[Living conditions and pattern of acute poisonings in Oslo].
Hospitalized patients with acute poisoning come from all classes of society. The relationship between living conditions and pattern of poisoning is, however, unclear. The aim of this study was to examine the connection between living conditions in Oslo and the pattern of acute poisonings, measured by incidence, main toxic agents and intention. A one-year multi-centre study with prospective inclusion of all patients ≥ 18 years of age with a registered address in Oslo admitted to an Oslo hospital with acute poisoning from 1 April 2003 through 31 March 2004. The 15 city districts were grouped into three, according to the official living conditions index in Oslo: city district group 1 (best living conditions), city district group 2 (average living conditions) and city district group 3 (most difficult living conditions). Of a total of 947 patients admitted with acute poisoning as their main diagnosis in the study period, 691 were included in the study, 660 of whom had self-inflicted poisoning. In city district group 3, the annual incidence of acute poisonings was 2.14 per 1000 inhabitants, significantly higher than city district group 2, with 1.50 (p < 0.001), and city district group 1, with 1.36 (p < 0.001). Measured as intention assessed by the treating physician, suicidal and drug related poisonings and those induced by a "cry for help" were more common in city district group 3 (0.74, 0.59 and 0.74 per 1000 inhabitants, respectively) than in city district group 2 (0.62, 0.40 and 0.41, respectively) and city district group 1 (0.52, 0.32 and 0.45, respectively). The main toxic agents were predominantly benzodiazepines (20 %), ethanol (18 %) and paracetamol (12 %). There were no statistically significant differences in the distribution of main toxic agents between the city district groups. The findings show a social gradient, with the highest incidence of poisonings in the city district group with the most difficult living conditions.


Safety and Efficacy of Resident-Performed Functional Upper Eyelid Blepharoplasty.
To determine the safety and efficacy of resident-performed functional upper eyelid blepharoplasty. The authors retrospectively looked at functional upper eyelid blepharoplasty surgery performed on 836 eyes of 448 patients under the supervision of one oculoplastic surgery attending at the University of California Davis Eye Center from January 1, 2013, to December 31, 2017. The primary surgeon was a resident on 427 eyes and was an attending on 409 eyes. Patients (73.5%) were female, and the mean age was 66.0 ± 10.0. All patients had at least 2 postoperative visits, and eyes that underwent other concurrent upper eyelid or brow procedures were excluded. The authors looked at major and minor complications, percentage of initially dissatisfied patients, and percentage of cases that required a revision procedure within 6 months. Chi-square tests were used for statistical analysis. There were no major complications in either group. There was no difference in the rate of minor complications (10.8% vs. 7.6%, p = 0.11), percentage of patients who were initially dissatisfied with the procedure (3.5% vs. 2.0%, p = 0.17), or percentage of patients requiring a revision procedure (5.2% vs. 3.2%, p = 0.15). The most common minor complications were inclusion cysts (45, 5.4%), wound dehiscence (9, 1.1%), and hypertrophic scars (9, 1.1%), and the most common revision procedures were removal of inclusion cyst(s) (17, 2.0%) and suturing or placement of topical skin adhesive for wound dehiscence (9, 1.1%). Ophthalmology residents can perform functional upper eyelid blepharoplasty safely and effectively under the supervision of an attending physician.Resident-performed functional upper eyelid blepharoplasty under the direct supervision of an attending is a safe and effective procedure with similar complication rate, number of revision procedures, and patient satisfaction to attending-performed functional upper eyelid blepharoplasty.


Flood induced phenotypic plasticity in amphibious genus Elatine (Elatinaceae).
Vegetative characters are widely used in the taxonomy of the amphibious genus Elatine L. However, these usually show great variation not just between species but between their aquatic and terrestrial forms. In the present study we examine the variation of seed and vegetative characters in nine Elatine species (E. brachysperma, E. californica, E. gussonei, E. hexandra, E. hungarica, E. hydropiper, E. macropoda, E. orthosperma and E. triandra) to reveal the extension of plasticity induced by the amphibious environment, and to test character reliability for species identification. Cultivated plant clones were kept under controlled conditions exposed to either aquatic or terrestrial environmental conditions. Six vegetative characters (length of stem, length of internodium, length of lamina, width of lamina, length of petioles, length of pedicel) and four seed characters (curvature, number of pits / lateral row, 1st and 2nd dimension) were measured on 50 fruiting stems of the aquatic and on 50 stems of the terrestrial form of the same clone. MDA, NPMANOVA Random Forest classification and cluster analysis were used to unravel the morphological differences between aquatic and terrestrial forms. The results of MDA cross-validated and Random Forest classification clearly indicated that only seed traits are stable within species (i.e., different forms of the same species keep similar morphology). Consequently, only seed morphology is valuable for taxonomic purposes since vegetative traits are highly influenced by environmental factors.


Maximizing algebraic connectivity in interconnected networks.
Algebraic connectivity, the second eigenvalue of the Laplacian matrix, is a measure of node and link connectivity on networks. When studying interconnected networks it is useful to consider a multiplex model, where the component networks operate together with interlayer links among them. In order to have a well-connected multilayer structure, it is necessary to optimally design these interlayer links considering realistic constraints. In this work, we solve the problem of finding an optimal weight distribution for one-to-one interlayer links under budget constraint. We show that for the special multiplex configurations with identical layers, the uniform weight distribution is always optimal. On the other hand, when the two layers are arbitrary, increasing the budget reveals the existence of two different regimes. Up to a certain threshold budget, the second eigenvalue of the supra-Laplacian is simple, the optimal weight distribution is uniform, and the Fiedler vector is constant on each layer. Increasing the budget past the threshold, the optimal weight distribution can be nonuniform. The interesting consequence of this result is that there is no need to solve the optimization problem when the available budget is less than the threshold, which can be easily found analytically.


Safety issues of hysteroscopic surgery.
The term hysteroscopy is used to determine the procedure during which an endoscopic view of the endometrial cavity is achieved with the help of a type of endoscopic device called "the hysteroscope." Hysteroscopy is used to assist the diagnosis for a series of female pathology. Apart from its diagnostic value, hysteroscopy can also be used for operative procedures including ablation and resection. Both diagnostic and operative hysteroscopy have been used for a number of years and various studies have been published to describe their success and complication rates throughout this period. Diagnostic hysteroscopy is relatively safe, whereas complications occur more frequently when operative hysteroscopy is used. These complications include uterine perforation, hemorrhage, fluid overload, gas embolization, and hyponatremia. The rate in the appearance of these complications is dependent on the type of the hysteroscopic procedure, the distending medium, and the experience of the hysteroscopist. To avoid any problems concerning the application of hysteroscopic procedures, it is important to take the necessary precautions both preoperatively and intraoperatively. For example, the preoperative use of thinning agents of the endometrium and the reduction of the operating time, or the avoidance of cutting too deeply into the myometrium, are some of the parameters to be considered when hysteroscopy is in argument.


Parenting-by-gender interactions in child psychopathology: attempting to address inconsistencies with a Canadian national database.
Research has shown strong links between parenting and child psychopathology. The moderating role of child gender is of particular interest, due to gender differences in socialization history and in the prevalence of psychiatric disorders. Currently there is little agreement on how gender moderates the relationship between parenting and child psychopathology. This study attempts to address this lack of consensus by drawing upon two theories (self-salience vs. gender stereotyped misbehaviour) to determine how child gender moderates the role of parenting, if at all. Using generalized estimating equations (GEE) associations between three parenting dimensions (hostile-ineffective parenting, parental consistency, and positive interaction) were examined in relationship to child externalizing (physical aggression, indirect aggression, and hyperactivity-inattention) and internalizing (emotional disorder-anxiety) dimensions of psychopathology. A sample 4 and 5 year olds from the National Longitudinal Survey of Children and Youth (NLSCY) were selected for analysis and followed over 6 years (N = 1214). Two models with main effects (Model 1) and main effects plus interactions (Model 2) were tested. No child gender-by-parenting interactions were observed for child physical aggression and indirect aggression. The association between hostile-ineffective parenting and child hyperactivity was stronger for girls, though this effect did not reach conventional levels of statistical significance (p = .059). The associations between parenting and child emotional disorder did vary as a function of gender, where influences of parental consistency and positive interaction were stronger for boys. Despite the presence of a few significant interaction effects, hypotheses were not supported for either theory (i.e. self-salience or gender stereotyped misbehaviour). We believe that the inconsistencies in the literature regarding child gender-by-parenting interactions is due to the reliance on gender as an indicator of a different variable which is intended to explain the interactions. This may be problematic because there is likely within-gender and between-sample variability in such constructs. Future research should consider measuring and modelling variables that are assumed to explain such interactions when conducting gender-by-parenting research.


Morphometric variables of developing primary maxillary first molar crowns in humans.
The following morphometric variables were examined in 18 primary maxillary first molars at various stages of development, collected from archaeological excavation sites in Israel: perimeters and areas from the occlusal view; buccolingual and mesiodistal dimensions and intercusp distances; the angle between the line joining the distobuccal, mesiobuccal and lingual cusps; and the height of the mesiobuccal cusp. An image-analysing technique comprising a photographic camera, a monitor, a computer with appropriate software and a digital caliper was used. Significant correlations were demonstrated between most variables. Teeth were divided into two groups according to their stage of development: stage one included all teeth at an early stage of development in which mesiobuccal cusp height was less than 5 mm; stage two included all teeth in later stages of development where mesiobuccal cusp height was greater than 5 mm. All external variables showed an increase in size between the two stages (while, among the internal ones, only the angle between the cusps showed a very small increase). The small sample is a limitation but the results suggest the following: (1) growth of the primary maxillary molar crown occurs with 'bursts' of development ; and (2) a change in the shape of the crown occurs during its formation where the mesiobuccal cusp moves buccally and distally, and the lingual cusp moves mesially.


