Neonatal quinpirole treatment produces prepulse inhibition deficits in adult male and female rats.
We have shown that repeated neonatal quinpirole (QUIN; a dopamine D2-like receptor agonist) treatment in rats produces long-lasting supersensitization of dopamine D2 receptors that persists into adulthood but without producing a change in receptor number. The current study was designed to analyze the effects of neonatal QUIN on auditory sensorimotor gating as measured through prepulse inhibition (PPI). Male and female Sprague-Dawley rats were neonatally treated with QUIN (1mg/kg) or saline from postnatal days (P)1-21. At P60, the number of yawns was recorded for a 1h period in response to an acute QUIN (1mg/kg) injection as yawning is a D2-like receptor mediated behavioral event. Five days later, rats began (PPI) behavioral testing in two phases. In phase I, three different prepulse intensities (73, 76, and 82dB) were administered 100-ms before a 115dB pulse on 10 consecutive days. In phase II, three different interstimulus intervals (ISI; 50, 100, and 150ms) were inserted between the 73 or 76dB prepulse and 115dB pulse over 10 consecutive days of testing. A PPI probe trial was administered at the end of each phase after an acute 100μg/kgi.p. injection of QUIN to all animals. Replicating previous work, neonatal QUIN enhanced yawning compared to controls, verifying D2 receptor supersensitization. Regarding PPI, neonatal QUIN resulted in deficits across both phases of testing persistent across all testing days. Probe trial results revealed that acute QUIN treatment resulted in more robust PPI deficits in neonatal QUIN animals, although this deficit was related to prepulse intensity and ISI. These findings provide evidence that neonatal QUIN treatment results in deficits of auditory sensorimotor gating in adulthood as measured through PPI.


The clinical evaluation of new drugs for sepsis. A prospective study design based on survival analysis.
To develop a survival model and severity assessment method to estimate the 28-day mortality risk for patients with sepsis syndrome entering phase 2 and 3 drug evaluations. Retrospective analysis of intensive care unit admissions with sepsis syndrome by means of log-normal regression to identify risk factors for 28-day mortality. Prospective application of the model to patients with gram-negative infection meeting sepsis syndrome criteria from separate data collection (validation group). A total of 58,737 intensive care unit admissions at 107 hospitals in the United States and Western Europe screened to yield 1195 patients meeting entry criteria for the sepsis syndrome study for the original model; 295 hospitalized patients with gram-negative infection meeting criteria for sepsis syndrome for validation. Survival time and mortality at 28 days after fulfillment of the sepsis syndrome criteria. Acute physiologic abnormalities were the most important prognostic factors influencing outcome (82% of total chi 2). Specific disease resulting in intensive care unit admission and the time the patient was in the hospital and intensive care unit before qualification were also independent risks, as were age and a clinical history of cirrhosis. The model's overall classification accuracy was a Somers' Dyx of .52 (rank correlation between predicted risk and 28-day mortality) (receiver operating characteristic area, 0.76), with equal accuracy (Dyx = .59; receiver operating characteristic area, 0.80) in the independent group of patients. We created an accurate independent estimate for 28-day mortality risk for patients with sepsis syndrome (severe sepsis). This estimate could improve the evaluation of new drugs by investigating whether the drug's benefit varies by patient risk and then determining the amount of benefit for individual patients.


Isolation and characterization of Bacillus subtilis groE regulatory mutants: evidence for orf39 in the dnaK operon as a repressor gene in regulating the expression of both groE and dnaK.
An inverted repeat sequence known as CIRCE (controlling inverted repeat of chaperone expression) in the Bacillus subtilis groE operon has been suggested to function as an operator. To identify the regulatory gene directly or indirectly involved in CIRCE-mediated heat-inducible groE expression, B. subtilis WBG2, carrying an integrated groE-bgaB transcription fusion in the amyE locus, was mutagenized. Dark blue colonies formed at 37 degrees C represent mutants which constitutively produce BgaB (a thermostable beta-galactosidase) at high levels. Seven mutants (WBG101 to WBG107) were selected for further characterization. They all overproduced BgaB, GroEL, and DnaK simultaneously at 37 degrees C. These mutants could be restored to normal by introducing a plasmid carrying a functional copy of orf39, the first gene in the B. subtilis dnaK operon. Genomic sequencing of these mutants demonstrated that they all carried a single mutation in orf39. These mutations can be divided into three groups: (i) Gly-307 to Asp, (ii) Ser-122 to Phe, and (iii) Gly-63 to Glu. By using a binary vector system in E. coli, production of ORF39 was found to negatively regulate the expression of groE-bgaB in a CIRCE-specific manner. Under the heat shock condition, the negative regulation mediated by ORF39 was abolished. Mobility shift of the CIRCE-containing probe was also observed with the crude extract prepared from the E. coli strain that overproduced ORF39. Therefore, ORF39 is the negative regulatory factor which regulates both groE and dnaK expression in B. subtilis. It is likely to function as a CIRCE-specific repressor.


Global meta-analysis of the C-11377G alteration in the ADIPOQ gene indicates the presence of population-specific effects: challenge for global health initiatives.
Type II diabetes mellitus is currently globally one of the fastest growing non-communicable diseases, especially in developing countries. This investigation reports on a meta-analysis undertaken of the C-11377G locus within the adiponectin gene in a black South African, a Cuban Hispanic and a German Caucasian cohort. Genotyping was performed via a real-time PCR strategy. Both fixed- and random-effects models were tested to describe the diabetes risk at both the cohort and population levels. The 2,2 genotype may only be associated with increased diabetes risk in the Cuban Hispanic cohort. Population-specific effects may have masked these associations upon meta-analytical analysis, as no significant odds ratio could be determined. Thus, to examine diabetes risk, a more global approach including the design of population-specific experimental strategies should be used, which will be crucial in developing health education and policies in a global health programme.


Fractures of the lesser tuberosity of the humerus.
Fractures of the lesser tuberosity are rare injuries, and little is known of their epidemiology. Operative treatment is generally recommended for displaced fractures; however, the outcome of this method of treatment has not previously been studied. The aims of our study were to determine the approximate incidence of lesser tuberosity fractures, as well as the functional outcome following operative treatment in a consecutive series of patients. Over an eight-year period, we studied the demographic details of a consecutive series of twenty-two adult patients who had a fracture of the lesser tuberosity. We used age and sex-specific local census data to estimate the annual incidence of this injury in our local population. Seventeen of the original cohort of twenty-two patients, who were medically fit and had a displaced (two-part) fracture, were treated with open reduction and internal fixation of the fracture. We assessed the outcome using the Short Form-36 (SF-36) general health measure, the Constant score, and the Disabilities of the Arm, Shoulder and Hand (DASH) score. The estimated annual incidence of these fractures was low at 0.46 per 100,000 population per year during the study period. There were fifteen men and seven women, with a median age of forty-three years. There was an even distribution of fractures across the age cohorts, and most fractures were sustained from a high-energy transfer mechanism. The median Constant score was 95 points at two years, and the median DASH score was 12 points at two years after the injury. Most patients regained nearly normal range of motion in the affected shoulder by three months. One patient had development of posttraumatic shoulder stiffness, which responded to arthroscopic release. All patients who were in regular employment prior to the injury returned to their jobs within six months. There were no significant differences between each component of the SF-36 at two years compared with age and sex-matched controls. A lesser tuberosity fracture, without an associated humeral head or greater tuberosity fracture, is a rare injury. Open reduction and internal fixation provides excellent restoration of function and range of shoulder movement, with a low risk of complications.


Does group size have an impact on welfare indicators in fattening pigs?
Production systems for fattening pigs have been characterized over the last 2 decades by rising farm sizes coupled with increasing group sizes. These developments resulted in a serious public discussion regarding animal welfare and health in these intensive production systems. Even though large farm and group sizes came under severe criticism, it is still unknown whether these factors indeed negatively affect animal welfare. Therefore, the aim of this study was to assess the effect of group size (30 pigs/pen) on various animal-based measures of the Welfare Quality(®) protocol for growing pigs under conventional fattening conditions. A total of 60 conventional pig fattening farms with different group sizes in Germany were included. Moderate bursitis (35%) was found as the most prevalent indicator of welfare-related problems, while its prevalence increased with age during the fattening period. However, differences between group sizes were not detected (P>0.05). The prevalence of moderately soiled bodies increased from 9.7% at the start to 14.2% at the end of the fattening period, whereas large pens showed a higher prevalence (15.8%) than small pens (10.4%; P<0.05). With increasing group size, the incidence of moderate wounds with 8.5% and 11.3% in small- and medium-sized pens, respectively, was lower (P<0.05) than in large-sized ones (16.3%). Contrary to bursitis and dirtiness, its prevalence decreased during the fattening period. Moderate manure was less often found in pigs fed by a dry feeder than in those fed by a liquid feeding system (P<0.05). The human-animal relationship was improved in large in comparison to small groups. On the contrary, negative social behaviour was found more often in large groups. Exploration of enrichment material decreased with increasing live weight. Given that all animals were tail-docked, tail biting was observed at a very low rate of 1.9%. In conclusion, the results indicate that BW and feeding system are determining factors for the welfare status, while group size was not proved to affect the welfare level under the studied conditions of pig fattening.


