Laboratory and field evaluation of the Partec CyFlow miniPOC for absolute and relative CD4 T-cell enumeration.
A new CD4 point-of-care instrument, the CyFlow miniPOC, which provides absolute and percentage CD4 T-cells, used for screening and monitoring of HIV-infected patients in resource-limited settings, was introduced recently. We assessed the performance of this novel instrument in a reference laboratory and in a field setting in Senegal. A total of 321 blood samples were obtained from 297 adults and 24 children, all HIV-patients attending university hospitals in Dakar, or health centers in Ziguinchor. Samples were analyzed in parallel on CyFlow miniPOC, FACSCount CD4 and FACSCalibur to assess CyFlow miniPOC precision and accuracy. At the reference lab, CyFlow miniPOC, compared to FACSCalibur, showed an absolute mean bias of -12.6 cells/mm3 and a corresponding relative mean bias of -2.3% for absolute CD4 counts. For CD4 percentages, the absolute mean bias was -0.1%. Compared to FACSCount CD4, the absolute and relative mean biases were -31.2 cells/mm3 and -4.7%, respectively, for CD4 counts, whereas the absolute mean bias for CD4 percentages was 1.3%. The CyFlow miniPOC was able to classify HIV-patients eligible for ART with a sensitivity of ≥ 95% at the different ART-initiation thresholds (200, 350 and 500 CD4 cells/mm3). In the field lab, the room temperature ranged from 30 to 35°C during the working hours. At those temperatures, the CyFlow miniPOC, compared to FACSCount CD4, had an absolute and relative mean bias of 7.6 cells/mm3 and 2.8%, respectively, for absolute CD4 counts, and an absolute mean bias of 0.4% for CD4 percentages. The CyFlow miniPOC showed sensitivity equal or greater than 94%. The CyFlow miniPOC showed high agreement with FACSCalibur and FACSCount CD4. The CyFlow miniPOC provides both reliable absolute CD4 counts and CD4 percentages even under the field conditions, and is suitable for monitoring HIV-infected patients in resource-limited settings.


An orientation-tuned component in the contrast masking of stereopsis.
A masking paradigm was used to evaluate the orientation selectivity of the mechanisms mediating human stereopsis. Two experienced and eleven naive observers viewed stereograms, spatially filtered to contain contrast energy with Gaussian passbands in spatial frequency and orientation. Using forced-choice procedures we measured contrast thresholds for stereopsis in the presence of oriented masking patterns. Our results show that the masking of stereopsis consists of two components: one is orientation dependent, the other is non-oriented and has greatest magnitude at lower spatial frequencies. Contrary to an earlier study, these results imply that stereopsis mechanisms may have similar orientation tuning to mechanisms mediating contrast detection.


Fucoidan present in brown algae induces apoptosis of human colon cancer cells.
Fucoidan is a sulfated polysaccharide found in brown algae; it has been shown to exhibit a number of biological effects, including anti-tumor effects. In this study, we evaluated the effects of fucoidan on apoptosis in HT-29 and HCT116 human colon cancer cells. HT-29 and HCT116 cells were cultured with various concentrations of fucoidan (0 - 20 microg/mL). Apoptosis was assayed via Hoechst staining and Annexin V staining followed by flow cytometric analysis. Western blot analyses and JC-1 staining were conducted to determine the levels of apoptosis-regulating proteins and mitochondrial membrane permeability, respectively. Fucoidan induced substantial reductions in viable cell numbers and apoptosis of HT-29 and HCT116 cells in a dose-dependent manner. In HT-29 cells, fucoidan also increased the levels of cleaved caspases-8, -9, -7, and -3, and cleaved poly (ADP-ribose) polymerase (PARP) levels. The levels of the X-linked inhibitor of apoptosis protein and survivin were attenuated in the fucoidan-treated cells. Fucoidan was also shown to enhance mitochondrial membrane permeability, as well as the cytochrome c and Smac/Diablo release from the mitochondria. Fucoidan increased the levels of the Bak and truncated Bid proteins, but reduced the levels of Mcl-1. Additionally, fucoidan increased the levels of the tumor necrosis factor-related apoptosis-inducing ligand, Fas and death receptor 5 proteins. The caspase-8 and -9 inhibitors Z-IETD-FMK and Z-LEHD-FMK induced a reduction in fucoidan-mediated apoptosis. Caspase-8 inhibitor inhibited the fucoidan-induced cleavage of Bid, caspases-9 and -3, and PARP. The findings of this study indicate that fucoidan induces apoptosis in HT-29 and HCT116 human colon cancer cells, and that this phenomenon is mediated via both the death receptor-mediated and mitochondria-mediated apoptotic pathways. These results suggest that fucoidan may prove useful in the development of a colon cancer-preventive protocol.