Impact of coronary revascularization on the clinical and scintigraphic outlook of patients with myocardial ischemia.
The impact of coronary revascularization on outcomes and ischemic burden among patients with objective proof of ischemia is not yet established. We appraised the impact of revascularization on outcomes and residual ischemia in patients with objective evidence of ischemia at myocardial perfusion scintigraphy (MPS). We queried our database for stable patients with myocardial ischemia at MPS, excluding those with prior myocardial infarction, systolic dysfunction, or cardiomyopathy. The impact of revascularization (defined as revascularization as first follow-up event) on outcomes and changes in myocardial ischemia at repeat MPS was appraised with propensity-matched analyses. From 6195 patients, propensity matching yielded 1262 pairs of patients undergoing revascularization versus not undergoing revascularization. After 35.2 ± 23.9 months, revascularization was associated with lower risks of cardiac death [2 (0.2%) versus 10 (0.8%) in those not revascularized, P = 0.038] and of the composite of cardiac death or myocardial infarction [17 (1.3%) versus 37 (2.9%), P = 0.007]. In addition, revascularization was associated with a higher rate of improvement in ischemia degree after 28.1 ± 20.7 months of follow-up (P < 0.001), with 257 (69.3%) patients with moderate or severe ischemia at baseline MPS improving after revascularization versus 136 (42.0%) in the nonrevascularization group. Conversely, revascularization did not prove impactful on follow-up MPS in patients with only minimal or mild ischemia at baseline MPS (P < 0.001). In a large series of patients with objective evidence of myocardial ischemia at MPS, especially when moderate or severe, revascularization was associated with a better clinical prognosis and a lower ischemic burden at repeat MPS.


Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes.
An established model for mechanistic analysis of lung carcinogenesis involves administration of 3-methylcholanthrene to mice followed by several weekly injections of the tumor promoter 2,6-di-tert-butyl-4-methylphenol (BHT). BHT is metabolized to quinone methides (QMs) responsible for promoting tumor formation. QMs are strongly electrophilic and readily form adducts with proteins. The goal of the present study was to identify adducted proteins in the lungs of mice injected with BHT and to assess the potential impact of these modifications on tumorigenesis. Cytosolic proteins from treated mouse lungs were separated by two-dimensional electrophoresis, adducts detected by immunoblotting, and proteins identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Eight adducts were detected in the lungs of most, or all, of six experimental groups of BALB mice. Of these adducts, several were structural proteins, but others, namely, peroxiredoxin 6 (Prx6), Cu,Zn-superoxide dismutase (SOD1), carbonyl reductase, and selenium-binding protein 1, have direct or indirect antioxidant functions. When the 9000g supernatant fraction of mouse lung was treated with BHT-QM (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone), substantial lipid peroxidation and increases in hydrogen peroxide and superoxide formation were observed. Studies with human Prx6 and bovine SOD1 demonstrated inhibition of enzyme activity concomitant with adduct formation. LC-MS/MS analysis of digests of adducted Prx6 demonstrated adduction of both Cys 91 and Cys 47; the latter residue is essential for peroxidatic activity. Analysis of QM-treated bovine SOD1 by matrix-assisted laser desorption/ionization time-of-flight MS demonstrated the predominance of a monoadduct at His 78. This study provides evidence that indicates Prx6, SOD1, and possibly other antioxidant enzymes in mouse lung are inhibited by BHT-derived QMs leading to enhanced levels of reactive oxygen species and inflammation and providing a mechanistic basis for the effects of BHT on lung tumorigenesis.


[Achalasia in children and adolescents, a therapeutic challenge].
Treatment of achalasia in children is in permanent discussion. It is a rare disorder without cure, which makes its management challenging. Retrospective review of patients under 18 years old treated for achalasia in our Hospital between 2000 and 2012, by either pneumatic dilatation (PD) or Heller myotomy (HM). Thirteen children were treated during this time. Mean age was 12 years (4-18), interval time between the onset of symptoms and diagnosis was 15 months (2-48) and mean follow-up was 66,8 months (4-144). Dysphagia and vomits were the main symptoms (61%). A single PD was performed in 5 patients; four were the oldest children of the series (16-18). Three girls remain asymptomatic and 2 boys suffer from moderate dysphagia. Six patients required multiple PD and, after a mean of 3 dilatations, HM was needed in all of them. The last 2 children of the series received surgery as the first treatment. In total, eight patients underwent HM and fundoplication, with 6 laparoscopic procedures. Two boys suffer from low-moderate dysphagia, but additional treatments have not been required. The mean of total hospital stay was 12,7 days (2-45) for PD and 9 days (3-30) for HM. Two patients were reoperated because of oesophagic perforation, one after PD and one after open HM. Although PD and HM could be complementary, laparoscopic Heller myotomy should be considered the first therapeutic option, specially in young boys.


High-resolution light-field microscopy with patterned illumination.
Light-field fluorescence microscopy can record large-scale population activity of neurons expressing genetically-encoded fluorescent indicators within volumes of tissue. Conventional light-field microscopy (LFM) suffers from poor lateral resolution when using wide-field illumination. Here, we demonstrate a structured-illumination light-field microscopy (SI-LFM) modality that enhances spatial resolution over the imaging volume. This modality increases resolution by illuminating sample volume with grating patterns that are invariant over the axial direction. The size of the SI-LFM point-spread-function (PSF) was approximately half the size of the conventional LFM PSF when imaging fluorescent beads. SI-LFM also resolved fine spatial features in lens tissue samples and fixed mouse retina samples. Finally, SI-LFM reported neural activity with approximately three times the signal-to-noise ratio of conventional LFM when imaging live zebrafish expressing a genetically encoded calcium sensor.


Associations of presenting symptoms and subsequent adverse clinical outcomes in people with unipolar depression: a prospective natural language processing (NLP), transdiagnostic, network analysis of electronic health record (EHR) data.
To investigate the associations of symptoms of mania and depression with clinical outcomes in people with unipolar depression. A natural language processing electronic health record study. We used network analysis to determine symptom network structure and multivariable Cox regression to investigate associations with clinical outcomes. The South London and Maudsley Clinical Record Interactive Search database. All patients presenting with unipolar depression between 1 April 2006 and 31 March 2018. (1) Symptoms of mania: Elation; Grandiosity; Flight of ideas; Irritability; Pressured speech. (2) Symptoms of depression: Disturbed mood; Anhedonia; Guilt; Hopelessness; Helplessness; Worthlessness; Tearfulness; Low energy; Reduced appetite; Weight loss. (3) Symptoms of mania or depression (overlapping symptoms): Poor concentration; Insomnia; Disturbed sleep; Agitation; Mood instability. (1) Bipolar or psychotic disorder diagnosis. (2) Psychiatric hospital admission. Out of 19 707 patients, at least 1 depression, overlapping or mania symptom was present in 18 998 (96.4%), 15 954 (81.0%) and 4671 (23.7%) patients, respectively. 2772 (14.1%) patients subsequently developed bipolar or psychotic disorder during the follow-up period. The presence of at least one mania (HR 2.00, 95% CI 1.85 to 2.16), overlapping symptom (HR 1.71, 95% CI 1.52 to 1.92) or symptom of depression (HR 1.31, 95% CI 1.07 to 1.61) were associated with significantly increased risk of onset of a bipolar or psychotic disorder. Mania (HR 1.95, 95% CI 1.77 to 2.15) and overlapping symptoms (HR 1.76, 95% CI 1.52 to 2.04) were associated with greater risk for psychiatric hospital admission than symptoms of depression (HR 1.41, 95% CI 1.06 to 1.88). The presence of mania or overlapping symptoms in people with unipolar depression is associated with worse clinical outcomes. Symptom-based approaches to defining clinical phenotype may facilitate a more personalised treatment approach and better predict subsequent clinical outcomes than psychiatric diagnosis alone.


Bacterial lyso-form lipoproteins are synthesized via an intramolecular acyl chain migration.
All bacterial lipoproteins share a variably acylated N-terminal cysteine residue. Gram-negative bacterial lipoproteins are triacylated with a thioether-linked diacylglycerol moiety and an N-acyl chain. The latter is transferred from a membrane phospholipid donor to the α-amino terminus by the enzyme lipoprotein N-acyltransferase (Lnt), using an active-site cysteine thioester covalent intermediate. Many Gram-positive Firmicutes also have N-acylated lipoproteins, but the enzymes catalyzing N-acylation remain uncharacterized. The integral membrane protein Lit (lipoprotein intramolecular transacylase) from the opportunistic nosocomial pathogen Enterococcus faecalis synthesizes a specific lysoform lipoprotein (N-acyl S-monoacylglycerol) chemotype by an unknown mechanism that helps this bacterium evade immune recognition by the Toll-like receptor 2 family complex. Here, we used a deuterium-labeled lipoprotein substrate with reconstituted Lit to investigate intramolecular acyl chain transfer. We observed that Lit transfers the sn-2 ester-linked lipid from the diacylglycerol moiety to the α-amino terminus without forming a covalent thioester intermediate. Utilizing Mut-Seq to analyze an alanine scan library of Lit alleles, we identified two stretches of functionally important amino acid residues containing two conserved histidines. Topology maps based on reporter fusion assays and cysteine accessibility placed both histidines in the extracellular half of the cytoplasmic membrane. We propose a general acid base-promoted catalytic mechanism, invoking direct nucleophilic attack by the substrate α-amino group on the sn-2 ester to form a cyclic tetrahedral intermediate that then collapses to produce lyso-lipoprotein. Lit is a unique example of an intramolecular transacylase differentiated from that catalyzed by Lnt, and provides insight into the heterogeneity of bacterial lipoprotein biosynthetic systems.


