Pattern of head and neck malignant tumours in a Tuzla ENT clinic--a five year experience.
Head and neck neoplasia can affect certain fundamental functions, including eating, drinking, speaking and respiration. One overriding factor in deciding on treatment policy is the tendency for head and neck malignancy to be limited to the primary site and regional lymph nodes with surgery and chemotherapy and radiotherapy. The aim of the study was to analyze the occurrence of Head and Neck tumours operated at ENT clinic Tuzla, University Clinical Center Tuzla, Bosnia and Herzegovina. Medical records of patients with histopathologically confirmed head and neck malignancies over a 5 year period (2003-2007) were analyzed. Eight hundred and eight one (881) cases, made up of 519 (58,8%) males and 362 (41,1%) females were found. The most common sites for head and neck malignancies were found to be in the larynx (26,1%), oral cavity (21,7%), the thyroid gland (14,64 %) and the neck (8,51%). A total of 230 patients were diagnosed with laryngeal carcinoma (M:173; F:57), showing the increasing number of female patients. The histopathological tumour types found in this work were mostly squamous cell carcinoma (72,09%), papillary carcinoma (12,2%), while many other minor histopathological variants accounted for 13%. The most patients were presented with stage I and stage III of disease (27% and 28,3%), and 19,9% with stage IV. About 40% of patients did not have data about smoking habit and alcohol drinking. The incidence of head and neck tumours seems to be relatively high, but without significant increase during investigated period. More investigation concerning risk factors, diagnostic procedures, and management strategies should be done in future.


The frequency of herpes simplex virus changes in anal Pap smear and its association with squamous intraepithelial lesions in high-risk male patients.
While there are studies postulating a model of synergism between human papillomavirus (HPV) and herpes simplex virus (HSV) in cervical carcinogenesis, the frequency of anal herpes as well as its association with anal squamous intraepithelial lesions (ASILs) has been understudied in men. This study evaluates the frequency of HSV changes in anal Pap smears and its association with ASILs in a high-risk population. A computerized search for specimens associated with anal cytology that had positive findings of HSV was performed. The electronic medical records were examined for past diagnosis of herpes, HSV serology prior to or after cytology, and if the patient received treatment after cytologic diagnosis of HSV. Of the 470 anal Pap smears (Thin-prep) examined, seven had cellular changes consistent with HSV infection. All patients were asymptomatic human immunodeficiency virus (HIV) positive males with no prior HSV serology tests. Two patients had prior diagnoses of HSV infection. Cytologic abnormalities were identified in 86% ranging from atypical squamous cells of undetermined significance to high grade squamous intraepithelial lesion. Three patients were treated after the HSV cytologic diagnosis. The frequency of HSV changes in anal Pap smear is low (1.48%), but the presence of concomitant cytologic abnormalities is high (86%). While our findings suggest the possible role of HSV as a HPV co-factor in ASILs, larger studies are needed to support this. Identification of HSV infection on anal Pap smear is important for institution of patient treatment and subsequent reduction of transmission.


Design of a dual-effect lens on lanthanum-modified lead zirconate titanate for continuous variation of focal length.
The design of a Fresnel lens with continuous focal length is proposed for use in optical processing. A convex lens is induced in lanthanum-modified lead zirconate titanate through the application of an electric-field profile supplied by the indium tin oxide electrodes that make up the zones of a Fresnel lens. The use of a numerical method based on fast Fourier transform algorithms was required to analyze accurately the induced field inside a Fresnel lens with an initial focal length of 0.4 m (at 470 nm) and 20 indium tin oxide electrodes. The effective focal location obtained by the combined mechanisms is derived. This design is expected to produce continuous variations of ~16% in focal length; the ability of previous designs to achieve focal length switching is maintained.


Cannabinoids Reduce Inflammation but Inhibit Lymphocyte Recovery in Murine Models of Bone Marrow Transplantation.
Cannabinoids, the biologically active constituents of Cannabis, have potent neuronal and immunological effects. However, the basic and medical research dedicated to medical cannabis and cannabinoids is limited. The influence of these treatments on hematologic reconstitution and on the development of graft versus host disease (GVHD) after bone marrow transplantation (BMT) is largely unknown. In this research, we compared the influence of D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on lymphocyte activation in vitro and in murine BMT models. Our in vitro results demonstrate that these treatments decrease activated lymphocyte proliferation and affect cytokine secretion. We also discovered that CBD and THC utilize different receptors to mediate these effects. In vivo, in a syngeneic transplantation model, we demonstrate that all treatments inhibit lymphocyte reconstitution and show the inhibitory role of the cannabinoid receptor type 2 (CB2) on lymphocyte recovery. Although pure cannabinoids exhibited a superior effect in vitro, in an allogeneic (C57BL/6 to BALB/c) BMT mouse model, THC-high and CBD-high cannabis extracts treatment reduced the severity of GVHD and improved survival significantly better than the pure cannabinoids. Our results highlights the complexity of using cannabinoids-based treatments and the need for additional comparative scientific results.


An optoelectrokinetic technique for programmable particle manipulation and bead-based biosignal enhancement.
Technologies that can enable concentration of low-abundance biomarkers are essential for early diagnosis of diseases. In this study, an optoelectrokinetic technique, termed Rapid Electrokinetic Patterning (REP), was used to enable dynamic particle manipulation in bead-based bioassays. Various manipulation capabilities, such as micro/nanoparticle aggregation, translation, sorting and patterning, were developed. The technique allows for versatile multi-parameter (voltage, light intensity and frequency) based modulation and dynamically addressable manipulation with simple device fabrication. Signal enhancement of a bead-based bioassay was demonstrated using dilute biotin-fluorescein isothiocyanate (FITC) solutions mixed with streptavidin-conjugated particles and rapidly concentrated with the technique. As compared with a conventional ELISA reader, the REP-enabled detection achieved a minimal readout of 3.87 nM, which was a 100-fold improvement in sensitivity. The multi-functional platform provides an effective measure to enhance detection levels in more bead-based bioassays.


Financial Stress and Smoking within a Large Sample of Socially Disadvantaged Australians.
Financial stress is associated with fewer quit attempts and higher relapse rates. This study aimed to compare financial stress among smokers, ex-smokers and never smokers in a highly socioeconomically disadvantaged sample. The study also aimed to determine whether specific indicators of financial stress differ according to smoking status. Adult clients seeking welfare assistance from two Social and Community Service Organisation sites in New South Wales, Australia, were invited to complete a cross-sectional survey between March 2012 and December 2013. Responses to a financial stress scale, smoking status and demographics were collected. Linear and logistic regression modelling was used to examine associations between smoking status and financial stress. A total of 1463 participants completed the survey. Current smokers had significantly higher total financial stress scores than ex-smokers and non-smokers respectively. Current smokers also had higher odds of severe financial stress indicators, such as going without meals (Odds Ratio = 2.2 and 2.0), than both non-smokers and ex-smokers. Even among a highly socioeconomically disadvantaged sample with high levels of financial stress, smoking status further exacerbates experiences of deprivation. Given the relationship between financial stress, socioeconomic disadvantage and difficulty quitting, it is important to provide enhanced cessation support to smokers experiencing financial stress.


Serum neopterin levels as a diagnostic marker of hemophagocytic lymphohistiocytosis syndrome.
The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients.


Reconstructing long-term dengue virus immunity in French Polynesia.
Understanding the underlying risk of infection by dengue virus from surveillance systems is complicated due to the complex nature of the disease. In particular, the probability of becoming severely sick is driven by serotype-specific infection histories as well as age; however, this has rarely been quantified. Island communities that have periodic outbreaks dominated by single serotypes provide an opportunity to disentangle the competing role of serotype, age and changes in surveillance systems in characterising disease risk. We develop mathematical models to analyse 35 years of dengue surveillance (1979-2014) and seroprevalence studies from French Polynesia. We estimate the annual force of infection, serotype-specific reporting probabilities and changes in surveillance capabilities using the annual age and serotype-specific distribution of dengue. Eight dengue epidemics occurred between 1979 and 2014, with reporting probabilities for DENV-1 primary infections increasing from 3% to 5%. The reporting probability for DENV-1 secondary infections was 3.6 times that for primary infections. We also observed heterogeneity in reporting probabilities by serotype, with DENV-3 having the highest probability of being detected. Reporting probabilities declined with age after 14 y.o. Between 1979 and 2014, the proportion never infected declined from 70% to 23% while the proportion infected at least twice increased from 4.5% to 45%. By 2014, almost half of the population had acquired heterotypic immunity. The probability of an epidemic increased sharply with the estimated fraction of susceptibles among children. By analysing 35 years of dengue data in French Polynesia, we characterised key factors affecting the dissemination profile and reporting of dengue cases in an epidemiological context simplified by mono-serotypic circulation. Our analysis provides key estimates that can inform the study of dengue in more complex settings where the co-circulation of multiple serotypes can greatly complicate inference.


Consensus-based recommendations for titrating cannabinoids and tapering opioids for chronic pain control.
Opioid misuse and overuse have contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids. In patients with chronic pain taking opioids not reaching treatment goals, there was consensus that cannabinoids may be considered for patients experiencing or displaying opioid-related complications, despite psychological or physical interventions. There was consensus observed to initiate with a cannabidiol (CBD)-predominant oral extract in the daytime and consider adding tetrahydrocannabinol (THC). When adding THC, start with 0.5-3 mg, and increase by 1-2 mg once or twice weekly up to 30-40 mg/day. Initiate opioid tapering when the patient reports a minor/major improvement in function, seeks less as-needed medication to control pain and/or the cannabis dose has been optimised. The opioid tapering schedule may be 5%-10% of the morphine equivalent dose (MED) every 1 to 4 weeks. Clinical success could be defined by an improvement in function/quality of life, a ≥30% reduction in pain intensity, a ≥25% reduction in opioid dose, a reduction in opioid dose to <90 mg MED and/or reduction in opioid-related adverse events. This five-stage modified Delphi process led to the development of consensus-based recommendations surrounding the safe introduction and titration of cannabinoids in concert with tapering opioids.