Honeybee foraging in differentially structured landscapes.
Honeybees communicate the distance and location of resource patches by bee dances, but this spatial information has rarely been used to study their foraging ecology. We analysed, for the first time to the best of the authors' knowledge, foraging distances and dance activities of honeybees in relation to landscape structure, season and colony using a replicated experimental approach on a landscape scale. We compared three structurally simple landscapes characterized by a high proportion of arable land and large patches, with three complex landscapes with a high proportion of semi-natural perennial habitats and low mean patch size. Four observation hives were placed in the centre of the landscapes and switched at regular intervals between the six landscapes from the beginning of May to the end of July. A total of 1137 bee dances were observed and decoded. Overall mean foraging distance was 1526.1 +/- 37.2 m, the median 1181.5 m and range 62.1-10037.1 m. Mean foraging distances of all bees and foraging distances of nectar-collecting bees did not significantly differ between simple and complex landscapes, but varied between month and colonies. Foraging distances of pollen-collecting bees were significantly larger in simple (1743 +/- 95.6 m) than in complex landscapes (1543.4 +/- 71 m) and highest in June when resources were scarce. Dancing activity, i.e. the number of observed bee dances per unit time, was significantly higher in complex than in simple landscapes, presumably because of larger spatial and temporal variability of resource patches in complex landscapes. The results facilitate an understanding of how human landscape modification may change the evolutionary significance of bee dances and ecological interactions, such as pollination and competition between honeybees and other bee species.


Primary signet ring cell carcinoma of the appendix: a rare case report and our 18-year experience.
Primary adenocarcinoma of the appendix is a rare malignancy that constitutes < 0.5% of all gastrointestinal neoplasms. Moreover, primary signet ring cell carcinoma of the appendix is an exceedingly rare entity. We have encountered 15 cases of primary appendiceal cancer among 3389 patients who underwent appendectomy over the past 18 years. In the present report, we describe a rare case of primary signet ring cell carcinoma of the appendix with ovarian metastases and unresectable peritoneal dissemination occurring in a 67-year-old female patient. She underwent appendectomy and bilateral salpingo-oophorectomy with a laparoscopy procedure. She then received palliative systemic chemotherapy with 12 cycles of oxaliplatin, 5-flurorouracil, and leucovorin (FOLFOX-4). The patient currently is well without progression of disease 12 mo after beginning chemotherapy.


Major histocompatibility complex class II DR and DQ evolution and variation in wild capuchin monkey species (Cebinae).
The major histocompatibility complex (MHC) is an important gene complex contributing to adaptive immunity. Studies of platyrrhine MHC have focused on identifying experimental models of immune system function in the equivalent Human Leukocyte Antigen (HLA). These genes have thus been explored primarily in captive platyrrhine individuals from research colonies. However, investigations of standing MHC variation and evolution in wild populations are essential to understanding its role in immunity, sociality and ecology. Capuchins are a promising model group exhibiting the greatest habitat diversity, widest diet breadth and arguably the most social complexity among platyrrhines, together likely resulting in varied immunological challenges. We use high-throughput sequencing to characterize polymorphism in four Class II DR and DQ exons for the first time in seven capuchin species. We find evidence for at least three copies for DQ genes and at least five for DRB, with possible additional unrecovered diversity. Our data also reveal common genotypes that are inherited across our most widely sampled population, Cebus imitator in Sector Santa Rosa, Costa Rica. Notably, phylogenetic analyses reveal that platyrrhine DQA sequences form a monophyletic group to the exclusion of all Catarrhini sequences examined. This result is inconsistent with the trans-species hypothesis for MHC evolution across infraorders in Primates and provides further evidence for the independent origin of current MHC genetic diversity in Platyrrhini. Identical allele sharing across cebid species, and more rarely genera, however, does underscore the complexity of MHC gene evolution and the need for more comprehensive assessments of allelic diversity and genome structure.