[Spontaneous peritonitis in a cirrhotic patient with a cat: Pasteurella multocida infection of the ascitic fluid].
Spontaneous peritonitis due to Pasteurella multocida is exceptional. As far as we know only 11 other cases have been reported. We describe a 45 year old patient who presented with a spontaneous Pasteurella multocida peritonitis as the first complication of a previously undiagnosed cirrhosis. The patient used to play with his pet cat, not recalling having ever sustained any injury. Cultures of the cat's mouth grew the same strain of Pasteurella multocida than was found in the patient's ascitic fluid. The clinical findings of the previous cases, most of which were also related to non traumatic exposure to domestic animals, are here described. Pasteurella multocida in one potential agent in the cirrhotic patient presenting with spontaneous peritonitis, especially if in close contact with animals, cats being the most often carriers.


Accurate Transfer Efficiencies, Distance Distributions, and Ensembles of Unfolded and Intrinsically Disordered Proteins From Single-Molecule FRET.
Intrinsically disordered proteins (IDPs) sample structurally diverse ensembles. Characterizing the underlying distributions of conformations is a key step toward understanding the structural and functional properties of IDPs. One increasingly popular method for obtaining quantitative information on intramolecular distances and distributions is single-molecule Förster resonance energy transfer (FRET). Here we describe two essential elements of the quantitative analysis of single-molecule FRET data of IDPs: the sample-specific calibration of the single-molecule instrument that is required for determining accurate transfer efficiencies, and the use of state-of-the-art methods for inferring accurate distance distributions from these transfer efficiencies. First, we illustrate how to quantify the correction factors for instrument calibration with alternating donor and acceptor excitation measurements of labeled samples spanning a wide range of transfer efficiencies. Second, we show how to infer distance distributions based on suitably parameterized simple polymer models, and how to obtain conformational ensembles from Bayesian reweighting of molecular simulations or from parameter optimization in simplified coarse-grained models.


Evaluation of Electronic Health Record-Based Suicide Risk Prediction Models on Contemporary Data.
Suicide risk prediction models have been developed by using information from patients' electronic health records (EHR), but the time elapsed between model development and health system implementation is often substantial. Temporal changes in health systems and EHR coding practices necessitate the evaluation of such models in more contemporary data. A set of published suicide risk prediction models developed by using EHR data from 2009 to 2015 across seven health systems reported c-statistics of 0.85 for suicide attempt and 0.83 to 0.86 for suicide death. Our objective was to evaluate these models' performance with contemporary data (2014-2017) from these systems. We evaluated performance using mental health visits (6,832,439 to mental health specialty providers and 3,987,078 to general medical providers) from 2014 to 2017 made by 1,799,765 patients aged 13+ across the health systems. No visits in our evaluation were used in the previous model development. Outcomes were suicide attempt (health system records) and suicide death (state death certificates) within 90 days following a visit. We assessed calibration and computed c-statistics with 95% confidence intervals (CI) and cut-point specific estimates of sensitivity, specificity, and positive/negative predictive value. Models were well calibrated; 46% of suicide attempts and 35% of suicide deaths in the mental health specialty sample were preceded by a visit (within 90 days) with a risk score in the top 5%. In the general medical sample, 53% of attempts and 35% of deaths were preceded by such a visit. Among these two samples, respectively, c-statistics were 0.862 (95% CI: 0.860-0.864) and 0.864 (95% CI: 0.860-0.869) for suicide attempt, and 0.806 (95% CI: 0.790-0.822) and 0.804 (95% CI: 0.782-0.829) for suicide death. Performance of the risk prediction models in this contemporary sample was similar to historical estimates for suicide attempt but modestly lower for suicide death. These published models can inform clinical practice and patient care today.


The Impact of Cholecystectomy on the Gut Microbiota: A Case-Control Study.
Cholecystectomy alters the bile flow into the intestine and the enterohepatic circulation of the bile acids; this may affect the gut microbiota. We assessed the gut microbiota composition of patients who had undergone cholecystectomy and compared with those who had not. From a cohort of 1463 adult participants who underwent comprehensive health screening examinations, 27 subjects who had undergone cholecystectomy (cholecystectomy group) and 81 age- and sex-matched subjects who had not (control group) were selected. Clinical parameters were collected and compared. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from fecal samples. We evaluated differences in the overall microbial composition and in the abundance of taxa. The two groups were comparable with respect to clinical characteristics and laboratory results. The actual number of taxa observed in a sample (observed features) was significantly lower in the cholecystectomy group than in the control group (p = 0.042). The beta diversity of Jaccard distance index was significantly different between the two groups (p = 0.027). Blautia obeum and Veillonella parvula were more abundant in the cholecystectomy group. The difference in the diversity of the gut microbiota between the cholecystectomy and control groups was subtle. However, B. obeum and V. parvula, which have azoreductase activity, were more abundant in the cholecystectomy group. The impact of such changes in the gut microbiota on health remains to be determined.


Pediatric-type follicular lymphoma in a Crohn's disease patient receiving anti-α4β7-integrin therapy: A case report.
Patients with autoimmune conditions receiving immunosuppressants are at risk of non-Hodgkin lymphomas (NHL). Vedolizumab (anti-α4β7-integrin antibody), a treatment-of-choice for Crohn's disease (CD), reduces inflammatory lymphocyte trafficking into the intestinal mucosa. This effect is believed to be confined to the colon. We report the case of a CD patient on vedolizumab for five years who developed pediatric-type follicular lymphoma. Work-up prior to therapy revealed a reduction in circulating T-lymphocytes and their suppressed response to mitogens. Rituximab, cyclophosphamide, vincristine, and prednisone chemo-immunotherapy resulted in durable lymphoma remission, and vedolizumab treatment was continued. While the patient's T-lymphocyte population and immunoglobulin production recovered, the T-lymphocyte mitogen response remained suppressed. This patient's NHL may be linked to receiving anti-α4β7 therapy. Further research could be beneficial to determine if proactive surveillance for NHL and other systemic diseases is indicated in patients on vedolizumab.


Impact of enteral and parenteral nutrition on hepatic and muscle glucose metabolism.
Liver and muscle metabolism were assessed in dogs adapted to long-term total parenteral (TPN) and enteral (TEN) nutrition. Studies were done in 13 conscious long-term catheterized dogs in which sampling (artery, portal and hepatic vein, and iliac vein), infusion catheters (inferior vena cava, duodenum), and transonic flow probes (hepatic artery, portal vein, and iliac artery) were implanted. Fourteen days after surgery dogs were grouped to receive TPN or TEN. After 5 days of TPN/TEN, substrate balances across the liver and limb were assessed. The liver was a marked net consumer of glucose in both groups (23.6 +/- 3.3 vs 22.6 +/- 2.8 micromol x kg(-1) x min(-1), TPN vs TEN) despite near normoglycemia (6.5 +/- 0.3 vs 6.7 +/- 0.2 mmol/L). Arterial insulin levels were higher during TEN (96 +/- 6 vs 144 +/- 30 pmol/L; p < .05). The majority (79 +/- 13 vs 76% +/- 7%) of the glucose taken up by the liver was released as lactate. Despite higher insulin levels during TEN the nonsplanchnic tissues consumed a lessor quantity of glucose (25.9 +/- 3.3 vs 16.1 +/- 3.9 micro x mol x kg(-1) x min(-1)). In summary, the liver undergoes a profound adaptation to TPN and TEN making it a major site of glucose uptake and conversion to lactate irrespective of the route of nutrient delivery. However, the insulin requirements are higher with TEN possibly secondary to impaired peripheral glucose removal.


Synthetic discriminant function-based binary nonlinear optical correlator.
We describe a binary nonlinear optical correlator that uses a synthetic discrimination function (SDF) at the input plane to store the reference images. The SDF is displayed at the input plane side by side the input scene. The input scene, the SDF, and their joint power spectrum are thresholded to only two values. Thus, binary spatial light modulators can be used to implement the correlator. The correlation performance of the SDF-based binary nonlinear optical correlator is compared to that of the classical SDF-based correlator in the areas of correlation peak intensity, peak-to-sidelobe ratio, signal-to-noise ratio, and correlation width. We show that the SDF-based binary nonlinear optical correlator performs reasonably well. Furthermore, a single binary SLM can be used to read in sequentially the binarized input signals and the binarized joint power spectrum which results in a reduction in cost, size, and complexity of the system.


Design and development of stable, water-soluble, human Toll-like receptor 2 specific monoacyl lipopeptides as candidate vaccine adjuvants.
Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of Toll-like receptor 2 (TLR2) are devoid of significant proinflammatory activity in ex vivo human blood models and yet are potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models.


