Epidural needle with embedded optical fibers for spectroscopic differentiation of tissue: ex vivo feasibility study.
Epidural injection is commonly used to provide intraoperative anesthesia, postoperative and obstetric analgesia, and to treat acute radicular pain. Identification of the epidural space is typically carried out using the loss of resistance (LOR) technique, but the usefulness of this technique is limited by false LOR and the inability to reliably detect intravascular or subarachnoid needle placement. In this study, we present a novel epidural needle that allows for the acquisition of optical reflectance spectra from tissue close to the beveled surface. This needle has optical fibers embedded in the cannula that deliver and receive light. With two spectrometers, light received from tissue is resolved across the wavelength range of 500 to 1600 nm. To determine the feasibility of optical tissue differentiation, spectra were acquired from porcine tissues during a post mortem laminectomy. The spectra were processed with an algorithm that derives estimates of the hemoglobin and lipid concentrations. The results of this study suggest that the optical epidural needle has the potential to improve the accuracy of epidural space identification.


Particle size effects on bioaccessible amounts of ingestible soil-borne toxic elements.
The unified BARGE method was used to examine the effects of soil particle size on the bioaccessible amounts of potentially toxic elements in multi-contaminated soils from a closed landfill site. The results show that bioaccessible As, Al, Cd, Cr, Cu, Mn, Ni, Pb and Zn increased with decreasing soil particle size and the <0.002 mm soil fraction contained much greater amounts of the bioaccessible elements, as compared to other soil fractions (0.002-0.063 mm, 0.063-0.125 mm, and 0.125-0.250 mm). As, Al and Cr had much lower bioaccessibility, as compared to the six cationic heavy metals. In contrast with other elements, As bioaccessibility tended to be higher in the gastrointestinal phase than in the gastric phase. There was a significant soil particle size effect on bioaccessibility of As and Al in the gastrointestinal phase: As bioaccessibility decreased with decreasing particle size, and the finer soil fractions tended to have a higher Al bioaccessibility, as compared to the coarser soil fractions. The research findings prompt the need for further division of soil particle size fractions in order to more accurately assess the bioaccessible amounts of soil-borne potentially toxic elements in contaminated lands.


National responsibility for ecological breakdown: a fair-shares assessment of resource use, 1970-2017.
Human impacts on earth-system processes are overshooting several planetary boundaries, driving a crisis of ecological breakdown. This crisis is being caused in large part by global resource extraction, which has increased dramatically over the past half century. We propose a novel method for quantifying national responsibility for ecological breakdown by assessing nations' cumulative material use in excess of equitable and sustainable boundaries. For this analysis, we derived national fair shares of a sustainable resource corridor. These fair shares were then subtracted from countries' actual resource use to determine the extent to which each country has overshot its fair share over the period 1970-2017. Through this approach, each country's share of responsibility for global excess resource use was calculated. High-income nations are responsible for 74% of global excess material use, driven primarily by the USA (27%) and the EU-28 high-income countries (25%). China is responsible for 15% of global excess material use, and the rest of the Global South (ie, the low-income and middle-income countries of Latin America and the Caribbean, Africa, the Middle East, and Asia) is responsible for only 8%. Overshoot in higher-income nations is driven disproportionately by the use of abiotic materials, whereas in lower-income nations it is driven disproportionately by the use of biomass. These results show that high-income nations are the primary drivers of global ecological breakdown and they need to urgently reduce their resource use to fair and sustainable levels. Achieving sufficient reductions will likely require high-income nations to adopt transformative post-growth and degrowth approaches. None.


Re-examining advice to complete antibiotic courses: a qualitative study with clinicians and patients.
Antibiotic treatment duration may be longer than sometimes needed. Stopping antibiotics early, rather than completing pre-set antibiotic courses, may help reduce unnecessary exposure to antibiotics and antimicrobial resistance (AMR). To identify clinicians' and patients' views on stopping antibiotics when better (SAWB) for urinary tract infections (UTIs), and to explore comparisons with other acute infections. An exploratory qualitative study with general practice clinicians and patients in England. Primary care clinicians and patients who had recent UTI experience were recruited in England. Remote one-to-one interviews with clinicians and patients, and one focus group with patients, were conducted. Data were audiorecorded, transcribed, and analysed thematically. Eleven clinicians (seven GPs) and 19 patients (14 with experience of recurrent and/or chronic UTIs) were included. All participants considered SAWB unfamiliar and contradictory to well-known advice to complete antibiotic courses, but were interested in the evidence for risks and benefits of SAWB. Clinicians were amenable if evidence and guidelines supported it, whereas patients were more averse because of concerns about the risk of UTI recurrence and/or complications and AMR. Participants viewed SAWB as potentially more appropriate for longer antibiotic courses and other infections (with longer courses and lower risk of recurrence and/or complications). Participants stressed the need for unambiguous advice and SAWB as part of shared decision making and personalised advice. Patients were less accepting of SAWB, whereas clinicians were more amenable to it. Patients and clinicians require good evidence that this novel approach to self-determining antibiotic duration is safe and beneficial. If evidence based, SAWB should be offered with an explanation of why the advice differs from the 'complete the course' instruction, and a clear indication of when exactly to stop antibiotics should be given.


Depression and literacy are important factors for missed appointments.
Multiple variables are related to missed clinic appointments. However, the prevalence of missed appointments is still high suggesting other factors may play a role. The purpose of this study was to investigate the relationship between missed appointments and multiple variables simultaneously across a health care system, including patient demographics, psychiatric symptoms, cognitive functioning and literacy status. Chart reviews were conducted on 147 consecutive patients who were seen by a primary care psychologist over a six month period and completed measures to determine levels of depression, anxiety, sleep, cognitive functioning and health literacy. Demographic information and rates of missed appointments were also collected from charts. The average rate of missed appointments was 15.38%. In univariate analyses, factors related to higher rates of missed appointments included younger age (p = .03), lower income (p = .05), probable depression (p = .05), sleep difficulty (p = .05) and limited reading ability (p = .003). There were trends for a higher rate of missed appointments for patients identifying as black (p = .06), government insurance (p = .06) and limited math ability (p = .06). In a multivariate model, probable depression (p = .02) and limited reading ability (p = .003) were the only independent predictors. Depression and literacy status may be the most important factors associated with missed appointments. Implications are discussed including regular screening for depression and literacy status as well as interventions that can be utilized to help improve the rate of missed appointments.


Global mRNA sequencing of human skeletal muscle: Search for novel exercise-regulated myokines.
Skeletal muscle is an important secretory organ, producing and releasing numerous myokines, which may be involved in mediating beneficial health effects of physical activity. More than 100 myokines have been identified by different proteomics approaches, but these techniques may not detect all myokines. We used mRNA sequencing as an untargeted approach to study gene expression of secreted proteins in skeletal muscle upon acute as well as long-term exercise. Twenty-six middle-aged, sedentary men underwent combined endurance and strength training for 12 weeks. Skeletal muscle biopsies from m. vastus lateralis and blood samples were taken before and after an acute bicycle test, performed at baseline as well as after 12 weeks of training intervention. We identified transcripts encoding secretory proteins that were changed more than 1.5-fold in muscle after exercise. Secretory proteins were defined based on either curated UniProt annotations or predictions made by multiple bioinformatics methods. This approach led to the identification of 161 candidate secretory transcripts that were up-regulated after acute exercise and 99 that where increased after 12 weeks exercise training. Furthermore, 92 secretory transcripts were decreased after acute and/or long-term physical activity. From these responsive transcripts, we selected 17 candidate myokines sensitive to short- and/or long-term exercise that have not been described as myokines before. The expression of these transcripts was confirmed in primary human skeletal muscle cells during in vitro differentiation and electrical pulse stimulation (EPS). One of the candidates we identified was macrophage colony-stimulating factor-1 (CSF1), which influences macrophage homeostasis. CSF1 mRNA increased in skeletal muscle after acute and long-term exercise, which was accompanied by a rise in circulating CSF1 protein. In cultured muscle cells, EPS promoted a significant increase in the expression and secretion of CSF1. We identified 17 new, exercise-responsive transcripts encoding secretory proteins. We further identified CSF1 as a novel myokine, which is secreted from cultured muscle cells and up-regulated in muscle and plasma after acute exercise.


Serum 25-hydroxyvitamin D status in hip and spine-fracture patients in Japan.
Serum 25-hydroxyvitamin D (25(OH)D) is used as an index that reflects the level of vitamin D. We have previously reported, on the basis of a study in Sado in Niigata, that patients with hip fracture have lower serum 25(OH)D levels than non-hip-fracture cases. In this study, the serum 25(OH)D status in hip-fracture cases was examined in four regions in Japan. Although most hip-fracture patients have experienced past spine-compression fractures, the relationship of these fractures and 25(OH)D is unknown. Therefore, we also examined the 25(OH)D level in spine-compression fracture patients in the same locations and time periods. The levels of 25(OH)D, intact parathyroid hormone (intact PTH), undercarboxylated osteocalcin (ucOC), urine N-terminal crosslinking telopeptide of type I collagen (NTX), and bone mineral density were examined in patients with hip and spine fracture due to osteoporosis in several regions in Japan. There were no significant differences in age, BMI, serum 25(OH)D, serum intact PTH, and serum ucOC among the regions. Levels of serum 25(OH)D were low in patients with hip fracture and spine fracture. The average serum 25(OH)D level was significantly lower in hip-fracture patients than in spine-fracture patients (16.3 vs. 18.1 ng/mL, P < 0.05). High serum ucOC was found in 37% of hip-fracture patients and 44% of spine-fracture patients. Both hip and spine-fracture patients have vitamin D insufficiency, with similar results found in elderly patients in four areas of Japan. The severity of this condition tends to be more serious in hip-fracture patients than in spine-fracture patients.