Angiographic manifestations and operative findings with 70 cases of hemifacial spasm: relation of common trunk anomalies.
The relations between angiographic manifestations and operative findings of hemifacial spasm were studied in 70 cases between 1988 and 2001. Vertebral angiography was performed, and Towne, straight AP, and lateral projections were routinely examined. The dominant anterior inferior cerebellar artery (AICA) directly compressed the facial nerve root exit zone in 26 cases, the dominant posterior inferior cerebellar artery (PICA) in 20, the AICA in 13, the PICA in 2, and the vertebral artery (VA) in 9. Compression by multiple vessels was observed in 11 cases. Anatomical variations of the affected AICA and PICA were classified into 3 groups according to their origins and distributions of blood supply: normal distribution of AICA and PICA in 18%, common trunk anomaly with dominant AICA (basilar artery origin) in 48% and common trunk anomaly with dominant PICA (vertebral artery origin) in 34%. Analyses of the angiograms revealed significantly increased numbers of common trunk anomalies compared with cases with normal angiograms. In 18 of the 20 cases of unilateral common trunk anomalies, facial nerves were compressed by the dominant artery. Preoperative vertebral angiograms may clarify the offending vessels and their sites in most hemifacial spasm cases, thus increasing the safety of surgical interventions.


Design and Rationale of the Cognitive Intervention to Improve Memory in Heart Failure Patients Study.
Memory loss is an independent predictor of mortality among heart failure patients. Twenty-three percent to 50% of heart failure patients have comorbid memory loss, but few interventions are available to treat the memory loss. The aims of this 3-arm randomized controlled trial were to (1) evaluate efficacy of computerized cognitive training intervention using BrainHQ to improve primary outcomes of memory and serum brain-derived neurotrophic factor levels and secondary outcomes of working memory, instrumental activities of daily living, and health-related quality of life among heart failure patients; (2) evaluate incremental cost-effectiveness of BrainHQ; and (3) examine depressive symptoms and genomic moderators of BrainHQ effect. A sample of 264 heart failure patients within 4 equal-sized blocks (normal/low baseline cognitive function and gender) will be randomly assigned to (1) BrainHQ, (2) active control computer-based crossword puzzles, and (3) usual care control groups. BrainHQ is an 8-week, 40-hour program individualized to each patient's performance. Data collection will be completed at baseline and at 10 weeks and 4 and 8 months. Descriptive statistics, mixed model analyses, and cost-utility analysis using intent-to-treat approach will be computed. This research will provide new knowledge about the efficacy of BrainHQ to improve memory and increase serum brain-derived neurotrophic factor levels in heart failure. If efficacious, the intervention will provide a new therapeutic approach that is easy to disseminate to treat a serious comorbid condition of heart failure.


Do medical journals provide clear and consistent guidelines on authorship?
Determining the authorship of scientific papers can be difficult and authorship disputes are common. Less experienced authors may benefit from clear advice about authorship from journals while both authors and readers would benefit from consistent policies between journals. However, previous surveys of authors have suggested that there are no universally known or accepted criteria for determining authorship. To review instructions to contributors from a broad sample of biomedical journals to discover how much guidance they provide about authorship and whether their advice is consistent with one another and with international guidelines. Review and analysis of published instructions to authors. Biomedical journals that publish instructions in English on the Internet. I examined the instructions to contributors from 234 biomedical journals (randomly selected from the membership list of the World Association of Medical Editors and from Medline). Of the 234 instructions examined, 100 (41%) gave no guidance about authorship, 68 (29%) were based on the International Committee of Medical Journal Editors' (ICMJE) criteria, 33 (14%) proposed other criteria, and 33 (14%) said nothing except that all authors should have approved the manuscript. Of those instructions that were based on the ICMJE criteria, 18/51 (35%) cited an outdated version. Only 21 of the journals (9%) required individuals' contributions to be described. Journals do not provide consistent guidance about authorship and many editors are therefore missing an important opportunity to educate potential contributors and to improve the accuracy, fairness, and transparency of author listing.


Inhibition of herpes simplex type 1 and type 2 infections by Oximacro(®), a cranberry extract with a high content of A-type proanthocyanidins (PACs-A).
In the absence of efficient preventive vaccines, topical microbicides offer an attractive alternative in the prevention of Herpes simplex type 1 (HSV-1) and type 2 (HSV-2) infections. Because of their recognized anti-adhesive activity against bacterial pathogens, cranberry (Vaccinium macrocarpon Ait.) extracts may represent a natural source of new antiviral microbicides. However, few studies have addressed the applications of cranberry extract as a direct-acting antiviral agent. Here, we report on the ability of the novel cranberry extract Oximacro(®) and its purified A-type proanthocyanidins (PACs-A), to inhibit HSV-1 and HSV-2 replication in vitro. Analysis of the mode of action revealed that Oximacro(®) prevents adsorption of HSV-1 and HSV-2 to target cells. Further mechanistic studies confirmed that Oximacro(®) and its PACs-A target the viral envelope glycoproteins gD and gB, thus resulting in the loss of infectivity of HSV particles. Moreover, Oximacro(®) completely retained its anti-HSV activity even at acidic pHs (3.0 and 4.0) and in the presence of 10% human serum proteins; conditions that mimic the physiological properties of the vagina - a potential therapeutic location for Oximacro(®). Taken together, these findings indicate Oximacro(®) as an attractive candidate for the development of novel microbicides of natural origin for the prevention of HSV infections.


Paroxysmal tonic upgaze of childhood with co-existent absence epilepsy.
Paroxysmal tonic upgaze (PTU) is a childhood oculomotor syndrome of unclear etiology characterized by episodic tonic upward eye deviation with neck flexion. Neuroimaging findings are often normal and the electroencephalography during episodes is typically normal. We describe a 2-year-old boy who presented with macrocephaly, hypotonia, developmental delay and episodes of eye fluttering, head nodding and unresponsiveness. Video-EEG captured absence seizures and he was treated with valproate, which led to improvement of his seizures. However, two weeks after treatment, he developed paroxysmal episodes of "eyes up and chin down" movements lasting for hours at a time which were captured by home video. The episodes were relieved by sleep and exacerbated by fever, stress and even tactile stimulation. Increasing the dose of valproate resulted in increased frequency of the episodes. A repeat video-EEG disclosed the non-epileptic nature of these events. Discontinuation of valproate dramatically decreased the episodes. This case illustrates that paroxysmal tonic upgaze of childhood may co-exist with early onset absence epilepsy. Furthermore, valproate treatment may be associated with the development or unmasking of PTU suggesting that the pathophysiology of PTU may involve abnormal GABA neurotransmission. [Published with videosequences].


Small animal positron emission tomography during vagus nerve stimulation in rats: a pilot study.
Vagus nerve stimulation (VNS) is an effective neurophysiological treatment for patients with refractory epilepsy, however, the mechanism of action remains unclear. Small animal positron emission tomography (PET) permits the monitoring of biochemical processes during multiple scans in the same animal. The aim of this pilot study was to explore the potential of 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-PET to investigate the effect of acute and chronic VNS on glucose metabolism in the rat brain. One week after EEG and VNS electrode implantation, a baseline FDG-PET scan was acquired during which animals were not stimulated. Secondly, scans were taken after first activation of the VNS electrode (acute VNS) and after one week of continuous VNS (chronic VNS). On the same time points, images were obtained in a control group. After acquisition, PET images were manually fused with MRI data. Normalized brain activities and left/right activity ratios of different brain structures were compared between control measurements and VNS group. During acute VNS, glucose metabolism was significantly decreased in the left hippocampus (P<0.05). Significant increases were found in both olfactory bulbs (P<0.05). During chronic VNS, a significant decrease in left/right ratio in the striatum (P<0.05) was found. Acute and chronic VNS induced changes in glucose metabolism in regions important for seizure control (hippocampus and striatum). Our results promote further brain research on VNS using small animal PET in rats.


A systematic review of non-pharmacological interventions for primary Sjögren's syndrome.
To evaluate the effects of non-pharmacological interventions for primary SS (pSS) on outcomes falling within the World Health Organization International Classification of Functioning Disability and Health domains. We searched the following databases from inception to September 2014: Cochrane Database of Systematic Reviews; Medline; Embase; PsychINFO; CINAHL; and clinical trials registers. We included randomized controlled trials of any non-pharmacological intervention. Two authors independently reviewed titles and abstracts against the inclusion/exclusion criteria and independently assessed trial quality and extracted data. A total of 1463 studies were identified, from which 17 full text articles were screened and 5 studies were included in the review; a total of 130 participants were randomized. The included studies investigated the effectiveness of an oral lubricating device for dry mouth, acupuncture for dry mouth, lacrimal punctum plugs for dry eyes and psychodynamic group therapy for coping with symptoms. Overall, the studies were of low quality and at high risk of bias. Although one study showed punctum plugs to improve dry eyes, the sample size was relatively small. Further high-quality studies to evaluate non-pharmacological interventions for PSS are needed.


The trans-generational impact of population density signals on host-parasite interactions.
The density of a host population is a key parameter underlying disease transmission, but it also has implications for the expression of disease through its effect on host physiology. In response to higher densities, individuals are predicted to either increase their immune investment in response to the elevated risk of parasitism, or conversely to decrease their immune capacity as a consequence of the stress of a crowded environment. However, an individual's health is shaped by many different factors, including their genetic background, current environmental conditions, and maternal effects. Indeed, population density is often sensed through the presence of info-chemicals in the environment, which may influence a host's interaction with parasites, and also those of its offspring. All of which may alter the expression of disease, and potentially uncouple the presumed link between changes in host density and disease outcomes. In this study, we used the water flea Daphnia magna and its obligate bacterial parasite Pasteuria ramosa, to investigate how signals of high host density impact on host-parasite interactions over two consecutive generations. We found that the chemical signals from crowded treatments induced phenotypic changes in both the parental and offspring generations. In the absence of a pathogen, life-history changes were genotype-specific, but consistent across generations, even when the signal of density was removed. In contrast, the influence of density on infected animals depended on the trait and generation of exposure. When directly exposed to signals of high-density, host genotypes responded differently in how they minimised the severity of disease. Yet, in the subsequent generation, the influence of density was rarely genotype-specific and instead related to ability of the host to minimise the onset of infection. Our findings reveal that population level correlations between host density and infection capture only part of the complex relationship between crowding and the severity of disease. We suggest that besides its role in horizontal transmission, signals of density can influence parasite epidemiology by modifying mechanisms of resistance across multiple generations, and elevating variability via genotype-by-environment interactions. Our results help resolve why some studies are able to find a positive correlation between high density and resistance, while others uncover a negative correlation, or even no direct relationship at all.