Family planning, antenatal and delivery care: cross-sectional survey evidence on levels of coverage and inequalities by public and private sector in 57 low- and middle-income countries.
The objective of this study was to assess the role of the private sector in low- and middle-income countries (LMICs). We used Demographic and Health Surveys for 57 countries (2000-2013) to evaluate the private sector's share in providing three reproductive and maternal/newborn health services (family planning, antenatal and delivery care), in total and by socio-economic position. We used data from 865 547 women aged 15-49, representing a total of 3 billion people. We defined 'met and unmet need for services' and 'use of appropriate service types' clearly and developed explicit classifications of source and sector of provision. Across the four regions (sub-Saharan Africa, Middle East/Europe, Asia and Latin America), unmet need ranged from 28% to 61% for family planning, 8% to 22% for ANC and 21% to 51% for delivery care. The private-sector share among users of family planning services was 37-39% across regions (overall mean: 37%; median across countries: 41%). The private-sector market share among users of ANC was 13-61% across regions (overall mean: 44%; median across countries: 15%). The private-sector share among appropriate deliveries was 9-56% across regions (overall mean: 40%; median across countries: 14%). For all three healthcare services, women in the richest wealth quintile used private services more than the poorest. Wealth gaps in met need for services were smallest for family planning and largest for delivery care. The private sector serves substantial numbers of women in LMICs, particularly the richest. To achieve universal health coverage, including adequate quality care, it is imperative to understand this sector, starting with improved data collection on healthcare provision.


Biocompatibility and tissue integration of a novel shape memory surgical mesh for ventral hernia: in vivo animal studies.
Approximately 400,000 ventral hernia repair surgeries are performed each year in the United States. Many of these procedures are performed using laparoscopic minimally invasive techniques and employ the use of surgical mesh. The use of surgical mesh has been shown to reduce recurrence rates compared to standard suture repairs. The placement of surgical mesh in a ventral hernia repair procedure can be challenging, and may even complicate the procedure. Others have attempted to provide commercial solutions to the problems of mesh placement, but these have not been well accepted by the clinical community. In this article, two versions of shape memory polymer (SMP)-modified surgical mesh, and unmodified surgical mesh, were compared by performing laparoscopic manipulation in an acute porcine model. Also, SMP-integrated polyester surgical meshes were implanted in four rats for 30-33 days to evaluate chronic biocompatibility and capacity for tissue integration. Porcine results show that the modified mesh provides a controlled, temperature-activated, automated deployment when compared to an unmodified mesh. In rats, results indicate that implanted SMP-modified meshes exhibit exceptional biocompatibility and excellent integration with surrounding tissue with no noticeable differences from the unmodified counterpart. This article provides further evidence that an SMP-modified surgical mesh promises reduction in surgical placement time and that such a mesh is not substantially different from unmodified meshes in chronic biocompatibility.


Further benefits by early start of HIV treatment in low income countries: survival estimates of early versus deferred antiretroviral therapy.
International HIV guidelines have recently shifted from a medium-late to an early-start treatment strategy. As a consequence, more people will be eligible to Highly Active Antiretroviral Therapy (HAART). We estimate mean life years gained using different treatment indications in low income countries. We carried out a systematic search to identify relevant studies on the treatment effect of HAART. Outcome from identified observational studies were combined in a pooled-analyses and we apply these data in a Markov life cycle model based on a hypothetical Tanzanian HIV population. Survival for three different HIV populations with and without any treatment is estimated. The number of patients included in our pooled-analysis is 35,047. Providing HAART early when CD4 is 200-350 cells/microl is likely to be the best outcome strategy with an expected net benefit of 14.5 life years per patient. The model predicts diminishing treatment benefits for patients starting treatment when CD4 counts are lower. Patients starting treatment at CD4 50-199 and <50 cells/microl have expected net health benefits of 7.6 and 7.3 life years. Without treatment, HIV patients with CD4 counts 200-350; 50-199 and < 50 cells/microl can expect to live 4.8; 2.0 and 0.7 life years respectively. This study demonstrates that HIV patients live longer with early start strategies in low income countries. Since low income countries have many constraints to full coverage of HAART, this study provides input to a more transparent debate regarding where to draw explicit eligibility criteria during further scale up of HAART.


The extraction and integration framework: a two-process account of statistical learning.
The term statistical learning in infancy research originally referred to sensitivity to transitional probabilities. Subsequent research has demonstrated that statistical learning contributes to infant development in a wide array of domains. The range of statistical learning phenomena necessitates a broader view of the processes underlying statistical learning. Learners are sensitive to a much wider range of statistical information than the conditional relations indexed by transitional probabilities, including distributional and cue-based statistics. We propose a novel framework that unifies learning about all of these kinds of statistical structure. From our perspective, learning about conditional relations outputs discrete representations (such as words). Integration across these discrete representations yields sensitivity to cues and distributional information. To achieve sensitivity to all of these kinds of statistical structure, our framework combines processes that extract segments of the input with processes that compare across these extracted items. In this framework, the items extracted from the input serve as exemplars in long-term memory. The similarity structure of those exemplars in long-term memory leads to the discovery of cues and categorical structure, which guides subsequent extraction. The extraction and integration framework provides a way to explain sensitivity to both conditional statistical structure (such as transitional probabilities) and distributional statistical structure (such as item frequency and variability), and also a framework for thinking about how these different aspects of statistical learning influence each other.


Conversion of methionine into homocysteic acid in heavily oxidized proteomics samples.
Analysis of protein oxidation is necessary in numerous areas of biochemistry, including hydroxyl radical surface mapping, oxidative stress assays, and pharmaceutical stability testing. Mass spectrometry is one of the tools most often used to identify protein oxidation products, and previous studies have attempted to identify and characterize all of the major oxidation products detected by mass spectrometry for each amino acid residue. In this note, we present evidence that in heavily oxidized protein samples, such as those produced by hydroxyl radical surface mapping, a major oxidation product of methionine is homocysteic acid. The formation of homocysteic acid from methionine was previously unrecognized in other mass spectrometric analyses, and has important implications for the analysis of oxidized samples, as well as potential implications as to the functional consequences of methionine oxidation.


Acute exercise ameliorates craving and inhibitory deficits in methamphetamine: An ERP study.
This study aimed to determine the effect of acute exercise in the potential context of non-pharmacological intervention for methamphetamine (MA)-related craving; we additionally determine its effect on the inhibitory control induced by standard and MA-related tasks according to behavioral and neuroelectric measurements among MA-dependent individuals. The present study employed a within-subjects, counterbalanced design. A total of 24 participants who met the DSM-IV criteria for MA dependence were recruited. The craving level, reaction time, and response accuracy, as well as the event-related potential (ERP) components N2 and P3, were measured following exercise and the control treatment in a counterbalanced order. The exercise session consisted of an acute stationary cycle exercise at a moderate intensity, whereas the control treatment consisted of an active reading session. The self-reported MA craving was significantly attenuated during, immediately following, and 50min after the exercise session compared with the pre-exercise ratings, whereas the craving scores at these time points following exercise were lower than those for the reading control session. Acute exercise also facilitated inhibitory performance in both the standard and MA-related Go/Nogo tasks. A larger N2 amplitude, but not a larger P3 amplitude, was observed during both tasks in the exercise session and the Nogo condition compared with the reading control session and the Go condition. This is the first empirical study to demonstrate these beneficial effects of acute aerobic exercise at a moderate intensity on MA-related craving and inhibitory control in MA-dependent individuals. These results suggest a potential role for acute aerobic exercise in treating this specific type of substance abuse.


Improper Light Curing of Bulkfill Composite Drives Surface Changes and Increases S. mutans Biofilm Growth as a Pathway for Higher Risk of Recurrent Caries around Restorations.
How dentists cure a resin-based material has deleterious effects on the material's properties and its interaction with surrounding dental tissues. Biofilm accumulation has been implicated in the pathogenesis of carious lesions around dental restorations, with its composition manifesting expressed dysbiosis in patients suffering from dental caries. To evaluate the influence of varying radiant exposure on the degree of conversion (DC%), Streptococcus mutans biofilm growth, and surface roughness of bulk-fill composites under different light-curing conditions. Two light-curing units (LCU) at 600 and 1000 mW/cm2 were used to simulate curing conditions with different angulations (∢20° and ∢35°) or 2 mm-distance displacements of the LCU tip. The radiant exposure (RE) was assessed, and the composites were analyzed for DC%. Biofilm formation was induced over the bulk-fill composites and analyzed via colony-forming units counting and scanning electron microscopy (SEM). The surface roughness was analyzed via a profilometer and SEM after biofilm formation. Curing conditions with different angulation or displacement decreased RE compared to the "optimal condition". The moderately (∢35°) angulated LCU tip and low (600 mW/cm2) radiant emittance significantly reduced the DC% (p < 0.05). The difference in DC% between the top and bottom of the composites ranged from 8 to 11% for 600 mW/cm2 and 10 to 20% for 1000 mW/cm2. Greater S. mutans biofilm and surface changes were found in composites with non-optimal RE delivery (e.g., tip displacement and angulation) (p < 0.05). Inadequate polymerization of bulk-fill composites was associated with more biofilm accumulation and surface topography changes. Overall, non-optimally performed curing procedures reduced the amount of delivered RE, which led to low DC%, more biofilm formation, and higher surface roughness. The improper light-curing of bulk-fill composites compromises their physicochemical and biological properties, which could lead to inferior clinical performance and reduced restorative treatments' longevity.