Stray-light analysis for the SCORE coronagraphs of HERSCHEL.
The HERSCHEL (Helium Resonance Scattering in the Corona and Heliosphere) suborbital mission scientific payload consists of two extreme ultraviolet (EUV) coronagraphs forming the SCORE (Sounding Coronagraph Experiment) and an EUV Sun disk imager. The mission will be of great importance for the investigation of solar wind dynamics by obtaining the first global image of the Sun (disk and corona) in the He ii30.4 nm line. The most stringent requirement for the optical design of a coronagraph is stray-light reduction. We summarize the stray-light analysis for the SCORE coronagraphs, which are characterized by an innovative optical design, optimized for stray-light reduction.


Increased distractibility in schizophrenic patients. Electrophysiologic and behavioral evidence.
The inability of schizophrenics to filter irrelevant information has often been implicated in the psychopathology of schizophrenia. Despite numerous attempts at characterizing the behavior of schizophrenics in the presence of distractors, evidence of increased distractibility has been equivocal due to the difficulty of assessing simultaneously the behavioral and neurophysiological effects of distracting stimuli. We report the results of an experiment in which event-related potential and performance measures were used to assess distractibility during reaction time tasks under different distracting conditions. The results supported the view of an increased distractibility in schizophrenic patients. Event-related potential data suggested that in schizophrenic patients, a reduced amount of processing resources is allocated to process external stimuli and attention is abnormally apportioned to task-irrelevant vs task-relevant stimuli.


The welfare of growing pigs in five different production systems: assessment of feeding and housing.
Ninety-one farms were visited over a 2-year period to assess the welfare of growing pigs in five different production systems found either in France or in Spain using the Welfare Quality® protocol. This study focused on animal-based measures as indicators of 'good feeding' and 'good housing'. Multiple Generalized Linear Mixed Models were performed for each measure to evaluate the differences between production systems and to detect possible causal factors. Pigs in the conventional system presented the lowest prevalence of poor body condition, whereas extensive Mallorcan Black pigs and extensive Iberian pigs were associated with a decreased prevalence of bursitis and pig dirtiness. The straw-bedded system presented a lower prevalence of bursitis, but poorer hygiene and more susceptibility of poor body condition than the conventional system. The age of the animals had a significant effect on the appearance of bursitis in the three intensive systems studied. The type of floor was a significant causal factor of bursitis and pig dirtiness in the conventional system and among intensive Iberian pigs. The feeding system was another causal factor of pig dirtiness on more than 50% of the body in the conventional system, whereas pig dirtiness on less than 50% of the body was influenced by the age of the animals. The prevalence of huddling animals in the conventional system was associated with the highest stocking densities and the lowest environmental temperatures. The results indicate that there were important differences between production systems based on animal-based indicators of the good feeding and housing principles. The recording of the age of the animals, type of floor, feeding system, stocking density and environmental temperature can be useful to predict the appearance of a given welfare measure of 'good housing' on a farm.


Feed-forward and visual feedback control of head roll orientation in wasps (Polistes humilis, Vespidae, Hymenoptera).
Flying insects keep their visual system horizontally aligned, suggesting that gaze stabilization is a crucial first step in flight control. Unlike flies, hymenopteran insects such as bees and wasps do not have halteres that provide fast, feed-forward angular rate information to stabilize head orientation in the presence of body rotations. We tested whether hymenopteran insects use inertial (mechanosensory) information to control head orientation from other sources, such as the wings, by applying periodic roll perturbations to male Polistes humilis wasps flying in tether under different visual conditions indoors and in natural outdoor conditions. We oscillated the thorax of the insects with frequency-modulated sinusoids (chirps) with frequencies increasing from 0.2 to 2 Hz at a maximal amplitude of 50 deg peak-to-peak and maximal angular velocity of ±245 deg s(-1). We found that head roll stabilization is best outdoors, but completely absent in uniform visual conditions and in darkness. Step responses confirm that compensatory head roll movements are purely visually driven. Modelling step responses indicates that head roll stabilization is achieved by merging information on head angular velocity, presumably provided by motion-sensitive neurons and information on head orientation, presumably provided by light level integration across the compound eyes and/or ocelli (dorsal light response). Body roll in free flight reaches amplitudes of ±40 deg and angular velocities greater than 1000 deg s(-1), while head orientation remains horizontal for most of the time to within ±10 deg. In free flight, we did not find a delay between spontaneous body roll and compensatory head movements, and suggest that this is evidence for the contribution of a feed-forward control to head stabilization.


The Gaggle: an open-source software system for integrating bioinformatics software and data sources.
Systems biologists work with many kinds of data, from many different sources, using a variety of software tools. Each of these tools typically excels at one type of analysis, such as of microarrays, of metabolic networks and of predicted protein structure. A crucial challenge is to combine the capabilities of these (and other forthcoming) data resources and tools to create a data exploration and analysis environment that does justice to the variety and complexity of systems biology data sets. A solution to this problem should recognize that data types, formats and software in this high throughput age of biology are constantly changing. In this paper we describe the Gaggle -a simple, open-source Java software environment that helps to solve the problem of software and database integration. Guided by the classic software engineering strategy of separation of concerns and a policy of semantic flexibility, it integrates existing popular programs and web resources into a user-friendly, easily-extended environment. We demonstrate that four simple data types (names, matrices, networks, and associative arrays) are sufficient to bring together diverse databases and software. We highlight some capabilities of the Gaggle with an exploration of Helicobacter pylori pathogenesis genes, in which we identify a putative ricin-like protein -a discovery made possible by simultaneous data exploration using a wide range of publicly available data and a variety of popular bioinformatics software tools. We have integrated diverse databases (for example, KEGG, BioCyc, String) and software (Cytoscape, DataMatrixViewer, R statistical environment, and TIGR Microarray Expression Viewer). Through this loose coupling of diverse software and databases the Gaggle enables simultaneous exploration of experimental data (mRNA and protein abundance, protein-protein and protein-DNA interactions), functional associations (operon, chromosomal proximity, phylogenetic pattern), metabolic pathways (KEGG) and Pubmed abstracts (STRING web resource), creating an exploratory environment useful to 'web browser and spreadsheet biologists', to statistically savvy computational biologists, and those in between. The Gaggle uses Java RMI and Java Web Start technologies and can be found at http://gaggle.systemsbiology.net.


HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
In the United States, clade B is the predominant human immunodeficiency virus (HIV) subtype, whereas in sub-Saharan Africa, clades A, C, and D are the predominant subtypes. HIV subtype may have an impact on HIV disease progression. The effect of HIV subtype on the risk of dementia has, to our knowledge, not been examined. The objective of this study was to examine the relationship between HIV subtype and the severity of HIV-associated cognitive impairment among individuals initiating antiretroviral therapy in Uganda. Sixty antiretroviral-naive HIV-infected individuals with advanced immunosuppression who were at risk of HIV-associated cognitive impairment underwent neurological, neuropsychological, and functional assessments, and gag and gp41 regions were subtyped. Subtype assignments were generated by sequence analysis using a portion of the gag and gp41 regions. Thirty-three HIV-infected individuals were infected with subtype A, 2 with subtype C, 9 with subtype D, and 16 with A/D recombinants. Eight (89%) of 9 HIV-infected individuals with subtype D had dementia, compared with 7 (24%) of 33 HIV-infected individuals with subtype A (P = .004). These results suggest that, in untreated HIV-infected individuals with advanced immunosuppression who are at risk of developing HIV-associated cognitive impairment, HIV dementia may be more common among patients infected with subtype D virus than among those infected with subtype A virus. These findings provide the first evidence, to our knowledge, to demonstrate that HIV subtypes may have a pathogenetic factor with respect to their capacity to cause cognitive impairment. Additional studies are needed to confirm this observation and to define the mechanism by which subtype D leads to an increased risk of neuropathogenesis.


High-potency ligands for DREADD imaging and activation in rodents and monkeys.
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.


Notch1-induced transformation of RKE-1 cells requires up-regulation of cyclin D1.
RKE-1 cells induced to overexpress activated Notch1 (RKE-ER-N(ic)) exhibit increased cyclin D1 transcripts and become transformed. However, the oncogenic pathway of Notch1-induced transformation is not known. Here, we use mutational analysis to functionally identify the sole region of the cyclin D1 promoter that responds to activated Notch1. The same region responds to activated Notch4 as well as to physiologic Notch ligand-induced Notch receptor signaling. The cyclin D1 gene was subsequently found to be a physiologic target of Notch signaling in Pofut1(-/-) mouse embryos defective in canonical Notch signaling and in embryos with an inactivating mutation in Notch1. To determine if Notch1-induced cyclin D1 expression in RKE-ER-N(ic) cells plays a direct role in transformation, cyclin D1 up-regulation was inhibited using a cyclin D1 antisense cDNA. We report here that transformation of RKE-ER-N(ic) cells is dependent on increased expression of cyclin D1 protein, which represents a new mechanism of Notch1-induced transformation.