Inpatient cancer treatment: an analysis of financial and nonfinancial performance measures by hospital-ownership type.
This study uses longitudinal data of inpatient treatment from the Agency for Healthcare Research and Quality's (AHRQ's) Healthcare Cost and Utilization Project (HCUP) to examine the differences in historical trends and build future projections of charges, costs, and lengths of stay (LOS) for inpatient treatment of four of the most prevalent cancer types: breast, colon, lung, and prostate. We stratify our data by hospital ownership type and for the aforementioned four major cancer types. We use the Kruskal Wallis (nonparametric ANOVA) Test and time series models to analyze variance and build projections, respectively, for mean charges per discharge, mean costs per discharge, mean LOS per discharge, mean charges per day, and mean costs per day. We find that significant differences exist in both the mean charges per discharge and mean charges per day for breast, colon, lung, and prostate cancers and in the mean LOS per discharge for breast cancer. Additionally, we find that both mean charges and mean costs are forecast to continue increasing while mean LOS are forecast to continue decreasing over the forecast period 2008 to 2012. The methodologies we employ may be used by individual hospital systems, and by health care policy-makers, for various financial planning purposes. Future studies could examine additional financial and nonfinancial variables for these and other cancer types, test for geographic disparities, or focus on procedural-level hospital measures.


Gait assessment in Parkinson's disease: toward an ambulatory system for long-term monitoring.
An ambulatory gait analysis method using body-attached gyroscopes to estimate spatio-temporal parameters of gait has been proposed and validated against a reference system for normal and pathologic gait. Later, ten Parkinson's disease (PD) patients with subthalamic nucleus deep brain stimulation (STN-DBS) implantation participated in gait measurements using our device. They walked one to three times on a 20-m walkway. Patients did the test twice: once STN-DBS was ON and once 180 min after turning it OFF. A group of ten age-matched normal subjects were also measured as controls. For each gait cycle, spatio-temporal parameters such as stride length (SL), stride velocity (SV), stance (ST), double support (DS), and gait cycle time (GC) were calculated. We found that PD patients had significantly different gait parameters comparing to controls. They had 52% less SV, 60% less SL, and 40% longer GC. Also they had significantly longer ST and DS (11% and 59% more, respectively) than controls. STN-DBS significantly improved gait parameters. During the stim ON period, PD patients had 31% faster SV, 26% longer SL, 6% shorter ST, and 26% shorter DS. GC, however, was not significantly different. Some of the gait parameters had high correlation with Unified Parkinson's Disease Rating Scale (UPDRS) subscores including SL with a significant correlation (r = -0.90) with UPDRS gait subscore. We concluded that our method provides a simple yet effective way of ambulatory gait analysis in PD patients with results confirming those obtained from much more complex and expensive methods used in gait labs.