Sodium excretion and racial differences in ambulatory blood pressure patterns.
The influence of Na+ excretion and race on casual blood pressure and ambulatory blood pressure patterns was examined in a biracial sample of healthy, normotensive children and adolescents (10-18 years; n = 140). The slopes relating 24-hour urinary Na+ excretion to systolic blood pressure were different for both black and white subjects for casual blood pressure (p less than 0.001) and blood pressure during sleep (p less than 0.03). For casual blood pressure, the slope was significant for black subjects (beta = 0.17; p less than 0.001) but not for white subjects. For blood pressure during sleep, the slope was again significant for black subjects (beta = 0.08; p less than 0.01) but not for white subjects. Na+ excretion was also related to awake levels of systolic blood pressure for black subjects (beta = 0.08, r = 0.36; p less than 0.01), although the slopes for both black and white subjects were not significantly different. Further analyses indicated the results were not due to racial differences in 24-hour urinary K+ excretion. However, plasma renin activity was marginally related to Na+ excretion in white subjects (r = 0.22; p less than 0.06) but not black subjects, a finding that is consistent with previous studies. Na+ excretion was not associated with diastolic blood pressure or heart rate in either group under any condition. The results of this study support research that has demonstrated a stronger relation between Na+ handling and casual blood pressure in black subjects and extend these findings to blood pressure while the subject is both awake and asleep.


Early experience with employee choice of consumer-directed health plans and satisfaction with enrollment.
To assess the initial impact of offering consumer-defined health plan (CDHP) options on employees. A mail survey of 4,680 employees in the corporate offices of Humana Inc. in June 2001. The study was a cross-sectional mail survey of employees aged 18 and older who were eligible for health care benefits. The survey was conducted following open enrollment. The primary outcome is the choice of consumer-directed health plan or not; the secondary outcome is satisfaction with the enrollment process. Important covariates include sociodemographic characteristics (age, gender, race, educational level, exempt or nonexempt status, type of coverage), health status, health care utilization, and plan design preferences. A six-page questionnaire was mailed to the home of each employee, followed by a reminder postcard and two subsequent mailings to nonrespondents. The response rate was 66.2 percent. Seven percent selected one of the two new plan options. Because there were no meaningful differences between employees choosing either of the two new options, these groups were combined in multivariate analysis. A logistic regression modeled the likelihood of choosing the novel plan options. Those selecting the new plans were less likely to be black (odds ratio [OR] 0.46), less likely to have only Humana coverage (OR 0.30), and more likely to have single coverage (OR 1.77). They were less likely to have a chronic health problem (OR 0.56) and more likely to have had no recent medical visits (OR 3.21). They were more likely to believe that lowest premiums were the most important plan attribute (OR 2.89) and to think there were big differences in the premiums of available plans (OR 5.19). Employees in fair or poor health were more likely to have a difficult time during the online enrollment process. They were more likely to find the communications very helpful (OR 0.42) and the benefits information very understandable (OR 0.38). They were less likely to feel that they had enough time to make their enrollment decision (OR 0.47). Employees who were attracted to the new CDHP plan options valued the attributes that distinguished these plans from other choices. The shift to consumer-defined plans and to the electronic provision of information, however, requires a significant increase in the communication support for all employees, but particularly for those in fair or poor health whose information needs are the most complex and individualized.


Electron microscopy in rhinology.
In rhinology, electron microscopy has been a useful research tool for the past 15 years, but provided only a few direct clinical applications. In this review, the author's work on the human nasal mucosa and the studies of other investigators are discussed, with the emphasis on allergic reactions and disturbances of the autonomous nervous system as well as the immotile cilia syndrome.


lncRNA CCAT2 Enhanced Resistance of Glioma Cells Against Chemodrugs by Disturbing the Normal Function of miR-424.
Aggressive metastasis of tumor cells assumed a constructive role in strengthening chemoresistance of tumors, so this investigation was intended to elucidate if lncRNA CCAT2 sponging downstream miR-424 regulated chemotolerance of glioma cells by boosting metastasis of glioma cells. One hundred and twenty-eight pairs of glioma tissues and corresponding adjacent tissues were resected from glioma patients during their operation, and we also purchased a series of glioma cell lines, including U251, U87, A172 and SHG44. Furthermore, pcDNA3.1-CCAT2, si-CCAT2, miR-424 mimic and miR-424 inhibitor were transfected into SHG44 and U251 cell lines, so as to evaluate impacts of CCAT2 and miR-424 on chemosensitivity of the glioma cells. Besides, proliferation, invasion and metastasis of the cells were determined through the implementation of colony formation assay, transwell assay and scratch assay. Glioma tissues and cells were monitored with higher CCAT2 expression and lower miR-424 expression than adjacent normal tissues and NHA cell line (P<0.05). Among the glioma cell lines, the SHG44 cell line showed the strongest resistance against teniposide, temozolomide and cisplatin (P<0.05), whereas the U251 cell line was more sensitive to teniposide, temozolomide, vincristine and cisplatin than any other cell line (P<0.05). Besides, pcDNA3.1-CCAT2 and miR-424 inhibitor could enhance tolerance of glioma cell lines against drugs (P<0.05). Moreover, in-vitro transfection of si-CCAT2 and miR-424 mimic could significantly retard proliferation, invasion and migration of SHG44 and U251 cells (P<0.05), and CCAT2 was found to negatively regulate miR-424 expression by sponging it (P<0.05). In addition, CHK1 was deemed as the molecule targeted by upstream miR-424, and its overexpression can changeover the effects of miR-424 mimic on proliferation and metastasis of SHG44 and U251 cells. lncRNA CCAT2/miR-424/Chk1 axis might serve as a promising target for improving chemotherapeutic efficacies in glioma treatment.


Informal caregivers and racial/ethnic variation in health service use of stroke survivors.
We investigated the racial and ethnic variation in health service use among stroke survivors with informal caregivers in a number of Department of Veterans Affairs Medical Centers in one Veterans Integrated Service Network in the southeastern United States. We focused on the role of caregivers as an enabling factor in the use of health services. One hundred twenty-five veterans who had been hospitalized after an acute stroke, been released home, and identified an informal caregiver were enrolled in the study. Veterans and caregivers were surveyed at four time points over 12 months. Poisson multivariate regression analyses were used to model the relative risk (RR) of health service use. African Americans and Puerto Ricans were half as likely as Caucasians to use inpatient therapy services (RR = 0.522 and 0.494, respectively; p < 0.01), Puerto Ricans were less likely to be admitted to the hospital (RR = 0.689, p < 0.05), and Puerto Ricans were more likely to use outpatient services than Caucasians (RR = 1.230, p < 0.01). Stroke survivors that received more hours of informal care were associated with a higher likelihood of outpatient service use (RR = 1.01, p < 0.01). Stroke survivors living with their caregiver had a lower likelihood of inpatient therapy use (RR = 0.791, p < 0.01) and a higher likelihood of outpatient service use (RR = 1.17, p < 0.01). Greater likelihood of inpatient therapy (RR = 1.340, p < 0.01) and outpatient services (RR = 1.160, p < 0.05) was related to caregivers who received outside help. This study provides insight into the role of informal care in health service use for stroke survivors.


The role of mitochondrial DNA mutations in a Han Chinese population on sepsis pathogenesis.
Individual susceptibility to sepsis has received increasing attention in recent years, and the study of genetic variations has become a hotspot regarding sepsis pathogenesis. We, therefore, investigated the association between mitochondrial genotype and sepsis susceptibility. One hundred patients admitted with sepsis and registered by five intensive care units (ICUs) in the People's Liberation Army Hospital and the Beijing Aerospace Center Hospital between January 2015 and January 2016 were enrolled as a case group, and 100 healthy persons were recruited as a control group. Patients' general information was obtained, and clinical evaluations and mitochondrial sequence screening were performed. A total of 718 single nucleotide polymorphisms (SNPs) were detected in 708 loci in 100 patients. There were 1754 mutations in 456 loci in the coding region and 567 mutations were found in the RNA region. A total of 34 loci (from 40 cases) were novel mutations. A10398G (52.52%), C5178A (24.24%), C150T (17.17%), G3010A (17.17%), and T16189C (16.16%) were the most frequently observed conserved non-synonymous mutations that were differently expressed between the case and control groups (p<0.05). A5863T and C3270 deletion mutations were located on the genes encoding tRNATyr and tRNALeu, respectively. Small changes in the tRNA gene were likely to result in protein level changes. We suggest that mitochondrial SNPs may be associated with the pathogenesis of sepsis.


TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function.
While TGFβ signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFβ appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFβ pathway, we first generated mouse models of neoplastic disease with TGFβ receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFβ led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFβ-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFβ-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFβ signals, yet may also contribute to detrimental TGFβ signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFβ-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFβ and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFβ-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFβ, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFβ-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFβ signaling.