EGF-stimulation activates the nuclear localization signal of SHP-1.
Protein tyrosine phosphatase SHP-1 plays a critical role in the regulation of a variety of intracellular signaling pathways. SHP-1 is predominantly expressed in the cells of hematopoietic origin, and is recognized as a negative regulator of lymphocyte development and activation. SHP-1 consists of two Src homology 2 (SH2) domains and one protein tyrosine phosphatase (PTP) domain followed by a highly basic C-terminal tail containing tyrosyl phosphorylation sites. It is unclear how the C-terminal tail regulates SHP-1 function. We report the examination of the subcellular localization of a variety of truncated or mutated SHP-1 proteins fused with enhanced green fluorescent protein (EGFP) protein at either the N-terminal or the C-terminal end in different cell lines. Our data demonstrate that a nuclear localization signal (NLS) is located in the C-terminal tail of SHP-1 and the signal is primarily defined by three amino-acid residues (KRK) at the C-terminus. This signal is generally blocked in the native protein and can be exposed by fusing EGFP at the appropriate position or by domain truncation. We have also revealed that this NLS of SHP-1 is triggered by epidermal growth factor (EGF) stimulation and mediates translocation of SHP-1 from the cytosol to the nucleus in COS7 cell lines. These results not only demonstrate the importance of the C-terminal tail of SHP-1 in the regulation of nuclear localization, but also provide insights into its role in SHP-1-involved signal transduction pathways.


Bilateral renal vein thrombosis and subsequent acute renal failure due to IVC filter migration and thrombosis.
A 53-year-old man developed a deep venous thrombus (DVT) and pulmonary embolism (PE) shortly after an open Roux-en-Y gastric bypass was performed. He later suffered a life-threatening gastrointestinal bleed while on anticoagulation for the DVT. Thus, anticoagulation was held and an inferior vena cava (IVC) filter (G2, Bard Inc., Tempe, AZ, USA) was placed for PE prophylaxis. About 10 days after filter placement, he presented with severe low back pain and syncope. He also presented with hypotension and anuria unresponsive to intravenous fluids. A STAT non-contrast CT scan of the abdomen revealed that his IVC filter had migrated from an infrarenal to a suprarenal position. Given the high clinical suspicion for renal vein thrombosis, an attempt at IVC filter retrieval was made. The filter could not be retrieved because it was embedded in a large IVC thrombus that extended from the hepatic veins down to the common iliac veins. The patient received nearly 4 days of tPA that was administered at the site of the thrombus with a long thrombolytic catheter (UNIFUSE, Angiodynamics, Queensbury, NY, USA). While his creatinine peaked at 7.6 on hospital Day 4, he eventually began to produce urine and his creatinine had declined to his baseline of 1.0 on follow-up 1 month later. About 18 months after admission, his creatinine had further declined to 0.8. We report the first published case of acute renal failure due to bilateral renal vein thrombosis in the setting of IVC filter migration and thrombosis. This report highlights an important, but rare complication of IVC filter placement as well as the non-operative management of acute bilateral renal vein thrombosis.


Biodiversity assessment among two Nebraska prairies: a comparison between traditional and phylogenetic diversity indices.
Conservation of the evolutionary diversity among organisms should be included in the selection of priority regions for preservation of Earth's biodiversity. Traditionally, biodiversity has been determined from an assessment of species richness (S), abundance, evenness, rarity, etc. of organisms but not from variation in species' evolutionary histories. Phylogenetic diversity (PD) measures evolutionary differences between taxa in a community and is gaining acceptance as a biodiversity assessment tool. However, with the increase in the number of ways to calculate PD, end-users and decision-makers are left wondering how metrics compare and what data are needed to calculate various metrics. In this study, we used massively parallel sequencing to generate over 65,000 DNA characters from three cellular compartments for over 60 species in the asterid clade of flowering plants. We estimated asterid phylogenies from character datasets of varying nucleotide quantities, and then assessed the effect of varying character datasets on resulting PD metric values. We also compared multiple PD metrics with traditional diversity indices (including S) among two endangered grassland prairies in Nebraska (U.S.A.). Our results revealed that PD metrics varied based on the quantity of genes used to infer the phylogenies; therefore, when comparing PD metrics between sites, it is vital to use comparable datasets. Additionally, various PD metrics and traditional diversity indices characterize biodiversity differently and should be chosen depending on the research question. Our study provides empirical results that reveal the value of measuring PD when considering sites for conservation, and it highlights the usefulness of using PD metrics in combination with other diversity indices when studying community assembly and ecosystem functioning. Ours is just one example of the types of investigations that need to be conducted across the tree of life and across varying ecosystems in order to build a database of phylogenetic diversity assessments that lead to a pool of results upon which a guide through the plethora of PD metrics may be prepared for use by ecologists and conservation planners.


Gender differences in the clinical characteristics and psychiatric comorbidity in patients with antisocial personality disorder.
Gender is an important variable in the study of mental health because of the actual and perceived differences between men and women. Relatively little is known how males and females differ in their manifestations of antisocial personality disorder (ASPD). Demographic and clinical features of 323 participants with ASPD were assessed and recorded. Women had fewer episodes of antisocial behavior involving or not involving police, higher scores on the Childhood Trauma Questionnaire (CTQ) and on Emotional Abuse and Sexual Abuse subscales of the CTQ compared to men. CTQ scores positively correlated with the number of episodes of antisocial behavior involving police in men but not in women. The percentage of patients with comorbid borderline and histrionic personality disorders was higher and the percentage of participants with cocaine use disorder was lower among women compared to men. Comorbid alcohol use disorder was frequent in both groups, while a higher percentage of women had comorbid mood disorders compared to men. Logistic regression analysis demonstrates that CTQ scores, histrionic personality disorder, and antisocial behavior involving the police drive the difference between the groups. Our findings indicate that treatment of individuals with ASPD should focus on the management of comorbid psychiatric disorders.


Effect of varying computed tomography acquisition and reconstruction parameters on semi-automated clot volume quantification.
To examine effects of computed tomography (CT) image acquisition/reconstruction parameters on clot volume quantification in vitro for research method validation purposes. This study was performed in conformance with HIPAA and IRB Regulations (March 2015-November 2016). A ten blood clot phantom was designed and scanned on a dual-energy CT scanner (SOMATOM Force, Siemens Healthcare GmBH, Erlangen, Germany) with varying pitch, iterative reconstruction, energy level and slice thickness. A range of clot and tube sizes were used in an attempt to replicate in vivo emboli found within central and segmental branches of the pulmonary arteries in patients with pulmonary emboli. Clot volume was the measured parameter and was analyzed by a single image analyst using a semi-automated region growing algorithm implemented in the FDA-approved Siemens syngo.via image analysis platform. Mixed model analysis was performed on the data. On the acquisition side, the continuous factor of energy showed no statistically significant effect on absolute clot volume quantification (P = 0.9898). On the other hand, when considering the fixed factor of pitch, there were statistically significant differences in clot volume quantification (P < 0.0001). On the reconstruction side, with the continuous factor of reconstruction slice thickness no statistically significant effect on absolute clot volume quantification was demonstrated (P = 0.4500). Also on the reconstruction side, with the fixed factor of using iterative reconstructions there was also no statistically significant effect on absolute clot volume quantification (P = 0.3011). In addition, there was excellent R2 correlation between the scale-measured mass of the clots both with respect to the CT measured volumes and with respect to volumes measure by the water displacement method. Aside from varying pitch, changing CT acquisition parameters and using iterative reconstructions had no significant impact on clot volume quantification with a semi-automated region growing algorithm.


Metagenomes from high-temperature chemotrophic systems reveal geochemical controls on microbial community structure and function.
The Yellowstone caldera contains the most numerous and diverse geothermal systems on Earth, yielding an extensive array of unique high-temperature environments that host a variety of deeply-rooted and understudied Archaea, Bacteria and Eukarya. The combination of extreme temperature and chemical conditions encountered in geothermal environments often results in considerably less microbial diversity than other terrestrial habitats and offers a tremendous opportunity for studying the structure and function of indigenous microbial communities and for establishing linkages between putative metabolisms and element cycling. Metagenome sequence (14-15,000 Sanger reads per site) was obtained for five high-temperature (>65 degrees C) chemotrophic microbial communities sampled from geothermal springs (or pools) in Yellowstone National Park (YNP) that exhibit a wide range in geochemistry including pH, dissolved sulfide, dissolved oxygen and ferrous iron. Metagenome data revealed significant differences in the predominant phyla associated with each of these geochemical environments. Novel members of the Sulfolobales are dominant in low pH environments, while other Crenarchaeota including distantly-related Thermoproteales and Desulfurococcales populations dominate in suboxic sulfidic sediments. Several novel archaeal groups are well represented in an acidic (pH 3) Fe-oxyhydroxide mat, where a higher O2 influx is accompanied with an increase in archaeal diversity. The presence or absence of genes and pathways important in S oxidation-reduction, H2-oxidation, and aerobic respiration (terminal oxidation) provide insight regarding the metabolic strategies of indigenous organisms present in geothermal systems. Multiple-pathway and protein-specific functional analysis of metagenome sequence data corroborated results from phylogenetic analyses and clearly demonstrate major differences in metabolic potential across sites. The distribution of functional genes involved in electron transport is consistent with the hypothesis that geochemical parameters (e.g., pH, sulfide, Fe, O2) control microbial community structure and function in YNP geothermal springs.


