Ontogenetic changes in the venom of the snake Lachesis muta stenophrys (bushmaster) from Costa Rica.
A comparative study was performed on some enzymatic and toxic activities of venoms collected from newborn, one-year old, two-years old and adult (more than five-years old) specimens of Lachesis muta stenophrys. There was an increase in lethal, hemorrhagic, edema-forming, myotoxic, proteolytic and phospholipase A2 activities of venoms as snakes aged. The venom of newborn specimens was almost devoid of toxicity. On the other hand, venom from newborn specimens showed the highest coagulant effect of human plasma. Electrophoretic and immunochemical results demonstrated conspicuous differences between venoms of different ages. Observations on the feeding behavior indicated that specimens of L. muta of different ages displayed a similar pattern, characterized by rapid strike and bite, holding the prey until they stopped their movements and swallowing them afterwards. It is concluded that venom of newborn L. muta has very low toxic and proteolytic activities and that it undergoes conspicuous changes during the first year of life.


Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor.
The viral reverse transcriptase (RT) provides an attractive target in the search for anti-HIV therapies. The nonnucleoside inhibitors (NNIs) are a diverse set of compounds (usually HIV-1 specific) that function by distorting the polymerase active site upon binding in a nearby pocket. Despite being potent and of generally low toxicity, their clinical use has been limited by rapid selection for resistant viral populations. The 2.65-A resolution structure of the complex between HIV-1 RT and the bis(heteroaryl)piperazine (BHAP) NNI, 1-(5-methanesulfonamido-1H-indol-2-yl-carbonyl)-4- [3-(1-methyl-ethylamino) pyridinyl] piperazine (U-90152), reveals the inhibitor conformation and bound water molecules. The bulky U-90152 molecule occupies the same pocket as other NNIs, but the complex is stabilized quite differently, in particular by hydrogen bonding to the main chain of Lys-103 and extensive hydrophobic contacts with Pro-236. These interactions rationalize observed resistance mutations, notably Pro-236-Leu, which occurs characteristically for BHAPs. When bound, part of U-90152 protrudes into the solvent creating a channel between Pro-236 and the polypeptide segments 225-226 and 105-106, giving the first clear evidence of the entry mode for NNIs. The structure allows prediction of binding modes for related inhibitors [(altrylamino)piperidine-BHAPs] and suggests changes to U-90152, such as the addition of a 6 amino group to the pyridine ring, which may make binding more resilient to mutations in the RT. The observation of novel hydrogen bonding to the protein main chain may provide lessons for the improvement of quite different inhibitors.


The Secretion of Toxins and Other Exoproteins of Cronobacter: Role in Virulence, Adaption, and Persistence.
: Cronobacter species are considered an opportunistic group of foodborne pathogenic bacteria capable of causing both intestinal and systemic human disease. This review describes common virulence themes shared among the seven Cronobacter species and describes multiple exoproteins secreted by Cronobacter, many of which are bacterial toxins that may play a role in human disease. The review will particularly concentrate on the virulence factors secreted by C. sakazakii, C. malonaticus, and C. turicensis, which are the primary human pathogens of interest. It has been discovered that various species-specific virulence factors adversely affect a wide range of eukaryotic cell processes including protein synthesis, cell division, and ion secretion. Many of these factors are toxins which have been shown to also modulate the host immune response. These factors are encoded on a variety of mobile genetic elements such as plasmids and transposons; this genomic plasticity implies ongoing re-assortment of virulence factor genes which has complicated our efforts to categorize Cronobacter into sharply defined genomic pathotypes.


Suicidal Ideation and Suicide Attempts in Middle-Aged Women Attending a Primary Care Center: A Cross-Sectional Study in Mexico.
Very little is known about suicide attempts in middle-aged women in Mexico. The aims of this study were to determine: 1) the prevalence of suicidal ideation and suicide attempts in middle-aged women in Durango City, Mexico; and 2) the suicide attempt prevalence association with the sociodemographic, clinical, and behavioral characteristics of the women studied. Through a cross-sectional study, 395 middle-aged women were surveyed. Suicidal ideation, suicide attempt data, and the characteristics of the women were obtained with the aid of a questionnaire. Bivariate and multivariate analyses were used to determine the association between suicide attempts and the characteristics of women. Of the 395 women (mean age: 46.97 ± 5.34 years) studied, 50 (12.7%) had suicide ideation, and 20 (5.1%) had suicide attempts. The number of suicide attempts among these 20 women varied from 1 to 10 times. The most frequent method used for suicide attempt was intake of medicaments (in 11 women). None of the sociodemographic characteristics was associated with suicide attempts. Women with suicide ideation, abdominal pain frequently, and reflexes impairment had a significantly higher frequency of suicide attempts than those without these characteristics. Logistic regression of behavioral variables showed that only the variable alcohol consumption was independently associated with suicide attempts (odds ratio = 2.82; 95% confidence interval: 1.01 - 7.84; P = 0.04). Results suggest that suicidal ideation and suicide attempts are prevalent among women of middle-age attending a public primary care center in Durango City. This is the first report of an association between suicide attempts and reflexes impairment. Factors associated with suicide attempts found in this study may help in the design of preventive measures against suicide.


Family analysis of malaria infection in Dienga, Gabon.
Fifty children from 9 families were enrolled in a longitudinal study of 8 months to evaluate individual levels of Plasmodium falciparum density in blood during asymptomatic infections. Individual parasite densities were adjusted for age and date of blood intake. The arithmetic means of these adjusted parasite densities (MAPD) were not influenced by sickle cell trait nor by G6PD enzyme activity. On the contrary, family analysis revealed the presence of similar MAPD values according to the sibships. Moreover, sibships frequently infected with P. malariae exhibited the highest P. falciparum MAPDs. The difference in aggressiveness of malaria vectors between the northern and southern halves of the village did not explain the distribution of MAPD, nor did it explain the differences in mean frequency of P. malariae infection among the sibships. We conclude that the familial characteristic of susceptibility to both P. falciparum and P. malariae infections is more likely influenced by the host's genetic background than by differences in the levels of malaria transmission.


Irregular activity arises as a natural consequence of synaptic inhibition.
Irregular neuronal activity is observed in a variety of brain regions and states. This work illustrates a novel mechanism by which irregular activity naturally emerges in two-cell neuronal networks featuring coupling by synaptic inhibition. We introduce a one-dimensional map that captures the irregular activity occurring in our simulations of conductance-based differential equations and mathematically analyze the instability of fixed points corresponding to synchronous and antiphase spiking for this map. We find that the irregular solutions that arise exhibit expansion, contraction, and folding in phase space, as expected in chaotic dynamics. Our analysis shows that these features are produced from the interplay of synaptic inhibition with sodium, potassium, and leak currents in a conductance-based framework and provides precise conditions on parameters that ensure that irregular activity will occur. In particular, the temporal details of spiking dynamics must be present for a model to exhibit this irregularity mechanism and must be considered analytically to capture these effects.


[Allergic drug reactions].
This review addresses the most recent published literature regarding drug allergy, in order to provide physicians with a background for a better understanding of this problem of great relevance for public health. The sources of data for obtaining the original and review articles published in the last 10 years were MEDLINE, Pubmed and Lilacs. The articles chosen for this review relate drug allergy to immunological mechanisms, epidemiology, clinical and laboratory evaluation, skin lesions, clinical management, and re-exposure to the drug. Allergic reactions represent one third of adverse drug reactions. They are considered rare but with high morbimortality. Gell and Coombs' definition has been useful for classifying some types of drug allergic reactions; however, some still remain without classification because of poor knowledge of the mechanisms involved. The existence of T cell subpopulations with diverse characteristics reveals the complexity of the subject and, at the same time, elucidates several questions raised about it. It was recently postulated a new concept of chemically inert drug presentation to T cells, restricted to the major histocompatibility complex, but in a non-covalent and labile way. In clinical practice, without adequate laboratory tests, it is difficult to correlate clinical symptoms and immunological mechanisms. In vitro and in vivo skin tests have been employed in cases of suspected drug allergy reaction. However, there are very few commercially available reagents. Drug allergy constitutes an important problem in adverse drug reactions because of its potential of morbidity and mortality. It is necessary to emphasize the relevance of pharmacovigilance during treatment of patients, as well as the identification of possible immunological mechanisms involved in the events, through laboratory tests and detailed history and clinical evaluation.


Comparison of urine protein profiles in cats without urinary tract disease and cats with idiopathic cystitis, bacterial urinary tract infection, or urolithiasis.
To characterize and compare the urine protein content in cats without urinary tract disease and cats with idiopathic cystitis (IdC), bacterial urinary tract infection (UTI), or urolithiasis. Control cats (n = 18) and cats with IdC (18), UTI (12), and urolithiasis (12) from which urine samples were obtained and 2 cats with obstructive IdC and 4 additional control cats from which postmortem urinary bladder biopsy specimens were obtained. Protein contents in urine samples obtained via cystocentesis or catheterization were measured via the Bradford method. Urine proteins were separated by means of 1-dimensional gel electrophoresis. Evaluation of fibronectin content was performed via western blotting and immunohistochemical analysis. Urinary bladder biopsy specimens were examined histologically and analyzed immunohistochemically for fibronectin. Urine fibronectin content was significantly greater in cats with IdC, compared with control cat findings. Urine fibronectin contents did not differ significantly among controls and cats with UTI or urolithiasis. Histologic examination of bladder biopsy specimens obtained from 2 cats with obstructive IdC revealed destruction of the urothelial lining of the urinary bladder and severe fibrosis; immunohistochemical analysis revealed few fluorescence signals for fibronectin, unlike findings in control bladder biopsy specimens. Results indicated that urine fibronectin content in cats with IdC was greater than that in controls, cats with UTI, or cats with urolithiasis. In cats with IdC, increased permeability of damaged urothelium may result in detachment and leakage of fibronectin into urine. Urine fibronectin might serve as a biomarker for diagnosis of IdC in cats.