Effect of Anabolic-Androgenic Steroid Abuse on the Contact Activation System.
The effect of anabolic-androgenic steroid (AAS) abuse on the contact activation system (CAS) is not known in detail. We hypothesized that current AAS abuse reduces the kallikrein-generating capacity of CAS significantly and investigated the impact of AAS on the proteins and capacity of CAS in current and former AAS abusers and healthy age-matched controls. Men 18 to 50 years of age were included as current AAS abusers, former AAS abusers, or controls. Blood samples were collected after overnight fasting. Kallikrein generation (lag time, peak height, and endogenous kallikrein potential [EKP]), coagulation factor XII (FXII), prekallikrein, high-molecular-weight kininogen (HK), and Complement C1 esterase inhibitor (C1inh) were assessed. Groups were compared by analysis of variance or Kruskal-Wallis test and probabilities were corrected for multiple comparisons. Associations were evaluated by linear regression models. The EKP was significantly reduced in current (n = 37) AAS abusers (984 ± 328 nmol/L × min) compared with former (n = 33) abusers (1,543 ± 481 nmol/L × min) and controls (n = 30) (1,521 ± 339 nmol/L × min), p < 0.001. Current abusers had higher levels of FXII and C1inh and lower levels of prekallikrein and HK than controls, p ≤ 0.025. Stepwise regression analysis showed that EKP was associated with C1inh and prekallikrein in current AAS abusers, R 2 = 0.70, p < 0.001. We conclude that current AAS abuse reduces the kallikrein-generating capacity of CAS by increasing the concentration of C1inh and reducing the concentration of prekallikrein. These changes may contribute to the anti-inflammatory effect of testosterone.


Cardiac compression of a hepatic cyst in polycystic liver disease: A rare cause of hemodynamic instability.
Polycystic liver disease (PLD) develops due to embryonic ductal plate malformation of intrahepatic bile ducts. Cysts in the liver can range from a simple compression effect to severe liver failure. The most common complication is rupture and inflammation of cyst. It can sometimes progress to the extent of pushing the heart to the left or compressing the inferior vena cava, thereby reducing the venous return. Here, we present a case with giant liver cyst-related symptoms that caused external compression of the right ventricle and atrium. A 71-year-old female patient was admitted to our emergency department with increasing dyspnea, chest pain, and abdominal distension. Her vital signs were as follows: temperature 38°C, pulse 140 beats/min, and blood pressure 70/40 mmHg. Her abdomen was distended, and there was minimal epigastric tenderness. Hepatomegaly was also present. Posteroanterior chest radiography revealed opacity that erased the right diaphragm contour at the right inferior hemithorax. In thoracoabdominal computed tomography, the heart was deviated toward the left due to the compression of a large cystic formation located in the hepatic right lobe, pushing the diaphragm to the superior. Piperacillin/tazobactam 3 g × 4.5 g treatment was initiated, and external drainage was performed by interventional radiology. Following this procedure, significant improvement was observed in the patient's condition. Her symptoms significantly improved, and the drainage catheter was removed on the seventh day. Hepatic cysts in patients with PLD may compress adjacent structures, and cardiac compression can be life-threatening if hemodynamic instability occurs.


Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.
Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.


Guaiane sesquiterpenes from seaweed Ulva fasciata Delile and their antibacterial properties.
Two new guaiane sesquiterpene derivatives, guai-2-en-10alpha-ol (1) and guai-2-en-10alpha-methanol (2), were chromatographically purified as major constituents of the CHCl3/CH3OH (1:1, v/v) soluble fraction of Ulva fasciata. Acetylation of 2 furnished guai-2-en-10alpha-methyl methanoate (3) with acetyl group at C11 position. The structures of the compounds were elucidated using one and two-dimensional NMR and mass spectrometric analysis. Compounds 2 and 3 exhibited significant inhibition to the growth of Vibrio parahaemolyticus with minimum inhibitory concentrations of 25 and 35 microg/mL, respectively. The electronegative C10 acetyl group with high polarisability (7.02x10(-24) cm3) in 3 appeared to withdraw electron cloud from substituted cycloheptyl ring and (R)-3-methylcyclohept-1-ene moiety, thus acting as the nucleophilic center of the molecule resulting in high bioactivity.


[Method and use of intracranial cine MR imaging].
The authors introduce a dynamic, non-invasive MR method for the examination of liquorspaces and liquor flow in 221 patients. This method is suitable not only for a dynamic imaging of liquor-flow but also for the semi-quantitative evaluation of flow through the aqueduct. This later measurement can help to select the shuntresponsive NPH cases as well. Cine MR examination along with the routine protocol seems to be most helpful in the differential-diagnostics of different hydrocephalus cases.


Killer proteases and little strokes--how the things that do not kill you make you stronger.
The phenomenon of ischemic preconditioning was initially observed over 20 years ago. The basic tenant is that if stimuli are applied at a subtoxic level, cells upregulate endogenous protective mechanisms to block injury induced by subsequent stress. Since this discovery, many conserved signaling mechanisms that contribute to activation of this potent protective program have been identified in the brain. A clinical correlate of this basic research finding can be found in patients with a history of transient ischemic attack (TIA), who have a decreased morbidity after stroke. In spite of multidisciplinary efforts to design safer, more effective stroke therapies, we have thus far failed to translate our understanding of endogenous protective pathways to treatments for neurodegeneration. This review is designed to provide clinicians and basic scientists with an overview of stress biology after TIA and preconditioning, discuss new therapeutic strategies to target the protein dysfunction that follows ischemic injury, and propose enhanced biochemical profiling to identify individuals at risk of stroke after TIA. We pay particular attention to the unanticipated consequences of overly aggressive intervention after TIA in which we have found that traditional cytotoxic agents such as free radicals and apoptosis associated proteases is essential for neuroprotection and communication in the stressed brain. These data emphasize the importance of understanding the complex interplay between chaperones, apoptotic proteases including caspases, and the proteolytic degradation machinery in adaptation to neurological injury.


Notch signaling regulates myogenic regenerative capacity of murine and human mesoangioblasts.
Somatic stem cells hold attractive potential for the treatment of muscular dystrophies (MDs). Mesoangioblasts (MABs) constitute a myogenic subset of muscle pericytes and have been shown to efficiently regenerate dystrophic muscles in mice and dogs. In addition, HLA-matched MABs are currently being tested in a phase 1 clinical study on Duchenne MD patients (EudraCT #2011-000176-33). Many reports indicate that the Notch pathway regulates muscle regeneration and satellite cell commitment. However, little is known about Notch-mediated effects on other resident myogenic cells. To possibly potentiate MAB-driven regeneration in vivo, we asked whether Notch signaling played a pivotal role in regulating MAB myogenic capacity. Through different approaches of loss- and gain-of-function in murine and human MABs, we determined that the interplay between Delta-like ligand 1 (Dll1)-activated Notch1 and Mef2C supports MAB commitment in vitro and ameliorates engraftment and functional outcome after intra-arterial delivery in dystrophic mice. Furthermore, using a transgenic mouse model of conditional Dll1 deletion, we demonstrated that Dll1 ablation, either on the injected cells, or on the receiving muscle fibers, impairs MAB regenerative potential. Our data corroborate the perspective of advanced combinations of cell therapy and signaling tuning to enhance therapeutic efficaciousness of somatic stem cells.


Neopterin and beta 2-microglobulin as prognostic indices in human immunodeficiency virus type 1 infection.
The great majority of individuals with human immunodeficiency virus type 1 (HIV-1) infection presents with no signs or symptoms, or only lymphadenopathy. To initiate prophylactic measures in time it is necessary to establish risk criteria. CD4+ cell counts are significant predictors. Supplementary methods to improve the predictive information of CD4+ cell counts are still required. In addition, CD4+ cell counting is laborious, expensive, and restricted to specialized laboratories. Thus, there is also a place for more easily performed laboratory tests with similar predictive value as CD4+ cell counts. Neopterin and beta 2-microglobulin levels proved to be significant predictors of AIDS risk in HIV-1 seropositives. The predictive value of both parameters is equal to CD4+ cell counts and both markers are significant joint predictors in addition to CD4+ cell counts. Measurement of the parameters is done in serum (neopterin and beta 2-microglobulin) or urine (neopterin) specimens which reduces the risk of HIV-1 transmission compared to handling of whole-blood samples as it is required for cell counting. Although more studies are needed, especially in developing countries and in persons receiving zidovudine, it can be recommended to use neopterin and beta 2-microglobulin as additional marker to estimate AIDS risk in HIV-1 seropositive individuals. Moreover, both markers may be useful for this purpose without CD4+ cell counts if cell counting is not available.


Trichomonas vaginalis Macrophage Migration Inhibitory Factor Mediates Parasite Survival during Nutrient Stress.
Trichomonas vaginalis is responsible for the most prevalent non-viral sexually transmitted disease worldwide, and yet the mechanisms used by this parasite to establish and maintain infection are poorly understood. We previously identified a T. vaginalis homologue (TvMIF) of a human cytokine, human macrophage migration inhibitory factor (huMIF). TvMIF mimics huMIF's role in increasing cell growth and inhibiting apoptosis in human host cells. To interrogate a role of TvMIF in parasite survival during infection, we asked whether overexpression of TvMIF (TvMIF-OE) confers an advantage to the parasite under nutrient stress conditions by comparing the survival of TvMIF-OE parasites to that of empty vector (EV) parasites. We found that under conditions of serum starvation, overexpression of TvMIF resulted in increased parasite survival. Serum-starved parasites secrete 2.5-fold more intrinsic TvMIF than unstarved parasites, stimulating autocrine and paracrine signaling. Similarly, we observed that addition of recombinant TvMIF increased the survival of the parasites in the absence of serum. Recombinant huMIF likewise increased the parasite survival in the absence of serum, indicating that the parasite may use this host survival factor to resist its own death. Moreover, TvMIF-OE parasites were found to undergo significantly less apoptosis and reactive oxygen species (ROS) generation under conditions of serum starvation, consistent with increased survival being the result of blocking ROS-induced apoptosis. These studies demonstrated that a parasitic MIF enhances survival under adverse conditions and defined TvMIF and huMIF as conserved survival factors that exhibit cross talk in host-pathogen interactions.IMPORTANCE Macrophage migration inhibitory factor (MIF) is a conserved protein found in most eukaryotes which has been well characterized in mammals but poorly studied in other eukaryotes. The limited analyses of MIF proteins found in unicellular eukaryotes have focused exclusively on the effect of parasitic MIF on the mammalian host. This was the first study to assess the function of a parasite MIF in parasite biology. We demonstrate that the Trichomonas vaginalis MIF functions to suppress cell death induced by apoptosis, thereby enhancing parasite survival under adverse conditions. Our research reveals a conserved survival mechanism, shared by a parasite and its host, and indicates a role for a conserved protein in mediating cross talk in host-pathogen interactions.