1H-NMR-based metabolic profiling of maternal and umbilical cord blood indicates altered materno-foetal nutrient exchange in preterm infants.
Adequate foetal growth is primarily determined by nutrient availability, which is dependent on placental nutrient transport and foetal metabolism. We have used (1)H nuclear magnetic resonance (NMR) spectroscopy to probe the metabolic adaptations associated with premature birth. The metabolic profile in (1)H NMR spectra of plasma taken immediately after birth from umbilical vein, umbilical artery and maternal blood were recorded for mothers delivering very-low-birth-weight (VLBW) or normo-ponderal full-term (FT) neonates. Clear distinctions between maternal and cord plasma of all samples were observed by principal component analysis (PCA). Levels of amino acids, glucose, and albumin-lysyl in cord plasma exceeded those in maternal plasma, whereas lipoproteins (notably low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) and lipid levels were lower in cord plasma from both VLBW and FT neonates. The metabolic signature of mothers delivering VLBW infants included decreased levels of acetate and increased levels of lipids, pyruvate, glutamine, valine and threonine. Decreased levels of lipoproteins glucose, pyruvate and albumin-lysyl and increased levels of glutamine were characteristic of cord blood (both arterial and venous) from VLBW infants, along with a decrease in levels of several amino acids in arterial cord blood. These results show that, because of its characteristics and simple non-invasive mode of collection, cord plasma is particularly suited for metabolomic analysis even in VLBW infants and provides new insights into the materno-foetal nutrient exchange in preterm infants.


Is smoking tobacco an independent risk factor for HIV infection and progression to AIDS? A systemic review.
To systematically review the evidence of the relation between smoking tobacco and HIV seroconversion and progression to AIDS. A systematic review was undertaken of studies to look at tobacco smoking as a risk factor for either HIV seroconversion or progression to AIDS. Six studies were identified with HIV seroconversion as an outcome measure. Five of these indicated that smoking tobacco was an independent risk factor after adjusting for important confounders with adjusted odds ratios ranging from 1.6 to 3.5. 10 studies were identified using progression to AIDS as an end point of which nine found no relation with tobacco smoking. Tobacco smoking may be an independent risk factor for HIV infection although residual confounding is another possible explanation. Smoking did not appear to be related to progression to AIDS although this finding may not be true in developing countries or with the longer life expectancies seen with highly active antiretroviral therapy.


Seroprevalence of Schmallenberg virus in the United Kingdom and the Republic of Ireland: 2011-2013.
Since its identification in late 2011, Schmallenberg virus (SBV) spread rapidly across Europe. Using archived samples from domestic ruminants collected between October 2011 and June 2013, the seroprevalence in the United Kingdom (UK) and Republic of Ireland (IE) was estimated using a serum neutralisation test. There was no significant difference (P>0.05) in seroprevalence between sheep and cows suggesting that neither species is significantly more at risk of SBV infection in the UK. A single 2011 sample tested positive; the sample was taken in November from a cow in Wiltshire. There was a steady increase in overall seroprevalence during the first three quarters of 2012, which then more than doubled in quarter 4 (October-December), which may reflect a peak of vector activity. By the end of June 2013, overall seroprevalence was around 72%. However, although seroprevalence was over 50% in Wales and southern and central counties of England, it was below 50% in all other areas of the UK and IE. This suggests that there were still substantial numbers of animals at risk of infection in the latter half of 2013.


Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder.
The repair-deficient form of trichothiodystrophy (TTD) most often results from mutations in the genes XPB or XPD, encoding helicases of the transcription/repair factor TFIIH. The genetic defect in a third group, TTD-A, is unknown, but is also caused by dysfunctioning TFIIH. None of the TFIIH subunits carry a mutation and TFIIH from TTD-A cells is active in both transcription and repair. Instead, immunoblot and immunofluorescence analyses reveal a strong reduction in the TFIIH concentration. Thus, the phenotype of TTD-A appears to result from sublimiting amounts of TFIIH, probably due to a mutation in a gene determining the complex stability. The reduction of TFIIH mainly affects its repair function and hardly influences transcription.


Cancer prevention with natural compounds.
Botanical and nutritional compounds have been used for the treatment of cancer throughout history. These compounds also may be useful in the prevention of cancer. Population studies suggest that a reduced risk of cancer is associated with high consumption of vegetables and fruits. Thus, the cancer chemopreventive potential of naturally occurring phytochemicals is of great interest. There are numerous reports of cancer chemopreventive activity of dietary botanicals, including cruciferous vegetables such as cabbage and broccoli, Allium vegetables such as garlic and onion, green tea, Citrus fruits, soybeans, tomatoes, berries, and ginger, as well as medicinal plants. Several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin (from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli), and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals have great potential in cancer prevention because of their safety, low cost, and oral bioavailability. In this review, we discuss potential natural cancer preventive compounds and their mechanisms of action.


A systematic review of the impact of adherence on the effectiveness of e-therapies.
As the popularity of e-therapies grows, so too has the body of literature supporting their effectiveness. However, these interventions are often plagued by high attrition rates and varying levels of user adherence. Understanding the role of adherence may be crucial to understanding how program usage influences the effectiveness of e-therapy interventions. The aim of this study was to systematically review the e-therapy literature to (1) describe the methods used to assess adherence and (2) evaluate the association of adherence with outcome of these interventions. A systematic review of e-therapy interventions was conducted across disease states and behavioral targets. Data were collected on adherence measures, outcomes, and analyses exploring the relationship between adherence measures and outcomes. Of 69 studies that reported an adherence measure, only 33 (48%) examined the relationship between adherence and outcomes. The number of logins was the most commonly reported measure of adherence, followed by the number of modules completed. The heterogeneity of adherence and outcome measures limited analysis. However, logins appeared to be the measure of adherence most consistently related to outcomes in physical health interventions, while module completion was found to be most related to outcomes in psychological health interventions. There is large variation in the reporting of adherence and the association of adherence with outcomes. A lack of agreement about how best to measure adherence is likely to contribute to the variation in findings. Physical and psychological outcomes seem influenced by different types of adherence. A composite measure encompassing time online, activity completion, and active engagements with the intervention may be the best measure of adherence. Further research is required to establish a consensus for measuring adherence and to understand the role of adherence in influencing outcomes.


Underwater Photogrammetry and Object Modeling: A Case Study of Xlendi Wreck in Malta.
In this paper we present a photogrammetry-based approach for deep-sea underwater surveys conducted from a submarine and guided by knowledge-representation combined with a logical approach (ontology). Two major issues are discussed in this paper. The first concerns deep-sea surveys using photogrammetry from a submarine. Here the goal was to obtain a set of images that completely covered the selected site. Subsequently and based on these images, a low-resolution 3D model is obtained in real-time, followed by a very high-resolution model produced back in the laboratory. The second issue involves the extraction of known artefacts present on the site. This aspect of the research is based on an a priori representation of the knowledge involved using systematic reasoning. Two parallel processes were developed to represent the photogrammetric process used for surveying as well as for identifying archaeological artefacts visible on the sea floor. Mapping involved the use of the CIDOC-CRM system (International Committee for Documentation (CIDOC)-Conceptual Reference Model)-This is a system that has been previously utilised to in the heritage sector and is largely available to the established scientific community. The proposed theoretical representation is based on procedural attachment; moreover, a strong link is maintained between the ontological description of the modelled concepts and the Java programming language which permitted 3D structure estimation and modelling based on a set of oriented images. A very recently discovered shipwreck acted as a testing ground for this project; the Xelendi Phoenician shipwreck, found off the Maltese coast, is probably the oldest known shipwreck in the western Mediterranean. The approach presented in this paper was developed in the scope of the GROPLAN project (Généralisation du Relevé, avec Ontologies et Photogrammétrie, pour l'Archéologie Navale et Sous-marine). Financed by the French National Research Agency (ANR) for four years, this project associates two French research laboratories, an industrial partner, the University of Malta, and Texas A & M University.


Acute-care nurse practitioners: 'strangers in a strange land'.
In 1961, Heinlein described a "stranger" from another planet struggling to comprehend and integrate the cultural idiosyncracies of earthlings in his adopted land. One could compare that situation with what confronts acute-care nurse practitioners (ACNPs) as they embark into the practitioner's world of acute care. Rather than embrace the expensive and fragmented patient-care world through collaboration with its "strangers," ACNPs would benefit from clinging to elements of their own native nursing culture and become "nesters" rather than "perchers" in the quest for improved health care.


Targeting tumour-initiating cells to improve the cure rates for triple-negative breast cancer.
Tumour recurrence is one of the biggest challenges in breast cancer management because it affects 25-30% of women with breast cancer and the tumours are often incurable. Women with triple-negative breast cancer (TNBC--lacking expression of the oestrogen receptor, progesterone receptor and the receptor HER2/ERBB2) have the highest rates of early recurrence relative to other breast cancer subtypes. Early recurrence might be due to tumour-initiating cells (TICs), which are resistant to conventional therapies, can remain dormant and can subsequently give rise to secondary tumours. In breast cancer, TICs are identified by the cell-surface markers CD44+/CD24-/EpCAM+ and/or possess ALDH1 enzyme activity. This subpopulation has the ability to self-renew, grow as mammospheres and initiate tumour formation. Fuelling the problem of relapse is the fact that chemotherapy and radiation can induce or select for TICs; this was reported in preclinical models and more recently in women being treated for breast cancer. Thus, new therapeutic agents for TNBC are presently being sought to overcome this problem. Here we review the roles of receptor tyrosine kinases, signalling intermediates and transcription factors in sustaining the TIC subpopulation. Particular emphasis is placed on targeting these molecules in order to eliminate and/or prevent the induction of TICs and ultimately reduce the frequency of TNBC recurrence.