Epilepsy and employment. A community based survey in an area of high unemployment.
A community based survey was undertaken to assess the work record of patients with epilepsy in an area of high unemployment. One hundred and thirty seven epileptic patients were identified from a population of 23,837 persons of employable age registered with three urban group practices in North East England. The unemployment rate for economically active patients with epilepsy was 46% compared with 19% for an age and sex matched control population (p less than 0.01). Fifty nine per cent of patients with active epilepsy were unemployed. In those with an associated neurological or psychiatric handicap and those who were unskilled manual workers the unemployment rates were 79% and 77%, respectively. Patients with epilepsy were less likely to leave school with qualifications or undergo subsequent training or apprenticeships. They were more likely to be unskilled manual workers, single and living in rented accommodation. In an area of high unemployment patients with epilepsy have disproportionately greater difficulty finding work. High unemployment rates among patients with epilepsy are only one aspect of a spectrum of social and economic disadvantage.


Patterns and predictors of long-term glycemic control in patients with type 2 diabetes.
Aims/Introduction. To describe patterns of long-term glycemic control among patients with type 2 diabetes in Isfahan, Iran and identify factors associated with glycemic control. Methods. During the mean (standard deviation (SD)) follow-up period of 8.4 (4.2) (range 1-18) years, 4,582 patients with type 2 diabetes have been examined to determine glycemic changes. Their glycated hemoglobin (GHb) at the last clinic visit was compared with the initial visit data. The mean (SD) age of participants was 49.3 (9.6) years with a mean (SD) duration of diabetes of 5.0 (5.1) years at initial registration. Results. Mean (SD) GHb was 8.7% (2.3) at baseline and 7.9% (1.9) at the study end and decreased by mean of 0.8% (95% confidence interval (CI) 0.74, 0.87; P < 0.001) and varied by the severity of baseline GHb. 74.6% at the initial visit versus 64.4% at the last clinic visit had GHb values above the target level of 7.0%. Using a stepwise multiple regression models, age, higher GHb, FPG, follow-up period, and number of follow-up visits increased and higher systolic BP and female gender significantly decreased the percent glycemic change. Conclusions. This study highlights that more than 64.4% of the patients have GHb values higher than 7.0% at last clinic visit andindicatesthe difficult challenges physicians face when treating their patients with type 2 diabetes. Clinical efforts should focus on more effective methods for glycemic control in diabetic patients.


Enthalpy changes during the photochemical cycle of bacteriorhodopsin.
We have used a capacitor microphone calorimeter to measure rapid enthalpy changes that occur when bacteriorhodopsin-containing membrane fragments are excited with short flashes of light. We resolved the enthalpy changes into three phases. At about 100 microsecond after the flash, the bacteriorhodopsins converted into metastable states have an enthalpy about 15-20 kcal mol-1 greater than the enthalpy before excitation. Some of this energy (approximately 10 kcal) is then released to the surroundings as the membrane fragments release protons to the solution. After proton release and before proton rebinding, a large amount of heat is released to the surroundings, equivalent to about 40-45 kcal/mol of bacteriorhodopsin reacting. At this point the energy of the system is about 35 kcal/mol less than it was before the flash; i.e., the system has released all of the energy of the photon (49 kcal/E) plus an additional 35 kcal/mol. Nevertheless, the free energy of the system must still be greater than it was originally, because relaxation to the original state occurs spontaneously. An entropy decrease of at least 125 cal/mol per deg is required to compensate for the heat release. An entropy decrease of this magnitude implies a major increase in molecular order in the purple membrane.


Cdk5: a novel role in learning and memory.
Learning and memory are processes by which organisms acquire, retain and retrieve information. They result in modifications of behavior in response to new or previously encountered stimuli thereby enabling adaptation to a permanently changing environment. Protein phosphorylation has long been known to play a key role in triggering synaptic changes underlying learning and memory. Although intracellular phosphorylation and dephosphorylation is orchestrated by a complex network of interactions between a number of protein kinases and phosphatases, significant advances in the understanding of neuronal mechanisms underlying learning and memory have been achieved by investigating the actions of individual molecules under defined experimental conditions, brain areas, neuronal cells and their subcellular compartments. On the basis of these approaches, the cyclic AMP protein kinase (PKA), protein kinase C (PKC) and extracellularly regulated protein kinases 1 and 2 (Erk-1/2) have been identified as the core signaling pathways in memory consolidation. Here we review recent findings demonstrating an important novel role for Cdk5 in learning and memory. We suggest that some of the well-characterized roles of Cdk5 during neurodevelopmental processes, such as interactions with distinct cytoplasmic and synaptic target molecules, may be also involved in synaptic plasticity underlying memory consolidation within the adult central nervous system.


Temporal and spatial expression of tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and -2) in the bovine corpus luteum.
The matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), may mediate the dramatic structural and functional changes in the corpus luteum (CL) over the course of its life span. In addition to regulating MMP activity, TIMPs are also involved in a variety of cellular processes, including cell proliferation and steroidogenesis. In a series of initial studies, we determined that matrix metalloproteinase inhibitory activity was present in protein extracts from early (4 days old, estrus = day 0), mid (10-12 days old) and late (16 days old) CL (n = 3 for each stage). Reverse zymography revealed four metalloproteinase inhibitory protein bands with relative molecular masses that are consistent with those reported for TIMP-1 to -4. In order to gain a better understanding of TIMPs and their role in luteal function, we further characterized this inhibitory activity with a particular focus on the temporal and spatial expression of TIMP-1 and TIMP-2 in the bovine CL. Northern blotting revealed that the TIMP-1 transcript (0.9 kb) was expressed at a higher (p < 0.05) level in early and mid cycle CL than in the late stage. In contrast, two TIMP-2 mRNA species, one major 1 kb species and one minor 3.5 kb species, were significantly (p < 0.05) increased in the mid and late cycle CL than in the early. Western blotting analyses demonstrated no differences in TIMP-1 (29 kDa) protein levels between early and mid stages, while its levels decreased (p < 0.05) from the mid to late stage CL. Conversely, TIMP-2 (22 kDa) protein was detected at a low level in the early CL, but significantly (p < 0.05) increased in the mid and late stages. Immunohistochemistry revealed that both TIMP-1 and -2 were localized to large luteal cells from all three ages of CL. TIMP-1 was also localized in capillary smooth muscle cells, while TIMP-2 was restricted to the endothelial cells in the capillary compartment. In conclusion, the different temporal expression patterns of TIMP-1 and TIMP-2 suggest that TIMP-1 may be important for luteal formation and development, while TIMP-2 may play significant roles during luteal development and maintenance. Furthermore, the distinct localization of these two inhibitors in the vascular compartment indicates that they may serve diverse physiological functions during different stages of luteal angiogenesis.


Rapidly measured indicators of recreational water quality and swimming-associated illness at marine beaches: a prospective cohort study.
In the United States and elsewhere, recreational water quality is monitored for fecal indicator bacteria to help prevent swimming-associated illnesses. Standard methods to measure these bacteria take at least 24 hours to obtain results. Molecular approaches such as quantitative polymerase chain reaction (qPCR) can estimate these bacteria faster, in under 3 hours. Previously, we demonstrated that measurements of the fecal indicator bacteria Enterococcus using qPCR were associated with gastrointestinal (GI) illness among swimmers at freshwater beaches. In this paper, we report on results from three marine beach sites. We interviewed beach-goers and collected water samples at marine beaches affected by treated sewage discharges in Mississippi in 2005, and Rhode Island and Alabama in 2007. Ten to twelve days later, we obtained information about gastrointestinal, respiratory, eye, ear and skin symptoms by telephone. We tested water samples for fecal indicator organisms using qPCR and other methods. We enrolled 6,350 beach-goers. The occurrence of GI illness among swimmers was associated with a log10-increase in exposure to qPCR-determined estimates of fecal indicator organisms in the genus Enterococcus (AOR = 2.6, 95% CI 1.3-5.1) and order Bacteroidales (AOR = 1.9, 95% CI 1.3-2.9). Estimates of organisms related to Clostridium perfringens and a subgroup of organisms in the genus Bacteroides were also determined by qPCR in 2007, as was F+ coliphage, but relationships between these indicators and illness were not statistically significant. This study provides the first evidence of a relationship between gastrointestinal illness and estimates of fecal indicator organisms determined by qPCR at marine beaches.


Comparison of visual vs. automated detection of lipemic, icteric and hemolyzed specimens: can we rely on a human eye?
Results from hemolyzed, icteric, and lipemic samples may be inaccurate and can lead to medical errors. These preanalytical interferences may be detected using visual or automated assessment. Visual inspection is time consuming, highly subjective and not standardized. Our aim was to assess the comparability of automated spectrophotometric detection and visual inspection of lipemic, icteric and hemolyzed samples. This study was performed on 1727 routine biochemistry serum samples. Automated detection was performed using the Olympus AU2700 analyzer. We assessed: 1) comparability of visual and automated detection of lipemic, icteric and hemolyzed samples, 2) precision of automated detection, and 3) inter-observer variability for visual inspection. Weighted kappa coefficients for comparability of visual and automated detection were: 0.555, 0.529 and 0.638, for lipemic, icteric and hemolyzed samples, respectively. The precision for automated detection was high for all interferences, with the exception of samples being only slightly lipemic. The best overall agreement between observers was present in assessing lipemia (mean weighted kappa=0.698), whereas the lowest degree of agreement was observed in assessing icterus (mean weighted kappa=0.476). Visual inspection of lipemic, icteric and hemolyzed samples is highly unreliable and should be replaced by automated systems that report serum indices.