Physico-chemical and bacterial evaluation of packaged drinking water marketed in delhi - potential public health implications.
Quality of drinking water is a powerful environmental determinant of health. The main objective of introduction of bottled water in the society was its better safety, taste and convenience over tap water. The present study was conducted to assess physicochemical and bacterial qualities of bottled water and sachet water which were available in various markets of Delhi. Sixteen water bottles and four water sachets were selected through stratified random sampling from various public places in Delhi and their analysis was done at National Test House, Ghaziabad. RESULTS were then compared with national (IS10500, IS14543) and international (WHO, FDA, USEPA) standards. Bottled water showed better quality than sachet water. The mean value of copper (0.0746mg/l) in bottles exceeded the standard values of IS10500 and IS14543(0.05), while the mean value of lead (0.008mg/l) exceeded the FDA standard value (0.005). When the results of sachets were compared with those of standards, the mean values of selenium (0.1195mg/l) and lead (0.862mg/l) were found to exceed values of both Indian and International standards. For the biological parameter i.e. coliform count, the mean value for bottles was 0 (nil), whereas the mean value for sachets was 16.75, which showed the unhealthy nature of sachets. The parameters which were tested in the present study showed excess of various chemical and bacterial parameters in drinking water, which could pose serious threats to consumers. Thus, these results suggest a more stringent standardization of bottled water market with special attention to quality, identity and licensing by concerned authorities, to safeguard health of consumers.


Body composition in 18- to 88-year-old adults--comparison of multifrequency bioimpedance and dual-energy X-ray absorptiometry.
This study compared bioimpedance analysis (BIA) in the assessment of body composition with dual-energy X-ray absorptiometry (DXA) in 18- to 88-year-old adults. Body composition of 882 adults was estimated by eight-polar BIA and DXA. In addition, estimates of lean mass, fat mass, and percentage of fat were investigated across a range of age and leisure time physical activity (LTPA) groups. Compared to DXA, larger lean masses (mean difference 2.9 and 1.6 kg) and smaller fat masses (3.1 and 2.6 kg) were estimated by BIA in both women and men, respectively. Differences between the methods' mean values were evident in all age and LTPA groups, except in the oldest men (over 70 years). Age, waist circumference, grip strength, and LTPA explained 21% or less of the variance observed in the differences between methods. Compared to DXA, BIA provided systematically different body composition estimates throughout the adult age span with considerable amount of intraindividual variation. The differences between estimates may be related to the BIAs' algorithm or body geometry or composition of the population used in this study. Knowledge about the methodological limitations and device comparability is essential for researchers, clinicians, and persons working in rehabilitation and sport centers.


Salivary gland tumors. Fine-needle aspiration vs frozen-section diagnosis.
We examined the relative accuracy of fine-needle aspiration biopsy (FNAB) and frozen section (FS) in the diagnosis of salivary gland tumors; FNAB completely and accurately diagnosed 35 (88%) of 40 cases, including ten (100%) of ten nonneoplastic lesions, 20 (87%) of 23 benign, and five (71%) of seven malignant tumors. No complications were encountered with this procedure. These results compare favorably with previously published reports. Twenty-one of 40 tumors diagnosed by FNAB and FS at surgery. Sixteen (76%) of 21 of these were correctly diagnosed by FNAB, and 15 (71%) of 21 by FS. Cystic lesions gave the most diagnostic difficulties both on FNAB and FS. Worldwide, FNAB has been demonstrated to be a cost-effective, accurate, and safe procedure. Furthermore, the use of FNAB allows for better preoperative management and overall treatment planning.


Echocardiographic assessment of left ventricular filling characteristics after mitral valve replacement with the St Jude medical prosthesis.
The major cause of late mortality and morbidity after prosthetic valve replacement is thromboembolism. The nidus for initiation of thrombus formation has been blood metal interfaces, and a new valve--the St Jude prosthesis--has therefore been developed without any metal components. We have assessed echocardiographically in 27 patients the effects of this valve on left ventricular filling characteristics when inserted in the mitral position and compared the findings with those in patients having mitral valve replacement with Starr-Edwards or Björk-Shiley prostheses and with those in patients undergoing repair of the native mitral valve. Echocardiograms were recorded and digitised. Measurements were made of the peak rate of increase of dimension (dD/dt) and duration of rapid filling. Values for the St Jude valve were 13.2 +/- 3.4 cm/s and 160 +/- 40 ms, respectively. The peak rate of dD/dt increase was significantly greater than with either the Björk-Shiley valve or the Starr-Edwards valve and was comparable with findings in mitral valve repair. The duration of the rapid filling phase was not significantly different from control values but was less than that of the Starr-Edwards valve. This study indicates that the new St Jude medical valve is less obstructive than either the Björk-Shiley or Starr-Edwards prostheses. This together with its low thrombogenicity suggests that further trials of this new valve should be undertaken.


Benefits realization management in the context of a national digital transformation initiative in English provider organizations.
The Global Digital Exemplar (GDE) Programme is a national initiative to promote digitally enabled transformation in English provider organizations. The Programme applied benefits realization management techniques to promote and demonstrate transformative outcomes. This work was part of an independent national evaluation of the GDE Programme. We explored how benefits realization management was approached and conceptualized in the GDE Programme. We conducted a series of 36 longitudinal case studies of provider organizations participating in the GDE Programme, 12 of which were in depth. Data collection included a combination of 628 interviews (with implementation staff in provider organizations, national programme management staff, and suppliers), 499 documents (of national and local implementation plans and lessons learned), and 190 nonparticipant observations (of national and local programme management meetings to develop insights into the broader context of benefits realization activities, tensions arising, and how these were negotiated). Data were coded drawing on a sociotechnical framework developed in related work and thematically analyzed, initially within and then across cases, with the help of NVivo 11 software. Most stakeholders broadly agreed with the rationale of benefits realization in the GDE Programme to show due diligence that public money was appropriately spent, and to develop an evidence base supporting the value of digitally enabled transformation. Differing national and local reporting purposes, however, created tensions. Central requirements, for progress reporting and tracking high-level benefits, had limited perceived local value and were seen to impose an unnecessary burden on provider organizations. This was accentuated by the lack of harmonization of reporting requirements to different stakeholders (which differed in content and timing). There were tensions between the desire for early evidence of outcomes and the slow processes of infrastructural change (which created problems of attribution of benefits to causes as benefits emerged gradually and over long timeframes), and also between reporting immediately visible local changes and showing how these flowed through to high level organization wide benefits (eg, in terms of health outcomes or cost savings/return on investment). The attempt to fulfill these diverging agendas and informational needs within a single reporting tool had limited success. These difficulties were mitigated by efforts to simplify reporting requirements and to support targeted collection of key national outcome measures. Although progress was hampered by an initial lack of benefits realization expertise in provider organizations, some providers subsequently retained these skills for their own change management purposes. There is a need to recognize the limitations and cost of benefits realization management practices in the context of healthcare digitalization where benefits may materialize over long timeframes and in unanticipated ways. Although diverse stakeholder information needs may create tensions, prior agreement about rationales for collecting information and a targeted approach to tracking local and high-level benefits may enhance local relevance, reduce perceived reporting burdens, and improve acceptance/effectiveness. A single integrated reporting mechanism is unlikely to fulfill both national and local requirements.


Paternity and Genetic Heterogeneity in the Polygynous Bat, Phyllostomus hastatus.
Wild colonies of greater spearnose bats were marked, censused regularly, and genotyped at three polymorphic allozyme loci. While adult composition of social units is very stable and strong polygyny results in marked changes in gene frequencies between generations, dispersal of offspring is sufficient to prevent significant genetic heterogeneities between social units. Kin selection cannot explain social cohesiveness in these highly social mammals.


Unidirectional influence of vision on locomotion in multimodal spatial representations acquired from navigation.
Visual and idiothetic information is coupled in forming multimodal spatial representations during navigation (Tcheang et al. in Proc Natl Acad Sci USA 108(3):1152-1157, 2011). We investigated whether idiothetic representations activate visual representations but not vice versa (unidirectional coupling) or whether these two representations activate each other (bidirectional coupling). In a virtual reality environment, participants actively rotated in place to face certain orientations to become adapted to a new vision-locomotion relationship (gain). In particular, the visual turning angle was equal to 0.7 times the physical turning angle. After adaptation, participants walked a path with a turn in darkness (idiothetic input only) or watched a video of the traversed path (visual input only). Then, the participants pointed to the origin of the path. The participants who were presented with only idiothetic input showed that their pointing responses were influenced by the new gain (adaptation effect). By contrast, the participants who were presented with only visual input did not show any adaptation effect. These results suggest that idiothetic input contributed to spatial representations indirectly via the coupling, which resulted in the adaptation effect, whereas vision alone contributed to spatial representations directly, which did not result in the adaptation effect. Hence, the coupling between vision and locomotion is unidirectional.