Tetranitrile-anthracene as a probe for fluorescence detection of viscosity in fluid drinks via aggregation-induced emission.
Viscosity is an important quality parameter for fluid drinks, which can serve as an indicator for the extent of food spoilage, since the viscosity of fluid drinks varies during the spoilage process. In this study, a near-infrared fluorophore based on tetranitrile-anthracene (TPAEQ) was designed for viscosity determination via aggregation-induced emission (AIE). With increased viscosity, TPAEQ showed enhanced emission at around 759 nm with a large Stokes shift of 195 nm in water. The probe TPAEQ was successfully used to monitor the viscosity changes during the food spoilage process for fluid drinks. Moreover, the probe TPAEQ has effectively been utilized to determine the mass concentrations of food thickeners added in the real fruit drinks. The approach for the viscosity determination could enable the on-site direct detection with convenient operation in food safety inspection applications.


Physiological, subjective and reinforcing effects of oral and intravenous cocaine in humans.
There is little comparative information on the qualitative similarity, relative potency and reinforcing effects of oral cocaine versus cocaine administered via other routes. The present study used a within-subject, double-blind, double-dummy design to compare the physiological, subjective and reinforcing effects of placebo and oral (62.5, 125, 250 mg/70 kg) and intravenous (IV) (12.5, 25, 50 mg/70 kg) cocaine in volunteers with histories of cocaine abuse. Cocaine produced dose-dependent increases on heart rate and blood pressure, with effects lasting longer after oral than IV cocaine. Subjective ratings (e.g., "rush," "drug effect," "liking") were qualitatively similar and dose-dependently increased after oral and IV administration, and the duration of effects was similar under both routes. On a money versus drug choice measure of reinforcement, the monetary amounts at which participants chose drug over money increased as a function of cocaine dose under both routes of administration. At doses that produced comparable subjective, physiological, and reinforcing effects, oral cocaine was not identified as cocaine as frequently as IV cocaine. Across measures, the data suggested that IV cocaine was approximately 10 times more potent than oral cocaine. Overall, the results of this study support qualitatively similar effects of oral and IV cocaine and suggest that oral cocaine may be an effective tool for studying cocaine's effects in human laboratory studies.


Parent and child asthma illness representations: a systematic review.
The purpose of this article is to synthesize the current literature on parent and child asthma illness representations and their consequent impact on parent-child asthma shared management. This systematic review was conducted in concordance with the PRISMA statement. An electronic search of five computerized databases (PubMed, PsycINFO, CINAHL, Cochrane, and EMBASE) was conducted using the following key words: asthma, illness representation, and child. Due to the limited number of articles identified, the search was broadened to include illness perceptions as well. Studies were included if they were specific to asthma and included parent and/or child asthma illness representations or perception, were published after 2000, and available in English. Fifteen articles were selected for inclusion. All of the articles are descriptive studies that used cross-sectional designs. Seven of the studies used parent and child participants, eight used parents only, and none used only child participants. None of the selected studies describe child asthma illness representations, and only three describe parental asthma illness representations. Domains of illness representations, including symptoms, timeline, consequences, cause, and controllability were described in the remaining articles. Symptoms and controllability appear to have the most influence on parental asthma management practices. Parents prefer symptomatic or intermittent asthma management and frequently cite concerns regarding daily controller medication use. Parents also primarily rely on their own objective symptom observations rather than the child's report of symptoms. Asthma illness representations are an important area of future study to better understand parent-child shared asthma management.


Physical activity and risk of severe gastrointestinal hemorrhage in older persons.
To assess whether regular physical activity is associated with a decreased risk of severe gastrointestinal hemorrhage (GIH) in older persons. Cohort study with 3 years of follow-up. Three communities of the Established Populations for Epidemiologic Studies of the Elderly. A total of 8205 persons aged 68 years or older, yielding 22,277 person-years of follow-up. The occurrence of severe GIH was defined as either a hospital discharge diagnosis of gastrointestinal bleeding associated with blood transfusion or death during the hospital stay or a nonhospital death with mention of GIH on the death certificate. Physical activity was measured by self-reported frequency of walking, gardening, or doing vigorous physical activity. Those participants doing the activity three times per week or more were compared with the remaining participants. Adjusted relative risks (RRs) of GIH were controlled for age, gender, body mass index, blood pressure, chronic conditions, number of hospital admissions in the past year, and number and types of drugs taken. Severe GIH occurred in 241 participants (rate, 10.8 per 1000 person-years). After adjusting for potential confounding variables, the RRs and 95% confidence intervals (CIs) for severe GIH associated with walking, gardening, and vigorous physical activity were 0.6 (0.4 to 0.8), 0.8 (0.5 to 1.1), and 0.7 (0.4 to 1.2), respectively. The RR associated with a summary variable for the three activities was 0.7 (95% CI, 0.5 to 0.9). These results were consistent after stratifying on health status and disability or by excluding those who were not mobile, ie, not able to walk half a mile or climb a flight of stairs. Regular physical activity is associated with a decreased risk for severe GIH in older persons.


A return-on-investment simulation model of workplace obesity interventions.
To calculate return-on-investment (ROI) from workplace obesity interventions, employers require information about costs saved by the intervention. This article presents a simulation model used to calculate ROI for workplace obesity interventions. We estimated annual savings in medical expenditures and absenteeism costs by amount of average weight loss for a nationally representative company. We also present several examples that use the model to evaluate the ROI for published workplace obesity interventions. Across all overweight and obese employees, 5% weight loss would result in a reduction in total annual costs (medical plus absenteeism) of $90 per person. The results suggest that low-cost policy or environmental change interventions in worksites may be more likely to be cost saving than high cost, individually targeted behavioral change interventions unless they result in substantial weight loss.


Culture-independent analysis of bacterial communities in hemolymph of American lobsters with epizootic shell disease.
Epizootic shell disease (ESD) of the American lobster Homarus americanus H. Milne Edwards, 1837 is a disease of the carapace that presents grossly as large, melanized, irregularly shaped lesions, making the lobsters virtually unmarketable because of their grotesque appearance. We analyzed the bacterial communities present in the hemolymph of lobsters with and without ESD using nested-PCR of the 16S rRNA genes followed by denaturing gradient gel electrophoresis. All lobsters tested (n = 42) had bacterial communities in their hemolymph, and the community profiles were highly similar regardless of the sampling location or disease state. A number of bacteria were detected in a high proportion of samples and from numerous locations, including a Sediminibacterium sp. closely related to a symbiont of Tetraponera ants (38/42) and a Ralstonia sp. (27/42). Other bacteria commonly encountered included various Bacteroidetes, Pelomonas aquatica, and a Novosphingobium sp. One bacterium, a different Sediminibacterium sp., was detected in 20% of diseased animals (n = 29), but not in the lobsters without signs of ESD (n = 13). The bacteria in hemolymph were not the same as those known to be present in lesion communities except for the detection of a Thalassobius sp. in 1 individual. This work demonstrates that hemolymph bacteremia and the particular bacterial species present do not correlate with the incidence of ESD, providing further evidence that microbiologically, ESD is a strictly cuticular disease. Furthermore, the high incidence of the same species of bacteria in hemolymph of lobsters may indicate that they have a positive role in lobster fitness, rather than in disease, and further investigation of the role of bacteria in lobster hemolymph is required.


Complete gene sequence of spider attachment silk protein (PySp1) reveals novel linker regions and extreme repeat homogenization.
Spiders use a myriad of silk types for daily survival, and each silk type has a unique suite of task-specific mechanical properties. Of all spider silk types, pyriform silk is distinct because it is a combination of a dry protein fiber and wet glue. Pyriform silk fibers are coated with wet cement and extruded into "attachment discs" that adhere silks to each other and to substrates. The mechanical properties of spider silk types are linked to the primary and higher-level structures of spider silk proteins (spidroins). Spidroins are often enormous molecules (>250 kDa) and have a lengthy repetitive region that is flanked by relatively short (∼100 amino acids), non-repetitive amino- and carboxyl-terminal regions. The amino acid sequence motifs in the repetitive region vary greatly between spidroin type, while motif length and number underlie the remarkable mechanical properties of spider silk fibers. Existing knowledge of pyriform spidroins is fragmented, making it difficult to define links between the structure and function of pyriform spidroins. Here, we present the full-length sequence of the gene encoding pyriform spidroin 1 (PySp1) from the silver garden spider Argiope argentata. The predicted protein is similar to previously reported PySp1 sequences but the A. argentata PySp1 has a uniquely long and repetitive "linker", which bridges the amino-terminal and repetitive regions. Predictions of the hydrophobicity and secondary structure of A. argentata PySp1 identify regions important to protein self-assembly. Analysis of the full complement of A. argentata PySp1 repeats reveals extreme intragenic homogenization, and comparison of A. argentata PySp1 repeats with other PySp1 sequences identifies variability in two sub-repetitive expansion regions. Overall, the full-length A. argentata PySp1 sequence provides new evidence for understanding how pyriform spidroins contribute to the properties of pyriform silk fibers.


Nest and nest-site reuse within and between breeding seasons by three neotropical flycatchers (Tyrannidae).
Nest and or nest site reuse within and between breeding seasons was reported by the Euler's Flycatcher (Lathrotriccus euleri), the Sepia-capped Flycatcher (Leptopogon amaurocephalus) and the Gray-hooded Flycatcher (Mionectes -rufiventris) in forest fragments from southeastern Brazil. Nest and or nest site reuse between some years was frequent within a single breeding season by the Sepia-capped Flycatcher. Nest reuse, however, was not related to nesting success in the previous breeding attempt. Nest turnover rates (movement to a new site between years) were low for L. amaurocephalus, intermediate for L. euleri and high for M. rufiventris.


Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung injury in minipigs.
To assess the effects of the lazaroid, tirilazad mesylate, a potent lipid peroxidation inhibitor, in an animal model of Pseudomonas sepsis. Comparison of four experimental groups: a) saline control; b) Pseudomonas sepsis control; c) tirilazad mesylate control; and d) sepsis with tirilazad mesylate pre treatment. University animal laboratory. Hanford minipigs (20 to 25 kg), anesthetized with pentobarbital and mechanically ventilated on an FIO2 of 0.4. Sepsis was induced by infusing Pseudomonas aeruginosa at 1 x 10(6) colony-forming units/kg/min over 120 mins. The tirilazad mesylate-treated group received a 5-mg/kg bolus 30 mins before, and a 3-mg/kg bolus 3 hrs after, the onset of sepsis. Hemodynamics, PaO2, and neutrophil counts were measured for 6 hrs. Thiobarbituric acid reactive material (TBARM) in tissue (lung, liver, and intestine), lung wet/dry weight ratio, lung myeloperoxidase activity, plasma tumor necrosis factor (TNF)-alpha concentrations, protein content, and percent neutrophils in bronchoalveolar lavage fluid were evaluated at the time the animals were killed (6 hrs). Sepsis induced significant systemic hypotension, pulmonary hypertension, hypoxemia, and neutropenia. Sepsis also significantly increased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, plasma TNF-alpha concentrations, and bronchoalveolar lavage neutrophil percentage. Treatment with tirilazad mesylate significantly attenuated hypoxemia and decreased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, bronchoalveolar lavage protein, and bronchoalveolar lavage neutrophil percentage, but did not affect sepsis-induced hemodynamics, including systemic hypotension and pulmonary hypertension, plasma TNF-alpha concentrations, or neutropenia. Pretreatment with the tirilazad mesylate did not change P. aeruginosa sepsis-induced hemodynamic consequences. However, tirilazad mesylate attenuated sepsis-induced acute lung injury.


Medicare Reimbursement for Total Joint Arthroplasty: The Driving Forces.
Total joint arthroplasty is a large and growing part of the U.S. Medicare budget, drawing attention to how much providers are paid for their services. The purpose of this study was to examine the variables that affect total joint arthroplasty reimbursement. Along with standard economic variables, we include unique health-care variables. Given the focus on value in the Affordable Care Act, the model examines the relationship of the quality of care to total joint arthroplasty reimbursement. We hoped to find that reimbursement patterns reward quality and reflect standard economic principles. Multivariable regression was performed to identify variables that correlate with Medicare reimbursement for total joint arthroplasty. Inpatient charge or reimbursement data on Medicare reimbursements were available for 2,750 hospitals with at least 10 discharges for uncomplicated total joint arthroplasty from the Centers for Medicare & Medicaid Services (CMS) for fiscal year 2011. Reimbursement variability was examined by using the Dartmouth Atlas to group institutions into hospital referral regions and hospital service areas. Independent variables were taken from the Dartmouth Atlas, CMS, the WWAMI (Washington, Wyoming, Alaska, Montana, Idaho) Rural Health Research Center, and the United States Census. There were 427,207 total joint arthroplasties identified, with a weighted mean reimbursement of $14,324.84 (range, $9,103 to $38,686). Nationally, the coefficient of variation for reimbursements was 0.19. The regression model accounted for 52.5% of reimbursement variation among providers. The total joint arthroplasty provider volume (p < 0.001) and patient satisfaction (p < 0.001) were negatively correlated with reimbursement. Government ownership of a hospital (p < 0.001) and higher Medicare costs (p < 0.001) correlated positively with reimbursement. Medicare reimbursements for total joint arthroplasty are highly variable. Greater reimbursement was associated with lower patient volume, lower patient satisfaction, a healthier patient population, and government ownership of a hospital. As value-based reimbursement provisions of the Affordable Care Act are implemented, there will be dramatic changes in total joint arthroplasty reimbursements. To meet these changes, providers should expect qualities such as high patient volume, willingness to care for sicker patient populations, patient satisfaction, safe outcomes, and procedural demand to correlate with their reimbursement. Practicing orthopaedic surgeons and hospital administrators should be aware of discrepancies in inpatient reimbursement for total joint arthroplasty from Medicare. Furthermore, these discrepancies are not associated with typical economic factors. These findings warrant further investigation and collaboration between policymakers and providers to develop value-based reimbursement.


Synchronization of two ensembles of atoms.
We propose a system for observing the correlated phase dynamics of two mesoscopic ensembles of atoms through their collective coupling to an optical cavity. We find a dynamical quantum phase transition induced by pump noise and cavity output coupling. The spectral properties of the superradiant light emitted from the cavity show that at a critical pump rate the system undergoes a transition from the behavior of two independent oscillators to the phase locking that is the signature of quantum synchronization.


XIPOU 2 is a potential regulator of Spemann's Organizer.
XIPOU 2, a member of the class III POU-domain family, is expressed initially at mid-blastula transition (MBT) and during gastrulation in the entire marginal zone mesoderm, including Spemann's Organizer (the Organizer). To identify potential targets of XIPOU 2, the interaction of XIPOU 2 with other genes co-expressed in the Organizer was examined by microinjecting XIPOU 2's mRNA into the lineage of cells that contributes to the Organizer, head mesenchyme and prechordal plate. XIPOU 2 suppresses the expression of a number of dorsal mesoderm-specific genes, including gsc, Xlim-1, Xotx2, noggin and chordin, but not Xnot. As a consequence of the suppression of dorsal mesoderm gene expression, bone morphogenetic factor-4 (Bmp-4), a potent inducer of ventral mesoderm, is activated in the Organizer. Gsc is a potential target of XIPOU 2. XIPOU 2 is capable of binding a class III POU protein binding site (CATTAAT) that is located within the gsc promoter, in the activin-inducible (distal) element. Furthermore, XIPOU 2 suppresses the activation of the gsc promoter by activin signaling. At the neurula and tailbud stages, dorsoanterior structures are affected: embryos displayed micropthalmia and the loss of the first branchial arch, as detected by the expression of pax-6, Xotx2 and en-2. By examining events downstream from the Wnt and chordin pathways, we determined that XIPOU 2, when overexpressed, acts specifically in the Organizer, downstream from GSK-3beta of the Wnt pathway and upstream from chordin. The interference in dorsalizing events caused by XIPOU 2 was rescued by chordin. Thus, in addition to its direct neuralizing ability, in a different context, XIPOU 2 has the potential to antagonize dorsalizing events in the Organizer.


Reduction of image noise in elastography.
Elastography is a method for imaging the elastic properties of compliant tissues which produces gray scale elasticity images called elastograms. The elastograms of phantoms with homogeneous elastic properties exhibit a noisy appearance. We demonstrate that this noisy appearance of the elastograms is due to the nonstationary relationship between the pre- and postcompression signals that results in an artifactual modulation of the strain estimates by the amplitude variations of the envelope of the rf signal. We have identified two methods to reduce the strain modulation artifact. The first method consists of reducing the signal amplitude swings within the observation windows by logarithmically or otherwise compressing the rf signal. The sensitivity of this method to amplitude compression strength and the ability to reduce the noise in the elastograms without affecting the spatial resolution are investigated through simulations. The second method to reduce the strain modulation artifact consists of temporal stretching of the signal obtained after physical compression to approximate the shape of the signal obtained before compression. In this paper, we discuss the first method. The results show that significant improvement in image noise can be obtained with logarithmic amplitude compression. This improvement is obtained in conjunction with improved spatial resolution.


How compatible are participatory ergonomics programs with occupational health and safety management systems?
Musculoskeletal disorders (MSD) are a major cause of pain, disability, and costs. Prevention of MSD at work is frequently described in terms of implementing an ergonomics program, often a participatory ergonomics (PE) program. Most other workplace injury prevention activities take place under the umbrella of a formal or informal occupational health and safety management system (OHSMS). This study assesses the similarities and differences between OHSMS and PE as such knowledge could help improve MSD prevention activities. Methods Using the internationally recognized Occupational Health and Safety Assessment Series (OHSAS 18001), 21 OHSMS elements were extracted. In order to define PE operationally, we identified the 20 most frequently cited papers on PE and extracted content relevant to each of the OHSAS 18001 elements. The PE literature provided a substantial amount of detail on five elements: (i) hazard identification, risk assessment and determining controls; (ii) resources, roles, responsibility, accountability, and authority; (iii) competence, training and awareness; (iv) participation and consultation; and (v) performance measurement and monitoring. However, of the 21 OHSAS elements, the PE literature was silent on 8 and provided few details on 8 others. The PE literature did not speak to many elements described in OHSMS and even when it did, the language used was often different. This may negatively affect the effectiveness and sustainability of PE initiatives within organizations. It is expected that paying attention to the approaches and language used in management system frameworks could make prevention of MSD activities more effective and sustainable.


Prolactin studies in "functionless" pituitary tumours.
Hyperprolactinaemia was found in all 17 women and in one out of six men who presented with hypogonadism and a radiologically enlarged sella turcica but no other clinical endocrine dysfunction. Some of the women also had galactorrhoea. The greater the level of hyperprolactinaemia in these 18 patients the larger their sellae turcica except in two patients with unusual features. The sella turcica was usually asymmetrically enlarged and there was rearly an upward extension of tumour, though the sella floor often showed some erosion on tomography. An oral dose of bromocriptine suppressed the hyperprolactinaemia in mose patients at the same rate as in normal post-partum women. Nine of the 18 patients with hyperprolactinaemia had low basal luteinizing hormone (LH) levels. The LH responsiveness to 100 mug of LH-releasing hormone (LHRH) was tested in 12, and eight showed subnormal values. Of eight biopsy specimens obtained four showed acidophil granules on light microscopy, and in five granules of various sizes were seen on electron microscopy.