Factors influencing medication adherence beliefs and self-efficacy in persons naive to antiretroviral therapy: a multicenter, cross-sectional study.
It is widely recognized that adherence to antiretroviral therapy is critical to long-term treatment success, yet rates of adherence to antiretroviral medications are frequently subtherapeutic. Beliefs about antiretroviral therapy and psychosocial characteristics of HIV-positive persons naive to therapy may influence early experience with antiretroviral medication adherence and therefore could be important when designing programs to improve adherence to antiretroviral therapy. As part of a multicenter AIDS Clinical Trial Group (ACTG 384) study, 980 antiretroviral-naive subjects (82% male, 47% White, median age 36 years, and median CD4 cell count 278 cells/mm3) completed a self-administered questionnaire prior to random treatment assignment of initial antiretroviral medications. Measures of symptom distress, general health and well-being, and personal and situational factors including demographic characteristics, social support, self-efficacy, depression, stress, and current adherence to (nonantiretroviral) medications were recorded. Associations among variables were explored using correlation and regression analyses. Beliefs about the importance of antiretroviral adherence and ability to take antiretroviral medications as directed (adherence self-efficacy) were generally positive. Fifty-six percent of the participants were "extremely sure" of their ability to take all medications as directed and 48% were "extremely sure" that antiretroviral nonadherence would cause resistance, but only 37% were as sure that antiretroviral therapy would benefit their health. Less-positive beliefs about antiretroviral therapy adherence were associated with greater stress, depression, and symptom distress. More-positive beliefs about antiretroviral therapy adherence were associated with better scores on health perception, functional health, social-emotional-cognitive function, social support, role function, younger age, and higher education (r values = 0.09-0.24, all p < .001). Among the subset of 325 participants reporting current use of medications (nonantiretrovirals) during the prior month, depression was the strongest correlate of nonadherence ( r = 0.33, p < .001). The most common reasons for nonadherence to the medications were "simply forgot" (33%), "away from home" (27%), and "busy" (26%). In conclusion, in a large, multicenter survey, personal and situational factors, such as depression, stress, and lower education, were associated with less certainty about the potential for antiretroviral therapy effectiveness and one's perceived ability to adhere to therapy. Findings from these analyses suggest a role for baseline screening for adherence predictors and focused interventions to address modifiable factors placing persons at high risk for poor adherence prior to antiretroviral treatment initiation.


Influence of Onset to Imaging Time on Radiological Thrombus Characteristics in Acute Ischemic Stroke.
Introduction: Radiological thrombus characteristics are associated with patient outcomes and treatment success after acute ischemic stroke. These characteristics could be expected to undergo time-dependent changes due to factors influencing thrombus architecture like blood stasis, clot contraction, and natural thrombolysis. We investigated whether stroke onset-to-imaging time was associated with thrombus length, perviousness, and density in the MR CLEAN Registry population. Methods: We included 245 patients with M1-segment occlusions and thin-slice baseline CT imaging from the MR CLEAN Registry, a nation-wide multicenter registry of patients who underwent endovascular treatment for acute ischemic stroke within 6.5 h of onset in the Netherlands. We used multivariable linear regression to investigate the effect of stroke onset-to-imaging time (per 5 min) on thrombus length (in mm), perviousness and density (both in Hounsfield Units). In the first model, we adjusted for age, sex, intravenous thrombolysis, antiplatelet use, and history of atrial fibrillation. In a second model, we additionally adjusted for observed vs. non-observed stroke onset, CT-angiography collateral score, direct presentation at a thrombectomy-capable center vs. transfer, and stroke etiology. We performed exploratory subgroup analyses for intravenous thrombolysis administration, observed vs. non-observed stroke onset, direct presentation vs. transfer, and stroke etiology. Results: Median stroke onset-to-imaging time was 83 (interquartile range 53-141) min. Onset to imaging time was not associated with thrombus length nor perviousness (β 0.002; 95% CI -0.004 to 0.007 and β -0.002; 95% CI -0.015 to 0.011 per 5 min, respectively) and was weakly associated with thrombus density in the fully adjusted model (adjusted β 0.100; 95% CI 0.005-0.196 HU per 5 min). The subgroup analyses showed no heterogeneity of these findings in any of the subgroups, except for a significantly positive relation between onset-to-imaging time and thrombus density in patients transferred from a primary stroke center (adjusted β 0.18; 95% CI 0.022-0.35). Conclusion: In our population of acute ischemic stroke patients, we found no clear association between onset-to-imaging time and radiological thrombus characteristics. This suggests that elapsed time from stroke onset plays a limited role in the interpretation of radiological thrombus characteristics and their effect on treatment results, at least in the early time window.


Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases.
Urokinase-type plasminogen activator (uPA) gene transcription is increased > or = 50-fold in chicken embryo fibroblasts (CEF) following transformation by the protein tyrosine kinase pp60v-src. Protein phosphorylation appears to play a critical role in uPA gene expression in these cells; protein kinase C-activating phorbol esters cooperate with pp60v-src to synergistically increase uPA mRNA, whereas cyclic AMP (cAMP)-dependent protein kinase-activating agents (e.g., 8-bromo cAMP) repress uPA mRNA levels. To explore the relationship between transforming oncogenes and uPA gene expression, uPA mRNA levels were measured in CEF infected with selected avian retroviruses. We report that v-ras and the transforming protein tyrosine kinases v-src, v-yes, and v-ros all increase cellular uPA mRNAs. However, transformation with the protein tyrosine kinase encoded by v-erbB, or the nuclear proteins encoded by v-jun, v-ski, or v-myc, did not increase uPA mRNA detectably. Ras and all of the protein tyrosine kinases analyzed, including the v-erbB product, but none of the nuclear oncoproteins sensitized cells to phorbol ester induction of uPA gene expression. Thus, increased uPA gene expression is not simply a secondary consequence of cell transformation but, rather, is regulated or comodulated by only a subset of oncogene products. Analysis of cells expressing site-directed mutants of pp60v-src showed that the induction of the uPA gene is dependent on protein tyrosine kinase catalytic activity, myristylation, and plasma membrane localization. However, these properties together are not sufficient; an additional feature in the src homology 2 domain is also required. The major sites of serine phosphorylation, serines 12 and 17, and the autophosphorylation site, tyrosine 416, are not essential for uPA gene induction. However, the reduction of uPA mRNA in pp60v-src-transformed cells by 8-bromo cAMP is dependent on tyrosine 416.


Corner height influences center of mass kinematics and path trajectory during turning.
Despite the prevalence of directional changes during every-day gait, relatively little is known about turning compared to straight gait. While the center of mass (COM) movement during straight gait is well characterized, the COM trajectory and the factors that influence it are less established for turning. This study investigated the influence of a corner׳s height on the COM trajectory as participants walked around the corner. Ten participants (25.3±3.74 years) performed both 90° step and spin turns to the left at self-selected slow, normal, and fast speeds while walking inside a marked path. A pylon was placed on the inside corner of the path. Four different pylon heights were used to correspond to heights of everyday objects: 0 cm (no object), 63 cm (box, crate), 104 cm (desk, table, counter), 167 cm (shelf, cabinet). Obstacle height was found to significantly affect the COM trajectory. Taller obstacles resulted in more distance between the corner and the COM, and between the corner and the COP. Taller obstacles also were associated with greater curvature in the COM trajectory, indicating a smaller turning radius despite the constant 90° corner. Taller obstacles correlated to an increased required coefficient of friction (RCOF) due to the smaller turning radii. Taller obstacles also tended towards greater mediolateral (ML) COM-COP angles, contrary to the initial hypothesis. Additionally, the COM was found to remain outside the base of support (BOS) for the entire first half of stance phase for all conditions indicating a high risk of falls resulting from slips.


Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association.
Many widely used medications may cause or exacerbate a variety of arrhythmias. Numerous antiarrhythmic agents, antimicrobial drugs, psychotropic medications, and methadone, as well as a growing list of drugs from other therapeutic classes (neurological drugs, anticancer agents, and many others), can prolong the QT interval and provoke torsades de pointes. Perhaps less familiar to clinicians is the fact that drugs can also trigger other arrhythmias, including bradyarrhythmias, atrial fibrillation/atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, monomorphic ventricular tachycardia, and Brugada syndrome. Some drug-induced arrhythmias (bradyarrhythmias, atrial tachycardia, atrioventricular node reentrant tachycardia) are significant predominantly because of their symptoms; others (monomorphic ventricular tachycardia, Brugada syndrome, torsades de pointes) may result in serious consequences, including sudden cardiac death. Mechanisms of arrhythmias are well known for some medications but, in other instances, remain poorly understood. For some drug-induced arrhythmias, particularly torsades de pointes, risk factors are well defined. Modification of risk factors, when possible, is important for prevention and risk reduction. In patients with nonmodifiable risk factors who require a potentially arrhythmia-inducing drug, enhanced electrocardiographic and other monitoring strategies may be beneficial for early detection and treatment. Management of drug-induced arrhythmias includes discontinuation of the offending medication and following treatment guidelines for the specific arrhythmia. In overdose situations, targeted detoxification strategies may be needed. Awareness of drugs that may cause arrhythmias and knowledge of distinct arrhythmias that may be drug-induced are essential for clinicians. Consideration of the possibility that a patient's arrythmia could be drug-induced is important.


A survey of complementary and alternative medicine (CAM) awareness among neurosurgeons in Washington State.
Use of complementary and alternative medicine (CAM) by the U.S. population increased significantly in the past 2 decades. To maximize a patient's recovery from a neurosurgical procedure, it is critical that neurosurgeons be aware of the benefits and potential adverse complications of CAM therapies. The survey's purpose was to assess the current patterns of CAM utilization by neurosurgery patients and neurosurgeon knowledge of CAM therapies among Washington State Association of Neurological Surgeons (WSANS) members. Members of the WSANS were surveyed in 2005. The survey was sent via e-mail and the data were anonymously collected using an online survey tool, Catalyst WebQ. The majority of responses (79%) stated that their neurosurgery practice was > or =75% adults. Acupuncture, herbs, massage therapy, prayer, and yoga were the most common CAM treatments patients used or discussed with their neurosurgeon. Fifty percent (50%) of neurosurgeons discussed the use of acupuncture among their colleagues. Concerning prayer and spirituality, 38% of the surveyed neurosurgeons stated that > or =25% of their patients have disclosed that they pray for their health; 42% stated that spirituality and prayer may affect neurosurgery outcome; and 38% stated that they pray for their patients. Overall, 63% of surveyed neurosurgeons stated that CAM treatments have a role in neurosurgery. The use of CAM may influence neurosurgical care; and the role of spirituality and prayer should be further explored. Because CAM utilization is ubiquitous, open discussion and familiarity with CAM treatments are becoming increasingly important in the field of neurosurgery.