Complete Genome Sequence of a Staphylococcus aureus Sequence Type 612 Isolate from an Australian Horse.
Staphylococcus aureus is a serious pathogen of humans and animals. Multilocus sequence type 612 is dominant and highly virulent in South African hospitals but relatively uncommon elsewhere. We present the complete genome sequence of methicillin-resistant Staphylococcus aureus strain SVH7513, isolated from a horse at a veterinary clinic in New South Wales, Australia.


Antimicrobial screening of Mentha piperita essential oils.
Essential oils of peppermint Mentha piperita L. (Lamiaceae), which are used in flavors, fragrances, and pharmaceuticals, were investigated for their antimicrobial properties against 21 human and plant pathogenic microorganisms. The bioactivity of the oils menthol and menthone was compared using the combination of in vitro techniques such as microdilution, agar diffusion, and bioautography. It was shown that all of the peppermint oils screened strongly inhibited plant pathogenic microorganisms, whereas human pathogens were only moderately inhibited. Chemical compositions of the oils were analyzed by GC and GC/MS. Using the bioautography assay, menthol was found to be responsible for the antimicrobial activity of these oils.


Dietary Micronutrient Intake and Its Relationship with the Malnutrition-Inflammation-Frailty Complex in Patients Undergoing Peritoneal Dialysis.
The relationship between dietary patterns and the malnutrition-inflammation-frailty complex in patients undergoing peritoneal dialysis (PD) is currently unknown. Our objective was to measure dietary nutrient intake and evaluate its association with malnutrition, inflammation, and frailty. We prospectively recruited adult PD patients. We assessed their dietary nutrient intake using a food frequency questionnaire. Frailty, malnutrition, and inflammation were evaluated by validated Frailty Score (FQ), Subjective Global Assessment (SGA), and Malnutrition-Inflammation Score (MIS). A total of 209 patients were recruited for the study. Among them, 89 patients (42.6%) had an insufficient protein intake, and 104 patients (49.8%) had an insufficient energy intake. Additionally, 127 subjects were identified as frail, characterized by being older (61.9 ± 9.5 vs. 55.6 ± 12.8, p < 0.001), malnourished (SGA: 21.0 ± 2.7 vs. 22.7 ± 3.1, p < 0.001), and having a high inflammation burden (MIS: 10.55 ± 3.72 vs. 7.18 ± 3.61, p < 0.001). There was a significant correlation between dietary zinc intake and body mass index (r = 0.31, p < 0.001), SGA (r = 0.22, p = 0.01), and MIS (r = -0.22, p = 0.01). In the multivariate model, a higher dietary zinc intake predicted a higher SGA (beta 0.03, p = 0.003) and lower FQ (beta -0.38, p < 0.001) and MIS (beta -0.14, p < 0.001), indicating a better nutrition, less frail and inflamed state. A higher dietary zinc intake was also associated with a lower odds of being frail (adjusted odds ratio 0.96, p = 0.009). Dietary inadequacy and micronutrient deficiency are common among the PD population. Dietary zinc intake is independently associated with an improved nutrition, physical condition, and reduced inflammatory state.


Pulmonary Rehabilitation in COPD: A Reappraisal (2008-2012).
Chronic Obstructive Pulmonary Disease (COPD) is a complex pathological condition associated with an important reduction in physical activity and psychological problems that contribute to the patient's disability and poor health-related quality of life. Pulmonary rehabilitation is aimed to eliminate or at least attenuate these difficulties, mainly by promoting muscular reconditioning. The scope of this paper has been the analysis of the literature on pulmonary rehabilitation in COPD patients has appeared in the last five years, focusing on the principal outcomes obtained. The results demonstrate that pulmonary rehabilitation has a beneficial effect on dyspnoea relief, improving muscle strength and endurance. Moreover, pulmonary rehabilitation appears to be a highly effective and safe treatment for reducing hospital admissions mortality and improving health-related quality of life in COPD patients. It represents, therefore, a very important therapeutic option that, along with standard pharmachological therapy, can be used to obtain the best patient management. The favourable results obtained with pulmonary rehabilitation programs should stimulate researchers to improve our understanding of the mechanisms that form the basis of the beneficial effects of this therapeutic intervention. This would in turn increase the effectiveness of pulmonary rehabilitation in COPD patients.


Collective autoionization in multiply-excited systems: a novel ionization process observed in helium nanodroplets.
Free electron lasers (FELs) offer the unprecedented capability to study reaction dynamics and image the structure of complex systems. When multiple photons are absorbed in complex systems, a plasma-like state is formed where many atoms are ionized on a femtosecond timescale. If multiphoton absorption is resonantly-enhanced, the system becomes electronically-excited prior to plasma formation, with subsequent decay paths which have been scarcely investigated to date. Here, we show using helium nanodroplets as an example that these systems can decay by a new type of process, named collective autoionization. In addition, we show that this process is surprisingly efficient, leading to ion abundances much greater than that of direct single-photon ionization. This novel collective ionization process is expected to be important in many other complex systems, e.g. macromolecules and nanoparticles, exposed to high intensity radiation fields.


Balancing medical accuracy and diagnostic consequences: diagnosing medically unexplained symptoms in primary care.
Focusing on the case of medically unexplained symptoms (MUS), this article explores diagnostic classification in the absence of biomedical evidence or other strong medical warrants for diagnosis. The data are from three focus group interviews with Norwegian general practitioners (GPs) conducted in 2015, that centred on the issue of what diagnoses to use (or not) for MUS. The qualitative analysis reconstructs the logic underlying GPs' diagnostic accounts, which centred on the meaning of diagnostic categories and on anticipating how 'generalised others' would respond to those meanings (called 'diagnosing by anticipation'). The analysis suggests that GPs confer diagnoses by balancing unwarranted medical accuracy and anticipated harmful diagnostic consequences; the goal of diagnosis was finding categories in the International Classification of Primary Care that would yield acceptable results, without making a liar of the GP in the process. Drawing on the distinction between diagnosis as colligation and classification, the findings and their relevance for medical sociology are discussed. Counter to frequent descriptions as 'illness that cannot be diagnosed', the analysis shows how GPs can diagnose MUS in the bureaucratic sense of diagnosis as classification - a sense that has been missing from sociological view.


Resolving the halogen vs. hydrogen bonding dichotomy in solutions: intermolecular complexes of trihalomethanes with halide and pseudohalide anions.
Halogen- and hydrogen-bonded complexes between trihalomethanes, CHX3, and (pseudo-)halide anions, A-, co-existing in acetonitrile solutions were identified and characterized via a combination of UV-vis and NMR spectral measurements with the results of X-ray structural and computational analyses. Halogen-bonded [CHX3, A-] complexes displayed strong absorption bands in the UV range (showing Mulliken correlations with the frontier orbital energies of the interacting species) and a decreased shift of the NMR signal of trihalomethanes' protons. Hydrogen bonding led to the opposite (increased) NMR signal shift and the UV-vis absorption bands of the hydrogen-bonded [CHX3, A-] complexes were similar in intensity to those of the separate CHX3 molecules. The simultaneous multivariable treatment of the results of UV-vis and NMR titrations of CHX3 with A- anions afforded formation constants of both halogen- and hydrogen-bonded complexes between these species, which existed side-by-side in the acetonitrile solutions. The relative values of the formation constants were consistent with the magnitudes of the positive potentials on the surfaces of the halogen or hydrogen atoms if the effects of the polarization of the trihalomethanes due to the presence of the anions were taken into account.


[Identification of aerobic actinomycetes isolated from fresh water].
This paper presents the methods used for the study and identification of 172 actinomycetes strains isolated from samples of surface water and of sediments (soft water). For this analysis, two main criteria were used; the morphological and the biochemical study of the cellular constituents. A key for identification is proposed.


Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression.
High-throughput screening (HTS) assays used in drug discovery frequently use reporter enzymes such as firefly luciferase (FLuc) as indicators of target activity. An important caveat to consider, however, is that compounds can directly affect the reporter, leading to nonspecific but highly reproducible assay signal modulation. In rare cases, this activity appears counterintuitive; for example, some FLuc inhibitors, acting through posttranslational Fluc reporter stabilization, appear to activate gene expression. Previous efforts to characterize molecules that influence luciferase activity identified a subset of 3,5-diaryl-oxadiazole-containing compounds as FLuc inhibitors. Here, we evaluate a number of compounds with this structural motif for activity against FLuc. One such compound is PTC124 {3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid}, a molecule originally identified in a cell-based FLuc assay as having nonsense codon suppression activity [Welch EM, et al., Nature (2007) 447:87-91]. We find that the potency of FLuc inhibition for the tested compounds strictly correlates with their activity in a FLuc reporter cell-based nonsense codon assay, with PTC124 emerging as the most potent FLuc inhibitor (IC(50) = 7 +/- 1 nM). However, these compounds, including PTC124, fail to show nonsense codon suppression activity when Renilla reniformis luciferase (RLuc) is used as a reporter and are inactive against the RLuc enzyme. This suggests that the initial discovery of PTC124 may have been biased by its direct effect on the FLuc reporter, implicating firefly luciferase as a molecular target of PTC124. Our results demonstrate the value of understanding potential interactions between reporter enzymes and chemical compounds and emphasize the importance of implementing the appropriate control assays before interpreting HTS results.


Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial.
Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin-angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo. Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia.