantly the interfacial properties of the system. Pseudo-ternary phase diagrams of drug free and drug loaded microemulsions were built at constant ethanol/lecithin weight ratio (40/60). Lithium loaded microemulsion has totally disappeared in the Peceol(®) rich part of phase diagram; critical fractions of lecithin and ethanol were required for the formation of stable microemulsion. The effect of lithium concentration on the properties and physical stability of microemulsions were studied using microscopy, Karl Fischer titrations, rheology analyses, conductivity measurements and centrifugation tests. The investigated microemulsions were found to be stable under accelerated storage conditions. The systems exhibited low viscosity and behaved as Newtonian fluid and no structural transition was shown.


Appraisals Generate Specific Configurations of Facial Muscle Movements in a Gambling Task: Evidence for the Component Process Model of Emotion.
Scherer's Component Process Model provides a theoretical framework for research on the production mechanism of emotion and facial emotional expression. The model predicts that appraisal results drive facial expressions, which unfold sequentially and cumulatively over time. In two experiments, we examined facial muscle activity changes (via facial electromyography recordings over the corrugator, cheek, and frontalis regions) in response to events in a gambling task. These events were experimentally manipulated feedback stimuli which presented simultaneous information directly affecting goal conduciveness (gambling outcome: win, loss, or break-even) and power appraisals (Experiment 1 and 2), as well as control appraisal (Experiment 2). We repeatedly found main effects of goal conduciveness (starting ~600 ms), and power appraisals (starting ~800 ms after feedback onset). Control appraisal main effects were inconclusive. Interaction effects of goal conduciveness and power appraisals were obtained in both experiments (Experiment 1: over the corrugator and cheek regions; Experiment 2: over the frontalis region) suggesting amplified goal conduciveness effects when power was high in contrast to invariant goal conduciveness effects when power was low. Also an interaction of goal conduciveness and control appraisals was found over the cheek region, showing differential goal conduciveness effects when control was high and invariant effects when control was low. These interaction effects suggest that the appraisal of having sufficient control or power affects facial responses towards gambling outcomes. The result pattern suggests that corrugator and frontalis regions are primarily related to cognitive operations that process motivational pertinence, whereas the cheek region would be more influenced by coping implications. Our results provide first evidence demonstrating that cognitive-evaluative mechanisms related to goal conduciveness, control, and power appraisals affect facial expressions dynamically over time, immediately after an event is perceived. In addition, our results provide further indications for the chronography of appraisal-driven facial movements and the underlying cognitive processes.


Skin tags are not a risk factor for colorectal polyps.
To ascertain whether acrochordons (simple skin tags) are associated with a higher risk for colon polyps, we prospectively studied 218 male and female patients, age 40 or older without history of colon cancer, polyps, ulcerative colitis, familial polyposis, or recent lower intestinal symptoms. Each patient was assessed for the presence of skin tags. A screening flexible sigmoidoscopy was then performed without knowledge of the dermatologic findings. All polypoid lesions were recorded, and patients with polyps greater than or equal to 3 mm in diameter underwent full colonoscopy and polypectomy. Twenty patients (9.2%) had documented adenomatous polyps on colonoscopy. Nineteen other patients had hyperplastic polyps and mamillations. There was no significant difference in the prevalence of polypoid lesions in those with skin tags compared with those without skin tags, either analyzed as group totals or stratified by age, sex, or type of polyp. We conclude that skin tags are not associated with a higher than usual risk for colonic polyps and should not be used as a marker for more intensive screening.