Activation of multiple pathways during photoreceptor apoptosis in the rd mouse.
The primary purpose of this study was to characterize photoreceptor apoptosis in the rd mouse. Given that apoptosis is the final common pathway in many cases of retinal degeneration, the ability to retard or even arrest this process may ameliorate retinal disorders such as retinitis pigmentosa (RP). The absence of any recognized therapy emphasizes the fact that a detailed knowledge of the molecular events involved is necessary to identify rational targets for therapeutic intervention. Flow cytometry was used to measure physical and chemical characteristics in the photoreceptor population. Individual cells flow in suspension past one or more lasers, scattering light and emitting fluorescence. Western blot techniques demonstrated cleavage of calpain-specific substrates. Retinal explant cultures were used for inhibitor studies. Postnatal day 10 (P(10)) rd retinas were cultured without retinal pigment epithelium (RPE) attached up to P(17). This study demonstrated calcium overload in the cytosol and subsequently in mitochondria. Mitochondrial membrane depolarization and reactive oxygen species (ROS) were detected later, during the peak of cell death. Analysis of downstream events indicated early activation of calcium-activated calpains. Treatment of rd retinal explants with the calpain inhibitor N-acetyl-Leu-Leu-Nle-CHO (ALLN) successfully inhibited calpain-induced alpha-fodrin cleavage, yet it did not protect against photoreceptor degeneration. Finally, the results demonstrate an increase in the levels of both precursor and processed forms of the aspartate protease cathepsin D. Excessive calcium influx is an early event that initiates the activation of calcium-activated proteases. However, these proteases are not singularly the cause of death, because their inhibition does not prevent apoptosis. Indeed, the results presented herein suggest that multiple pathways are involved and that each of these components may have to be addressed for cell death to be successfully inhibited.


Anti-VEGF intravitreal injections in the era of COVID-19: responding to different levels of epidemic pressure.
Following the first wave of the COVID-19 pandemic in early 2020, the easing of strict measures to reduce its spread has led to a resurgence of cases in many countries at both the national and local level. This article addresses how guidance for ophthalmologists on managing patients with retinal disease receiving intravitreal injections of anti-vascular endothelial growth factor (VEGF) during the pandemic should be adapted to the local epidemic pressure, with more or less stringent measures implemented according to the ebb and flow of the pandemic. The Vision Academy's membership of international retinal disease experts analyzed guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic and graded the recommendations according to three levels of increasing epidemic pressure. The revised recommendations were discussed, refined, and voted on by the 14-member Vision Academy Steering Committee for consensus. Protocols to minimize the exposure of patients and healthcare staff to COVID-19, including use of personal protective equipment, physical distancing, and hygiene measures, should be routinely implemented and intensified according to local infection rates and pressure on the hospital/clinic or healthcare system. In areas with many COVID-19-positive clusters, additional measures including pre-screening of patients, postponement of non-urgent appointments, and simplification of complex intravitreal anti-VEGF regimens should be considered. Treatment prioritization for those at greatest risk of irreversible vision loss should be implemented in areas where COVID-19 cases are increasing exponentially and healthcare resources are strained. Consistency in monitoring of local infection rates and adjustment of clinical practice accordingly will be required as we move forward through the COVID-19 era. Ophthalmologists must continue to carefully weigh the risk-benefits to minimize the exposure of patients and healthcare staff to COVID-19, ensure that patients receive sight-saving treatment, and avoid the potential long-term impact of prolonged treatment postponement.


Copper and copper proteins in Parkinson's disease.
Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson's disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found in substantia nigra and caudate nucleus of Parkinson's disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson's disease; for instance, it is known that CTR1 is decreased in substantia nigra pars compacta in Parkinson's disease and that a mutation in ATP7B could be associated with Parkinson's disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology.


Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain.
Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.


The clinical relevance of serum CYFRA 21-1 assay in patients with ovarian cancer.
CYFRA 21-1 assay, which detects serum fragments of cytokeratin 19, has been widely assessed as a serum marker of several malignancies. Preoperative serum CYFRA 21-1 levels were retrospectively measured in 60 patients with ovarian cancer and in 59 control patients with benign ovarian disease. CYFRA 21-1 levels were also serially measured in 90 serum samples drawn from patients with advanced (FIGO stage III-IV) ovarian cancer followed after surgery and chemotherapy. Preoperative serum CYFRA 21-1 levels were higher in patients with ovarian cancer compared with controls (median, range = 2.6, 0.1-51.4 ng/ml versus 0.4, 0.0-3.6 ng/ml, P < 0.0001), and among the former, antigen values were higher in the 39 patients with advanced-stage than in the 21 patients with early (FIGO stage I-II) disease (P < 0.0001). In advanced ovarian cancer patients, the 25%, 50%, and 75% quantiles of preoperative CYFRA 21-1 levels were 1.9, 4.8 and 14.4 ng/ml, respectively. Preoperative CYFRA 21-1 levels were lower in the 11 patients who achieved a pathologic complete response at second-look compared with those who had clinically or surgically detectable persistent disease after first-line chemotherapy (median, range 1.9, 0.6-9.2 ng/ml versus 10.2, 0.1-51.4 ng/ml, P = 0.007). The pathologic complete response rate was significantly greater in patients with low preoperative CYFRA 21-1 levels compared with those with elevated CYFRA 21-1 levels at any cut-off limit for the antigen (1.9, 4.8 and 14.4 ng/ml). However, Cox regression analysis failed to detect a significant association between preoperative CYFRA 21-1 assay and survival. As for the follow-up of advanced ovarian cancer patients, CYFRA 21-1 levels were higher in the 42 samples drawn from patients with clinically detectable disease compared with the 48 specimens collected from patients with no clinical evidence of disease (median, range = 1.15, 0.3-40.7 ng/ml versus 0.4, 0.1-9.1 ng/ml, P < 0.0001). In conclusion, preoperative serum CYFRA 21-1 assay appears to be predictive of response to chemotherapy, but not prognostic of survival, for patients with advanced ovarian cancer. Moreover, the serial measurement of CYFRA 21-1 levels might have a potential clinical relevance for the assessment of disease status in patients followed after surgery and chemotherapy.


Lipid management in patients with chronic kidney disease.
An increased risk of cardiovascular disease, independent of conventional risk factors, is present even at minor levels of renal impairment and is highest in patients with end-stage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease (CKD) or ESRD have a characteristic lipid pattern of hypertriglyceridaemia and low HDL cholesterol levels but normal LDL cholesterol levels. In the general population, a clear relationship exists between LDL cholesterol and major atherosclerotic events. However, in patients with ESRD, LDL cholesterol shows a negative association with these outcomes at below average LDL cholesterol levels and a flat or weakly positive association with mortality at higher LDL cholesterol levels. Overall, the available data suggest that lowering of LDL cholesterol is beneficial for prevention of major atherosclerotic events in patients with CKD and in kidney transplant recipients but is not beneficial in patients requiring dialysis. The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD provides simple recommendations for the management of dyslipidaemia in patients with CKD and ESRD. However, emerging data and novel lipid-lowering therapies warrant some reappraisal of these recommendations.


Private health insurance in Germany and Chile: two stories of co-existence, segmentation and conflict.
In Germany and Chile, substitutive private health insurance has been shaped by its co-existence with statutory social health insurance. Despite differences in the way choice is available to users in the health insurance regimes of Chile and Germany, the way in which each country has managed choice between private health insurance and statutory social health insurance provides a unique opportunity to comparatively assess the consequences of such an arrangement that has been previously underexamined. We conducted a Most Similar Systems Design comparative policy analysis of the co-occurring private health insurance and statutory social health insurance systems in Germany and Chile. We describe and review the origins and development of the German and Chilean health care insurance systems with an emphasis on the substitutive co-existence between private health insurance and statutory social health insurance. We provide a critique of the market performance of the private health insurance regime in each country followed by a comparative assessment of the impact of private health insurance on financial protection, equity, and risk segmentation. Segmentation of insurance markets in both Germany and Chile has had significant consequences for equity, fairness, and financial protection. Due to market failures in health insurance and differences in the regulatory frameworks governing public and private insurers, the choice of public or private coverage has produced strong incentives for private insurers to select for risks, compromising equity in health care funding, heightening the financial risk borne by public insurers and lowering incentives for private insurers to operate efficiently. The degree of conflict arising from the substitutive parallel private health insurance system and the statutory social health insurance system varies between Germany and Chile, though policy goals remain similar. Recent reforms in both countries have attempted to improve the financial protection of the privately insured through regulation; nevertheless, concerns about risk segmentation remain largely unresolved.