Usefulness of a cognitive behavioural and rehabilitative approach to enhance long lasting benefit after lumbar spinal stenosis and degenerative spondylolisthesis surgery. A case report.
Most spine-surgically treated patients are considered eligible for rehabilitative treatment. Unfortunately, an evidence-based consensus on the best postsurgical conservative treatment is not mentioned. In absence of a shared pathway, physical therapies, exercises, back schools, massages and other manual therapies are sometimes recommended by surgeons and clinicians. Like common low back pain, spinal problems in the postsurgical phase should be reconsidered through a bio-psycho-social model, advocating comprehensive evaluations and broader answers to patient-perceived pain, disability, and quality of life needs. The Authors report the clinical case of a 60-year-old woman, operated for lumbar spinal stenosis (LSS) and L4-L5 degenerative spondylolisthesis, early entered in a Rehabilitation Hospital Unit, undergoing rehabilitative and cognitive behavioural therapy. Physical and psychological evaluation, outcome measures, physical and psychological therapies are here illustrated. The obtained results are encouraging for pain, disability and quality of life, assessing usefulness of a bio-psycho-social approach for spine-operated patients. A randomized controlled trial for rehabilitative and cognitive behavioural postsurgical treatment for patients with lumbar spinal stenosis and degenerative spondylolisthesis is advocated to provide further evidence to approaches and results. Proper outcome measures, correct clinical relevance evaluation and adequate follow-ups are needed.


Misexpression of the white (w) gene triggers male-male courtship in Drosophila.
We report here that the general ectopic expression of a tryptophan/guanine transmembrane transporter gene, white (w), induces male-male courtship in Drosophila. Activation of a hsp-70/miniwhite (mini-w) transgene in mature males results in a marked change in their sexual behavior such that they begin to vigorously court other mature males. In transformant populations containing equal numbers of both sexes, most males participate, thus forming male-male courtship chains, circles, and lariats. Mutations that ablate the w transgene function also abolish this inducible behavior. Female sexual behavior does not appear to be altered by ectopic w expression. By contrast, when exposed to an active homosexual courtship environment, non-transformant males alter their behavior and actively participate in the male-male chaining. These findings demonstrate that, in Drosophila, both genetic and environmental factors play a role in male sexual behavior.


The psychological implications of concealing a stigma: a cognitive-affective-behavioral model.
Many assume that individuals with a hidden stigma escape the difficulties faced by individuals with a visible stigma. However, recent research has shown that individuals with a concealable stigma also face considerable stressors and psychological challenges. The ambiguity of social situations combined with the threat of potential discovery makes possessing a concealable stigma a difficult predicament for many individuals. The increasing amount of research on concealable stigmas necessitates a cohesive model for integrating relevant findings. This article offers a cognitive-affective-behavioral process model for understanding the psychological implications of concealing a stigma. It ends with discussion of potential points of intervention in the model as well as potential future routes for investigation of the model.


Diet-induced metabolic improvements in a hamster model of hypercholesterolemia are strongly linked to alterations of the gut microbiota.
The mammalian gastrointestinal microbiota exerts a strong influence on host lipid and cholesterol metabolism. In this study, we have characterized the interplay among diet, gut microbial ecology, and cholesterol metabolism in a hamster model of hypercholesterolemia. Previous work in this model had shown that grain sorghum lipid extract (GSL) included in the diet significantly improved the high-density lipoprotein (HDL)/non-HDL cholesterol equilibrium (T. P. Carr, C. L. Weller, V. L. Schlegel, S. L. Cuppett, D. M. Guderian, Jr., and K. R. Johnson, J. Nutr. 135:2236-2240, 2005). Molecular analysis of the hamsters' fecal bacterial populations by pyrosequencing of 16S rRNA tags, PCR-denaturing gradient gel electrophoresis, and Bifidobacterium-specific quantitative real-time PCR revealed that the improvements in cholesterol homeostasis induced through feeding the hamsters GSL were strongly associated with alterations of the gut microbiota. Bifidobacteria, which significantly increased in abundance in hamsters fed GSL, showed a strong positive association with HDL plasma cholesterol levels (r = 0.75; P = 0.001). The proportion of members of the family Coriobacteriaceae decreased when the hamsters were fed GSL and showed a high positive association with non-HDL plasma cholesterol levels (r = 0.84; P = 0.0002). These correlations were more significant than those between daily GSL intake and animal metabolic markers, implying that the dietary effects on host cholesterol metabolism are conferred, at least in part, through an effect on the gut microbiota. This study provides evidence that modulation of the gut microbiota-host metabolic interrelationship by dietary intervention has the potential to improve mammalian cholesterol homeostasis, which has relevance for cardiovascular health.


What is the role of a case manager in community aged care? A qualitative study in Australia.
This study aimed to explore the perceptions of case managers about their roles in providing community aged care in Australia. Purposeful sampling was used and 33 qualitative semi-structured interviews with 47 participants were conducted. Participants were drawn from a list of all case managers working in aged care organisations that provided publicly funded case-managed community aged care programmes in the State of Victoria, Australia. Participant selection criteria included age, gender, job titles, professional backgrounds, practice locations, organisational attributes and organisational size. Data collection was implemented between September 2012 and March 2013. Thematic analysis was performed. Participants believed that case managers performed diverse roles based on clients' needs. They also articulated 16 important roles of case managers, including advisors, advocates, carers, communicators, co-ordinators, educators, empowering clients, engaging clients and families, liaising with people, managing budgets, navigators, negotiators, networking with people, facilitators, problem solvers and supporters. However, they were concerned about brokers, mediators and counsellors in terms of the terminology or case managers' willingness to perform these roles. Moreover, they perceived that neither gatekeepers nor direct service provision was case managers' role. The findings of this study suggest that case managers working in community aged care sectors may be more effective if they practised the 16 roles aforementioned. With the value of helping rather than obstructing clients to access services, they may not act as gatekeepers. In addition, they may not provide services directly as opposed to their peers working in medical care settings. The findings will also assist organisations to design job descriptions specifying case managers' roles and associated job responsibilities. Clear job descriptions will further benefit the organisations in staff recruitment, orientation and ongoing development, as well as facilitate case managers to set professional boundaries in the delivery of case management interventions to their clients.


A new laboratory model using bull and boar spermatozoa and fluorescent beads to assess a membrane's occlusive potential.
The objective of the present study is to assess the potential of bull and boar spermatozoa and fluorescent beads to be used as a surrogate cell model to determine the cell occlusive potential in vitro using membranes of standardized porosities. A two-chamber model system consisting of upper and lower chambers, which could be separated by membranes, was constructed. Isopore polycarbonate membranes with different standardized pore diameters were used to assess the mobile cellular penetration behavior of spermatozoa or the more passive non-cellular permeability of fluorescent particles (beads) of different diameter and color. In a first experiment, spermatozoa were placed in the lower chamber, whereas semen extender only was placed in the upper chamber. After 10 min of incubation at 37 °C, the sperm number was assessed in the latter. In a second experiment, a bead solution was drawn through resorbable collagen membranes from the upper into the lower chamber by vacuum using a syringe and bead number and size was analyzed by flow cytometry. All experiments were carried out in triplicates. A non-porous polyester membrane was used as negative control to assess the overall tightness of the setup. Boar and bull spermatozoa had average cell body lengths and widths of 9 × 5 μm and were unable to pass through pores ≤2 μm, whereas they were detectable at pore sizes ≥3 μm. Their number increased with increasing pore diameters, i.e., from minimal concentrations of 0.1 × 106/ml for boar and 0.5 × 106/ml for bull spermatozoa at 3 μm to maximal concentrations of 2.1 × 106/ml for boar and 13.1 × 106/ml for bull spermatozoa at 8 μm. The fluorescent beads followed the expected pattern of permeability reliably correlating bead and pore diameter. Within the limitations of this laboratory study and the xenogeneic cell surrogate material, the model allows to easily assess cell and particle penetration through porous structures like membranes. We hope to further assess, improve, and validate this model, which we aim to use for the screening of dental membranes after being exposed to different degradation methods. Convenient and rapid test procedures to evaluate membranes for regenerative procedures are still warranted.


Genome-wide identification of soybean microRNAs and their targets reveals their organ-specificity and responses to phosphate starvation.
Phosphorus (P) plays important roles in plant growth and development. MicroRNAs involved in P signaling have been identified in Arabidopsis and rice, but P-responsive microRNAs and their targets in soybean leaves and roots are poorly understood. Using high-throughput sequencing-by-synthesis (SBS) technology, we sequenced four small RNA libraries from leaves and roots grown under phosphate (Pi)-sufficient (+Pi) and Pi-depleted (-Pi) conditions, respectively, and one RNA degradome library from Pi-depleted roots at the genome-wide level. Each library generated ~21.45-28.63 million short sequences, resulting in ~20.56-27.08 million clean reads. From those sequences, a total of 126 miRNAs, with 154 gene targets were computationally predicted. This included 92 new miRNA candidates with 20-23 nucleotides that were perfectly matched to the Glycine max genome 1.0, 70 of which belong to 21 miRNA families and the remaining 22 miRNA unassigned into any existing miRNA family in miRBase 18.0. Under both +Pi and -Pi conditions, 112 of 126 total miRNAs (89%) were expressed in both leaves and roots. Under +Pi conditions, 12 leaf- and 2 root-specific miRNAs were detected; while under -Pi conditions, 10 leaf- and 4 root-specific miRNAs were identified. Collectively, 25 miRNAs were induced and 11 miRNAs were repressed by Pi starvation in soybean. Then, stem-loop real-time PCR confirmed expression of four selected P-responsive miRNAs, and RLM-5' RACE confirmed that a PHO2 and GmPT5, a kelch-domain containing protein, and a Myb transcription factor, respectively are targets of miR399, miR2111, and miR159e-3p. Finally, P-responsive cis-elements in the promoter regions of soybean miRNA genes were analyzed at the genome-wide scale. Leaf- and root-specific miRNAs, and P-responsive miRNAs in soybean were identified genome-wide. A total of 154 target genes of miRNAs were predicted via degradome sequencing and computational analyses. The targets of miR399, miR2111, and miR159e-3p were confirmed. Taken together, our study implies the important roles of miRNAs in P signaling and provides clues for deciphering the functions for microRNA/target modules in soybean.