Task-Driven Activity Reduces the Cortical Activity Space of the Brain: Experiment and Whole-Brain Modeling.
How a stimulus or a task alters the spontaneous dynamics of the brain remains a fundamental open question in neuroscience. One of the most robust hallmarks of task/stimulus-driven brain dynamics is the decrease of variability with respect to the spontaneous level, an effect seen across multiple experimental conditions and in brain signals observed at different spatiotemporal scales. Recently, it was observed that the trial-to-trial variability and temporal variance of functional magnetic resonance imaging (fMRI) signals decrease in the task-driven activity. Here we examined the dynamics of a large-scale model of the human cortex to provide a mechanistic understanding of these observations. The model allows computing the statistics of synaptic activity in the spontaneous condition and in putative tasks determined by external inputs to a given subset of brain regions. We demonstrated that external inputs decrease the variance, increase the covariances, and decrease the autocovariance of synaptic activity as a consequence of single node and large-scale network dynamics. Altogether, these changes in network statistics imply a reduction of entropy, meaning that the spontaneous synaptic activity outlines a larger multidimensional activity space than does the task-driven activity. We tested this model's prediction on fMRI signals from healthy humans acquired during rest and task conditions and found a significant decrease of entropy in the stimulus-driven activity. Altogether, our study proposes a mechanism for increasing the information capacity of brain networks by enlarging the volume of possible activity configurations at rest and reliably settling into a confined stimulus-driven state to allow better transmission of stimulus-related information.


Point-of-care haemoglobin testing in African hospitals: a neglected essential diagnostic test.
Owing to the rapid turnaround time in the assessment of haemoglobin level by point-of-care tests (POC Hb), these have grown in popularity and scope in large parts of the world. However, whilst POC testing for malaria and HIV remains has been integrated into patient management in Africa, the use of POC haemoglobin testing remains neglected by health services. The main users of transfusions (paediatric, maternity and trauma services) present largely as emergencies. Ward-based POC Hb could result in more rapid and accurate diagnosis of anaemia, contributing to saving of lives and at the same time reduce unnecessary transfusions which deplete the limited supplies of donated blood in Africa. Severe anaemia requiring transfusion is a major cause of paediatric admission in Africa. At a dissemination meeting to discuss the results of a large phase III paediatric transfusion trial and steps to implementation of the findings participants strongly recommended that one of the most pressing actions required was to prioritise the use of POC haemoglobin testing. This would facilitate implementation of the new transfusion algorithm, developed at the meeting, which refines patient management including blood transfusions. We present the rationale for the strongly recommended prioritisation of POC Hb, using paediatric transfusion as an exemplar.


Accuracy and Precision of Consumer-Grade Wearable Activity Monitors for Assessing Time Spent in Sedentary Behavior in Children and Adolescents: Systematic Review.
A large number of wearable activity monitor models are released and used each year by consumers and researchers. As more studies are being carried out on children and adolescents in terms of sedentary behavior (SB) assessment, knowledge about accurate and precise monitoring devices becomes increasingly important. The main aim of this systematic review was to investigate and communicate findings on the accuracy and precision of consumer-grade physical activity monitors in assessing the time spent in SB in children and adolescents. Searches of PubMed (MEDLINE), Scopus, SPORTDiscus (full text), ProQuest, Open Access Theses and Dissertations, DART Europe E-theses Portal, and Networked Digital Library of Theses and Dissertations electronic databases were performed. All relevant studies that compared different types of consumer-grade monitors using a comparison method in the assessment of SB, published in European languages from 2015 onward were considered for inclusion. The risk of bias was estimated using Consensus-Based Standards for the Selection of Health Status Measurement Instruments. For enabling comparisons of accuracy measures within the studied outcome domain, measurement accuracy interpretation was based on group mean or percentage error values and 90% CI. Acceptable limits were predefined as -10% to +10% error in controlled and free-living settings. For determining the number of studies with group error percentages that fall within or outside one of the sides from previously defined acceptable limits, two 1-sided tests of equivalence were carried out, and the direction of measurement error was examined. A total of 8 studies complied with the predefined inclusion criteria, and 3 studies provided acceptable data for quantitative analyses. In terms of the presented accuracy comparisons, 14 were subsequently identified, with 6 of these comparisons being acceptable in terms of quantitative analysis. The results of the Cochran Q test indicated that the included studies did not share a common effect size (Q5=82.86; P<.001). I2, which represents the percentage of total variation across studies due to heterogeneity, amounted to 94%. The summary effect size based on the random effects model was not statistically significant (effect size=14.36, SE 12.04, 90% CI -5.45 to 34.17; P=.23). According to the equivalence test results, consumer-grade physical activity monitors did not generate equivalent estimates of SB in relation to the comparison methods. Majority of the studies (3/7, 43%) that reported the mean absolute percentage errors have reported values of <30%. This is the first study that has attempted to synthesize available evidence on the accuracy and precision of consumer-grade physical activity monitors in measuring SB in children and adolescents. We found very few studies on the accuracy and almost no evidence on the precision of wearable activity monitors. The presented results highlight the large heterogeneity in this area of research. PROSPERO CRD42021251922; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=251922.


Latent Feature Decompositions for Integrative Analysis of Multi-Platform Genomic Data.
Increased availability of multi-platform genomics data on matched samples has sparked research efforts to discover how diverse molecular features interact both within and between platforms. In addition, simultaneous measurements of genetic and epigenetic characteristics illuminate the roles their complex relationships play in disease progression and outcomes. However, integrative methods for diverse genomics data are faced with the challenges of ultra-high dimensionality and the existence of complex interactions both within and between platforms. We propose a novel modeling framework for integrative analysis based on decompositions of the large number of platform-specific features into a smaller number of latent features. Subsequently we build a predictive model for clinical outcomes accounting for both within- and between-platform interactions based on Bayesian model averaging procedures. Principal components, partial least squares and non-negative matrix factorization as well as sparse counterparts of each are used to define the latent features, and the performance of these decompositions is compared both on real and simulated data. The latent feature interactions are shown to preserve interactions between the original features and not only aid prediction but also allow explicit selection of outcome-related features. The methods are motivated by and applied to a glioblastoma multiforme data set from The Cancer Genome Atlas to predict patient survival times integrating gene expression, microRNA, copy number and methylation data. For the glioblastoma data, we find a high concordance between our selected prognostic genes and genes with known associations with glioblastoma. In addition, our model discovers several relevant cross-platform interactions such as copy number variation associated gene dosing and epigenetic regulation through promoter methylation. On simulated data, we show that our proposed method successfully incorporates interactions within and between genomic platforms to aid accurate prediction and variable selection. Our methods perform best when principal components are used to define the latent features.


Brain connectivity during verbal working memory in children and adolescents.
Working memory (WkM) is a fundamental cognitive process that serves as a building block for higher order cognitive functions. While studies have shown that children and adolescents utilize similar brain regions during verbal WkM, there have been few studies that evaluate the developmental differences in brain connectivity. Our goal was to study the development of brain connectivity related to verbal WkM in typically developing children and adolescents. Thirty-five healthy children and adolescents, divided into three groups: 9-12 (children), 13-16 (young adolescents), and 17-19 (older adolescents) years, were included in this functional magnetic resonance imaging (fMRI) study. The verbal WkM task involved a modified Sternberg item recognition paradigm using three different loads. Brain connectivity analysis was performed using independent component analyses and regressing the components with the design matrix to determine task-related networks. Connectivity analyses resulted in four components associated solely with encoding, four solely with recognition and two with both. Two networks demonstrated age-related differences with respect to load, (1) the left motor area and right cerebellum, and 2) the left prefrontal cortex, left parietal lobe, and right cerebellum. Post hoc analyses revealed that the first network showed significant effects of age between children and the two older groups. There was increasing connectivity with increasing load for adolescents. The second network demonstrated age-related differences between children and older adolescents. Children have higher task-related connectivity at lower loads, but they tend to equalize with the adolescents with higher loads. Finally, a non-load related network involving the orbital frontal and anterior cingulate cortices showed less connectivity in children. Hum Brain Mapp 35:698-711, 2014. © 2012 Wiley Periodicals, Inc.


Familial intracranial aneurysms: is anatomic vulnerability heritable?
Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study. We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family's proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and P values from the 1001 logistic regression analyses were used to represent the final results of the analysis. There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04-2.27]; P=0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22-3.22]; P=0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05-8.24], P=0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34-2.46]; P<0.001). In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.


Phase I/II study on kilovoltage surface brachytherapy in conjunctival cancer: preliminary results.
In ocular conjunctival carcinoma after surgery, adjuvant treatment has a role and kilovoltage surface brachytherapy opens a new door for the range of therapeutic options. Between October 2014 and June 2017, at the National Institute of Neoplastic Diseases (INEN) from Peru, 39 patients with squamous cell carcinoma of ocular conjunctiva, T1-T3, resected, were selected to receive adjuvant treatment. The portable accelerator of 50-kV INTRABEAM (Carl Zeiss Meditec) was used, after local anaesthesia and blocking of ocular muscles movement. The doses used were 18 Gy for patients with free margins and 22 Gy for positive edges, according to calculation of equivalent dose of 2Gy per fraction of 46 and 66 Gy, respectively, assuming a tumoural α/β ratio of 8 Gy. The prescription was done to 2 mm depth. The median age was 69 years, distributed evenly between both genders, with a median follow-up of 12 months. The surgical margins were 59% free and 41% committed, with no difference between the institutions where the surgery was performed (P = 0.069). The median tumour size was 7 mm with 2 mm of invasion, 61.5% was T2 and 35.9% T1. The mean time between surgery and irradiation was 1.5 months, 23.1% of patients developed grade I toxicity of spontaneous resolution, without evidence of greater degree in any case. The dose had no statistical relationship with toxicity (P = 0.533). One-year disease-free survival was 96.7%. Kilovoltage surface brachytherapy is an applicable and reproducible tool in the treatment of squamous cell carcinoma of ocular conjunctiva. The administered doses are well tolerated by patients with low levels of acute toxicity. Longer follow-up is needed to establish disease control rates and late toxicities.