Education and training to support physiotherapists working in dementia care: a scoping review protocol.
Background: The care of people with dementia is of global concern. Physiotherapeutic intervention can be of benefit to patients with dementia. Physiotherapists can play a role in assessment, falls prevention, pain management and gait re-education. Dementia care forms a significant part of the workload of a physiotherapist. However, there is a paucity of evidence on what constitutes effective education and training for physiotherapists working in dementia care. Objective: This scoping review aims to explore and map the evidence on education and training for physiotherapists working in dementia care. Inclusion criteria: Studies that explore dementia training and/or education for physiotherapists or for multidisciplinary teams, in which physiotherapists have been included. Studies that explore student physiotherapy training will also be considered. Systematic reviews, qualitative, quantitative, mixed methods studies, case studies and observational studies will be included. Methods: This scoping review will follow the Joanna Briggs Institute (JBI) methodology for scoping reviews. Databases to be searched as part of this review include: Medline, Cochrane Database of Systematic Reviews, SocINDEX, CINAHL and, PsycINFO, with no limitation on publication date. Google Scholar and Open-Grey will be searched for grey literature, limited to the first 100 searches. Titles and abstracts will be screened for inclusion and identified full texts reviewed independently by two reviewers. Data will be extracted using a draft data extraction tool based on the JBI data extraction tool. A chronological narrative synthesis of the data will outline how the results relate to the aims and objective of this scoping review.


Automatic imitation in a strategic context: players of rock-paper-scissors imitate opponents' gestures.
A compelling body of evidence indicates that observing a task-irrelevant action makes the execution of that action more likely. However, it remains unclear whether this 'automatic imitation' effect is indeed automatic or whether the imitative action is voluntary. The present study tested the automaticity of automatic imitation by asking whether it occurs in a strategic context where it reduces payoffs. Participants were required to play rock-paper-scissors, with the aim of achieving as many wins as possible, while either one or both players were blindfolded. While the frequency of draws in the blind-blind condition was precisely that expected at chance, the frequency of draws in the blind-sighted condition was significantly elevated. Specifically, the execution of either a rock or scissors gesture by the blind player was predictive of an imitative response by the sighted player. That automatic imitation emerges in a context where imitation reduces payoffs accords with its 'automatic' description, and implies that these effects are more akin to involuntary than to voluntary actions. These data represent the first evidence of automatic imitation in a strategic context, and challenge the abstraction from physical aspects of social interaction typical in economic and game theory.


Interleukin 1 induces endothelial cell synthesis of plasminogen activator inhibitor.
Human endothelial cells activated with IL-1 express a surface membrane-oriented procoagulant generating system characterized by increased tissue factor synthesis and decreased thrombomodulin activity. We now report that IL-1 also stimulates endothelial cell synthesis of plasminogen activator inhibitor. This array of IL-1-induced activities shifts the balance at the endothelial cell surface to a prothrombotic influence and may reflect an early response of the blood vessel wall to injury.


FBXL19 recruits CDK-Mediator to CpG islands of developmental genes priming them for activation during lineage commitment.
CpG islands are gene regulatory elements associated with the majority of mammalian promoters, yet how they regulate gene expression remains poorly understood. Here, we identify FBXL19 as a CpG island-binding protein in mouse embryonic stem (ES) cells and show that it associates with the CDK-Mediator complex. We discover that FBXL19 recruits CDK-Mediator to CpG island-associated promoters of non-transcribed developmental genes to prime these genes for activation during cell lineage commitment. We further show that recognition of CpG islands by FBXL19 is essential for mouse development. Together this reveals a new CpG island-centric mechanism for CDK-Mediator recruitment to developmental gene promoters in ES cells and a requirement for CDK-Mediator in priming these developmental genes for activation during cell lineage commitment.


The First United Workshop on Microsporidia from Invertebrate and Vertebrate Hosts.
The phylum Microsporidia is a large group of parasitic unicellular eukaryotes that infect a wide range of invertebrate and vertebrate taxa. These organisms are significant human and veterinary pathogens with impacts on medicine, agriculture and aquaculture. Scientists working on these pathogens represent diverse disciplines that have had limited opportunities for detailed interactions. A NATO Advanced Research Workshop 'Emergent Pathogens in the 21st Century: First United Workshop on Microsporidia from Invertebrate and Vertebrate Hosts' was held July 12-15, 2004 at the Institute of Parasitology of the Academy of Sciences of the Czech Republic to bring together experts in insect, fish, veterinary and human microsporidiosis for the exchange of information on these pathogens. At this meeting, discussions were held on issues related to taxonomy and phylogeny. It was recognized that microsporidia are related to fungi, but the strong opinion of the participants was that the International Code of Zoological Nomenclature should continue to be applied for taxonomic descriptions of the Microsporidia and that they be treated as an independent group emerging from a paraphyletic fungi. There continues to be exponential growth in the pace and volume of research on these ubiquitous intracellular protists. The small genomes of these organisms and the reduction in the size of many of their genes are of interest to many disciplines. Many microsporidia are dimorphic and the mechanisms underlying these morphologic changes remain to be elucidated. Epidemiologic studies to clarify the source of human microsporidiosis and ecologic studies to understand the multifaceted relationship of the Microsporidia and their hosts are important avenues of investigation. Studies on the Microsporidia should prove useful to many fields of biologic investigation.


Experimental cerebral infarction. Part 1: Production of thalamic infarction in dogs.
Difficulties in achieving focal temporary cerebral ischemia in experimental animals have delayed study of the prevention and treatment of cerebral infarction. We have succeeded in producing focal cerebral infarction by temporary occlusion of brain arteries. Infarction confined to the anterior portion of the thalamus was obtained by simultaneous occlusion of the 4 cerebral arteries: internal carotid, anterior cerebral, middle cerebral and posterior communicating arteries for 60-120 minutes. This experimental model in dogs is unique, since thalamic infarction can be produced with high frequency, and the dogs can be kept alive and managed for sufficient periods after temporary artery clipping. With this model it is possible to investigate cerebral infarction not only from the pathophysiological viewpoint, but also from the viewpoint of prevention and treatment of cerebral infarction in man.


In vivo x-ray luminescence tomographic imaging with single-view data.
X-ray luminescence computed tomography (XLCT) is a new molecular imaging modality. In this Letter, we first in vivo tomographically image the near-IR-emitting nanophosphor (Gd2O3:Eu3+) in nude mice (N=2). In practically, incorporating the compressive sensing technique, the XLCT reconstruction is performed only using single-view data. The experimental results indicate that the single-view reconstruction is feasible to image XLCT in vivo. The location error is less than 1.5 mm. Further, the imaging time can be greatly reduced compared with previous XLCT systems. Therefore, it is suited for imaging fast distribution of x-ray-excitable nanophosphors within a biological object.


Argon-like three-electron trajectories in intense-field double and triple ionization.
We present the double- and triple-ionization momentum distributions obtained from a 3-e planar classical calculation in a laser pulse with peak intensity of 0.8 PW/cm(2). The calculated distributions agree surprisingly well with the experimental Ar(2+) and Ar(3+) distributions at the same laser intensity. We demonstrate four recollision pathways that contribute significantly to the production of the doubly and triply charged ions. In particular, the intense-field double ionization pathways are discussed beyond the two-active-electron picture.


Comorbidity of Geo-Helminthes among Malaria Outpatients of the Health Facilities in Ethiopia: Systematic Review and Meta-Analysis.
Coinfection of malaria and intestinal helminths affects one third of the global population, largely among communities with severe poverty. The spread of these parasitic infections overlays in several epidemiological locations and the host shows different outcomes. This systematic review and meta-analysis determine the pooled prevalence of malaria and intestinal helminthiases coinfections among malaria suspected patients in Ethiopia. Primary studies published in English language were retrieved using appropriate search terms on Google Scholar, PubMed/MEDLINE, CINHAL, Scopus, and Embase. The Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) was used for critical appraisal of studies. A pooled statistical meta-analysis was conducted using STATA Version 14.0 software. The heterogeneity and publication bias were assessed using the I2 statistics and Egger's test, respectively. Duval and Tweedie's nonparametric trim and fill analysis using the random-effect analysis. The Random effects model was used to estimate the summary prevalence of comorbidity of malaria and soil transmitted helminthiases and the corresponding 95% confidence intervals (CI). The review protocol has registered in PROSPERO number CRD42019144803. We identified ten studies (n = 6633 participants) in this study. The overall pooled result showed 13% of the ambulatory patients infected by malaria and intestinal helminths concurrently in Ethiopia. The pooled prevalence of Plasmodium falciparum and Plasmodium vivax, and mixed infections were 12, 30, and 6%, respectively. The most common intestinal helminth parasites detected were Hookworm, Ascaris lumbricoides, and Tirchuris trichiura. The comorbidity of malaria and intestinal helminths causes lower hemoglobin level leading to maternal anemia, preterm delivery, and still birth in pregnant women and lactating mother. School-aged children and neonates coinfected by plasmodium species and soil transmitted helminths develop cognitive impairment, protein energy malnutrition, low birth weight, small for gestational age, and gross motor delay. The Ministry of Health of Ethiopia and its international partners working on malaria elimination programs should give more emphasis to the effect of the interface of malaria and soil transmitted helminths, which calls for an integrated disease control and prevention.


High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers.
Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (ρ 0.19, p = 0.006) and B (ρ 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.


Bilateral Idiopathic Carpal Tunnel Syndrome in a 4-Year-Old Girl.
Carpal tunnel syndrome (CTS), the most common entrapment neuropathy in adulthood, is rare in childhood. The symptoms may differ to those in adults, or may be misinterpreted owing to children's difficulties in expressing themselves. Cases of idiopathic, bilateral CTS under the age of 5 are rare. A 4-year-old girl presented with pain in both hands and difficulty opening them in the morning. Bilateral severe CTS was determined at electroneuromyography (ENMG). Bilateral wrist splints were advised for both hands. Improvement in ENMG was seen at 2 weeks following conservative treatment.