Evidence for association of OCTN genes and IBD5 with ulcerative colitis.
Genetic association between Crohn's disease (CD) and OCTN1 (SLC22A4) C1672T/OCTN2 (SLC22A5) G-207C variants in IBD5 has recently been reported. These genes encode solute carriers and the association was suggested to be distinct from the background IBD5 risk haplotype. There have been conflicting reports of the association between markers in the IBD5 region and ulcerative colitis (UC) and interaction (epistasis) between this locus and CARD15. Our aim was to ascertain the contribution of OCTN variants to UC and CD in a large independent UK dataset, to seek genetic evidence that the OCTN association is distinct from the IBD5 risk haplotype and to identify interactions between the IBD5 and CARD15 loci. A total of 1104 unrelated Caucasian subjects with inflammatory bowel disease (IBD) (496 CD, 512 UC, 96 indeterminate) and 750 ethnically matched controls were genotyped for three single nucleotide polymorphisms (SNPs) in the CD associated genes (OCTN1+1672, OCTN2-207, and IGR2230), and two flanking IBD5 tagging SNPs, IGR2096 and IGR3096. Data were analysed by logistic regression methods within STATA. OCTN variants were as strongly associated with UC and IBD overall as they were with CD (p = 0.0001; OR 1.3 (95% confidence interval 1.1-1.5)). OCTN variants were in tight linkage disequilibrium with the extended IBD5 risk haplotype D' 0.79 and 0.88, and r2 = 0.62 and 0.72 for IGR2096 and 3096, respectively. There was no deviation from a multiplicative model of interaction between CARD15 and IBD5 on the penetrance scale. The OCTN variants were associated with susceptibility to IBD overall. The effect was equally strong in UC and CD. Although OCTN variants may account for the increased risk of IBD associated with IBD5, a role for other candidate genes within this extended haplotype was not excluded. There was no statistical evidence of interaction between CARD15 and either OCTN or IBD5 variants in susceptibility to IBD.


Diffusion tensor imaging and ventricle volume quantification in patients with chronic shunt-treated hydrocephalus: a matched case-control study.
OBJECTIVEThe object of this study was to use diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) to characterize the long-term effects of hydrocephalus and shunting on white matter integrity and to investigate the relationship of ventricular size and alterations in white matter integrity with headache and quality-of-life outcome measures.METHODSPatients with shunt-treated hydrocephalus and age- and sex-matched healthy controls were recruited into the study and underwent anatomical and DTI imaging on a 3-T MRI scanner. All patients were clinically stable, had undergone CSF shunt placement before 2 years of age, and had a documented history of complaints of headaches. Outcome was scored based on the Headache Disability Inventory and the Hydrocephalus Outcome Questionnaire. Fractional anisotropy (FA) and other DTI-based measures (axial, radial, and mean diffusivity; AD, RD, and MD, respectively) were extracted in the corpus callosum and internal capsule with manual region-of-interest delineation and in other regions with TBSS. Paired t-tests, corrected with a 5% false discovery rate, were used to identify regions with significant differences between patients and controls. Within the patient group, linear regression models were used to investigate the relationship between FA or ventricular volume and outcome, as well as the effect of shunt-related covariates.RESULTSTwenty-one hydrocephalus patients and 21 matched controls completed the study, and their data were used in the final analysis. The authors found significantly lower FA for patients than for controls in 20 of the 48 regions, mostly posterior white matter structures, in periventricular as well as more distal tracts. Of these 20 regions, 17 demonstrated increased RD, while only 5 showed increased MD and 3 showed decreased AD. No areas of increased FA were observed. Higher FA in specific periventricular white matter tracts, tending toward FA in controls, was associated with increased ventricular size, as well as improved clinical outcome.CONCLUSIONSThe study shows that TBSS-based DTI is a sensitive technique for elucidating changes in white matter structures due to hydrocephalus and chronic CSF shunting and provides preliminary evidence that DTI may be a valuable tool for tailoring shunt procedures to monitor ventricular size following shunting and achieve optimal outcome, as well as for guiding the development of alternate therapies for hydrocephalus.


A Novel Mechanism of High Dose Radiation Sensitization by Metformin.
Introduction: Metformin, the most widely used treatment for diabetes, is lethal to cancer cells and increases in toxicity when used in combination with radiation. In addition to various molecular and metabolic mechanisms that have been previously proposed, the studies presented provide evidence of an additional, novel mechanism of sensitization following high dose radiotherapy; the magnitude of sensitization depends on the microenvironmental levels of glucose and oxygen which are in turn affected by high dose radiation. Methods: Cancer cells (A549 and MCF7) were studied in vitro under various controlled conditions. Endpoints included clonogenic cell survival and ROS expression measured by DHE and DCFDA. CD1 nu/nu athymic mice implanted with A549 cells received metformin alone (200 mg/kg, i.p.), radiation alone (15 Gy) or a combination of metformin and radiation; the effect of treatment sequence on efficacy was assessed by tumor growth delay and histology. In a separate set of experiments, tumor blood flow was measured using a tracer clearance technique using SPECT after the administration of metformin alone, radiation alone and the combined treatment. Results: In vivo, metformin provided equally effective tumor growth delay when given 24 h after radiation as when given 1 h or 4 h before radiation, an observation not previously reported and, in fact, unexpected based on published scientific literature. When drug followed radiation, the tumors were histologically characterized by massive cellular necrosis. In vitro, cancer cells when glucose depleted and/or hypoxic were preferentially killed by metformin, in a drug dose dependent manner. A549 cells exposed to 5.0 mM of metformin was reduced seven fold in survival when in a glucose deprived as compared to a low-glucose medium (0 vs. 1.0 g/L). Finally, using a SPECT detector to follow the washout of a radioactive tracer, it was shown that a high single dose of radiosurgery (15 Gy) could dramatically inhibit blood flow and presumably diminish glucose and oxygen. Discussion: Insight into the best timing of drug and radiation administration is gained through an understanding of the mechanisms of interaction. A new mechanism of metformin sensitization by high dose radiation is proposed based on the blood flow, glucose and oxygen.


Optical properties of single plasmonic holes probed with local electron beam excitation.
Similar to nanoparticles, nanoscale holes form a basic building block in a wide array of nanophotonic devices. Here we study the spectral and angular cathodoluminescence response of individual nanoholes with diameters ranging from 50 to 180 nm. Taking advantage of the deep-subwavelength excitation resolution, we find that the holes can be excited efficiently at the edge of the hole and that the response becomes stronger in the near-infrared part of the spectrum for larger holes. Using finite-difference time-domain simulations, we characterize the resonant modes inside the holes. We measure the angle-resolved cathodoluminescence response and observe strong beaming toward the side of electron beam excitation, complementary to what was shown for nanoparticles. The angular response can be explained by assuming a coherent superposition of radiating dipole moments, where the contribution of in-plane magnetic and electric dipole components increases for larger diameters.


Effects of locality based community hospital care on independence in older people needing rehabilitation: randomised controlled trial.
To determine the effects on independence in older people needing rehabilitation in a locality based community hospital compared with care on a ward for elderly people in a district general hospital. Randomised controlled trial. Care in a community hospital and district general hospital in Bradford, England. 220 patients needing rehabilitation after an acute illness that required hospital admission. Patients were randomly allocated to a locality based community hospital or to remain within a department for the care of elderly people in a district general hospital. Primary outcomes were Nottingham extended activities of daily living scale and general health questionnaire 28 (carer). Secondary outcomes were activities of daily living (Barthel index), Nottingham health profile, hospital anxiety and depression scale, mortality, destination after discharge, satisfaction with services, carer strain index, and carer's satisfaction with services. The median length of stay was 15 days for both the community hospital and the district general hospital groups (interquartile range: community hospital 9-25 days; district general hospital 9-24 days). Independence at six months was greater in the community hospital group (adjusted mean difference 5.30, 95% confidence interval 0.64 to 9.96). Results for the secondary outcome measures, including care satisfaction and measures of carer burden, were similar for both groups. Care in a locality based community hospital is associated with greater independence for older people than care in wards for elderly people in a district general hospital.


Mapping intra-urban malaria risk using high resolution satellite imagery: a case study of Dar es Salaam.
With more than half of Africa's population expected to live in urban settlements by 2030, the burden of malaria among urban populations in Africa continues to rise with an increasing number of people at risk of infection. However, malaria intervention across Africa remains focused on rural, highly endemic communities with far fewer strategic policy directions for the control of malaria in rapidly growing African urban settlements. The complex and heterogeneous nature of urban malaria requires a better understanding of the spatial and temporal patterns of urban malaria risk in order to design effective urban malaria control programs. In this study, we use remotely sensed variables and other environmental covariates to examine the predictability of intra-urban variations of malaria infection risk across the rapidly growing city of Dar es Salaam, Tanzania between 2006 and 2014. High resolution SPOT satellite imagery was used to identify urban environmental factors associated malaria prevalence in Dar es Salaam. Supervised classification with a random forest classifier was used to develop high resolution land cover classes that were combined with malaria parasite prevalence data to identify environmental factors that influence localized heterogeneity of malaria transmission and develop a high resolution predictive malaria risk map of Dar es Salaam. Results indicate that the risk of malaria infection varied across the city. The risk of infection increased away from the city centre with lower parasite prevalence predicted in administrative units in the city centre compared to administrative units in the peri-urban suburbs. The variation in malaria risk within Dar es Salaam was shown to be influenced by varying environmental factors. Higher malaria risks were associated with proximity to dense vegetation, inland water and wet/swampy areas while lower risk of infection was predicted in densely built-up areas. The predictive maps produced can serve as valuable resources for municipal councils aiming to shrink the extents of malaria across cities, target resources for vector control or intensify mosquito and disease surveillance. The semi-automated modelling process developed can be replicated in other urban areas to identify factors that influence heterogeneity in malaria risk patterns and detect vulnerable zones. There is a definite need to expand research into the unique epidemiology of malaria transmission in urban areas for focal elimination and sustained control agendas.


Bacteriological studies of the venom and mouth cavities of wild Malayan pit vipers (Calloselasma rhodostoma) in southern Thailand.
Venom and oropharyngeal swabs from freshly captured Malayan pit vipers (Calloselasma rhodostoma) in southern Thailand and captive specimens in England were cultured aerobically and anaerobically to identify the bacterial flora which might contaminate wounds inflicted by bites of this species. The snakes' mouths contained a wider range of organisms than their venoms, especially gut-related Gram-negative rods such as Enterobacter and Pseudomonas species and some staphylococci and clostridia. There were fewer positive cultures from captive snakes. C. rhodostoma venom inhibited the growth of group A streptococci and, to a lesser extent, that of Staphylococcus aureus and Clostridium perfringens but not that of 2 Gram-negative organisms. Secondary bacterial infection is an important complication of snake bite, especially of necrotic wounds. A combination of gentamicin with benzyl penicillin would have prevented infection with, or treated, most of the bacteria isolated from snake venoms and mouths in Thailand.