Effect of adrenomedullin on the production of endothelin-1 and on its vasoconstrictor action in resistance arteries: evidence for a receptor-specific functional interaction in patients with heart failure.
Endothelin-1 (ET-1) and adrenomedullin (ADM) are both produced in the arterial wall, but have opposing biological actions. Evidence from experimental animals suggests a functional interaction between ET-1 and ADM. We have tested this in humans. Small resistance arteries were obtained from gluteal biopsies taken from patients with chronic heart failure (CHF) due to coronary heart disease (CHD), or with CHD and preserved ventricular function. The contractile responses to big ET-1 and to ET-1 in both sets of vessels were studied in the absence (control) and presence of ADM at 20 pmol/l (low ADM) or 200 pmol/l (high ADM), using wire myography. ADM did not affect the conversion of big ET-1 into ET-1 in vessels from patients with either CHD or CHF. Low ADM did not alter the contractile response to ET-1 in vessels from patients with CHF. Low ADM was not tested in vessels from patients with CHD, but high ADM did not affect this response in arteries from these patients. High ADM did, however, significantly reduce the vasoconstrictor effect of ET-1 in vessels from patients with CHF. The maximum response, as a percentage of the response to high potassium, was 199% (S.E.M. 25%) in the control experiments (n=14), 205% (27%) in the low-ADM (n=7) studies and 150% (17%) in the high-ADM (n=6) experiments (P<0.001). Furthermore, the Hill coefficient increased from 0.57+/-0.05 in the absence of ADM to 1.16+/-0.15 in the high-ADM experiments, indicating that ADM at 200 pmol/l specifically antagonized one receptor type in vessels from patients with CHF. We conclude that there is a one-site receptor interaction between ADM and ET-1 that is specific for vessels from patients with CHF. This functional interaction between ADM and ET-1 in resistance arteries may be of pathophysiological importance in CHF.


DNA damage in children with scoliosis following X-ray exposure.
It has been suggested that cancer incidence is high in subjects with scoliosis who are relatively more often exposed to X-ray for diagnosis and follow-up. X-ray is a kind of ionizing radiation and leads to formation of oxygen free radicals which are capable of damage to DNA, thus altered gen expression and mutation. p53 tumor suppressor gene plays a crucial role in the damage response. It controls the checkpoint of cell cycle and redirects the cell metabolism to either repair of damaged DNA or apoptosis as response to DNA damage. The aim of the present study was to examine serum levels of 8-Hydroxydeoxyguanosine (8-OHdG), a strongly mutagenic product of oxidative DNA damage, p53, superoxide dismutase (SOD) and glutathione peroxidase (G-Px), as antioxidant activity, in children with scoliosis who had got whole spine radiograph two times during the last year. A total of 31 children with adolescent idiopathic scoliosis and 21 age-matched healthy children were included in the study. Serum levels of 8-OHdG and p53 were measured with ELISA kits. SOD and G-Px activities were determined with spectrophotometric assays. Serum levels of 8-OHdG and p53 were found to be higher (P<0.001 and P<0.01, respectively), SOD activity was found to be lower (P<0.001) in the children with scoliosis as compared to age-matched controls. There was no significant difference between the groups for G-Px activity. Our data show that X-ray exposure causes increased 8-OHdG level, and decreased SOD activity, which both may reflect a tumor promoting condition. Increased p53 level may be interpreted as a compensatory effort of cell to X-ray mediated DNA damage.


A review of auditing techniques for the Unified Medical Language System.
The study sought to describe the literature related to the development of methods for auditing the Unified Medical Language System (UMLS), with particular attention to identifying errors and inconsistencies of attributes of the concepts in the UMLS Metathesaurus. We applied the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) approach by searching the MEDLINE database and Google Scholar for studies referencing the UMLS and any of several terms related to auditing, error detection, and quality assurance. A qualitative analysis and summarization of articles that met inclusion criteria were performed. Eighty-three studies were reviewed in detail. We first categorized techniques based on various aspects including concepts, concept names, and synonymy (n = 37), semantic type assignments (n = 36), hierarchical relationships (n = 24), lateral relationships (n = 12), ontology enrichment (n = 8), and ontology alignment (n = 18). We also categorized the methods according to their level of automation (ie, automated systematic, automated heuristic, or manual) and the type of knowledge used (ie, intrinsic or extrinsic knowledge). This study is a comprehensive review of the published methods for auditing the various conceptual aspects of the UMLS. Categorizing the auditing techniques according to the various aspects will enable the curators of the UMLS as well as researchers comprehensive easy access to this wealth of knowledge (eg, for auditing lateral relationships in the UMLS). We also reviewed ontology enrichment and alignment techniques due to their critical use of and impact on the UMLS.