The stargazin-related protein gamma 7 interacts with the mRNA-binding protein heterogeneous nuclear ribonucleoprotein A2 and regulates the stability of specific mRNAs, including CaV2.2.
The role(s) of the novel stargazin-like gamma-subunit proteins remain controversial. We have shown previously that the neuron-specific gamma7 suppresses the expression of certain calcium channels, particularly Ca(V)2.2, and is therefore unlikely to operate as a calcium channel subunit. We now show that the effect of gamma7 on Ca(V)2.2 expression is via an increase in the degradation rate of Ca(V)2.2 mRNA and hence a reduction of Ca(V)2.2 protein level. Furthermore, exogenous expression of gamma7 in PC12 cells also decreased the endogenous Ca(V)2.2 mRNA level. Conversely, knockdown of endogenous gamma7 with short-hairpin RNAs produced a reciprocal enhancement of Ca(V)2.2 mRNA stability and an increase in endogenous calcium currents in PC12 cells. Moreover, both endogenous and expressed gamma7 are present on intracellular membranes, rather than the plasma membrane. The cytoplasmic C terminus of gamma7 is essential for all its effects, and we show that gamma7 binds directly via its C terminus to a heterogeneous nuclear ribonucleoprotein (hnRNP A2), which also binds to a motif in Ca(V)2.2 mRNA, and is associated with native Ca(V)2.2 mRNA in PC12 cells. The expression of hnRNP A2 enhances Ca(V)2.2 I(Ba), and this enhancement is prevented by a concentration of gamma7 that alone has no effect on I(Ba). The effect of gamma7 is selective for certain mRNAs because it had no effect on alpha2delta-2 mRNA stability, but it decreased the mRNA stability for the potassium-chloride cotransporter, KCC1, which contains a similar hnRNP A2 binding motif to that in Ca(V)2.2 mRNA. Our results indicate that gamma7 plays a role in stabilizing Ca(V)2.2 mRNA.


Leukemia inhibitory factor in rat fetal lung development: expression and functional studies.
Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) are members of the family of the glycoprotein 130 (gp130)-type cytokines. These cytokines share gp130 as a common signal transducer, which explains why they show some functional redundancy. Recently, it was demonstrated that IL-6 promotes fetal lung branching. Additionally, LIF has been implicated in developmental processes of some branching organs. Thus, in this study LIF expression pattern and its effects on fetal rat lung morphogenesis were assessed. LIF and its subunit receptor LIFRα expression levels were evaluated by immunohistochemistry and western blot in fetal rat lungs of different gestational ages, ranging from 13.5 to 21.5 days post-conception. Throughout all gestational ages studied, LIF was constitutively expressed in pulmonary epithelium, whereas LIFRα was first mainly expressed in the mesenchyme, but after pseudoglandular stage it was also observed in epithelial cells. These results point to a LIF epithelium-mesenchyme cross-talk, which is known to be important for lung branching process. Regarding functional studies, fetal lung explants were cultured with increasing doses of LIF or LIF neutralizing antibodies during 4 days. MAPK, AKT, and STAT3 phosphorylation in the treated lung explants was analyzed. LIF supplementation significantly inhibited lung growth in spite of an increase in p44/42 phosphorylation. On the other hand, LIF inhibition significantly stimulated lung growth via p38 and Akt pathways. The present study describes that LIF and its subunit receptor LIFRα are constitutively expressed during fetal lung development and that they have an inhibitory physiological role on fetal lung branching.


Hemorrhagic complications of thoracentesis and small-bore chest tube placement in patients taking clopidogrel.
Clopidogrel is a commonly used antiplatelet medication. The risk of local hemorrhage associated with use of this drug during routine thoracentesis or small-bore chest tube placement is not well established. We conducted a prospective cohort study to assess the risk of hemothorax in patients taking clopidogrel while undergoing either pleural procedure. Twenty-five consecutive adult patients who were taking clopidogrel at the time they were offered thoracentesis or small-bore (14 Fr) chest tube placement consented to continue taking the drug through their procedure. A control group consisted of 50 patients undergoing these pleural procedures who were not taking clopidogrel at the time they consented to undergo either procedure. All of the pleural procedures were performed under ultrasound guidance by an interventional pulmonologist or a fellow under direct faculty supervision. Hospitalized patients were screened for hemothorax by observing for a post-procedure drop in blood hemoglobin content of 2 g/dl or reaccumulation of their pleural effusion within 24 hours of the procedure. Outpatients were called within 2 weeks after their procedure to determine whether they had any symptoms suggestive of hemothorax. There was one case of hemothorax after thoracentesis in the clopidogrel group versus none in the control group. The one patient with hemothorax required transfusion with 2 units of packed red blood cells and small-bore chest tube placement, and clopidogrel was withheld. There were no other clinically apparent complications of either procedure. Considered in combination with other small previously published studies, this single-center, nonrandomized, controlled prospective cohort study suggests that the rate of clinically consequential hemorrhage after ultrasound-guided thoracentesis or chest tube placement in patients taking clopidogrel is sufficiently low to warrant a large, randomized clinical trial designed to determine the safety of performing these procedures without interrupting clopidogrel therapy.


The diagnostic sensitivity of dengue rapid test assays is significantly enhanced by using a combined antigen and antibody testing approach.
Serological tests for IgM and IgG are routinely used in clinical laboratories for the rapid diagnosis of dengue and can differentiate between primary and secondary infections. Dengue virus non-structural protein 1 (NS1) has been identified as an early marker for acute dengue, and is typically present between days 1-9 post-onset of illness but following seroconversion it can be difficult to detect in serum. To evaluate the performance of a newly developed Panbio® Dengue Early Rapid test for NS1 and determine if it can improve diagnostic sensitivity when used in combination with a commercial IgM/IgG rapid test. The clinical performance of the Dengue Early Rapid was evaluated in a retrospective study in Vietnam with 198 acute laboratory-confirmed positive and 100 negative samples. The performance of the Dengue Early Rapid in combination with the IgM/IgG Rapid test was also evaluated in Malaysia with 263 laboratory-confirmed positive and 30 negative samples. In Vietnam the sensitivity and specificity of the test was 69.2% (95% CI: 62.8% to 75.6%) and 96% (95% CI: 92.2% to 99.8) respectively. In Malaysia the performance was similar with 68.9% sensitivity (95% CI: 61.8% to 76.1%) and 96.7% specificity (95% CI: 82.8% to 99.9%) compared to RT-PCR. Importantly, when the Dengue Early Rapid test was used in combination with the IgM/IgG test the sensitivity increased to 93.0%. When the two tests were compared at each day post-onset of illness there was clear differentiation between the antigen and antibody markers. This study highlights that using dengue NS1 antigen detection in combination with anti-glycoprotein E IgM and IgG serology can significantly increase the sensitivity of acute dengue diagnosis and extends the possible window of detection to include very early acute samples and enhances the clinical utility of rapid immunochromatographic testing for dengue.


Taking action against malnutrition in Asian healthcare settings: an initiative of a Northeast Asia Study Group.
Malnutrition is common in Asia, especially among people who are critically ill and/or older. Study results from China, Japan, and Taiwan show that malnutrition or risk of malnutrition is found in up to 30% of communitydwelling people and as much as 50% of patients admitted to hospitals-with prevalence even higher among those older than 70 years. In Asia, malnutrition takes substantial tolls on health, physical function, and wellbeing of people affected, and it adds huge financial burdens to healthcare systems. Attention to nutrition, including protein intake, can help prevent or delay disease- and age-related disabilities and can speed recovery from illness or surgery. Despite compelling evidence and professional guidelines on appropriate nutrition care in hospital and community settings, patients' malnutrition is often overlooked and under-treated in Asian healthcare, as it is worldwide. Since the problem of malnutrition continues to grow as many Asian populations become increasingly "gray", it is important to take action now. A medical education (feedM.E.) Global Study Group developed a strategy to facilitate best-practice hospital nutrition care: screen-intervene-supervene. As members of a newly formed feedM.E. Northeast Asia Study Group, we endorse this care strategy, guiding clinicians to screen each patient's nutritional status upon hospital admission or at initiation of care, intervene promptly when nutrition care is needed, and supervene or follow-up routinely with adjustment and reinforcement of nutrition care plans, including post-discharge. To encourage best-practice nutrition in Asian patient care settings, our paper includes a simple, stepwise Nutrition Care Pathway (NCP) in multiple languages.


Lowering the temperature of solid oxide fuel cells.
Fuel cells are uniquely capable of overcoming combustion efficiency limitations (e.g., the Carnot cycle). However, the linking of fuel cells (an energy conversion device) and hydrogen (an energy carrier) has emphasized investment in proton-exchange membrane fuel cells as part of a larger hydrogen economy and thus relegated fuel cells to a future technology. In contrast, solid oxide fuel cells are capable of operating on conventional fuels (as well as hydrogen) today. The main issue for solid oxide fuel cells is high operating temperature (about 800°C) and the resulting materials and cost limitations and operating complexities (e.g., thermal cycling). Recent solid oxide fuel cells results have demonstrated extremely high power densities of about 2 watts per square centimeter at 650°C along with flexible fueling, thus enabling higher efficiency within the current fuel infrastructure. Newly developed, high-conductivity electrolytes and nanostructured electrode designs provide a path for further performance improvement at much lower temperatures, down to ~350°C, thus providing opportunity to transform the way we convert and store energy.