Setting Priorities for Optimizing Vascular Access Decision Making--An International Survey of Patients and Clinicians.
Many decisions around vascular access for haemodialysis warrant a collaborative treatment decision-making process, involving both clinician and patient. Yet, patients' experiences in this regard have been suboptimal. Although clinical practice guidelines could facilitate collaborative decision making, they often focus on the clinicians' side of the process, while failing to address the patients' perspective. The objective of this study was to explore and compare kidney patients' and clinicians' views on what vascular access-related decisions deserved priority for developing guidelines that will contribute to optimizing collaborative decision making. In the context of updating their vascular access guideline, European Renal Best Practice surveyed an international panel of 85 kidney patients, 687 nephrologists, 194 nurses, and 140 surgeons/radiologists. In an electronic questionnaire, respondents rated 42 vascular access-related topics on a 5-point Likert scale. Based on mean standardized ratings, we compared priority ratings between patients and each clinician group. Selection of access type and site, as well as prevention of access infections received top priority across all respondent groups. Patients generally assigned higher priority to decisions regarding managing adverse effects of arteriovenous access and patient involvement in care, while clinicians more often prioritized decisions around sustaining patients' access options, technical aspects of access creation, and optimizing fistula maturation and patency. Apart from identifying the most pressing knowledge gaps, our study provides pointers for developing guidelines that may improve healthcare professionals' understanding of when to involve patients along the vascular access pathway.


Anti-cyclic citrullinated Peptide frequency in patients with chronic hepatitis C virus infection and effect of presence of systemic disease.
Patients with chronic hepatitis C virus (HCV) infection may show a variety of rheumatic symptoms and signs. Anti-cyclic citrullinated peptide (anti-CCP) is widely used as as a marker, particularly for rheumatoid arthritis (RA), and may be positive in some diseases that also cause arthritis, such as systemic lupus erythematosus, familial Mediterranean fever, Behçet's disease, and psoriatic arthritis. Blood samples were obtained (in routine protocols) from 57 patients with chronic HCV infection from the Gastroenterology Clinic of Ataturk University and Infectious Disease Clinic of Erzurum Region Research and Education Hospital. Normal sera were obtained from volunteer blood donors at Ataturk University. Anti-CCP antibodies were found in 5 chronic HCV patients with RA. The patient with the highest anti-CCP antibody level had RA. No patient in the control group was positive for anti-CCP antibodies. Anti-cyclic citrullinated peptide (anti-CCP) antibodies should be measured frequently in patients with HCV and an additional systemic disease, such as end-stage chronic renal failure, chronic obstructive airway disease, and decompensated liver cirrhosis, to differentiate RA from non-RA arthropathy.


Outcomes of endoscopic sinus surgery for chronic rhinosinusitis associated with sinonasal polyposis.
The aim of this study was is to investigate the outcomes of endoscopic sinus surgery (ESS) when performed for chronic rhinosinusitis associated with sinonasal polyps. Forty-three patients with polyps were compared with 76 patients without polyps before and after ESS. Mean follow-up was 1.5 years. Patients were analyzed prospectively based on computed tomography (CT), endoscopy, quality-of-life (QOL) assessment, and visual analog scales (VASs). Univariate analyses were performed to evaluate whether the presence of polyps was predictive of outcome. Patients with polyps had worse CT and endoscopy scores both pre- and postoperatively when compared with patients without polyps (p < 0.0001 for each). All patients, regardless of polyps, improved on endoscopic exam; however, patients with polyps showed a greater degree of improvement (p = 0.002). Despite this, postoperative endoscopic scores in patients with polyps were worse than those without polyps (p < 0.0001). Patients with polyps had better QOL as measured by the Chronic Sinusitis Survey (CSS) both pre- and postoperatively (p = 0.001 and 0.044, respectively). The preoperative VAS indicated that patients with polyps had increased nasal obstruction compared with patients without polyps (p = 0.002) while having less facial pain and headache (p = 0.002 and 0.005, respectively). Patients with polyps showed a greater postoperative improvement in nasal congestion (p = 0.003) but no difference in level of improvement in postoperative headache or pressure. Despite significantly worse objective testing scores, patients with polyps report significantly better QOL as measured by the CSS and less facial pain/headache as measured by VAS scores pre- and postoperatively. Polyps were not found to be predictive of QOL or endoscopic outcome.


[Humero-scapular periarthrosis].
Humero-scapular periarthrosis (PH) is defined as an idiopathic painful condition in the shoulder with simultaneous limitation of active and passive movements in all directions. The condition is characterized by three phases: a painful period, a period dominated by stiffness and a period of recovery. PH is commonest between the ages of 40 and 60 years and the cumulated risk is estimated to be 2%. The incidence is higher in diabetics. The cause of PH is unknown and knowledge of the pathogenesis is very limited. Histological examination shows inflammation and fibrosis. Association with other pathological conditions of the upper limb or medical conditions, except diabetes mellitus, has not been documented with certainty. The average duration is 30 months but recovery without functional defects is common. Treatment is symptomatic and consists primarily of analgesics and rest during the painful phase. Local injections of steroids may be of effect. Exercises may be employed once the pain is under control and these have the object of improving mobility and increasing muscular strength.


Alpha-lipoic acid suppresses the development of collagen-induced arthritis and protects against bone destruction in mice.
To test the ability of alpha-lipoic acid (LA) to attenuate the development of collagen-induced arthritis (CIA) in mice. Mice were divided into three groups and treated with intraperitoneal administration of LA (10 or 100 mg/kg) or placebo. Clinical, histologic, and biochemical parameters were assessed. Human synovial fibroblasts and peripheral blood mononuclear cells were cocultured in various concentrations of LA to evaluate the effects on osteoclastogenesis. LA was associated with a dose-dependent reduction of CIA, as well as preventing bone erosion and destructive changes. Intracellular reactive oxygen species in lymphocytes obtained from inguinal lymph nodes, which was significantly higher in CIA than control mice, was significantly reduced in CIA by LA. The concentrations of TNF-alpha, IL-1beta, and IL-6 in the paws, and synovial NF-kappaB binding, all of which were markedly higher in CIA than control mice, were reduced by treatment with LA. In addition, LA inhibited the formation of human osteoclasts in vitro. Amelioration of joint disease by LA was associated with reduction in oxidative stress, as well as inhibition of inflammatory cytokine activation and NF-kappaB DNA binding activity. Moreover, LA inhibited bone destruction in vivo and osteoclastogenesis in vitro. Collectively, these results indicate that LA may be a new adjunctive therapy for rheumatoid arthritis.


Processes driving seagrass soils composition along the western Mediterranean: The case of the southeast Iberian Peninsula.
Seagrasses are distributed all along the coast of the Mediterranean Sea being Posidonia oceanica and Cymodocea nodosa the most common species. They promote sedimentation, leading to the formation of well-structured soils. Over the last decade, a growing attention has been paid to their role as CO2 sinks in the form of organic carbon (Corg) and to their use as environmental archives. However, most of the knowledge about pedogenetic processes in these soils refer to the rhizosphere. This study aims to understand seagrass soils biogeochemistry in the rhizosphere and below, which in turn can help to understand their long term formation processes. Fifteen cores were strategically sampled along a 350 km stretch of the Southeast Iberian coast, and analyzed for elemental composition (XRF core-scanning), magnetic susceptibility, Corg content and gran size distribution. The cores were dated by 210Pb and 14C-AMS techniques to estimate soil accretion. Principal component analysis was used to explore the main geochemical processes linked to soil formation. The results showed that terrestrial runoff plays a key role in meadow soil composition. Furthermore, Corg accumulation did not follow any general depth trend in our soil records, suggesting that temporal variation in Corg inputs is an important factor in determining carbon depth distribution within the soil. We obtained evidence that the establishment of well-developed, stable C. nodosa meadows in the Mediterranean Sea may be promoted by adverse environmental conditions to P. oceanica settlement. Metal's behavior within the meadow deposit and their interaction with organic matter and carbonates is unclear. The results presented in this paper highlight the importance of the influence of land-based inputs in the characteristics of seagrass meadow deposits, highly determining their Corg content, as well as the need for further studies on metal behavior, to understand their full potential as environmental records.


Case Report on Fear of Falling Syndrome: A Debilitating but Curable Gait Disorder.
BACKGROUND Fear of falling syndrome is a rare and often-missed disorder among patients with new-onset gait abnormality. The disorder is often mistaken for an organic neurologic problem, with some considering it to be a medical emergency. CASE REPORT This case report presents a 70-year-old man who presented to the Emergency Department due to inability to rise from a chair or ambulate independently. Onset of his chief complaint occurred subsequent to a traumatic fall in a public location. He underwent extensive workup, and an organic neurologic cause was ruled out. He was subsequently diagnosed with fear of falling syndrome after obtaining a detailed fall history, as well as utilizing a verified survey (the Falls Efficacy Scale-International). After extensive inpatient treatment, the patient improved significantly. However, upon discharge to a skilled nursing facility, he was not offered the recommended treatment. When he was readmitted for an unrelated reason 3 months later, he had regressed to the state he was in at the time of prior admission. CONCLUSIONS This case presents a rare debilitating but reversible gait disorder, and highlights the importance of assessing "fall history" and fear of falling in older adults. Uniquely, this case presents the rapid fluctuation in outcomes dependent on treatment, and what happens when a patient fails to complete treatment regimens. The report also provides an overview of fear of falling with the corresponding gait disorder.


Outpatient endovascular aortic aneurysm repair: experience in 100 consecutive patients.
To present the safety, feasibility, costs, and patient satisfaction of outpatient endovascular aneurysm repair (EVAR). Our experience in more than 1000 patients indicated that in technically uncomplicated EVAR procedures, the only need for hospitalization was for access vessel complications (bleeding or occlusion) requiring secondary procedures. These complications could always be identified within the first 3 hours after EVAR. Two-center retrospective analysis of prospectively gathered data on 100 consecutive elective outpatient EVAR cases (Outpt EVAR). Inclusion criteria for Outpt EVAR were as follows: asymptomatic clinical state, informed consent, travel time to the hospital if readmission was required of less than 60 minutes, adult observer assistance for the first 24 hours, and a technically uncomplicated EVAR procedure. EVAR was mostly performed under local anesthesia and with percutaneous access. Patients were discharged home after 4 to 6 hours of observation and checked the next morning and on the fifth postoperative day in the outpatient clinic. From 104 patients selected, 4 (3.8%) preferred primary hospitalization and were excluded from further analysis. Four patients (4%) with access vessel complications required additional procedures and had to be hospitalized overnight. The 30-day readmission rate was 4% (4), all due to access vessel stenosis (2) or false aneurysm (2). There was no 30-day mortality. From the 96 outpatients who completed Outpt EVAR, 93 (97%) would undergo Outpt EVAR again and would recommend it to others. Cost comparison showed in 42 matched contemporary patients treated with just a standard stent graft that costs were significantly lower in 21 Outpt EVAR patients than in 21 inpatient EVAR. Elective Outpt EVAR can be performed safely, provided certain criteria are fulfilled and specific precautions are taken. In this series, Outpt EVAR morbidity was minimal, especially delirium common in elderly patients recovering from inpatient vascular surgery and nosocomial infections did not occur. Finally, patient satisfaction was high and costs were less than with standard inpatient EVAR.


Open source tracking and analysis of adult Drosophila locomotion in Buridan's paradigm with and without visual targets.
Insects have been among the most widely used model systems for studying the control of locomotion by nervous systems. In Drosophila, we implemented a simple test for locomotion: in Buridan's paradigm, flies walk back and forth between two inaccessible visual targets [1]. Until today, the lack of easily accessible tools for tracking the fly position and analyzing its trajectory has probably contributed to the slow acceptance of Buridan's paradigm. We present here a package of open source software designed to track a single animal walking in a homogenous environment (Buritrack) and to analyze its trajectory. The Centroid Trajectory Analysis (CeTrAn) software is coded in the open source statistics project R. It extracts eleven metrics and includes correlation analyses and a Principal Components Analysis (PCA). It was designed to be easily customized to personal requirements. In combination with inexpensive hardware, these tools can readily be used for teaching and research purposes. We demonstrate the capabilities of our package by measuring the locomotor behavior of adult Drosophila melanogaster (whose wings were clipped), either in the presence or in the absence of visual targets, and comparing the latter to different computer-generated data. The analysis of the trajectories confirms that flies are centrophobic and shows that inaccessible visual targets can alter the orientation of the flies without changing their overall patterns of activity. Using computer generated data, the analysis software was tested, and chance values for some metrics (as well as chance value for their correlation) were set. Our results prompt the hypothesis that fixation behavior is observed only if negative phototaxis can overcome the propensity of the flies to avoid the center of the platform. Together with our companion paper, we provide new tools to promote Open Science as well as the collection and analysis of digital behavioral data.


Basic fibroblast growth factor selectively regulates ornithine decarboxylase gene expression in malignant H-ras transformed cells.
Cell growth regulation by fibroblast growth factors (FGFs) is highly complex. The present study demonstrates a novel link between alterations in bFGF regulation during malignant conversion and the expression of ornithine decarboxylase, a key rate-limiting and regulatory activity in the biosynthesis of polyamines. H-ras transformed mouse 10T 1/2 cell lines exhibiting increasing malignant potential were investigated for possible bFGF-mediated changes in ornithine decarboxylase gene expression. Selective induction of ornithine decarboxylase gene expression was observed, since, in contrast to nontransformed 10T 1/2 cells and cells capable of only benign tumor formation, H-ras transformed metastatic cells exhibited marked elevations in ornithine decarboxylase message levels. Evidence for regulation of ornithine decarboxylase gene expression by bFGF at both transcription and posttranscription was found. Actinomycin D pretreatment of malignant cells prior to bFGF exposure inhibited the increase in ornithine decarboxylase message. Furthermore, striking differences in the rates of ornithine decarboxylase message decay were observed when cells treated with bFGF were compared to untreated control cells, with the half-life of ornithine decarboxylase mRNA increasing from 2.4 h in untreated cells to 12.5 h in cells exposed to bFGF. Evidence was also obtained for a cycloheximide-sensitive regulator of ornithine decarboxylase gene expression whose effect, in combination with bFGF, resulted in a further augmentation of ornithine decarboxylase gene expression. Furthermore, evidence is presented to suggest a possible role for G-protein-coupled events in the bFGF-mediated regulation of ornithine decarboxylase gene expression. The bFGF regulation of ornithine decarboxylase expression in H-ras transformed malignant cells appeared to occur independent of protein kinase C-mediated events. These results show that bFGF can modulate ornithine decarboxylase gene expression in malignant H-ras transformed cells and further suggests a mechanism of growth factor stimulation of malignant cells wherein early alterations in the regulatory control of ornithine decarboxylase gene expression are critical.


Mental health of Syrian refugee adolescents: how far have we come?
Akgül S, Hüsnü Ş, Derman O, Özmert E, Bideci A, Hasanoğlu E. Mental health of Syrian refugee adolescents: how far have we come? Turk J Pediatr 2019; 61: 839-845. Among the consequences of war, its impact on the mental health of children and adolescents is one of the most significant. A previous study from our team evaluated the psychiatric symptoms of Syrian refugee adolescents living in one of Turkey`s Temporary Accommodation Centers (TACs) in 2016. Findings suggested that mental health had been compromised in these teens. Since then many measures have been taken to address this problem. The aim of the current study was to re-assess the mental health status of adolescents living in the same center. A total of 76 adolescents (35 female, 41 male) aged between 12-18 years (14.2 ± 0.83 years) received the Brief Symptom Inventory (BSI) which assessed their anxiety, depression, negative self-concept, somatization and hostility levels in addition to a Global Severity Index (GSI). Results > 1.0 indicated psychopathological symptoms. All BSI sub-scores decreased from 2016 to 2019 showing significant improvement in psychopathological symptoms. The most significant change was in the GSI score which decreased from 2.15 to 0.8. For the 2019 participants a significant correlation was found between years of stay at the camp and the depression subscale. Evaluation to assess gender differences found that adolescent girls reported significantly higher scores than males in anxiety, depression, somatization and the global severity index. This study has shown that interventions designed to tackle post-traumatic stress symptomology may have been effective in improving the mental health status of these teens and can provide a roadmap for tackling existing issues in vulnerable conditions. Additionally, females are under higher risk for psychopathology so gender targeted interventions may specifically be necessary to deal with such issues.


Is early stage endometrial cancer safely treated by laparoscopy? Complications of a multicenter study and review of recent literature.
To compare the complications after total laparoscopic hysterectomy (LPS) and abdominal hysterectomy with lymphadenectomy (LPT) for early stage endometrial cancer in a series of 226 women and to assess the disease-free survival and the recurrence rate. Two hundred and twenty six patients with clinical stage I endometrial cancer were enrolled in a multicenter study and underwent surgical staging consisting of inspecting the intraperitoneal cavity, peritoneal washing, total hysterectomy, bilateral salpingo-oophorectomy, and in all cases we performed systematic bilateral pelvic lymphadenectomy by LPS or LPT approach. One patient of the LPS group had an uretero-vaginal fistula and another patient had an ureteral stricture temporarily treated with a stent. One patient of the LPS group had a bowel perforation due to dense adhesions with the peritoneum under the umbilicus, resolved with a bowel resection and an end-to-end anastomosis. In three patients of the LPS group we observed a vaginal cuff dehiscence and in one case a pelvic lymphocyst was reported. The low intraoperative and postoperative complications rate, observed in the LPS group, highlights the feasibility, safety and efficacy of this surgical approach. The operating time was longer in the LPS group but the recurrence rate and the complication rate appear similar and not more than what is traditionally expected with the LPT approach, although further studies and cost-benefit analyses are required to determine whether the use of LPS improves the outcome over standard LPT and whether the advantages of this technique could be extended to a larger proportion of patients.


Older Adult Patients' Experience of Care in a Dental School Clinic.
The aim of this study was to assess older adults' experience of care in an academic dental practice to identify opportunities to improve the patient experience for older adults. A cross-sectional descriptive survey design with a sample of adults aged 65 and older was conducted using the Consumer Assessment of Healthcare Providers and Systems Clinician and Group (CG-CAHPS) 12-month survey 2.0, with supplemental survey item sets addressing cultural competence and health literacy. A total of 850 older adults were invited to participate in the survey in fall 2016, and a 43% response rate was achieved. Overall, participants reported a positive experience of care and high ratings for their dental providers. Significant differences were found based on age, education level, race, and health status. A significantly more favorable experience of care was reported by patients aged 75 and older, as well as adults without any college education. Non-white patients were less likely to highly rate their dental providers and gave lower ratings for experiencing trust with their dental providers than white patients. Patients reporting good/fair/poor health were also less likely than those reporting very good/excellent health to highly rate their dental providers, and they gave lower ratings for patient-provider communication. This study demonstrated the feasibility of using the CG-CAHPS survey to assess the patient experience for older adults in an academic dental practice. Results identified opportunities for improving the dental practice and underscored the importance of enhancing dental curricula in areas of cultural competence, health literacy, and diversity.


Differential Effects of Deep Brain Stimulation of the Internal Capsule and the Striatum on Excessive Grooming in Sapap3 Mutant Mice.
Deep brain stimulation (DBS) is an effective treatment for patients with obsessive-compulsive disorder (OCD) that do not respond to conventional therapies. Although the precise mechanism of action of DBS remains unknown, modulation of activity in corticofugal fibers originating in the prefrontal cortex is thought to underlie its beneficial effects in OCD. To gain more mechanistic insight into DBS in OCD, we used Sapap3 mutant mice. These mice display excessive self-grooming and increased anxiety, both of which are responsive to therapeutic drugs used in OCD patients. We selected two clinically relevant DBS targets through which activity in prefronto-corticofugal fibers may be modulated: the internal capsule (IC) and the dorsal part of the ventral striatum (dVS). IC-DBS robustly decreased excessive grooming, whereas dVS-DBS was on average less effective. Grooming was reduced rapidly after IC-DBS onset and reinstated upon DBS offset. Only IC-DBS was associated with increased locomotion. DBS in both targets induced c-Fos expression around the electrode tip and in different regions of the prefrontal cortex. This prefronto-cortical activation was more extensive after IC-DBS, but not associated with behavioral effects. Furthermore, we found that the decline in grooming cannot be attributed to altered locomotor activity and that anxiety, measured on the elevated plus maze, was not affected by DBS. DBS in both the IC and dVS reduces compulsive grooming in Sapap3 mutant mice. However, IC stimulation was more effective, but also produced motor activation, even though both DBS targets modulated activity in a similar set of prefrontal cortical fibers.


The expression in eukaryotes of a tyrosine kinase which is reactive with pp60v-src antibodies.
All specimens of Eumetazoa and Parazoa, ranging from mammals, birds, teleosts, sharks, lampreys, amphioxus, insects, down to sponges showed the pp60c-src associated kinase activity, indicating that c-src, which is the cellular homologue of the oncogene v-src of Rous sarcoma virus (RSV) is probably present in all multicellular animals. Protozoa and plants did not show pp60c-src kinase activity. The degree of c-src expression depends on the taxonomic rank of the Eumetazoa tested, and is organ-specific with nervous tissues displaying the highest kinase activities. In the central nervous system of mammals and birds we found a high c-src expression, and in that of the lampreys, amphioxus, and insects the lowest. Unexpectedly, total extracts of sponges showed an amount of pp60c-src kinase activity similar to that of brain cell extracts of mammals and birds. These findings suggest that pp60c-src is a phylogenetic old protein that might have evolved together with the multicellular organisation of Metazoa, and that might be of importance in proliferation and differentiation of nontransformed cells.


HuR-dependent expression of Wisp1 is necessary for TGFβ-induced cardiac myofibroblast activity.
Cardiac fibrosis is regulated by the activation and phenotypic switching of quiescent cardiac fibroblasts to active myofibroblasts, which have extracellular matrix (ECM) remodeling and contractile functions which play a central role in cardiac remodeling in response to injury. Here, we show that expression and activity of the RNA binding protein HuR is increased in cardiac fibroblasts upon transformation to an active myofibroblast. Pharmacological inhibition of HuR significantly blunts the TGFβ-dependent increase in ECM remodeling genes, total collagen secretion, in vitro scratch closure, and collagen gel contraction in isolated primary cardiac fibroblasts, suggesting a suppression of TGFβ-induced myofibroblast activation upon HuR inhibition. We identified twenty-four mRNA transcripts that were enriched for HuR binding following TGFβ treatment via photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Eleven of these HuR-bound mRNAs also showed significant co-expression correlation with HuR, αSMA, and periostin in primary fibroblasts isolated from the ischemic-zone of infarcted mouse hearts. Of these, WNT1-inducible signaling pathway protein-1 (Wisp1; Ccn4), was the most significantly associated with HuR expression in fibroblasts. Accordingly, we found Wisp1 expression to be increased in cardiac fibroblasts isolated from the ischemic-zone of mouse hearts following ischemia/reperfusion, and confirmed Wisp1 expression to be HuR-dependent in isolated fibroblasts. Finally, addition of exogenous recombinant Wisp1 partially rescued myofibroblast-induced collagen gel contraction following HuR inhibition, demonstrating that HuR-dependent Wisp1 expression plays a functional role in HuR-dependent MF activity downstream of TGFβ. In conclusion, HuR activity is necessary for the functional activation of primary cardiac fibroblasts in response to TGFβ, in part through post-transcriptional regulation of Wisp1.


Genomics and cancer drug resistance.
Cellular drug resistance is a major obstacle in cancer therapy. Mechanisms of resistance can be associated with altered expression of ATP-binding cassette (ABC) family of transporters on cell membrane transporters, the most common cause of multi-drug resistance (MDR), but can also include alterations of DNA repair pathways, resistance to apoptosis and target modifications. Anti-cancer treatments may be divided into different categories based on their purpose and action: chemotherapeutic agents damage and kill dividing cells; hormonal treatments prevent cancer cells from receiving signals essential for their growth; targeted drugs are a relatively new cancer treatment that targets specific proteins and pathways that are limited primarily to cancer cells or that are much more prevalent in cancer cells; and antibodies function by either depriving the cancer cells of necessary signals or by causing their direct death. In any case, resistance to anticancer therapies leads to poor prognosis of patients. Thus, identification of novel molecular targets is critical in development of new, efficient and specific cancer drugs. The aim of this review is to describe the impact of genomics in studying some of the most critical pathways involved in cancer drug resistance and in improving drug development. We shall also focus on the emerging role of microRNAs, as key gene expression regulators, in drug resistance. Finally, we shall address the specific mechanisms involved in resistance to tyrosine kinase inhibitors in chronic myeloid leukemia.


IL-7R-dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz-1.
T cells originate from early T lineage precursors that have entered the thymus and differentiate through well-defined steps. Mice deficient for the BTB/POZ domain of zinc finger protein-1 (Miz-1) almost entirely lack early T lineage precursors and have a CD4(-)CD8(-) to CD4(+)CD8(+) block causing a strong reduction in thymic cellularity. Miz-1(ΔPOZ) pro-T cells cannot differentiate in vitro and are unable to relay signals from the interleukin-7R (IL-7R). Both STAT5 phosphorylation and Bcl-2 up-regulation are perturbed. The high expression levels of SOCS1 found in Miz-1(ΔPOZ) cells probably cause these alterations. Moreover, Miz-1 can bind to the SOCS1 promoter, suggesting that Miz-1 deficiency causes a deregulation of SOCS1. Transgenic overexpression of Bcl-2 or inhibition of SOCS1 restored pro-T cell numbers and their ability to differentiate, supporting the hypothesis that Miz-1 is required for the regulation of the IL-7/IL-7R/STAT5/Bcl-2 signaling pathway by monitoring the expression levels of SOCS1.


Streptococcus mutans SpxA2 relays the signal of cell envelope stress from LiaR to effectors that maintain cell wall and membrane homeostasis.
Streptococcus mutans is a major etiologic agent of dental caries, which is the most common chronic infectious disease worldwide. S. mutans is particularly adept at causing caries due to its exceptional capacity to form biofilms and its ability to survive acidic conditions that arrest acid production and growth in many more benign members of the oral microbiota. Two mechanisms utilized by S. mutans to tolerate acid are: modulation of the membrane fatty acid content and utilization of the F1 F0 -ATPase to pump protons out of the cytosol. In this study, the role of the spxA2 transcriptional regulator in these two pathways, and overall cell envelope homeostasis, was examined. Loss of spxA2 resulted in an increase in the proportion of saturated fatty acids in the S. mutans membrane and altered transcription of several genes involved in the production of these membrane fatty acids, including fabT and fabM. Furthermore, activity of the F1 F0 -ATPase was increased in the ∆spxA2 strain. Transcription of spxA2 was elevated in the presence of a variety of membrane stressors, and highly dependent on the liaR component of the LiaFSR system, which is known to sense cell envelope stress in many Gram-positive bacteria. Finally, deletion of ∆spxA2 led to altered susceptibility of S. mutans to membrane stressors. Overall, the results of this study indicate that spxA2 serves a crucial role in transmitting the signal of cell wall/membrane damage from the LiaFSR sensor to downstream effectors in the SpxA2 regulon which restore and maintain membrane and cell wall homeostasis.


Real-time full field laser Doppler imaging.
We present a full field laser Doppler imaging instrument, which enables real-time in vivo assessment of blood flow in dermal tissue and skin. This instrument monitors the blood perfusion in an area of about 50 cm(2) with 480 × 480 pixels per frame at a rate of 12-14 frames per second. Smaller frames can be monitored at much higher frame rates. We recorded the microcirculation in healthy skin before, during and after arterial occlusion. In initial clinical case studies, we imaged the microcirculation in burned skin and monitored the recovery of blood flow in a skin flap during reconstructive surgery indicating the high potential of LDI for clinical applications. Small animal imaging in mouse ears clearly revealed the network of blood vessels and the corresponding blood perfusion.