Decayed and missing teeth and oral-health-related factors: predicting depression in homeless people.
The objective of the study was to determine the effect of dental health status, dental anxiety and oral-health-related quality of life (OHRQoL) upon homeless people's experience of depression. A cross-sectional survey was conducted on a sample of homeless people in seven National Health Service Boards in Scotland. All participants completed a questionnaire to assess their depression, dental anxiety and OHRQoL using reliable and valid measures. Participants had an oral examination to assess their experience of tooth decay (decayed and missing teeth). Latent variable path analysis was conducted to determine the effects of dental health status on depression via dental anxiety and OHRQoL using intensive resampling methods. A total of 853 homeless people participated, of which 70% yielded complete data sets. Three latent variables, decayed and missing teeth, dental anxiety (Modified Dental Anxiety Scale: five items) and depression (Center for Epidemiological Studies Depression Scale: two factors), and a single variable for OHRQoL (Oral Health Impact Profile total scale) were used in a hybrid structural equation model. The variable decayed and missing teeth was associated with depression through indirect pathways (total standardised indirect effects=0.44, P<.001), via OHRQoL and dental anxiety (χ²=75.90, df=40, comparative fit index=0.985, Tucker-Lewis index=0.977, root mean square error of approximation=0.051 [90% confidence interval: 0.037-0.065]). Depression in Scottish homeless people is related to dental health status and oral-health-related factors. Decayed and missing teeth may influence depression primarily through the psychological constructs of OHRQoL and, to a lesser extent, dental anxiety.


Association between serum levels of reactive nitrogen intermediates and coma in children with cerebral malaria in Papua New Guinea.
Serum levels of reactive nitrogen intermediates (RNI; nitrate plus nitrite) were measured in 92 patients with cerebral malaria in the Madang Province of Papua New Guinea. RNI levels were compared to disease severity and clinical outcome, and correlated with both the depth of coma on admission and its duration. Median levels were higher among children with deeper coma than among those with lighter coma (35.6 microM vs. 16.7 microM; P = 0.008) and also among children with longer duration of coma (72 h; 59.3 microM vs. 19.3 microM; P = 0.004). RNI levels also correlated with clinical outcome, fatal cases having significantly higher RNI levels than survivors (41.2 microM vs. 18.5 microM; P = 0.014). Thus, high RNI levels are associated with indices of disease severity and may predict outcome in children with cerebral malaria. These data are consistent with the hypothesis that nitric oxide is involved in the pathogenesis of coma in human cerebral malaria.


The reduced activity of PP-1α under redox stress condition is a consequence of GSH-mediated transient disulfide formation.
Heart failure is the most common cause of morbidity and hospitalization in the western civilization. Protein phosphatases play a key role in the basal cardiac contractility and in the responses to β-adrenergic stimulation with type-1 phosphatase (PP-1) being major contributor. We propose here that formation of transient disulfide bridges in PP-1α might play a leading role in oxidative stress response. First, we established an optimized workflow, the so-called "cross-over-read" search method, for the identification of disulfide-linked species using permutated databases. By applying this method, we demonstrate the formation of unexpected transient disulfides in PP-1α to shelter against over-oxidation. This protection mechanism strongly depends on the fast response in the presence of reduced glutathione. Our work points out that the dimerization of PP-1α involving Cys39 and Cys127 is presumably important for the protection of PP-1α active surface in the absence of a substrate. We finally give insight into the electron transport from the PP-1α catalytic core to the surface. Our data suggest that the formation of transient disulfides might be a general mechanism of proteins to escape from irreversible cysteine oxidation and to prevent their complete inactivation.


Unraveling the flavin-catalyzed photooxidation of benzylic alcohol with transient absorption spectroscopy from sub-pico- to microseconds.
Flavin-mediated photooxidations have been described for applications in synthetic organic chemistry for some time and are claimed to be a route to the use of solar energy. We present a detailed investigation of the involved photophysical and photochemical steps in methoxybenzyl alcohol oxidation on a timescale ranging from sub-picoseconds to tens of microseconds. The results establish the flavin triplet state as the key intermediate for the photooxidation. The initial step is an electron transfer from the alcohol to the triplet state of the flavin catalyst with (3)k(ET)≈ 2 × 10(7) M(-1) s(-1), followed by a proton transfer in ∼6 μs. In contrast, the electron transfer involving the singlet state of flavin is a loss channel. It is followed by rapid charge recombination (τ = 50 ps) without significant product formation as seen when flavin is dissolved in pure benzylic alcohol. In dilute acetonitrile/water solutions of flavin and alcohol the electron transfer is mostly controlled by diffusion, though at high substrate concentrations >100 mM we also find a considerable contribution from preassociated flavin-alcohol-aggregates. The model including a productive triplet channel and a competing singlet loss channel is confirmed by the course of the photooxidation quantum yield as a function of substrate concentration: We find a maximum quantum yield of 3% at 25 mM of benzylic alcohol and significantly smaller values for both higher and lower alcohol concentrations. The observations indicate the importance to perform flavin photooxidations at optimized substrate concentrations to achieve high quantum efficiencies and provide directions for the design of flavin photocatalysts with improved performance.


Extraction and Standardization of Patient Complaints from Electronic Medication Histories for Pharmacovigilance: Natural Language Processing Analysis in Japanese.
Despite the growing number of studies using natural language processing for pharmacovigilance, there are few reports on manipulating free text patient information in Japanese. This study aimed to establish a method of extracting and standardizing patient complaints from electronic medication histories accumulated in a Japanese community pharmacy for the detection of possible adverse drug event (ADE) signals. Subjective information included in electronic medication history data provided by a Japanese pharmacy operating in Hiroshima, Japan from September 1, 2015 to August 31, 2016, was used as patients' complaints. We formulated search rules based on morphological analysis and daily (nonmedical) speech and developed a system that automatically executes the search rules and annotates free text data with International Classification of Diseases, Tenth Revision (ICD-10) codes. The performance of the system was evaluated through comparisons with data manually annotated by health care workers for a data set of 5000 complaints. Of 5000 complaints, the system annotated 2236 complaints with ICD-10 codes, whereas health care workers annotated 2348 statements. There was a match in the annotation of 1480 complaints between the system and manual work. System performance was .66 regarding precision, .63 in recall, and .65 for the F-measure. Our results suggest that the system may be helpful in extracting and standardizing patients' speech related to symptoms from massive amounts of free text data, replacing manual work. After improving the extraction accuracy, we expect to utilize this system to detect signals of possible ADEs from patients' complaints in the future.


Results of treatment with pollen extract (Cernilton N) in chronic prostatitis and prostatodynia.
We report the results of a prospective study with the pollen extract, Cernilton N, in a dose of 1 tablet tid for 6 months for the treatment of chronic prostatitis syndrome in 90 patients. The factors documented before and after 3 and 6 months' treatment were digital rectal examination (DRE) of the prostate, uroflowmetry, bacterial studies, leucocyte counts in urine and measurement of complement C3/coeruloplasmin in the seminal fluid. The patients were divided into 2 groups: those without associated complicating factors (CFs) (n = 72) and those with complicating factors, i.e. urethral strictures, prostatic calculi, bladder neck sclerosis (n = 18). In the group without CFs, 56 (78%) had a favorable response; 26 (36%) were cured of their symptoms and signs and 30 (42%) improved significantly with an increase in flow rate, a reduction in leukocyturia in the post-prostate massage urine (VB3) and a decrease in complement C3/coeruloplasmin in the ejaculate. In the patients with CFs only 1 patient showed a response. Complicating factors should be considered in patients who fail to respond to treatment within 3 months. Cernilton N was well tolerated by 97% of patients.


Nutrition and health: guidelines for dental practitioners.
Good nutrition is vital to overall health, and poor diet and a sedentary lifestyle are major causes of morbidity and mortality worldwide. Nutritional factors are implicated in many oral and systemic diseases and conditions, including obesity, hypertension, dyslipidemia, type II diabetes, cardiovascular disease, osteoporosis, dental caries and some cancers including oral cancers. This review focuses on the evidence for the relations between key nutritional factors and health. Energy intake is related to body weight and obesity, highlighting the importance of lower-energy diets and regular physical activity for body weight maintenance and for preventing obesity. Evidence is presented for the health benefits of high quality carbohydrates, such as whole grain products, and fruits and vegetables, in reducing the risk of cardiovascular disease and cancer. The adverse effects of sugar, sweetened beverages, and trans and saturated fats on several diseases including caries, diabetes and cardiovascular disease are described. The health benefits of unsaturated fats, antioxidants, B vitamins and vitamin D in cardiovascular disease, periodontitis, cancer, and other conditions are documented. Both benefits and harmful effects of dairy product intake on health are discussed. Based on the evidence, nutritional guidelines are provided, as well as key recommendations for preventing obesity. Dentists can play a critical role in motivating and enabling healthy food choices.


Epidemiology and differential diagnosis of nasal polyps.
Chronic rhinosinusitis (CRS) is one of the most common chronic medical conditions, with a significant impact on patient quality of life. CRS is broadly classified into two groups: CRS with nasal polyposis (CRSwNP) and CRS without NP (CRSsNP). Clinically, the major subtypes of CRSwNP may be divided into eosinophilic chronic rhinosinusitis (e.g., allergic fungal rhinosinusitis and aspirin-exacerbated respiratory disease [AERD]) and nasal polyps associated with neutrophilic inflammation (e.g., cystic fibrosis [CF]). CF is characterized by mutation of the gene encoding the CF transmembrane conductance regulator. Functional endoscopic sinus surgery is usually required for most NP patients with increased frequency in patients with AERD. This study provides a review of the epidemiology and major classification of CRSwNP. A review was performed of the literature regarding different subtypes of CRSwNP. Many definitions of CRSwNP exist and estimates of prevalence vary. CRSwNP is a clinical syndrome with a heterogeneous inflammatory profile. Of the subtypes associated with eosinophilic inflammation, AERD remains the most recalcitrant to medical and surgical therapeutic interventions.


Electronic nicotine delivery systems and/or electronic non-nicotine delivery systems for tobacco smoking cessation or reduction: a systematic review and meta-analysis.
A systematic review and meta-analysis to investigate the impact of electronic nicotine delivery systems (ENDS) and/or electronic non-nicotine delivery systems (ENNDS) versus no smoking cessation aid, or alternative smoking cessation aids, in cigarette smokers on long-term tobacco use. Searches of MEDLINE, EMBASE, PsycInfo, CINAHL, CENTRAL and Web of Science up to December 2015. Randomised controlled trials (RCTs) and prospective cohort studies. Three pairs of reviewers independently screened potentially eligible articles, extracted data from included studies on populations, interventions and outcomes and assessed their risk of bias. We used the Grading of Recommendations Assessment, Development and Evaluation approach to rate overall certainty of the evidence by outcome. Three randomised trials including 1007 participants and nine cohorts including 13 115 participants proved eligible. Results provided by only two RCTs suggest a possible increase in tobacco smoking cessation with ENDS in comparison with ENNDS (RR 2.03, 95% CI 0.94 to 4.38; p=0.07; I2=0%, risk difference (RD) 64/1000 over 6 to 12 months, low-certainty evidence). Results from cohort studies suggested a possible reduction in quit rates with use of ENDS compared with no use of ENDS (OR 0.74, 95% CI 0.55 to 1.00; p=0.051; I2=56%, very low certainty). There is very limited evidence regarding the impact of ENDS or ENNDS on tobacco smoking cessation, reduction or adverse effects: data from RCTs are of low certainty and observational studies of very low certainty. The limitations of the cohort studies led us to a rating of very low-certainty evidence from which no credible inferences can be drawn. Lack of usefulness with regard to address the question of e-cigarettes' efficacy on smoking reduction and cessation was largely due to poor reporting. This review underlines the need to conduct well-designed trials measuring biochemically validated outcomes and adverse effects.


A phase II trial of erlotinib monotherapy in advanced pancreatic cancer as a first- or second-line agent.
Pancreatic adenocarcinoma carries a grim prognosis. In 2007, gemcitabine with erlotinib emerged as an appropriate treatment option for patients with advanced inoperable or metastatic disease (APC). In this phase II trial we sought to evaluate the efficacy of erlotinib monotherapy in patients with APC who had disease refractory to or ineligibility for gemcitabine-based therapy. Eligible patients who had received 0 or 1 non-EGFR inhibitor containing gemcitabine-based chemotherapy for APC were recruited prospectively and treated with erlotinib 150 mg orally daily until unacceptable toxicity or disease progression. Primary endpoint was progression-free survival (PFS). Correlations of clinical response with smoking, rash, steady-state concentration of erlotinib and its metabolite (OSI-420) as well as the nicotine metabolite cotinine were performed. The trial was terminated early for futility. Eighteen of the 34 planned subjects were recruited. Median PFS and OS were 42 and 95 days, respectively. Best response was stable disease (21%). There was a trend for improved PFS and OS in never smokers compared to current and past smokers (128.5, 39, 42 days and 173, 100, 88 days, respectively). Past/current smokers had lower steady-state concentrations of erlotinib and OSI-420 compared to never smokers. There was evidence of recent smoking exposure in 30% of patients self-identified as past smokers. Rash was infrequent, with no cases of grade III/IV rash and it was not related to treatment outcomes. Overall, erlotinib monotherapy failed to improve outcomes compared to historical controls in patients with APC after 0-1 prior systemic therapies. There was a trend for improved PFS and OS in never smokers.


LiSIs: An Online Scientific Workflow System for Virtual Screening.
Modern methods of drug discovery and development in recent years make a wide use of computational algorithms. These methods utilise Virtual Screening (VS), which is the computational counterpart of experimental screening. In this manner the in silico models and tools initial replace the wet lab methods saving time and resources. This paper presents the overall design and implementation of a web based scientific workflow system for virtual screening called, the Life Sciences Informatics (LiSIs) platform. The LiSIs platform consists of the following layers: the input layer covering the data file input; the pre-processing layer covering the descriptors calculation, and the docking preparation components; the processing layer covering the attribute filtering, compound similarity, substructure matching, docking prediction, predictive modelling and molecular clustering; post-processing layer covering the output reformatting and binary file merging components; output layer covering the storage component. The potential of LiSIs platform has been demonstrated through two case studies designed to illustrate the preparation of tools for the identification of promising chemical structures. The first case study involved the development of a Quantitative Structure Activity Relationship (QSAR) model on a literature dataset while the second case study implemented a docking-based virtual screening experiment. Our results show that VS workflows utilizing docking, predictive models and other in silico tools as implemented in the LiSIs platform can identify compounds in line with expert expectations. We anticipate that the deployment of LiSIs, as currently implemented and available for use, can enable drug discovery researchers to more easily use state of the art computational techniques in their search for promising chemical compounds. The LiSIs platform is freely accessible (i) under the GRANATUM platform at: http://www.granatum.org and (ii) directly at: http://lisis.cs.ucy.ac.cy.


Rabbit Microbiota Changes Throughout the Intestinal Tract.
To gain insight into the importance of carefully selecting the sampling area for intestinal microbiota studies, cecal and fecal microbial communities of Caldes meat rabbit were characterized. The animals involved in the study were divided in two groups according to the feed intake level they received during the fattening period; ad libitum (n = 10) or restricted to 75% of ad libitum intake (n = 11). Cecum and internal hard feces were sampled from sacrificed animals. Assessment of bacterial and archaeal populations was performed by means of Illumina sequencing of 16S rRNA gene amplicons in a MiSeq platform. A total of 596 operational taxonomic units (OTUs) were detected using QIIME software. Taxonomic assignment revealed that microbial diversity was dominated by phyla Firmicutes (76.42%), Tenericutes (7.83%), and Bacteroidetes (7.42%); kingdom Archaea was presented at low percentage (0.61%). No significant differences were detected between sampling origins in microbial diversity or richness assessed using two alpha-diversity indexes: Shannon and the observed number of OTUs. However, the analysis of variance at genus level revealed a higher presence of genera Clostridium, Anaerofustis, Blautia, Akkermansia, rc4-4, and Bacteroides in cecal samples. By contrast, genera Oscillospira and Coprococcus were found to be overrepresented in feces, suggesting that bacterial species of these genera would act as fermenters at the end of feed digestion process. At the lowest taxonomic level, 83 and 97 OTUs in feces and cecum, respectively, were differentially represented. Multivariate statistical assessment revealed that sparse partial least squares discriminant analysis (sPLS-DA) was the best approach for this purpose. Interestingly, the majority of the most discriminative OTUs selected by sPLS-DA were found to be differentially represented between sampling origins in univariate analysis. Our study provides evidence that the choice of intestinal sampling area is relevant due to important differences in some taxa's relative abundance that have been revealed between rabbits' cecal and fecal microbiota. An appropriate sampling intestinal area should be chosen in each microbiota assessment.


Climate change and ecosystems: threats, opportunities and solutions.
The rapid anthropogenic climate change that is being experienced in the early twenty-first century is intimately entwined with the health and functioning of the biosphere. Climate change is impacting ecosystems through changes in mean conditions and in climate variability, coupled with other associated changes such as increased ocean acidification and atmospheric carbon dioxide concentrations. It also interacts with other pressures on ecosystems, including degradation, defaunation and fragmentation. There is a need to understand the ecological dynamics of these climate impacts, to identify hotspots of vulnerability and resilience and to identify management interventions that may assist biosphere resilience to climate change. At the same time, ecosystems can also assist in the mitigation of, and adaptation to, climate change. The mechanisms, potential and limits of such nature-based solutions to climate change need to be explored and quantified. This paper introduces a thematic issue dedicated to the interaction between climate change and the biosphere. It explores novel perspectives on how ecosystems respond to climate change, how ecosystem resilience can be enhanced and how ecosystems can assist in addressing the challenge of a changing climate. It draws on a Royal Society-National Academy of Sciences Forum held in Washington DC in November 2018, where these themes and issues were discussed. We conclude by identifying some priorities for academic research and practical implementation, in order to maximize the potential for maintaining a diverse, resilient and well-functioning biosphere under the challenging conditions of the twenty-first century. This article is part of the theme issue 'Climate change and ecosystems: threats, opportunities and solutions'.


Impact of rest duration on Achilles tendon structure and function following isometric training.
Intervention programs are often sought to strengthen the Achilles tendon (AT) due to its high injury rate. Long rest periods between loading cycles have been found to increase collagen synthesis by tenocytes, suggesting rest duration may be important for tendon adaptation in vivo; however, exercise programs comparing long and short rest duration have not been directly compared. Fourteen adults completed a 12-week progressive training intervention; training sessions consisted of 5×10 isometric plantarflexion contractions each of 3-s duration performed at 90% of MVC three times weekly. Each leg was randomly allocated to long (LRT, 10-s rest) or short rest training (SRT, 3-s rest). We hypothesized that the leg allocated to LRT would demonstrate superior AT collagen organization compared to the leg receiving SRT, which would be related to improved biomechanical function. AT collagen organization and morphology were measured using ultrasound tissue characterization. AT properties were assessed before and after the intervention using a combination of dynamometry, ultrasound imaging, EMG, and motion capture. Contrary to our hypothesis, collagen organization did not improve following either training protocol; conversely, an unexpected decrease in echotype I proportion was seen after SRT (P<.001) but not LRT (P=.58), indicating an apparent protective effect of rest on collagen organization during isometric training. In contrast, AT adaptation was not appreciably enhanced by increasing intercycle rest duration; both protocols were equally effective at inducing significant strength gains and AT mechanical and material adaptation (P≤.001). Further research is necessary to identify optimal loading characteristics for injury prevention and rehabilitation.


Dynamic linear models guide design and analysis of microbiota studies within artificial human guts.
Artificial gut models provide unique opportunities to study human-associated microbiota. Outstanding questions for these models' fundamental biology include the timescales on which microbiota vary and the factors that drive such change. Answering these questions though requires overcoming analytical obstacles like estimating the effects of technical variation on observed microbiota dynamics, as well as the lack of appropriate benchmark datasets. To address these obstacles, we created a modeling framework based on multinomial logistic-normal dynamic linear models (MALLARDs) and performed dense longitudinal sampling of four replicate artificial human guts over the course of 1 month. The resulting analyses revealed how the ratio of biological variation to technical variation from sample processing depends on sampling frequency. In particular, we find that at hourly sampling frequencies, 76% of observed variation could be ascribed to technical sources, which could also skew the observed covariation between taxa. We also found that the artificial guts demonstrated replicable trajectories even after a recovery from a transient feed disruption. Additionally, we observed irregular sub-daily oscillatory dynamics associated with the bacterial family Enterobacteriaceae within all four replicate vessels. Our analyses suggest that, beyond variation due to sequence counting, technical variation from sample processing can obscure temporal variation from biological sources in artificial gut studies. Our analyses also supported hypotheses that human gut microbiota fluctuates on sub-daily timescales in the absence of a host and that microbiota can follow replicable trajectories in the presence of environmental driving forces. Finally, multiple aspects of our approach are generalizable and could ultimately be used to facilitate the design and analysis of longitudinal microbiota studies in vivo.


Enhanced voxelization and representation of objects with sharp details in truncated distance fields.
This paper presents a new method for voxelization of solid objects containing sharp details. Voxelization is a sampling process that transforms a continuously defined object into a discrete one represented as a voxel field. The voxel field can be used for rendering or other purposes, which often involve a reconstruction of a continuous approximation of the original object. Objects to be voxelized need to fulfill certain representability conditions; otherwise, disturbing artifacts appear during reconstruction. The method proposed here extends the traditional distance-based voxelization by an a-priori detection of sharp object details and their subsequent modification in such a way that the resulting object to be voxelized fulfills the representability conditions. The resulting discrete objects are represented by means of truncated (i.e., narrow-band) distance fields, which provide reduction of memory requirements and further processing by level set techniques. This approach is exemplified by two classes of solid objects that normally contain such sharp details: implicit solids and solids resulting from CSG operations. In both cases, the sharp details are rounded to a specific curvature dictated by the sampling distance.


High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation.
The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance. In recent years, several studies have been published that implicate subclinical chronic inflammation as an important pathogenic factor in the development of metabolic syndrome. Pro-inflammatory molecules produced by adipose tissue have been implicated in the development of insulin resistance. The present review will discuss experimental evidence showing that the metabolic syndrome, high fructose intake and low magnesium diet may all be linked to the inflammatory response. In many ways, fructose-fed rats display the changes observed in the metabolic syndrome and recent studies indicate that high-fructose feeding is associated with NADPH oxidase and renin-angiotensin activation. The production of reactive oxygen species results in the initiation and development of insulin resistance, hyperlipemia and high blood pressure in this model. In this rat model, a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration. Potential mechanisms include the priming of phagocytic cells, the opening of calcium channels, activation of N-methyl-D-aspartate (NMDA) receptors, the activation of nuclear factor-kappaB (NFkB) and activation of the renin-angiotensin system. Since magnesium deficiency has a pro-inflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the upregulation of markers of inflammation and oxidative stress.


Examining the association between patient-centered communication and provider avoidance, CAM use, and CAM-use disclosure.
Patients' perceptions of the quality of their relationships with health care providers may influence their health care-seeking behaviors and future interactions with providers, including use of conventional health care, use of complementary and alternative medicine (CAM), and disclosure of CAM use. The study examined the associations between perceived patient-centered communication and provider avoidance, CAM use, and CAM-use disclosure. This study used cross-sectional survey data from the Health Information National Trends Survey (HINTS) 3, a nationally representative survey of US adults collected between January 2008 and May 2008. Two questions asked about CAM use and CAM-use disclosure, and another asked about avoidance of doctors. For the independent variable, responses from 6 questions on patient-centered communication were averaged to create a scale score ranging from 1-4. The research team conducted multiple logistic regressions of the 3 primary outcome measures, adjusting for sociodemographic characteristics, presence or absence of a regular source of care, insurance status, frequency of visits to providers, and health status. All analyses were weighted to make the results representative of the US population aged ≥18 y. Approximately one-third of respondents (36%) had avoided seeing their doctors within the 12 mo prior to the survey. Approximately 24% had used CAM within the prior 12 mo, and 51.7% of CAM users had discussed their CAM use with their doctors. Higher levels of patient-centered communication were significantly associated with lower odds of provider avoidance (AOR=0.63; 95% CI=0.52, 0.76) and CAM use (AOR=0.60; 95% CI=0.46, 0.78) but were not associated with CAM-use disclosure. Findings suggest that patients may be more likely to avoid seeing their doctors and more likely to use CAM when they perceive low levels of patient-centered communication. Further research to understand the role of the characteristics of patient-provider relationships on provider avoidance, CAM use, and CAM-use disclosure is warranted.


Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos.
Peptide growth factors may play a role in patterning of the early embryo, particularly in the induction of mesoderm. We have explored the role of fibroblast growth factor (FGF) in early Xenopus development by expressing a dominant negative mutant form of the FGF receptor. Using a functional assay in frog oocytes, we found that a truncated form of the receptor effectively abolished wild-type receptor function. Explants from embryos expressing this dominant negative mutant failed to induce mesoderm in response to FGF. In whole embryos the mutant receptor caused specific defects in gastrulation and in posterior development, and overexpression of a wild-type receptor could rescue these developmental defects. These results demonstrate that the FGF signaling pathway plays an important role in early embryogenesis, particularly in the formation of the posterior and lateral mesoderm.


Conserved hydrophobic clusters on the surface of the Caf1A usher C-terminal domain are important for F1 antigen assembly.
The outer membrane usher protein Caf1A of the plague pathogen Yersinia pestis is responsible for the assembly of a major surface antigen, the F1 capsule. The F1 capsule is mainly formed by thin linear polymers of Caf1 (capsular antigen fraction 1) protein subunits. The Caf1A usher promotes polymerization of subunits and secretion of growing polymers to the cell surface. The usher monomer (811 aa, 90.5 kDa) consists of a large transmembrane β-barrel that forms a secretion channel and three soluble domains. The periplasmic N-terminal domain binds chaperone-subunit complexes supplying new subunits for the growing fiber. The middle domain, which is structurally similar to Caf1 and other fimbrial subunits, serves as a plug that regulates the permeability of the usher. Here we describe the identification, characterization, and crystal structure of the Caf1A usher C-terminal domain (Caf1A(C)). Caf1A(C) is shown to be a periplasmic domain with a seven-stranded β-barrel fold. Analysis of C-terminal truncation mutants of Caf1A demonstrated that the presence of Caf1A(C) is crucial for the function of the usher in vivo, but that it is not required for the initial binding of chaperone-subunit complexes to the usher. Two clusters of conserved hydrophobic residues on the surface of Caf1A(C) were found to be essential for the efficient assembly of surface polymers. These clusters are conserved between the FGL family and the FGS family of chaperone-usher systems.


Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy.
As cancer strikes, individuals vary not only in terms of factors that contribute to its occurrence and development, but as importantly, in their capacity to respond to treatment. While exciting new therapeutic options that mobilize the immune system against cancer have led to breakthroughs for a variety of malignancies, success is limited to a subset of patients. Pre-existing immunological features of both the host and the tumor may contribute to how patients will eventually fare with immunotherapy. A broad understanding of baseline immunity, both in the periphery and in the tumor microenvironment, is needed in order to fully realize the potential of cancer immunotherapy. Such interrogation of the tumor, blood, and host immune parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. To approach these opportunities for progress, the Society for Immunotherapy of Cancer (SITC) reconvened the Immune Biomarkers Task Force. Comprised of an international multidisciplinary panel of experts, Working Group 4 sought to make recommendations that focus on the complexity of the tumor microenvironment, with its diversity of immune genes, proteins, cells, and pathways naturally present at baseline and in circulation, and novel tools to aid in such broad analyses.


Hypoxia-inducible factor 3-alpha expression is associated with the stable chondrocyte phenotype.
The hypoxia-inducible factors HIF-1α and HIF-2α are important regulators of the chondrocyte phenotype but little is known about HIF-3α in cartilage. The objective of this study was to characterize HIF-3α (HIF3A) expression during chondrocyte differentiation in vitro and in native cartilage tissues. HIF3A, COL10A1, and MMP13 were quantified in mesenchymal stem cells (MSCs) and articular chondrocytes from healthy and osteoarthritic (OA) tissue in three-dimensional cultures and in human embryonic epiphyses and adult articular cartilage. HIF3A was found to have an inverse association with hypertrophic markers COL10A1 and MMP13 in chondrogenic cells and tissues. In healthy chondrocytes, HIF3A was induced by dexamethasone and increased during redifferentiation. By comparison, HIF3A expression was extremely low in chondrogenically differentiated MSCs expressing high levels of COL10A1 and MMP13. HIF3A was also lower in redifferentiated OA chondrocytes than in healthy chondrocytes. In human embryonic epiphyseal tissue, HIF3A expression was lowest in the hypertrophic zone. Distinct splice patterns were also found in embryonic cartilage when compared with adult articular cartilage and redifferentiated chondrocytes. These in vitro and in vivo findings suggest that HIF3A levels are indicative of the hypertrophic state of chondrogenic cells and one or more splice variants may be important regulators of the chondrocyte phenotype.


XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.


Smoking Dependent Alterations in Bone Formation and Inflammation Represent Major Risk Factors for Complications Following Total Joint Arthroplasty.
Numerous studies have described a correlation between smoking and reduced bone mass. This not only increases fracture risk but also impedes reconstruction/fixation of bone. An increased frequency of complications following surgery is common. Here, we investigate the effect of smoking on the clinical outcome following total joint arthroplasty (TJA). 817 patients receiving primary or revision (including clinical transfers) TJA at our level-one trauma center have been randomly interviewed twice (pre- and six months post-surgery). We found that 159 patients developed complications (infections, disturbed healing, revisions, thrombosis, and/or death). Considering nutritional status, alcohol and cigarette consumption as possible risk factors, OR was highest for smoking. Notably, mean age was significantly lower in smokers (59.2 ± 1.0a) than non-smokers (64.6 ± 0.8; p < 0.001). However, the number of comorbidities was comparable between both groups. Compared to non-smokers (17.8 ± 1.9%), the complication rate increases with increasing cigarette consumption (1⁻20 pack-years (PY): 19.2 ± 2.4% and >20 PY: 30.4 ± 3.6%; p = 0.002). Consequently, mean hospital stay was longer in heavy smokers (18.4 ± 1.0 day) than non-smokers (15.3 ± 0.5 day; p = 0.009) or moderate smokers (15.9 ± 0.6 day). In line with delayed healing, bone formation markers (BAP and CICP) were significantly lower in smokers than non-smokers 2 days following TJA. Although, smoking increased serum levels of MCP-1, OPG, sRANKL, and Osteopontin as well as bone resorption markers (TRAP5b and CTX-I) were unaffected. In line with an increased infection rate, smoking reduced 25OH vitamin D3 (immune-modulatory), IL-1β, IL-6, TNF-α, and IFN-γ serum levels. Our data clearly show that smoking not only affects bone formation after TJA but also suppresses the inflammatory response in these patients. Thus, it is feasible that therapies favoring bone formation and immune responses help improve the clinical outcome in smokers following TJA.


Progress testing: critical analysis and suggested practices.
Educators have long lamented the tendency of students to engage in rote memorization in preparation for tests rather than engaging in deep learning where they attempt to gain meaning from their studies. Rote memorization driven by objective exams has been termed a steering effect. Progress testing (PT), in which a comprehensive examination sampling all of medicine is administered repeatedly throughout the entire curriculum, was developed with the stated aim of breaking the steering effect of examinations and of promoting deep learning. PT is an approach historically linked to problem-based learning (PBL) although there is a growing recognition of its applicability more broadly. The purpose of this article is to summarize the salient features of PT drawn from the literature, provide a critical review of these features based upon the same literature and psychometric considerations drawn from the Standards for Educational and Psychological Testing and provide considerations of what should be part of best practices in applying PT from an evidence-based and a psychometric perspective.


Responsiveness and Predictive Validity of the Participation Measure-3 Domains, 4 Dimensions in Survivors of Stroke.
To examine the responsiveness and predictive validity of the Participation Measure-3 Domains, 4 Dimensions (PM-3D4D) in people receiving outpatient rehabilitation following stroke. Prospective cohort observational study. Outpatient rehabilitation settings. Volunteer patients (N=269) with stroke (mean age ± SD [y], 55.36±12.46; 70.26% male). Not applicable. The PM-3D4D was designed to measure 3 domains (Productivity, Social, and Community) and 4 dimensions (Diversity, Frequency, Desire for change, and Difficulty) of participation in individuals with rehabilitation needs. All participants completed the PM-3D4D, the Participation Assessment with Recombined Tools-Objective (PART-O), the Participation Measure for Post-Acute Care (PM-PAC), and the EuroQol-5-Dimension (EQ-5D) at the baseline assessment and again following 3 months of outpatient rehabilitation. Significant mean changes in scores were observed for most of the PM-3D4D subscales, with the largest score change observed in the Difficulty subscale (standardized response mean=0.57∼0.88). The minimal detectable change and meaningful clinically important differences were calculated for each subscale. The Frequency and Difficulty dimensions of the PM-3D4D demonstrated significantly greater responsiveness than the PART-O and PM-PAC, respectively. The baseline PM-3D4D scores, except for Desire for change subscales, were significantly correlated with the PART-O, PM-PAC, and EQ-5D scores after 3 months of rehabilitation. This study provides evidence supporting the responsiveness and predictive validity of the PM-3D4D in survivors of stroke. Among all subscales of the PM-3D4D, the Difficulty dimensional scale demonstrated the greatest responsiveness. The Desire for change dimension of the PM-3D4D showed less responsiveness, and we recommend that it be used as a goal-setting tool rather than an outcome measure. The PM-3D4D can potentially be used to predict participation outcomes and the health-related quality of life following rehabilitation interventions.


Role of Hypothalamic-pituitary-adrenal-axis in Affective Disorders: Anti-depressant and Anxiolytic Activity of Partial 5-HT1A Agonist in Adrenalectomised Rats.
Depression is a neurological disorder characterized by sad mood, loss of pleasure, agitation and retardation. Though most relevant neuronal pathophysiology is characterized by decrease in monoamine namely; serotonin (5-HT), dopamine, noradrenaline level in central areas regulating mood and behavior, it inadequately explains the exact mechanism involved. Buspirone (BUS), a partial 5-HT1A receptor agonist has shown promising anti-depressant and anxiolytic properties in various pre-clinical and clinical studies, but the molecular and cellular mechanisms are still unclear. The aim of this study was to investigate, in vivo, the role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation in pathophysiology of depression-related disorders and the anti-depressant like activity of BUS. To simulate HPA axis dysregulation, rats were subjected to bilateral adrenalectomy (ADX). We have analyzed effect of BUS (10 mg/kg, i.p.) in ADX and sham rats using open field, sucrose consumption, elevated plus maze and hyper-emotionality tests. In all animal models tested, ADX rats exhibited significant depressive and anxiogenic states while BUS was effective in reversing the psychological diseased condition developed. Taken together, these data showed a prominent role of HPA axis in depression and neuronal mechanism of BUS as anti-depressant and anxiolytic agent. Moreover, our findings suggest that BUS can be a better candidate for stress related depression and anxiety.


[Reliability of diagnoses on authorization forms for hospital admission].
The reliability of the diagnoses given on forms authorizing Hospital Admittance (AIH), financed by the official Health System, was analysed during the period January through December, 1992, in Maringá-PR, Brazil. A systematic method was used to sample 1,595 medical records of the admittances to 8 general hospitals. The diagnoses registered in the medical records were compared to those registered in the corresponding AIH forms. The level of agreement on the main diagnoses was analysed by using the Kappa test. The results of the study show that the agreement for the five leading chapters of International Classification Disease-9 (ICD-9) has ranged from k = 0.79 to k = 0.98. The agreement for the five leading groupings of diagnoses has ranged from k = 0.79 to k = 0.97. Some reasons for disagreement, such as miscoding and the hospital reimbursement system are discussed. It is also concluded that it may be possible to use the hospital admittance data of the Official Health System, according to the diagnostic chapters and groupings of the ICD-9, with some degree of confidence.


The Reliability and Validation of the Turkish Version of the Asthma Self-Management Knowledge Questionnaire.
There is no validated questionnaire in Turkish to assess asthma knowledge. In this study, we aimed to evaluate the reliability and validity of the Turkish version of the Asthma Self-Management Knowledge Questionnaire (AKQ) among asthmatic adults. The AKQ was translated into Turkish by two medical-text translators, followed by back translation and final review by two clinicians with experience in asthma management. The Turkish Asthma Self-Management Questionnaire was then applied to 202 adult asthma patients, and additional demographic and clinical features of the patients were collected for analysis. The internal reliability of the 24-item AKQ was not high (Cronbach's alpha=0.55). Tukey's test of additivity was significant (p<0.001). This result revealed that all questions are consistent and measure the same concepts. Factor analysis demonstrated a probable structure of 10 factors that together explained 63.7% of total variance in results. Intra-class reliability of the AKQ was quite high. This study shows that AKQ seems to be a suitable instrument to evaluate the effect of different components of asthma knowledge - such as triggers, medications, asthma exacerbations, and avoidance measures - in adult asthmatics.


Sprays and diffusers as indoor air fresheners: Exposure and health risk assessment based on measurements under realistic indoor conditions.
Noncombustible air fresheners are indoor air emission sources of concern. The associated health risks should be better understood. Based on 15 products (4 sprays, 6 passive diffusers, and 5 active diffusers), the health risk assessment (HRA) approach was applied to a national use survey in France and to concentrations measured in an experimental house. The targeted substances included volatile organic compounds (VOCs), carbonyls, and fine particles (PM2.5 ). Mean-use and reasonable worst-case generic scenarios were designed. No situation of concern occurred regarding chronic exposure associated with the mean use. Under the reasonable worst-case scenarios, the chronic risk could exceed selected health reference standards, mainly for acrolein (average inhaled concentration (AIC) up to 3.5 µg/m3 ), benzene (AIC up to 4 µg/m3 ), and limonene (AIC up to 8 mg/m3 ). The acute exposure, defined as a 1-h exposure, could exceed selected health standards, primarily for acrolein (up to 23 µg/m3 ) and formaldehyde (up to approximately 370 µg/m3 ). Furthermore, the 1-h average PM2.5 concentration, including ultrafine particles, could exceed 100 µg/m3 , typically for sprays. These results suggest that the highest exposures should be reduced and, as such, that the emissions of the highest-emissivity products should be lowered.


Mechanical impact of incisor loading on the primate midfacial skeleton and its relevance to human evolution.
The midfacial skeleton in the human lineage demonstrates a wide spectrum of variation that may be the consequence of different environmental and mechanical selective pressures. However, different facial configurations may develop under comparable selective regimes. For example, the Neanderthal high and projected face and the Inuit broad and flat face are hypothesized to be the consequence of (1) life in a cold climate, and (2) excessive paramasticatory stresses focused on the anterior dentition. In this study, the second of these two hypotheses is tested using finite element analyses of a monkey skull. Results indicate that incisor loading induces heavy stress in the anterior midface of macaques. Additional analyses using incremental increases in the anteroinferior tilt of the skull to simulate different magnitudes of facial projection revealed that comparable muscular force generates less stress in a less-projected face. However, the findings of our final analyses, which attempted to combine biting with the incisors and pulling with the hands, differed from the analyses that mimicked only incisor loading (without any sort of anterior pulling component). These findings suggest that shortening the face may be the most effective way to compensate for anterior dental loading but not necessarily offset the forces incurred when using the anterior dentition as a vice for various paramasticatory behaviors. Although Neanderthals may have frequently loaded their anterior dentition, countervailing selection pressures, such as the inclusion of tough foods in the diet that demanded molar grinding, may have selected for a longer face with a lower load- to lever-arm ratio.


A meta-analytic approach to examining the correlation between religion/spirituality and mental health in cancer.
Religion and spirituality (R/S) are patient-centered factors and often are resources for managing the emotional sequelae of the cancer experience. Studies investigating the correlation between R/S (eg, beliefs, experiences, coping) and mental health (eg, depression, anxiety, well being) in cancer have used very heterogeneous measures and have produced correspondingly inconsistent results. A meaningful synthesis of these findings has been lacking; thus, the objective of this review was to conduct a meta-analysis of the research on R/S and mental health. Four electronic databases were systematically reviewed, and 2073 abstracts met initial selection criteria. Reviewer pairs applied standardized coding schemes to extract indices of the correlation between R/S and mental health. In total, 617 effect sizes from 148 eligible studies were synthesized using meta-analytic generalized estimating equations, and subgroup analyses were performed to examine moderators of effects. The estimated mean correlation (Fisher z) was 0.19 (95% confidence interval [CI], 0.16-0.23), which varied as a function of R/S dimensions: affective R/S (z = 0.38; 95% CI, 0.33-0.43), behavioral R/S (z = 0.03; 95% CI, -0.02-0.08), cognitive R/S (z = 0.10; 95% CI, 0.06-0.14), and 'other' R/S (z = 0.08; 95% CI, 0.03-0.13). Aggregate, study-level demographic and clinical factors were not predictive of the relation between R/S and mental health. There was little indication of publication or reporting biases. The correlation between R/S and mental health generally was positive. The strength of that correlation was modest and varied as a function of the R/S dimensions and mental health domains assessed. The identification of optimal R/S measures and more sophisticated methodological approaches are needed to advance research.


High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008.
The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.


Quality of life after pharmacomechanical catheter-directed thrombolysis for proximal deep venous thrombosis.
After deep venous thrombosis (DVT), many patients have impaired quality of life (QOL). We aimed to assess whether pharmacomechanical catheter-directed thrombolysis (PCDT) improves short-term or long-term QOL in patients with proximal DVT and whether QOL is related to extent of DVT. The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial was an assessor-blinded randomized trial that compared PCDT with no PCDT in patients with DVT of the femoral, common femoral, or iliac veins. QOL was assessed at baseline and 1 month, 6 months, 12 months, 18 months, and 24 months using the Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms (VEINES-QOL/Sym) disease-specific QOL measure and the 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary general QOL measures. Change in QOL scores from baseline to assessment time were compared in the PCDT and no PCDT treatment groups overall and in the iliofemoral DVT and femoral-popliteal DVT subgroups. Of 692 ATTRACT patients, 691 were analyzed (mean age, 53 years; 62% male; 57% iliofemoral DVT). VEINES-QOL change scores were greater (ie, better) in PCDT vs no PCDT from baseline to 1 month (difference, 5.7; P = .0006) and from baseline to 6 months (5.1; P = .0029) but not for other intervals. SF-36 PCS change scores were greater in PCDT vs no PCDT from baseline to 1 month (difference, 2.4; P = .01) but not for other intervals. Among iliofemoral DVT patients, VEINES-QOL change scores from baseline to all assessments were greater in the PCDT vs no PCDT group; this was statistically significant in the intention-to-treat analysis at 1 month (difference, 10.0; P < .0001) and 6 months (8.8; P < .0001) and in the per-protocol analysis at 18 months (difference, 5.8; P = .0086) and 24 months (difference, 6.6; P = .0067). SF-36 PCS change scores were greater in PCDT vs no PCDT from baseline to 1 month (difference, 3.2; P = .0010) but not for other intervals. In contrast, in femoral-popliteal DVT patients, change scores from baseline to all assessments were similar in the PCDT and no PCDT groups. Among patients with proximal DVT, PCDT leads to greater improvement in disease-specific QOL than no PCDT at 1 month and 6 months but not later. In patients with iliofemoral DVT, PCDT led to greater improvement in disease-specific QOL during 24 months.


Beat-to-beat T-wave amplitude variability in the risk stratification of right ventricular outflow tract-premature ventricular complex patients.
Premature ventricular complexes (PVCs) originating from the right ventricular outflow tract (RVOT) may occasionally trigger monomorphic ventricular tachycardia (MVT), polymorphic ventricular tachycardia (PVT), or ventricular fibrillation (VF). We examined whether an analysis of the ventricular repolarization instability could differentiate PVT/VF triggered by RVOT-PVCs from benign RVOT-PVCs or MVT. We evaluated the ventricular repolarization instability as assessed by the beat-to-beat T-wave amplitude variability (TAV) using Holter recordings in patients with RVOT-PVCs but with no structural heart disease. We determined the prematurity index, defined as the ratio of the coupling interval of the first ventricular tachycardia (VT) beat or isolated PVC to the preceding R-R interval just before the VT or isolated PVC in the Holter recordings. The study patients were classified into RVOT-PVCs/MVT (n = 33) and PVT/VF (n = 10). The two groups did not differ with respect to the age, sex, and left ventricular ejection fraction. There was no significant difference in the prematurity index between the two groups (RVOT-PVCs/MVT 0.66 ± 0.16 vs. PVT/VF 0.61 ± 0.13, P = 0.60). The patients with PVT/VF had a significantly larger maximum TAV than those with RVOT-PVCs/MVT (31 ± 13 vs. 68 ± 40 µV, P < 0.001). Patients with a higher than median value of the TAV (33 µV) were at increased risk of PVT/VF vs. those with a lower than median value, after adjusting for the age and sex [9.25 (95% confidence interval: 1.27-19.2); P = 0.03]. The TAV analysis is a useful measure to identify the subset of usually benign RVOT-PVC/MVT patients prone to PVT/VF.


Microbial populations responsive to denitrification-inducing conditions in rice paddy soil, as revealed by comparative 16S rRNA gene analysis.
Rice paddy soil has been shown to have strong denitrifying activity. However, the microbial populations responsible for nitrate respiration and denitrification have not been well characterized. In this study, we performed a clone library analysis of >1,000 clones of the nearly full-length 16S rRNA gene to characterize bacterial community structure in rice paddy soil. We also identified potential key players in nitrate respiration and denitrification by comparing the community structures of soils with strong denitrifying activity to those of soils without denitrifying activity. Clone library analysis showed that bacteria belonging to the phylum Firmicutes, including a unique Symbiobacterium clade, dominated the clones obtained in this study. Using the template match method, several operational taxonomic units (OTUs), most belonging to the orders Burkholderiales and Rhodocyclales, were identified as OTUs that were specifically enriched in the sample with strong denitrifying activity. Almost one-half of these OTUs were classified in the genus Herbaspirillum and appeared >10-fold more frequently in the soils with strong denitrifying activity than in the soils without denitrifying activity. Therefore, OTUs related to Herbaspirillum are potential key players in nitrate respiration and denitrification under the conditions used.