Cross-cultural adaptation and psychometric evaluation of the Sinhala version of Lawton Instrumental Activities of Daily Living Scale.
Instrumental activities of daily living (IADL) are cognitively complex activities related to independent living in the community. Robust IADL scales are needed, however the psychometric properties of instruments have been little evaluated. There is no validated instrument for Sri Lankan older populations. Sri Lanka has the highest proportion of older people in South Asia with rapid population ageing. Therefore, it is essential to have standard instruments to assess activity limitations. We aimed to cross-culturally adapt the original Lawton Instrumental Activities of Daily Living Scale from English to Sinhala and evaluate the psychometric properties of the Sinhala version. Cross-cultural adaptation of the instrument was performed. The instrument was validated in a sample of 702 community-dwelling older adults aged 60 years and above in Sri Lanka. Reliability (internal consistency and inter-rater reliability) was assessed. Construct validity of the scale was evaluated by performing exploratory and confirmatory factor analysis and testing convergent and divergent validity. The Lawton IADL scale was successfully adapted to Sri Lankan context. Internal consistency of the scale was very high (Cronbach's alpha = 0.91). Very good inter-rater reliability was observed with very good agreement for all items. Inter-class correlations for overall IADL score ranged from 0.57 to 0.91. Results of the exploratory and confirmatory factor analyses supported the unidimensionality of the scale. Goodness of fit indices in confirmatory factor analysis were in acceptable range (CFI = 0.98, SRMR = 0.06, NNFI = 0.97). Strength of associations were significant and in the expected direction. Results of the known group validity were also significant, confirming the convergent and divergent validity. The Lawton IADL scale was successfully translated and culturally adapted to Sinhala language. The Sinhala version demonstrated excellent reliability and construct validity. Given good psychometric properties, this scale would be recommended for use in future research.


In situ performance tests of soft-x-ray multilayer mirrors exposed to synchrotron radiation from a bending magnet.
The performance of soft-x-ray multilayer mirrors of Mo/Si, Rh/Si, and Ru/Si has been tested in situ during ~ 15-h exposure to white synchrotron radiation from a bending magnet of the Photon Factory (Tsukuba, Japan) ring. The power density on the sample surface was ~ 0.14 W/mm(2). The tests were made by measuring the intensity of the reflected beam from the test mirrors with a detector unit consisting of a carbon filter and an aluminum cathode. The detector unit served as an effective narrow-band detector for the intense radiation of 85-105 eV reflected from the test mirrors. The Mo/Si and Rh/Si multilayer mirrors were found to be quite stable against continuous irradiation, whereas the Ru/Si multilayer mirror showed a definite decrease in the reflected-beam intensity.


PRISM: An open source framework for the interactive design of GPU volume rendering shaders.
Direct volume rendering has become an essential tool to explore and analyse 3D medical images. Despite several advances in the field, it remains a challenge to produce an image that highlights the anatomy of interest, avoids occlusion of important structures, provides an intuitive perception of shape and depth while retaining sufficient contextual information. Although the computer graphics community has proposed several solutions to address specific visualization problems, the medical imaging community still lacks a general volume rendering implementation that can address a wide variety of visualization use cases while avoiding complexity. In this paper, we propose a new open source framework called the Programmable Ray Integration Shading Model, or PRISM, that implements a complete GPU ray-casting solution where critical parts of the ray integration algorithm can be replaced to produce new volume rendering effects. A graphical user interface allows clinical users to easily experiment with pre-existing rendering effect building blocks drawn from an open database. For programmers, the interface enables real-time editing of the code inside the blocks. We show that in its default mode, the PRISM framework produces images very similar to those produced by a widely-adopted direct volume rendering implementation in VTK at comparable frame rates. More importantly, we demonstrate the flexibility of the framework by showing how several volume rendering techniques can be implemented in PRISM with no more than a few lines of code. Finally, we demonstrate the simplicity of our system in a usability study with 5 medical imaging expert subjects who have none or little experience with volume rendering. The PRISM framework has the potential to greatly accelerate development of volume rendering for medical applications by promoting sharing and enabling faster development iterations and easier collaboration between engineers and clinical personnel.


Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes.
Pioglitazone is used globally for the treatment of type 2 diabetes mellitus (T2DM) and is one of the most effective therapies for improving glucose homeostasis and insulin resistance in T2DM patients. However, its mechanism of action in the tissues and pathways that regulate glucose metabolism are incompletely defined. Here we investigated the direct effects of pioglitazone on hepatocellular pyruvate metabolism and the dependency of these observations on the purported regulators of mitochondrial pyruvate transport, MPC1 and MPC2. In cultured H4IIE hepatocytes, pioglitazone inhibited [2-14 C]-pyruvate oxidation and pyruvate-driven oxygen consumption and, in mitochondria isolated from both hepatocytes and human skeletal muscle, pioglitazone selectively and dose-dependently inhibited pyruvate-driven ATP synthesis. Pioglitazone also suppressed hepatocellular glucose production (HGP), without influencing the mRNA expression of key HGP regulatory genes. Targeted siRNA silencing of MPC1 and 2 caused a modest inhibition of pyruvate oxidation and pyruvate-driven ATP synthesis, but did not alter pyruvate-driven HGP and, importantly, it did not influence the actions of pioglitazone on either pathway. In summary, these findings outline a novel mode of action of pioglitazone relevant to the pathogenesis of T2DM and suggest that targeting pyruvate metabolism may lead to the development of effective new T2DM therapies.


Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia.
T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course. With the advent of novel treatment options that will potentially change the management of patients with T-PLL, it has become necessary to produce consensus guidelines for the design and conduct of clinical trials. The T-PLL International Study group (TPLL-ISG) set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria will facilitate comparison of results from clinical trials in T-PLL, and will thus support clinical decision making, as well as the approval of new therapeutics by healthcare authorities.


Implicit and explicit alcohol-related motivations among college binge drinkers.
Positive alcohol outcome expectancies and behavioral economic indices of alcohol consumption are related to binge drinking among college students and may reflect explicit and implicit motivations that are differentially associated with this behavior. The present study hypothesized that implicit (alcohol purchase task) and explicit (positive expectancy for alcohol's effects) motivations for drinking would not be correlated. It was also hypothesized that greater implicit and explicit motivations would predict alcohol-related risk. Participants were 297 college student binge drinkers (54% female; 88% European-American; Alcohol Use Disorders Identification Test: M = 9.53, SD = 5.04). Three indices from the alcohol purchase task (APT) were modeled as a latent implicit alcohol-related motivations variable. Explicit alcohol-related motivations were measured using a global positive expectancy subscale from the Comprehensive Effects of Alcohol Questionnaire. Alcohol Use Disorders Identification Test total, Rutgers Alcohol Problem Index total, and age of drinking onset were modeled as a latent alcohol-related risk variable. Structural equation modeling was used to examine associations amongst implicit motivations, explicit motivations, and alcohol-related risk. Implicit and explicit motivations were not correlated. Partially consistent with the second hypothesis, greater implicit motivations were associated with greater alcohol-related risk. Relations between explicit motivations and alcohol-related risk were marginally significant. Implicit and explicit drinking motivations are differentially associated with problem drinking behaviors. Future research should examine the underlying neurobiological mechanisms associated with these factors.


Studies on the oxidation-reduction systems of the erythrocyte.
1. Starvation for 3 days produces a decrease in methaemoglobin-reductase and glutathione-reductase activities, but it does not alter the glucose 6-phosphate-dehydrogenase activity of the rat erythrocyte. 2. The feeding of a protein-free diet for 11 days causes greater changes in the first two enzymes and also a diminution of the third. Under this experimental condition slight decreases in protein and haemoglobin contents were noted. 3. The experimental animals did not show methaemoglobinaemia, probably because the activity of methaemoglobin diaphorase is preserved. 4. The GSH content was not affected but the stability of the tripeptide in the presence of an oxidizing agent was diminished.


Hydrostatic pressure and temperature effects on the membranes of a seasonally migrating marine copepod.
Marine planktonic copepods of the order Calanoida are central to the ecology and productivity of high latitude ecosystems, representing the interface between primary producers and fish. These animals typically undertake a seasonal vertical migration into the deep sea, where they remain dormant for periods of between three and nine months. Descending copepods are subject to low temperatures and increased hydrostatic pressures. Nothing is known about how these organisms adapt their membranes to these environmental stressors. We collected copepods (Calanoides acutus) from the Southern Ocean at depth horizons ranging from surface waters down to 1000 m. Temperature and/or pressure both had significant, additive effects on the overall composition of the membrane phospholipid fatty acids (PLFAs) in C. acutus. The most prominent constituent of the PLFAs, the polyunsaturated fatty acid docosahexanoic acid [DHA - 22:6(n-3)], was affected by a significant interaction between temperature and pressure. This moiety increased with pressure, with the rate of increase being greater at colder temperatures. We suggest that DHA is key to the physiological adaptations of vertically migrating zooplankton, most likely because the biophysical properties of this compound are suited to maintaining membrane order in the cold, high pressure conditions that persist in the deep sea. As copepods cannot synthesise DHA and do not feed during dormancy, sufficient DHA must be accumulated through ingestion before migration is initiated. Climate-driven changes in the timing and abundance of the flagellated microplankton that supply DHA to copepods have major implications for the capacity of these animals to undertake their seasonal life cycle successfully.