From raw data to data-analysis for magnetic resonance spectroscopy--the missing link: jMRUI2XML.
Magnetic resonance spectroscopy provides metabolic information about living tissues in a non-invasive way. However, there are only few multi-centre clinical studies, mostly performed on a single scanner model or data format, as there is no flexible way of documenting and exchanging processed magnetic resonance spectroscopy data in digital format. This is because the DICOM standard for spectroscopy deals with unprocessed data. This paper proposes a plugin tool developed for jMRUI, namely jMRUI2XML, to tackle the latter limitation. jMRUI is a software tool for magnetic resonance spectroscopy data processing that is widely used in the magnetic resonance spectroscopy community and has evolved into a plugin platform allowing for implementation of novel features. jMRUI2XML is a Java solution that facilitates common preprocessing of magnetic resonance spectroscopy data across multiple scanners. Its main characteristics are: 1) it automates magnetic resonance spectroscopy preprocessing, and 2) it can be a platform for outputting exchangeable magnetic resonance spectroscopy data. The plugin works with any kind of data that can be opened by jMRUI and outputs in extensible markup language format. Data processing templates can be generated and saved for later use. The output format opens the way for easy data sharing- due to the documentation of the preprocessing parameters and the intrinsic anonymization--for example for performing pattern recognition analysis on multicentre/multi-manufacturer magnetic resonance spectroscopy data. jMRUI2XML provides a self-contained and self-descriptive format accounting for the most relevant information needed for exchanging magnetic resonance spectroscopy data in digital form, as well as for automating its processing. This allows for tracking the procedures the data has undergone, which makes the proposed tool especially useful when performing pattern recognition analysis. Moreover, this work constitutes a first proposal for a minimum amount of information that should accompany any magnetic resonance processed spectrum, towards the goal of achieving better transferability of magnetic resonance spectroscopy studies.


Mental health of survivors of 1984 Bhopal disaster: A continuing challenge.
Bhopal disaster is an important milestone in Indian Industrial Psychiatry. The disaster was not only the biggest industrial disaster but also one in which complex forces have joined hands to demy the mental health needs of the population. Though the biggest general population epidemiological study over 5 years was carried out to understand the mental health impact of the disaster, the findings of this study did not get reflected in mental health care for the population. Furthermore, the needed longitudinal studies and evaluation of the interventions were not undertaken. There was no sharing of information with the survivors about the impact of the disaster on their health and well-being and sharing of skills for self-care. A result of these factors is the extreme degree of dissatisfaction in the population. Looking back, it would have met the needs of the Bhopal population, if the mental health services were community based and reaching the population, rather than the clinic-based approaches, there was a wide range of services, especially rehabilitation, continuous research into the changing mental health needs of the population and the effectiveness of interventions and most importantly, there was a continuous dialogue with the population and sharing of information with the general population. These are the tasks for the immediate future to reorganize the focus of mental health initiatives in Bhopal. Many lessons can be learnt from the Bhopal disaster and the continuing tragedy for the population.


Chemical functionalization of polysilicon microparticles for single-cell studies.
In this work, two types of polycrystalline silicon (polysilicon) microparticles were modified with specific ligands in order to be selectively attached to chemical residues located at the plasma membrane and thus to be applied to study individual cells in culture. Two different functionalization approaches based on adsorption and covalent attachment were assayed. A comparative study of the efficiency of the ligand immobilization and stability of the modified particle in the culture medium was carried out using the selected ligands labeled with a fluorophore. Cylindrical microparticles (nonencoded microparticles) and shape-encoded microparticles (bar codes) were used with the aim of demonstrating the nondependence of the particle size and shape on the efficiency of the immobilization protocol. Fluorescence imaging and statistical analysis of the recorded fluorescence intensity showed that the covalent attachment of the ligand to the surface of the microparticle, previously modified with an aldehyde-terminated silane, gave the best results. As a proof of concept, Vero cells in culture were labeled with the covalently modified bar codes and successfully tracked for up to 1 week without observing any alteration in the viability of the cells. Bar code numbers could be easily read by eye using a bright-field optical microscope. It is anticipated that such modified microparticles could be feasible platforms for the introduction of other analytical functions of interest in single-cell monitoring and cell sorting in automatic analysis systems.


Immunocytochemical and pharmacological evidence for GABAergic spiking local interneurons in the locust.
In the locust thoracic nervous system, spiking local interneurons within a ventral midline population are stained by a polyclonal antibody raised against GABA. Their cell bodies, their primary neurites in ventral commissure II, and their prominent neurites in the perpendicular tract linking ventral and dorsal fields of fine branches are all stained. Individual interneurons in this population were labeled with Lucifer yellow after their receptive fields had been determined physiologically. Alternate sections were stained with the antibody. Some, but not all, of the spiking local interneurons labeled with Lucifer yellow are also stained with the antibody. Apart from having somata that lie more posteriorly within the midline population, the antibody-stained interneurons cannot be distinguished on morphological or physiological grounds from those that are unstained. The way in which this cytochemical heterogeneity within an otherwise homogenous population might arise during development is discussed. A second group of spiking local interneurons with similar sensory input to that of the ventral midline population, but with cell bodies in the anterior lateral region of the ganglion and primary neurites in ventral commissure I, are not stained. Interneurons in the midline group receive direct inputs from sensory neurons and some directly inhibit particular leg motor neurons that mediate interjoint and tactile reflexes. Picrotoxin reversibly blocks the inhibition of the motor neurons and therefore abolishes these reflexes. Immunocytochemical and pharmacological experiments thus suggest that inhibition by some spiking local interneurons may be mediated by GABA.


Detection of Pancreatic Ductal Adenocarcinoma by A qPCR-based Normalizer-free Circulating Extracellular Vesicles RNA Signature.
Background: Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose and many efforts have been made to evaluate EVs-derived RNAs as biomarkers to predict PDAC. However, lack of robust internal references largely limited their clinical application. Here we proposed an RNA ratio-based, normalizer-free algorithm to quantitate EVs-derived RNAs in PDAC. Methods: Differentially expressed RNAs in the training group were identified using "limma" package. The ratio of any two candidate RNAs in the same sample was calculated and used as a new biomarker. LASSO regression was performed to build prediction models based on those RNA ratios. RNA-seq data of 116 plasma samples and RT-qPCR data of 111 plasma samples were used for internal and external validation, separately. Three algorithms (lasso regression, logistic regression, and SVM) were compared to improve the performance of this RNA signature. Results: We developed an RNA-ratio based prediction model which comprised eight EVs-derived RNAs, including FBXO7, MORF4L1, DDX17, TALDO1, AHNAK, TUBA1B, CD44, and SETD3. This model could well differentiate PDAC patients with a minimal AUC of 0.86 in internal verification using testing group. External validation using RT-qPCR data also exhibited a good classifier ability with an AUC of 0.89 when distinguishing PDAC from healthy controls. Conclusion: We've developed a qPCR-based, normalizer-free circulating EVs RNA classifier, which could well distinguish PDAC patients from noncancerous controls.


Precise engineering of dapivirine-loaded nanoparticles for the development of anti-HIV vaginal microbicides.
Polymeric nanoparticles (NPs) have the potential to provide effective and safe delivery of antiretroviral drugs in the context of prophylactic anti-HIV vaginal microbicides. Dapivirine-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) NPs were produced by an emulsion-solvent evaporation method, optimized for colloidal properties using a 3-factor, 3-level Box-Behnken experimental design, and characterized for drug loading, production yield, morphology, thermal behavior, drug release, in vitro cellular uptake, cytotoxicity and pro-inflammatory potential. Also, drug permeability/membrane retention in well-established HEC-1-A and CaSki cell monolayer models as mediated by NPs was assessed in the absence or presence of mucin. Box-Behnken design allowed optimizing monodisperse 170nm drug-loaded NPs. Drug release experiments showed an initial burst effect up to 4h, followed by sustained 24h release at pH 4.2 and 7.4. NPs were readily taken up by different genital and macrophage cell lines as assessed by fluorescence microscopy. Drug-loaded NPs presented lower or at least similar cytotoxicity as compared to the free drug, with up to around one-log increase in half-maximal cytotoxic concentration values. In all cases, no relevant changes in cell pro-inflammatory cytokine/chemokine production were observed. Dapivirine transport across cell monolayers was significantly decreased when mucin was present at the donor side with either NPs or the free drug, thus evidencing the influence of this natural glycoprotein in membrane permeability. Moreover, drug retention in cell monolayers was significantly higher for NPs in comparison with the free drug. Overall, obtained dapivirine-loaded PLGA NPs possess interesting technological and biological features that may contribute to their use as novel safe and effective vaginal microbicides.


The embedded researcher model in Australian healthcare settings: comparison by degree of "embeddedness".
The embedded researcher model is a health-academic partnership where researchers are core members of a healthcare organization, with an aim to support evidence translation. The purpose of this study was to describe the characteristics and experiences of embedded researchers in Australian healthcare settings, and investigate how the model is experienced differently based on the level of "embeddedness." This exploratory study utilized a purpose-designed online survey. Responses were described using Word and Excel and analyzed using SPSS. To investigate how the model was experienced based on the level of "embeddedness," we tested for differences in responses between respondents with primary academic vs healthcare affiliations. A total of 104 embedded researchers from nursing and midwifery, allied health and medicine completed the survey, with equal numbers reporting a primary academic vs primary healthcare affiliation. Most indicated that research is a strategic objective of the healthcare organization (85.9%) yet almost a third (31%) reported that research outputs were not measured. While 60% agreed that clinical practice informed by research was valued, only 28% reported having adequate resources. Of those with a formal dual affiliation over a quarter reported conflict between expectations of the healthcare and academic organizations. Respondents with a primary academic affiliation were older, more qualified, had more research experience, had been in the role longer, and had more positive perceptions of the research culture of healthcare organizations. This study provides a starting point for healthcare organizations and academic institutions to partner in the further development and implementation of this model.