Genes encoding alpha and beta subunits of Na,K-ATPase are located on three different chromosomes in the mouse.
We have made use of a panel of mouse-hamster somatic cell hybrids and restriction fragment length polymorphisms between two mouse species (Mus musculus and Mus spretus) to determine the chromosomal localization of genes encoding the alpha and beta subunits of the Na,K-ATPase (Na+,K+-activated ATP phosphohydrolase, EC 22.214.171.124). DNA probes for three distinct isoforms of the Na,K-ATPase alpha subunit mapped to three different mouse chromosomes: the alpha 1 gene (Atpa-1) cosegregated with the Egf gene on chromosome 3; alpha 2 (Atpa-2) with the cytochrome P-450PB gene family/coumarin hydroxylase locus on chromosome 7; alpha 3 (Atpa-3) with the alpha-spectrin gene on chromosome 1. The Na,K-ATPase beta-subunit gene (Atpb) mapped to the same region of chromosome 1, but it was not tightly linked to the Atpa-3 gene. These results indicate that three isoforms of the Na,K-ATPase alpha subunit are encoded by three distinct genes. The dispersion of Na,K-ATPase genes suggests that their expression is not likely to be controlled by a common cis-acting regulatory element.


Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome.
The described phenotype of the polycystic ovary syndrome (PCOS) has been primarily based on findings in a referred (self or otherwise) population. It is possible that the phenotype of PCOS would be different if the disorder were to be detected and studied in its natural (unbiased) state. Our objective was to compare the phenotype of PCOS detected in an unselected population with that identified in a referral population. Participants included 292 PCOS patients identified at a tertiary care outpatient facility (referral PCOS) and 64 PCOS women (unselected PCOS) identified through the screening of a population of 668 seeking a pre-employment physical. Among the women undergoing a pre-employment physical, 563 did not demonstrate features of the disorder (unselected controls). All PCOS subjects met the National Institutes of Health 1990 criteria for the disorder. We estimated prevalence of obesity and severity of disease burden. Referral PCOS subjects had greater mean body mass index and hirsutism score and higher degrees of hyperandrogenemia, were more likely to be non-Hispanic White (83.90%), and demonstrated a more severe PCOS subphenotype than unselected PCOS or unselected controls. The prevalence of obesity and severe obesity in referral PCOS was 2.3 and 2.5 times greater than estimates of the same in unselected PCOS and 2.2 and 3.8 times greater than estimates in unselected controls, respectively. Alternatively, unselected PCOS subjects had a prevalence of obesity and severe obesity and a mean body mass index similar to those of the general population from which they were derived. The phenotype of PCOS, including the racial/ethnic mix, severity of presentation, and rate of obesity, is affected significantly by whether the PCOS subject arises from a referral population or through unselected screening, likely reflecting the degree of patient concern and awareness and access to healthcare.


Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project.
Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.


Stress-mapping sensors for high-power adaptive micro-optics.
Continuous deformable membrane mirrors are becoming more attractive for use in adaptive optics because they cause no diffraction in the reflected beam and ensure smooth and continuous phase variations across the mirrors. However, when such mirrors are used to correct a high-power incident wave front, the absorption in the coatings causes the temperature of the membrane to increase, thereby creating in-plane thermal stress due to the rigidly clamped boundaries. We present a technique to measure thermal stress in such nondeforming membrane structures. The directional stress and temperature effects are simultaneously measured and decoupled in micromachined membrane mirrors by using a group of three ion-implanted silicon resistors with different orientations. In stress measurements made with incident power, the sensors measure changes in compressive thermal stress to within 80-90 kPa.


Balancing individual rights versus collective good in public health enforcement.
This paper explores the balance between common good and individual liberty in the context of public health regulation. The issues are explored in reference to two areas of regulation, isolation and quarantine in the case of SARS, and the rights of parents to refuse mandatory childhood immunizations. In the case of SARS, the analysis explores the age old practice of isolation and quarantine, an important preventive measure with clear civil liberty implications. In reference to childhood immunization the paper considers the American controversy involving the refusal of parents to have their children vaccinated, fearing that mercury in vaccines will lead to autism. The analysis explores the US Supreme Court case of Jacobson v. Massachusetts which 100 years ago established a four part test for evaluating claims of individuals that government public health authorities were infringing on their liberty interests. The paper endorses the four elements of necessity, reasonableness, proportionality, and harm avoidance identified in Jacobson, but calls for a more rigorous scientific evaluation to accompany this traditional test.


Fracture risk following intermission of osteoporosis therapy.
Given the widespread practice of recommending drug holidays, we reviewed the impact of medication discontinuation of two common anti-osteoporosis therapies (bisphosphonates and denosumab). Trial evidence suggests the risk of new clinical fractures, and vertebral fracture increases when osteoporosis treatment with bisphosphonates or denosumab is stopped. The aim of this paper was to review the available literature to assess what evidence exists to inform clinical decision-making with regard to drug holidays following treatment with bisphosphonates (BiP) or denosumab. Systematic review. Differing pharmacokinetics lead to varying outcomes on stopping therapy. Prospective and retrospective analyses report that the risk of new clinical fractures was 20-40% higher in subjects who stopped BiP treatment, and vertebral fracture risk was approximately doubled. Rapid bone loss has been well described following denosumab discontinuation with an incidence of multiple vertebral fractures around 5%. Studies have not identified risk factors for fracture after stopping treatment other than those that provide an indication for treatment (e.g. prior fracture and low BMD). Studies that considered long-term continuation did not identify increased fracture risk, and reported only very low rates of adverse skeletal events such as atypical femoral fracture. The view that patients on long-term treatment with bisphosphonates or denosumab should always be offered a drug holiday is not supported by the existing evidence. Different pharmacokinetic properties for different therapies require different strategies to manage drug intermission. In contrast, long-term treatment with anti-resorptives is not associated with increased risk of fragility fractures and skeletal adverse events remain rare.


International Society for the Advancement of Cytometry cell sorter biosafety standards.
Flow cytometric cell sorting of biological specimens has become prevalent in basic and clinical research laboratories. These specimens may contain known or unknown infectious agents, necessitating precautions to protect instrument operators and the environment from biohazards arising from the use of sorters. To this end the International Society of Analytical Cytology (ISAC) was proactive in establishing biosafety guidelines in 1997 (Schmid et al., Cytometry 1997;28:99-117) and subsequently published revised biosafety standards for cell sorting of unfixed samples in 2007 (Schmid et al., Cytometry Part A J Int Soc Anal Cytol 2007;71A:414-437). Since their publication, these documents have become recognized worldwide as the standard of practice and safety precautions for laboratories performing cell sorting experiments. However, the field of cytometry has progressed since 2007, and the document requires an update. The new Standards provides guidance: (1) for laboratory design for cell sorter laboratories; (2) for the creation of laboratory or instrument specific Standard Operating Procedures (SOP); and (3) on procedures for the safe operation of cell sorters, including personal protective equipment (PPE) and validation of aerosol containment.


Evidence used in model-based economic evaluations for evaluating pharmacogenetic and pharmacogenomic tests: a systematic review protocol.
Decision models can be used to conduct economic evaluations of new pharmacogenetic and pharmacogenomic tests to ensure they offer value for money to healthcare systems. These models require a great deal of evidence, yet research suggests the evidence used is diverse and of uncertain quality. By conducting a systematic review, we aim to investigate the test-related evidence used to inform decision models developed for the economic evaluation of genetic tests. We will search electronic databases including MEDLINE, EMBASE and NHS EEDs to identify model-based economic evaluations of pharmacogenetic and pharmacogenomic tests. The search will not be limited by language or date. Title and abstract screening will be conducted independently by 2 reviewers, with screening of full texts and data extraction conducted by 1 reviewer, and checked by another. Characteristics of the decision problem, the decision model and the test evidence used to inform the model will be extracted. Specifically, we will identify the reported evidence sources for the test-related evidence used, describe the study design and how the evidence was identified. A checklist developed specifically for decision analytic models will be used to critically appraise the models described in these studies. Variations in the test evidence used in the decision models will be explored across the included studies, and we will identify gaps in the evidence in terms of both quantity and quality. The findings of this work will be disseminated via a peer-reviewed journal publication and at national and international conferences.