Grace Under Pressure: a drama-based approach to tackling mistreatment of medical students.
A positive and respectful learning environment is fundamental to the development of professional identities in healthcare. Yet medical students report poor behaviour from healthcare professionals that contradict professionalism teaching. An interdisciplinary group designed and implemented a drama-based workshop series, based on applied theatre techniques, to help students develop positive professional qualities and interpersonal skills to deal with challenges in the healthcare setting. We piloted the workshops at the University of Sydney in 2015. Attendees completed evaluation questionnaires and participated in a focus group or interview. Of 30 workshop attendances, there were 29 completed questionnaires and three participants attended a focus group or interview. Workshop activities were rated as 'very good' or 'good' by 21/22 (95.5%). Thematic analysis of qualitative data highlighted the rationale for participation (to deal with bullying, prevent becoming a bully, learn social skills), workshop benefits (express emotions, learn about status dynamics and deconstructing personalities, empathy, fun), challenges (meeting participants' expectations, participants' need for further practice) and implications for medical education (need to develop awareness of others' perspectives). Our research has shown that there is momentum to challenge mistreatment in medical education. While a multipronged approach is needed to generate systemic change, this pilot offers a positive and creative innovation. It helps students improve their interpersonal skills and sense of self to deal with challenges in the healthcare setting, including mistreatment.


Body condition score and live-weight effects on milk production in Irish Holstein-Friesian dairy cows.
The objective of the present study was to quantify the relationships among body condition score (BCS; scale 1 to 5), live weight (WT) and milk production in Irish Holstein-Friesian spring calving dairy cows. Data were from 66 commercial dairy herds during the years 1999 and 2000. The data consisted of up to 9886 lactations with records for BCS or WT at least once pre-calving, or at calving, nadir or 60 days post-calving. Change in BCS and WT was also calculated between time periods. Mixed models with cow included as a random effect were used to quantify the effect of BCS and WT, as well as change in each trait, on milk yield, milk fat concentration and milk protein concentration. Significant and sometimes curvilinear associations were observed among BCS at calving or nadir and milk production. Total 305-day milk yield was greatest in cows calving at a BCS of 4.25 units. However, cows calving at a BCS of 3.50 units produced only 68 kg less milk than cows calving at a BCS of 4.25 units while cows calving at 3.25 or 3.00 BCS units produced a further 50 and 114 kg less, respectively. Cows that lost more condition in early lactation produced more milk of greater fat and protein concentration, although the trend reversed in cows that lost large amounts of condition post-calving. Milk yield increased with WT although the marginal effect decreased as cows got heavier. Milk fat and protein concentration in early lactation also increased with WT pre-calving, calving and nadir, although WT did not significantly affect average lactation milk fat concentration.


Hyperplastic Luschka ducts: a mimic of adenocarcinoma in the gallbladder fossa.
Ducts of Luschka are a developmental abnormality found within the gallbladder fossa in up to 10% of cholecystectomy specimens. They are most often encountered by surgeons when injured during laparoscopic or open cholecystectomy, leading to bile leakage and subsequent peritonitis. Histologically, they are typically composed of lobular aggregates of small ductules lined by bland, cuboidal-to-columnar biliary-type epithelium, associated with centrally located, larger ductules surrounded by concentric fibrosis. We have identified 6 cases of florid Luschka duct proliferation in which the ductules demonstrated irregular growth pattern, loss of characteristic concentric fibrosis, and epithelial atypia that strongly suggested the diagnosis of invasive pancreatobiliary adenocarcinoma or metastatic adenocarcinoma involving the gallbladder serosa. Two of the cases were initially diagnosed as invasive adenocarcinoma, whereas the other 4 were sent for consultation to rule out adenocarcinoma. All cases were associated with marked acute and chronic cholecystitis with mucosal ulceration, cholelithiasis, and thickening of the gallbladder wall. The ducts of Luschka were located within the rim of adherent liver in all 6 cases and the gallbladder serosa in 5 cases. Limited follow-up information was available for all patients with no documentation of progressive disease. Awareness and proper recognition of the anatomic location and histologic features are imperative in distinguishing florid ducts of Luschka from both non-neoplastic conditions and most importantly adenocarcinoma.


Characteristics of pneumonia deaths after an earthquake and tsunami: an ecological study of 5.7 million participants in 131 municipalities, Japan.
On 11 March 2011, the Great East Japan Earthquake struck off Japan. Although some studies showed that the earthquake increased the risk of pneumonia death, no study reported whether and how much a tsunami increased the risk. We examined the risk for pneumonia death after the earthquake/tsunami. This is an ecological study. Data on population and pneumonia deaths obtained from the Vital Statistics 2010 and 2012, National Census 2010 and Basic Resident Register 2010 and 2012 in Japan. About 5.7 million participants residing in Miyagi, Iwate and Fukushima Prefectures during 1 year after the disaster were targeted. All municipalities (n=131) were categorised into inland (n=93), that is, the earthquake-impacted area, and coastal types (n=38), that is, the earthquake-impacted and tsunami-impacted area. The number of pneumonia deaths per week was totalled from 12 March 2010 to 9 March 2012. The number of observed pneumonia deaths (O) and the sum of the sex and age classes in the observed population multiplied by the sex and age classes of expected pneumonia mortality (E) were calculated. Expected pneumonia mortality was the pneumonia mortality during the year before. Standardised mortality ratios (SMRs) were calculated for pneumonia deaths (O/E), adjusting for sex and age using the indirect method. SMRs were then calculated by coastal and inland municipalities. 6603 participants died of pneumonia during 1 year after the earthquake. SMRs increased significantly during the 1st-12th weeks. In the 2nd week, SMRs in coastal and inland municipalities were 2.49 (95% CI 2.02 to 7.64) and 1.48 (95% CI 1.24 to 2.61), respectively. SMRs of coastal municipalities were higher than those of inland municipalities. An earthquake increased the risk of pneumonia death and tsunamis additionally increased the risk.


Effect of weight loss after weight loss surgery on plasma N-terminal pro-B-type natriuretic peptide levels.
Natriuretic peptides have multiple beneficial cardiovascular effects. Previous cross-sectional studies have indicated that obese subjects have lower natriuretic peptide concentrations than those of normal weight. It is not known whether this relative natriuretic peptide deficiency is reversible with weight loss. We studied 132 obese subjects undergoing weight loss surgery with serial measurement of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations at preoperative, early (1 to 2 months), and late postoperative (6 months) points. In addition, 20 subjects also underwent echocardiography at baseline and 6 months after surgery. Significant weight loss was observed after surgery (median body mass index 45.1, 41.0, and 32.9 kg/m(2) for the 3 corresponding points, analysis of variance p <0.001). The median NT-proBNP levels increased substantially (31.6, 66.9, and 84.9 pg/ml; p <0.001). The average intrasubject increase in NT-proBNP at the 2 postoperative points was 3.4 and 5.0 times the preoperative level (p <0.001 for both points vs preoperatively). In the multivariate regression models adjusted for clinical characteristics and insulin resistance, the strongest predictor of the change in NT-proBNP level 6 months after weight loss surgery was the change in weight (p = 0.03). Echocardiography showed a mean intrasubject reduction in left ventricular mass index of 18% (p <0.001) and mild improvements in diastolic function, with no change in ejection fraction. In conclusion, we have demonstrated that weight loss is associated with early and sustained increases in NT-proBNP concentrations, despite evidence of preserved systolic and improved diastolic function. These findings suggest a direct, reversible relation between obesity and reduced natriuretic peptide levels.


The impact of race on metabolic disease risk factors in women with and without posttraumatic stress disorder.
The literature on PTSD and metabolic disease risk factors has been limited by lacking investigation of the potential influence of commonly comorbid disorders and the role of race. In this study data were provided by a sample of 134 women (63 PTSD and 71 without PTSD). Separate sets of models examining associations of psychiatric disorder classifications with metabolic disease risk factors were used. Each model included race (African American or Caucasian), psychiatric disorder, and their interaction. There was an interaction of race and PTSD on body mass index, abdominal obesity, and triglycerides. While PTSD was not generally associated with deleterious health effects in African American participants, PTSD was related to worse metabolic disease risk factors in Caucasians. MDD was associated with metabolic disease risk factors, but there were no interactions with race. Results support the importance of race in the relationship between PTSD and metabolic disease risk factors. Future research would benefit from analysis of cultural factors to explain how race might influence metabolic disease risk factors in PTSD.


Interoperability of Disease Concepts in Clinical and Research Ontologies: Contrasting Coverage and Structure in the Disease Ontology and SNOMED CT.
To contrast the coverage of diseases between the Disease Ontology (DO) and SNOMED CT, and to compare the hierarchical structure of the two ontologies. We establish a reference list of mappings. We characterize unmapped concepts in DO semantically and structurally. Finally, we compare the hierarchical structure between the two ontologies. Overall, 4478 (65%) the 6931 DO concepts are mapped to SNOMED CT. The cancer and neoplasm subtrees of DO account for many of the unmapped concepts. The most frequent differentiae in unmapped concepts include morphology (for cancers and neoplasms), specific subtypes (for rare genetic disorders), and anatomical subtypes. Unmapped concepts usually form subtrees, and less often correspond to isolated leaves or intermediary concepts. This detailed analysis of the gaps in coverage and structural differences between DO and SNOMED CT contributes to the interoperability between these two ontologies and will guide further validation of the mapping.


A brief culturally tailored intervention for Puerto Ricans with type 2 diabetes.
The information-motivation-behavioral skills (IMB) model of health behavior change informed the design of a brief, culturally tailored diabetes self-care intervention for Puerto Ricans with type 2 diabetes. Participants (n = 118) were recruited from an outpatient, primary care clinic at an urban hospital in the northeast United States. ANCOVA models evaluated intervention effects on food label reading, diet adherence, physical activity, and glycemic control (HbA1c). At follow-up, the intervention group was reading food labels and adhering to diet recommendations significantly more than the control group. Although the mean HbA1c values decreased in both groups ( 0.48% vs. 0.27% absolute decrease), only the intervention group showed a significant improvement from baseline to follow-up (p < .008), corroborating improvements in diabetes self-care behaviors. Findings support the use of the IMB model to culturally tailor diabetes interventions and to enhance patients' knowledge, motivation, and behavior skills needed for self-care.