Modeling Key Drivers of Cholera Transmission Dynamics Provides New Perspectives for Parasitology.
Hydroclimatological and anthropogenic factors are key drivers of waterborne disease transmission. Information on human settlements and host mobility on waterways along which pathogens and hosts disperse, and relevant hydroclimatological processes, can be acquired remotely and included in spatially explicit mathematical models of disease transmission. In the case of epidemic cholera, such models allowed the description of complex disease patterns and provided insight into the course of ongoing epidemics. The inclusion of spatial information in models of disease transmission can aid in emergency management and the assessment of alternative interventions. Here, we review the study of drivers of transmission via spatially explicit approaches and argue that, because many parasitic waterborne diseases share the same drivers as cholera, similar principles may apply.


Vapor-Phase Hydrogen Peroxide Uptake by Silicone Tubing and Primary Packaging Components during Protein Drug Product Aseptic Filling: Impact of Pretreatment and Sterilization Process.
In the vapor-phase hydrogen peroxide (VPHP)-sanitized environment, VPHP uptake by product-contacting components could eventually lead to undesired oxidation of biological drug products. Silicone tubing and primary packaging materials are prominent examples of such product-contacting surfaces that are typically processed/sterilized prior to use. This study investigated the VPHP-uptake tendency of these components and how their respective processing/sterilization methods affect the uptake behaviors. Silicone tubing that was sterilized via autoclave or gamma irradiation exhibited different VPHP uptake patterns-decreased uptake rates post autoclaving vs. increased uptake rates post gamma irradiation. The reduced uptake tendency of autoclaved tubing is maintained for 14 days after sterilization, whereas the uptake tendency of irradiated tubing was mostly reversed to normal levels 1 month after irradiation. Empty glass vials adsorbed hydrogen peroxide via the diffusion of VPHP into the vial with high vial-to-vial variability. Vial pretreatment (i.e., depyrogenation) and surface hydrophilicity/hydrophobicity impacted the uptake tendency. Stoppers and empty syringes also adsorbed hydrogen peroxide but at a relatively low level. The uptake behavior of these components appeared to correlate with water levels at the surface (i.e., hydrophilicity). This study provides process development scientists and engineers an in-depth understanding of the VPHP uptake by critical product-contacting surfaces so that they can mitigate the impact on drug product quality.LAY ABSTRACT: This study investigated vapor-phase hydrogen peroxide (VPHP) absorption by biopharmaceutical drug products via VPHP uptake by critical product-contacting components during the aseptic manufacturing process with a focus on various pretreatments and processing of these components. Sterilization of silicone tubing by gamma irradiation or autoclaving resulted in different VPHP uptake profiles with different effect durations. Primary packaging components, such as vials, syringes, and stoppers, also showed different levels of VPHP uptake with surface hydrophilicity/hydrophobicity playing a critical role. These outcomes suggested that VPHP uptake is a complex phenomenon and should be carefully considered to minimize its impact on product quality. The approach and outcome of this study can benefit scientists and engineers who develop biological product manufacturing processes by providing an in-depth understanding of drug product process risks.


How many ritonavir cases are there still out there?
Based on a thorough and critical analysis of the commercial crystal structure prediction studies of 41 pharmaceutical compounds, we conclude that for between 15 and 45% of all small-molecule drugs currently on the market the most stable experimentally observed polymorph is not the thermodynamically most stable crystal structure and that the appearance of the latter is kinetically hindered.


Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma.
Conjunctival melanoma (CM) is a rare ocular malignancy with a high tendency to reoccur locally and with a high risk of metastatic disease. Metastases are often unresponsive to conventional treatment. Recently, an animal model was set up using human CM cells. Orthotopic xenografts from human CM were created by subconjunctival injection of three different CM cell lines into NOD.Cg-Prkdcscid IL2rgtm1Wjl /SzJ (NSG) mice. Subconjunctival injection of cultured CM cells led to excellent subconjunctival growth, but no metastases were found. When single-cell suspensions were obtained from the subconjunctival xenografts and passaged in vivo, all mice developed metastases. As recent findings indicate that cancer stem cells are linked to tumor recurrences, we used this new murine model to determine the expression of the stem cell marker ABCB5 during tumor progression. Expression of the ABCB5 protein was determined in three cell lines and during different stages of tumor development as observed in our model. All three cell lines contained a subpopulation of cells positive for ABCB5. During tumor development, expression of ABCB5 increased during phases of tumor expansion. Furthermore, expression of ABCB5 was increased in metastases. Using this model for CM, we were able to initiate metastatic spread and determine the expression of the stem cell marker ABCB5 during different stages of tumor development, identifying ABCB5 as a potential novel therapeutic target. This study illustrates the potential of our newly established murine model.


Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses.
The development of multivalent sialic acid-based inhibitors active against a variety of influenza A virus (IAV) strains has been hampered by high genetic and structural variability of the targeted viral hemagglutinin (HA). Here, we addressed this challenge by employing sialylated polyglycerols (PGs). Efficacy of prototypic PGs was restricted to a narrow spectrum of IAV strains. To understand this restriction, we selected IAV mutants resistant to a prototypic multivalent sialylated PG by serial passaging. Resistance mutations mapped to the receptor binding site of HA, which was accompanied by altered receptor binding profiles of mutant viruses as detected by glycan array analysis. Specifying the inhibitor functionalization to 2,6-α-sialyllactose (SL) and adjusting the linker yielded a rationally designed inhibitor covering an extended spectrum of inhibited IAV strains. These results highlight the importance of integrating virological data with chemical synthesis and structural data for the development of sialylated PGs toward broad anti-influenza compounds.


Kernel-based Joint Feature Selection and Max-Margin Classification for Early Diagnosis of Parkinson's Disease.
Feature selection methods usually select the most compact and relevant set of features based on their contribution to a linear regression model. Thus, these features might not be the best for a non-linear classifier. This is especially crucial for the tasks, in which the performance is heavily dependent on the feature selection techniques, like the diagnosis of neurodegenerative diseases. Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which progresses slowly while affects the quality of life dramatically. In this paper, we use the data acquired from multi-modal neuroimaging data to diagnose PD by investigating the brain regions, known to be affected at the early stages. We propose a joint kernel-based feature selection and classification framework. Unlike conventional feature selection techniques that select features based on their performance in the original input feature space, we select features that best benefit the classification scheme in the kernel space. We further propose kernel functions, specifically designed for our non-negative feature types. We use MRI and SPECT data of 538 subjects from the PPMI database, and obtain a diagnosis accuracy of 97.5%, which outperforms all baseline and state-of-the-art methods.


Golden Hours in Severe Paraquat Poisoning-The Role of Early Haemoperfusion Therapy.
Paraquat is a commonly ingested poison especially in Southern India. There is no antidote for paraquat poison and consumption is often fatal. The usual cause of death is either acute lung injury or multi-organ failure. To evaluate the role of early haemoperfusion as a therapy in paraquat poisoned patients. This study was a retrospective analysis of patients admitted to a Tertiary Medical College Hospital between January 2012 and December 2015 with history of paraquat consumption, comparing outcomes in those who received only gastric lavage and symptomatic treatment with those who received haemoperfusion as a therapy. The role of early haemoperfusion (≤ 6 hours) vs late haemoperfusion (> 6 hours) in paraquat poisoned patients was also compared. The data of these patients was extracted and analysed with respect to age, sex, mode of treatment, the outcome in patients who received early and late haemoperfusion. A total of 101 patients were studied out of which 62 died. Deaths were more in those patients who received only gastric lavage with symptomatic treatment as therapy compared to those who received haemoperfusion i.e., 92.1% vs 42.9% respectively. We also found that, the survival rate was better in patients who received early haemoperfusion. Early haemoperfusion was helpful in the management of severe paraquat poisoning and improved the survival rate in these patients.


Risk of major adverse cardiac events following noncardiac surgery in patients with coronary stents.
Guidelines recommend delaying noncardiac surgery in patients after coronary stent procedures for 1 year after drug-eluting stents (DES) and for 6 weeks after bare metal stents (BMS). The evidence underlying these recommendations is limited and conflicting. To determine risk factors for adverse cardiac events in patients undergoing noncardiac surgery following coronary stent implantation. A national, retrospective cohort study of 41,989 Veterans Affairs (VA) and non-VA operations occurring in the 24 months after a coronary stent implantation between 2000 and 2010. Nonlinear generalized additive models examined the association between timing of surgery and stent type with major adverse cardiac events (MACE) adjusting for patient, surgery, and cardiac risk factors. A nested case-control study assessed the association between perioperative antiplatelet cessation and MACE. A composite 30-day MACE rate of all-cause mortality, myocardial infarction, and cardiac revascularization. Within 24 months of 124,844 coronary stent implantations (47.6% DES, 52.4% BMS), 28,029 patients (22.5%; 95% CI, 22.2%-22.7%) underwent noncardiac operations resulting in 1980 MACE (4.7%; 95% CI, 4.5%-4.9%). Time between stent and surgery was associated with MACE (<6 weeks, 11.6%; 6 weeks to <6 months, 6.4%; 6-12 months, 4.2%; >12-24 months, 3.5%; P < .001). MACE rate by stent type was 5.1% for BMS and 4.3% for DES (P < .001). After adjustment, the 3 factors most strongly associated with MACE were nonelective surgical admission (adjusted odds ratio [AOR], 4.77; 95% CI, 4.07-5.59), history of myocardial infarction in the 6 months preceding surgery (AOR, 2.63; 95% CI, 2.32-2.98), and revised cardiac risk index greater than 2 (AOR, 2.13; 95% CI, 1.85-2.44). Of the 12 variables in the model, timing of surgery ranked fifth in explanatory importance measured by partial effects analysis. Stent type ranked last, and DES was not significantly associated with MACE (AOR, 0.91; 95% CI, 0.83-1.01). After both BMS and DES placement, the risk of MACE was stable at 6 months. A case-control analysis of 284 matched pairs found no association between antiplatelet cessation and MACE (OR, 0.86; 95% CI, 0.57-1.29). Among patients undergoing noncardiac surgery within 2 years of coronary stent placement, MACE were associated with emergency surgery and advanced cardiac disease but not stent type or timing of surgery beyond 6 months after stent implantation. Guideline emphasis on stent type and surgical timing for both DES and BMS should be reevaluated.


Evaluation of the endothelial cell antibodies in serum and perilymphatic fluid of cochlear implanted children with sensorineural hearing loss.
Serum Anti endothelial Cell Antibodies (AECAs) play a prominent role in idiopathic Sensorineural Hearing Loss (SNHL) in that they induce vascular damage (immune mediated). The of the current study is To compare AECAs in serum and perilymphatic fluid of idiopathic SNHL children (<15y) undergoing cochlear implant surgery. This was a cross sectional study performed in the cochlear implant ward in Rasoul Akram hospital, Tehran, Iran (2008 -2010) on 99 SNHL children undergoing cochlear implant surgery. The data collected from47 idiopathic and 52 non-idiopathic SNHL cases. AECAs were measured by indirect immuno fluorescence assay and compared in sera and perilymphatic fluids between the two groups. P-value < 0.05 was considered significant. Idiopathic SNHL was diagnosed in 47.5% of cases. Positive AECA results in serum and perilymphatic fluid were 10% and 12%, respectively. Although AECA results in perilymphatic fluids were different between idiopathic and non-Idiopathic SNHL patients (PV < 0.05), AECAs in serum showed no significant difference between the two (PV = 0.1). No significant difference was detected between the mean age of idiopathic and non-idiopathic SNHL patients with positive AECAs in serum and perilymphatic fluids (PV = 0.2; PV = 0.2). Idiopathic SNHL was diagnosed in 47.5% of studied cases. Idiopathic SNHL has a poor out come in children. In cases with idiopathic SNHL, finding AECAs in perilymphatic fluids are more valuable than in the serum. We suggest that serum and perilymphatic fluids testing for AECAs would be helpful in management of idiopathic SNHL cases. Specific immunosuppressive treatments for selected cases suffering from Idiopathic SNHL (only in those older than 5) might be successful in disease management. However, this theory should first be validated by randomized clinical trials.


Emergence and stability of interlimb coordination patterns in children with developmental coordination disorder.
The purpose of this study was to investigate the emergence and stability of coordination patterns in children with developmental coordination disorder (DCD) when performing a rhythmic interlimb coordination task on rigid (floor) and elastic (mini-trampoline) surfaces. Twelve typically developing (TD) children and 12 children with DCD were required to clap while jumping under different conditions: in a chosen pattern - Free; when the feet touched the surface - Clapping-surface; when the body reached the maximum jumping height - Clapping-jump; and when the feet touched the surface and the body reached the maximum jumping height - Clapping-both. The results showed that the coordination pattern of children with DCD was more variable in the Free, Clapping-surface, and Clapping-jumping conditions and more variable on the mini-trampoline than on the floor under the Free condition when compared with the TD children. Clapping-jumping was more difficult to perform than Clapping-surface for both groups. These findings suggest that the children with DCD were less capable of rhythmically coordinating the jumping-clapping task because they used a type of exploratory strategy regarding the physical properties of the surfaces, whereas the TD children used a type of adaptive strategy displaying behavior that was more consistent across the tasks/environmental demands.


Correlative in-resin super-resolution and electron microscopy using standard fluorescent proteins.
We introduce a method for correlative in-resin super-resolution fluorescence and electron microscopy (EM) of biological structures in mammalian culture cells. Cryo-fixed resin embedded samples offer superior structural preservation, performing in-resin super-resolution, however, remains a challenge. We identified key aspects of the sample preparation procedure of high pressure freezing, freeze substitution and resin embedding that are critical for preserving fluorescence and photo-switching of standard fluorescent proteins, such as mGFP, mVenus and mRuby2. This enabled us to combine single molecule localization microscopy with transmission electron microscopy imaging of standard fluorescent proteins in cryo-fixed resin embedded cells. We achieved a structural resolution of 40-50 nm (~17 nm average single molecule localization accuracy) in the fluorescence images without the use of chemical fixation or special fluorophores. Using this approach enabled the correlation of fluorescently labeled structures to the ultrastructure in the same cell at the nanometer level and superior structural preservation.


Right ventricular filling in dilated cardiomyopathy.
To assess right ventricular filling in dilated cardiomyopathy. 32 patients with dilated cardiomyopathy and 24 healthy controls. Stroke distances were measured by pulsed Doppler echocardiography at left ventricular outflow and left and right ventricular inflow. The inflow tract dimensions of both ventricles and the outflow tract dimension of the left ventricle were measured from two dimensional images. Right and left sided atrioventricular (AV) ring excursions were measured by M mode echocardiography at the tricuspid and mitral rings. Stroke volume was derived as stroke distance multiplied by left ventricular outflow tract area. Total stroke distances were calculated as the sum of AV valve Doppler stroke distances and ring excursion. The effective orifice areas of the two AV valves were thus defined as stroke volumes divided by total stroke distance. Total tricuspid stroke distance was normally less than mitral (6.0 (1.7) v 7.6 (1.7) cm, P < 0.05), implying that effective orifice area of the tricuspid valve was consistently greater (6.6 (1.6) v 4.5 (0.8) cm2, P < 0.01). Total tricuspid ring excursion was normally more than mitral (2.30 (0.30) v 1.62 (0.22) cm, P < 0.01). Total tricuspid stroke distance in dilated cardiomyopathy was also less than mitral (7.8 (2.4) v 9.7 (2.8) cm, P < 0.05). Tricuspid stroke distance was significantly increased in patients with dilated cardiomyopathy compared with that in healthy controls (P < 0.05 v controls), though stroke volume was much smaller (26 (10) v 63 (11) ml, P < 0.01) so that tricuspid effective orifice area was reduced to less than half normal (2.7 (1.2) cm2, P < 0.01). Total tricuspid ring long axis excursion was more than mitral (1.37 (0.6) v 0.74 (0.21) cm, P < 0.01). Right ventricular end diastolic inflow dimension was increased compared with that in healthy controls (3.9 (0.7) v 2.8 (0.5) cm, P < 0.01), correlating inversely with tricuspid effective orifice area (r = -0.71, P < 0.01). Total tricuspid ring excursion was bimodally distributed as a low amplitude group (less than 1.6 cm, n = 23) and a high amplitude group (more than 1.6 cm, n = 9), in which the interval P2 to onset of tricuspid flow was much longer (100 (35) v 50 (14) ms, P < 0.01). Enlargement of the right ventricular inflow tract in dilated cardiomyopathy, especially to more than 5 cm, is accompanied by a progressive decrease in effective tricuspid orifice area, sometimes to less than 1 cm2 and increased inflow velocities. Right ventricular relaxation was incoordinate in 28% of the patients studied. These disturbances of right ventricular filling are likely to compromise overall cardiac function independently of left ventricular disease.


Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages.
Recently, organoid technology has been used to generate a large repository of breast cancer organoids. Here we present an extensive evaluation of the ability of organoid culture technology to preserve complex stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Basal/stem and luminal progenitor cells can differentiate in culture to generate mature basal and luminal cell types, including ER+ cells that have been challenging to maintain in culture. Cells associated with increased cancer risk can also be propagated. Single-cell analyses of matched organoid cultures and native tissues by mass cytometry for 38 markers provide a higher resolution representation of the multiple mammary epithelial cell types in the organoids, and demonstrate that protein expression patterns of the tissue of origin can be preserved in culture. These studies indicate that organoid cultures provide a valuable platform for studies of mammary differentiation, transformation, and breast cancer risk.


Serum neurofilament light chain in FTLD: association with C9orf72, clinical phenotype, and prognosis.
The aim of the present study was to compare the levels of serum neurofilament light chain (sNfL) in frontotemporal lobar degeneration (FTLD) patients of different clinical subtypes (bvFTD, PPA, and FTLD-MND) and with or without the C9orf72 repeat expansion, and to correlate sNfL levels to disease progression, assessed by the brain atrophy rate and survival time. The sNfL levels were determined from 78 FTLD patients (C9orf72 repeat expansion carriers [n = 26] and non-carriers [n = 52]) with Single Molecule Array (SIMOA). The progression of brain atrophy was evaluated using repeated T1-weighted MRI scans and the survival time from medical records. In the total FTLD cohort, sNfL levels were significantly higher in C9orf72 repeat expansion carriers compared to non-carriers. Considering clinical phenotypes, sNfL levels were higher in the C9orf72 repeat expansion carriers than in the non-carriers in bvFTD and PPA groups. Furthermore, sNfL levels were the highest in the FTLD-MND group (median 105 pg/mL) and the lowest in the bvFTD group (median 27 pg/mL). Higher sNfL levels significantly correlated with frontal cortical atrophy rate and subcortical grey matter atrophy rate. The higher sNfL levels also associated with shorter survival time. Our results indicate that the C9orf72 repeat expansion carriers show elevated sNFL levels compared to non-carriers and that the levels differ among different clinical phenotypes of FTLD. Higher sNfL levels correlated with a shorter survival time and cortical and subcortical atrophy rates. Thus, sNfL could prove as a potential prognostic biomarker in FTLD.


Progression of GNE Myopathy Based on the Patient-Reported Outcome.
GNE myopathy is a rare progressive myopathy caused by biallelic mutations in the GNE gene, and frequently accompanied by rimmed vacuoles in muscle pathology. The initial symptom of foot drop or hip-girdle weakness eventually spreads to all limbs over a period of decades. Recent advances in pathophysiologic research have facilitated therapeutic trials aimed at resolving the core biochemical defect. However, there remains unsettled heterogeneity in its natural course, which confounds the analysis of therapeutic outcomes. We performed the first large-scale study of Korean patients with GNE myopathy. We gathered the genetic and clinical profiles of 44 Korean patients with genetically confirmed GNE myopathy. The clinical progression was estimated retrospectively based on a patient-reported questionnaire on the status of the functional joint sets and daily activities. The wrist and neck were the last joints to lose antigravity functionality irrespective of whether the weakness started from the ankle or hip. Two-thirds of the patients could walk either independently or with an aid. The order of losing daily activities could be sorted from standing to eating. Patients with limb-girdle phenotype showed an earlier age at onset than those with foot-drop onset. Patients with biallelic kinase domain mutations tended to progress more rapidly than those with epimerase and kinase domain mutations. The reported data can guide the clinical management of GNE myopathy, as well as provide perspective to help the development of clinical trials.


Designing medical and educational intervention studies. A review of some alternatives to conventional randomized controlled trials.
The advantages and limitations of RCT designs are discussed, and a range of alternative designs for medical and educational intervention studies considered. Designs selected are those that address the much neglected psychological issues involved in the recruitment of patients and allocation of patients to treatments within trials. Designs include Zelen's (18) randomized consent design, Brewin and Bradley's (20) partially randomized patient-centered design, and Korn and Baumrind's (21) partially randomized clinician-centered design. The possibilities of combining features from each of the last two designs are illustrated, and the advantages of adopting a more flexible and clinically relevant approach to the design of clinical trials are discussed.


Effects of adhesive powders on the mating and flight behavior of Mediterranean fruit fly (Diptera: Tephritidae).
Powders that adhere to insect cuticle can be used as carrier particles for synthetic insecticides, entomopathogens, or pheromones in insect control systems, and insects can be lured into contact with such powder mixtures by using attractants. Secondary transfer of adhesive powders to conspecifics during social interactions has been reported; however, this transfer relies on insects leaving the source of powder and continuing normal behavior when contaminated. We examined the ability of the Mediterranean fruit fly, Ceratitis capitata Wiedemann (Diptera: Tephritidae), to fly and mate after being contaminated with one of two adhesive powders: an electrostatic wax powder, Entostat, and a proprietary metallic powder, Entomag. During continuous observations for 1 h in a flight tunnel, male C. capitata made significantly more flights than females. Treating C. capitata with either powder significantly suppressed the flight activity of male C. capitata compared with untreated controls, whereas powder treatment had a negligible effect on female flight activity. Within 1 h, male C. capitata treated with Entomag recovered normal flight activity, but Entostat-treated males were not fully recovered. Virgin male C. capitata treated with either Entostat or Entomag were able to mate with virgin female C. capitata, but the onset of mating was delayed compared with control C. capitata by approximately 1 h. Even though the effect of powder uptake on behavior seemed to be temporary, scanning electron micrograph images of treated C. capitata showed that both powders were retained for > 24 h on most body parts. The adhesive powders showed potential for use as carrier particles for pesticides, entomopathogens, or pheromones in novel C. capitata control systems.


Age-related ultrastructural changes in human embryonic lung fibroblasts.
Scanning and transmission electron microscopy were used to examine human embryonic lung fibroblasts at different population doubling levels. Scanning electron microscopy of cells at population doubling levels 26, 45 and 59 did not reveal a significant change in cell size with increasing age. However, transmission electron microscopy of cells at population doubling levels 19 and 45 showed an increase in nuclear lobes, a decrease in the number of ribosomes associated with rough endoplasmic reticulum, and changes to the internal structure of mitochondria on increasing population doubling level. No other previously reported age-related changes were found.


Endoscopic gastric volume reduction with a novel articulating plication device is safe and effective in the treatment of obesity (with video).
Endoscopic volume reduction of the stomach may provide a minimally invasive alternative for surgical procedures in the treatment of obesity. To assess safety and preliminary effectiveness in the first human application of a novel endoscopic stapling technique. Prospective, observational, phase 1 study. Two university hospitals in The Netherlands. Patients with a body mass index (BMI) of 40 to 45 kg/m(2) or 30 to 39.9 kg/m(2) with obesity-related comorbidity. Gastric volume reduction with an endoscopic stapler. Primary outcome measure was the prevalence of serious or mild adverse events. Reduction of excess body weight after 12 months was assessed as a secondary outcome measure for effectiveness of the procedure. Seventeen patients with a median BMI of 40.2 kg/m(2) (interquartile range [IQR] 37.6-42.8) underwent an endoscopic stapling procedure. Median procedure time was 123 minutes (IQR 95-129). No serious adverse events occurred. Adverse events were gastric pain (n = 7, range 1-3 days), sore throat (n = 4, 2-3 days), diarrhea (n = 4, 2-15 days), nausea (n = 3, 2-4 days), constipation (n = 4, 3-14 days), and vomiting (n = 3, 1-4 days). All adverse events were mild and resolved with conservative treatment within 15 days after surgery. The median percentage excess weight loss in the first year was 34.9% (IQR 17.8-46.6). Limited number of patients. This first human application of this endoscopic stapler demonstrates that the procedure is technically feasible and safe. One hundred sixty plications were created in 17 patients without significant problems. Weight loss after 1 year is promising, but long-term follow-up and randomized, controlled studies should evaluate whether this procedure is an effective and durable minimally invasive endoscopic treatment for obesity. ( NCT01429194.).


TGF-alpha mediates genetic susceptibility to chronic kidney disease.
The mechanisms of progression of chronic kidney disease (CKD) are poorly understood. Epidemiologic studies suggest a strong genetic component, but the genes that contribute to the onset and progression of CKD are largely unknown. Here, we applied an experimental model of CKD (75% excision of total renal mass) to six different strains of mice and found that only the FVB/N strain developed renal lesions. We performed a genome-scan analysis in mice generated by back-crossing resistant and sensitive strains; we identified a major susceptibility locus (Ckdp1) on chromosome 6, which corresponds to regions on human chromosome 2 and 3 that link with CKD progression. In silico analysis revealed that the locus includes the gene encoding the EGF receptor (EGFR) ligand TGF-α. TGF-α protein levels markedly increased after nephron reduction exclusively in FVB/N mice, and this increase preceded the development of renal lesions. Furthermore, pharmacologic inhibition of EGFR prevented the development of renal lesions in the sensitive FVB/N strain. These data suggest that variable TGF-α expression may explain, in part, the genetic susceptibility to CKD progression. EGFR inhibition may be a therapeutic strategy to counteract the genetic predisposition to CKD.


Interaction with the inositol 1,4,5-trisphosphate receptor promotes Ca2+ sequestration in permeabilised insulin-secreting cells.
Electropermeabilised insulin-secreting RINm5F cells sequestered Ca2+, resulting in a steady-state level of the ambient free Ca2+ concentration corresponding to 723 +/- 127 nM (mean +/- SEM, n = 10), as monitored by a Ca(2+)-selective minielectrode. Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) promoted a rapid and pronounced release of Ca2+. This Ca2+ was resequestered and a new steady-state Ca2+ level was attained, which was always lower (460 +/- 102 nM, n = 10, P less than 0.001) than the steady-state Ca2+ level maintained before the addition of Ins(1,4,5)P3. Whereas the initial reuptake of Ca2+ subsequent to Ins(1,4,5)P3 stimulation was relatively slow, the later part of reuptake was fast as compared to the reuptake phases of a pulse addition of extraneous Ca2+. In the latter case the uptake of Ca2+ resulted in a steady-state level similar to that found in the absence of Ins(1,4,5)P3. Addition of Ins(1,4,5)P3 under this condition resulted in a further Ca2+ uptake and thus a lower steady-state Ca2+ level. Heparin, which binds to the Ins(1,4,5)P3 receptor, also lowered the steady-state free Ca2+ concentration. In contrast to Ins(1,4,5)P3, inositol 1,3,4,5-tetrakisphosphate was without effect on Ca2+ sequestration. These findings are consistent with the presence of a high-affinity Ins(1,4,5)P3 receptor promoting continuous release of Ca2+ under basal conditions and/or the Ins(1,4,5)P3 receptor being actively involved in Ca2+ sequestration.


Body mass index in midlife and risk of Alzheimer disease and vascular dementia.
Prior work has suggested that obesity and overweight as measured by body mass index (BMI) increases risk of dementia. It is unknown if there is a difference in the risk of developing Alzheimer disease (AD) versus vascular dementia (VaD) associated with high body weight. The goal of this study was to examine the association between midlife BMI and risk of both AD and VaD an average of 36 years later in a large (N= 10,136) and diverse cohort of members of a health care delivery system. Participants aged 40-45 participated in health exams between 1964 and 1968. AD and VaD diagnoses were obtained from Neurology visits between January 1, 1994 and June 15, 2006. Those with diagnoses of general dementia from primary care providers were excluded from the study. BMI was analyzed in WHO categories of underweight, overweight and obese, as well as in subdivisions of WHO categories. All models were fully adjusted for age, education, race, sex, marital status, smoking, hyperlipidemia, hypertension, diabetes, ischemic heart disease and stroke. Cox proportional hazard models showed that compared to those with a normal BMI (18.5-24.9), those obese (BMI > or = 30) at midlife had a 3.10 fold increase in risk of AD (fully adjusted model, Hazard Ratio=3.10, 95% CI 2.19-4.38), and a five fold increase in risk of VaD (fully adjusted model, HR=5.01, 95% CI 2.98-8.43) while those overweight ( BMI > or = 25 and <30) had a two fold increase in risk of AD and VaD (fully adjusted model, HR=2.09, 95% CI 1.69-2.60 for AD and HR=1.95, 95% CI 1.29-2.96 for VaD). These data suggest that midlife BMI is strongly predictive of both AD and VaD, independent of stroke, cardiovascular and diabetes co morbidities. Future studies need to unveil the mechanisms between adiposity and excess risk of AD and VaD.


[Gender identity disorder and related sexual behavior problems in children and adolescents: from the perspective of development and child psychiatry].
The present paper reviews the theoretical and empirical literature on children and adolescents with gender identity disorder. The organizational framework underlying this review is one that presents gender behavior in children and adolescents as a continuum rather than as a dichotomy of normal versus abnormal categories. Theories of normative gender development, prevalence, assessment, developmental trajectories, and comorbidity were investigated. There is a greater fluidity and likelihood of change in the pre-pubertal period. It was reported that the majority of affected children had been eventually developing a homosexual orientation. As an approach to determine the prevalence of GID in clinical samples in our child psychiatry clinic, screening instruments that include items on cross-gender or cross-sex identification were used. We applied the Child Behavior Checklist (CBCL). Of the 113 items in the Japanese version of the CBCL, there are two measures of cross-gender identification: "behaves like opposite sex" and "wishes to be opposite sex." Like the other items, they are scored on a 3-point scale of: 0-not true, 1- somewhat true, and 2-very true. Our study of 323 clinically-referred children aged 4-15 years reported that, among the boys, 9.6% assigned a score of 1 (somewhat true) or a score of 2 (very true) to the two items. The corresponding rates for the clinically-referred girls were 24.5%. The item of diagnosis of GID in our clinical sample was significantly higher than in non-referred children, reported as 2-5% using the same method. Two clinical case histories of screened children are also presented. Both of them were diagnosed with PDDNOS. Together with the literature review, most of the gender-related symptoms in autistic spectrum disorders (ASD) could be related to the behavioral and psychological characteristics of autism as shown in case histories. ASD subjects in adolescence can sometimes develop a unique confusion of identity that occasionally exaggerates to gender-related problems. However, these views do not explain all cases; true comorbidity of ASD and GID should be considered. A full assessment including evaluation of the family, school, and social environment is essential as other emotional and behavioral problems are very common and unresolved issues in the child's environment are often present e. g., loss. Separation problems are particularly common in the younger group. Intervention should aim to assist development, particularly that of gender identity. It should focus on ameliorating the comorbid problems and difficulties in the child's life and reducing the distress experienced by the child.


The prevention and management of urinary tract infections among people with spinal cord injuries. National Institute on Disability and Rehabilitation Research Consensus Statement. January 27-29, 1992.
The Urinary Tract Infection Consensus Conference brought together researchers, clinicians, and consumers to arrive at consensus on the best practices for preventing and treating urinary tract infections in people with spinal cord injuries; the risk factors and diagnostic studies that should be done; indications for antibiotic use; appropriate follow-up management; and needed future research. Urinary tract infection (UTI) was defined as bacteriuria (102 bacteria/ml of urine) with tissue invasion and resultant tissue response with signs and/or symptoms. Asymptomatic bacteriuria represents colonization of the urinary tract without symptoms or signs. Risk factors include: over-distention of bladder, vesicoureteral reflux, high pressure voiding, large post-void residuals, presence of stones in urinary tract, and outlet obstruction. Possible physiologic/structural, behavioral, and demographic risk factors were identified also. Indwelling catheterization, including suprapubic, and urinary diversion are the drainage methods most likely to lead to persistent bacteriuria. Infection risk is reduced with intermittent catheterization, but more severely disabled people who require catheterization by others are at greater risk for UTIs. Clean self-intermittent catheterization does not pose a greater risk of infection than sterile self-intermittent catheterization and is much more economic. However, care must be given to proper cleansing of reusable catheters. Quantitative urine-culture criteria for the diagnosis of bacteriuria include: catheter specimens from individuals on intermittent catheterization greater than or equal to 10(2) cfu/ml; clean-void specimens from catheter-free males using condom collection devices greater than or equal to 10(4) cfu/ml; and specimens from indwelling catheters of any detectable concentration. Dip stick screening tests may offer promise as an early warning system of UTI since they can be self-administered. Symptomatic UTI should be treated with antibiotics for 7 to 14 days. Longer courses have not been beneficial. In patients with symptomatic UTIs, it is not necessary to wait for the results of cultures before starting treatment. Asymptomatic bacteriuria need not be treated with antibiotics. There is little evidence presently to support the use of antibiotics to prevent infections. Following a recent episode of febrile UTI, possible contributing prior events should be reviewed. The upper tracts should be evaluated (imaging studies) to identify possible abnormalities. A common concern among people with spinal cord injuries is that physicians will alter bladder management programs without regard to lifestyle needs. Social/vocational flexibility may be more important to them than a state-of-the-art bladder management program. Future research should focus on obtaining more representative samples and investigate psycho-social-vocational implications as well as additional clinical-medical factors.


How often is low back pain not coming from the back?
Consecutive case series cohort. To determine the relative frequencies of the spine, the sacroiliac (SI) joint, and the hip joint being the primary pain generator among patients presenting at a spine surgery clinic for low back pain (LBP). Identification of the primary pain generator in a patient with LBP is difficult. Possible pain sources include the lumbar spine, the SI joint, and the hip joint. Their relative frequencies among patients presenting at a spine surgeon's clinic have not been well established. Three hundred sixty-eight new patients were seen at a single spine surgeon's clinic during a 10-month period. Of these, 289 (78.5%) complained primarily of LBP with or without leg pain. Seventy-seven had previous surgery. The remaining 200 cases were reviewed for all diagnostic tests performed, as well as the final diagnosis. One hundred sixty-four (82%) had spine pathology, but only 130 (65%) had spine-only pathology, whereas 35 (17.5%) had a combination of spine plus hip and/or SI joint pathology. An additional 16 (8%) had hip and/or SI joint pathology without spine pathology. Twenty (10%) had an undefined pain source. Overall, 25 (12.5%) had hip pathology, and 29 (14.5%) had SI joint pathology. For patients presenting to a spine surgeon's clinic for LBP, up to 25% of patients may have significant pain contribution from the hip or SI joints, and an additional 10% will still have an undefined pain source even after diagnostic workup. This underscores the need for clinicians to be aware of nonspinal pain generators and to appropriately pursue alternative diagnoses.


The structural diversity of carbohydrate antigens of selected gram-negative marine bacteria.
Marine microorganisms have evolved for millions of years to survive in the environments characterized by one or more extreme physical or chemical parameters, e.g., high pressure, low temperature or high salinity. Marine bacteria have the ability to produce a range of biologically active molecules, such as antibiotics, toxins and antitoxins, antitumor and antimicrobial agents, and as a result, they have been a topic of research interest for many years. Among these biologically active molecules, the carbohydrate antigens, lipopolysaccharides (LPSs, O-antigens) found in cell walls of gram-negative marine bacteria, show great potential as candidates in the development of drugs to prevent septic shock due to their low virulence. The structural diversity of LPSs is thought to be a reflection of the ability for these bacteria to adapt to an array of habitats, protecting the cell from being compromised by exposure to harsh environmental stress factors. Over the last few years, the variety of structures of core oligosaccharides and O-specific polysaccharides from LPSs of marine microrganisms has been discovered. In this review, we discuss the most recently encountered structures that have been identified from bacteria belonging to the genera Aeromonas, Alteromonas, Idiomarina, Microbulbifer, Pseudoalteromonas, Plesiomonas and Shewanella of the Gammaproteobacteria phylum; Sulfitobacter and Loktanella of the Alphaproteobactera phylum and to the genera Arenibacter, Cellulophaga, Chryseobacterium, Flavobacterium, Flexibacter of the Cytophaga-Flavobacterium-Bacteroides phylum. Particular attention is paid to the particular chemical features of the LPSs, such as the monosaccharide type, non-sugar substituents and phosphate groups, together with some of the typifying traits of LPSs obtained from marine bacteria. A possible correlation is then made between such features and the environmental adaptations undertaken by marine bacteria.


Increased analgesia and alterations in distribution and metabolism of methadone by desipramine in the rat.
Treatment of rats with desipramine (DMI) 1 hour before the subcutaneous administration of methadone increased the intensity and prolonged the duration of methadone analgesia, as determined by the hot plate method. DMI significantly reduced the analgesic ED50 of methadone from a control value of 3.4 to 1.6 or 0.5 mg/kg in rats treated with 20 or 30 mg/kg of DMI, respectively. DMI treatment also significantly reduced the LD50 of methadone. DMI (20 mg/kg i.p.) was given 1 hour prior to administration of 14C-methadone (5 mg/kg s.c.) and the distribution of total 14C, unchanged methadone and methadone metabolites in various tissues was studied. DMI treatment greatly increased the brain uptake of 14C and the methadone brain/plasma concentration ratios for up to 3 hours. The concentrations of 14C and unchanged methadone were higher in kidneys and lower in lungs of DMI-treated rats as compared to controls. However, the ratios of unchanged methadone to its metabolites in kidneys and lungs were not changed significantly by DMI treatment. The level of unchanged methadone in liver was markedly elevated by DMI treatment at 45 and 90 minutes (190 and 183% of controls, respectively). The level of a water-soluble glucuronide metabolite of methadone was significantly decreased at 45-, 90- and 180-minute intervals (37, 36 and 54% of controls, respectively.) However, the total 14C in liver and the concentrations of two N-demethylated metabolites of methadone were not changed significantly. In vitro addition of DMI to liver microsomal incubations resulted in inhibition of the N-demethylation of methadone. It is suggested that DMI potentiated and prolonged methadone analgesia by increasing the brain concentration of methadone and by inhibiting metabolism of methadone in the liver.


Contaminant-induced immunotoxicity in harbour seals: wildlife at risk?
Persistent, lipophilic polyhalogenated aromatic hydrocarbons (PHAHs) accumulate readily in the aquatic food chain and are found in high concentrations in seals and other marine mammals. Recent mass mortalities among several marine mammal populations have been attributed to infection by morbilliviruses, but a contributing role for immunotoxic PHAHs, including the polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) was not ruled out. We addressed this issue by carrying out a semi-field study in which captive harbour seals were fed herring from either the relatively uncontaminated Atlantic Ocean or the contaminated Baltic Sea for 2 years. We present here an overview of results obtained during this study. An impairment of natural killer (NK) cell activity, in vitro T-lymphocyte function, antigen-specific in vitro lymphocyte proliferative responses, and in vivo delayed-type hypersensitivity and antibody responses to ovalbumin was observed in the seals fed the contaminated Baltic herring. Additional feeding studies in PVG rats using the same herring batches suggested that an effect at the level of the thymus may be responsible for changes in cellular immunity, that virus-specific immune responses may be impaired, and that perinatal exposure to environmental contaminants represents a greater immunotoxic threat than exposure as a juvenile or adult. Together with the pattern of TCDD toxic equivalents of different PHAHs in the herring, these data indicate that present levels of PCBs in the aquatic food chain are immunotoxic to mammals. A review of contaminant levels in free-ranging harbour seals inhabiting polluted areas of Europe and North America suggests that many populations may be at risk to immunotoxicity. This could result in diminished host resistance and an increased incidence and severity of infectious disease.