Identification and analysis of three virulence-associated TonB-dependent outer membrane receptors of Pseudomonas fluorescens.
Pseudomonas fluorescens is a Gram-negative bacterium that can infect a wide range of farmed fish. However, very little is known about the virulence mechanism of P. fluorescens as a fish pathogen. In this study, we identified and analyzed 3 TonB-dependent outer membrane receptors (TDRs) from a pathogenic P. fluorescens strain isolated from fish. In silico analysis revealed that all 3 proteins (named Tdr1 to 3) possess structural domains typical of TDRs. Quantitative real time RT-PCR analysis showed that tdr1, tdr2, and tdr3 expressions were upregulated under iron-depleted conditions. Compared to the wild type, mutants defective in tdr1, tdr2, and tdr3 were retarded in growth to different extents. Infection in a turbot Scophthalmus maximus model showed that all 3 mutants were impaired in their ability to desseminate into and colonize host tissues. In addition, the tdr1 and tdr3 mutants exhibited significantly reduced virulence. When used as subunit vaccines, purified recombinant proteins of Tdr1, Tdr2, and, in particular, Tdr3 elicited significant protection in turbot against lethal P. fluorescens challenge. The vaccinated fish produced specific serum antibodies, which, when incubated with P. fluorescens, blocked infection of P. fluorescens in fish cells. Together these results indicate that Tdr1, Tdr2, and Tdr3 are iron-regulated factors that participate in bacterial virulence and induce protective immunity as subunit vaccines.


Does benefit justify research with children?
The inclusion of children in research gives rise to a difficult ethical question: What justifies children's research participation and exposure to research risks when they cannot provide informed consent? This question arises out of the tension between the moral requirement to obtain a subject's informed consent for research participation, on the one hand, and the limited capacity of most children to provide informed consent, on the other. Most agree that children's participation in clinical research can be justified. But the ethical justification for exposing children to research risks in the absence of consent remains unclear. One prevalent group of arguments aims to justify children's risk exposure by appealing to the concept of benefit. I call these 'benefit arguments'. Prominent versions of this argument defend the idea that broadening our understanding of the notion of benefit to include non-medical benefits (such as the benefit of a moral education) helps to justify children's research participation. I argue that existing benefit arguments are not persuasive and raise problems with the strategy of appealing to broader notions of benefit to justify children's exposure to research risk.


Molecular engineering of myoglobin: influence of residue 68 on the rate and the enantioselectivity of oxidation reactions catalyzed by H64D/V68X myoglobin.
In the elucidation of structural requirements of heme vicinity for hydrogen peroxide activation, we found that the replacement of His-64 of myoglobin (Mb) with a negatively charged aspartate residue enhanced peroxidase and peroxygenase activities by 78- and 580-fold, respectively. Since residue 68 is known to influence the ligation of small molecules to the heme iron, we constructed H64D/V68X Mb bearing Ala, Ser, Leu, Ile, and Phe at position 68 to improve the oxidation activity. The Val-68 to Leu mutation of H64D Mb accelerates the reaction with H(2)O(2) to form a catalytic species, called compound I, and improves the one-electron oxidation of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) (i.e., peroxidase activity) approximately 2-fold. On the other hand, H64D/V68I Mb oxygenates thioanisole 2.7- and 1600-fold faster than H64D and wild-type Mb, respectively. In terms of the enantioselectivity, H64D/V68A and H64D/V68S Mb were good chiral catalysts for thioanisole oxidation and produced the (R)-sulfoxide dominantly with 84% and 88% ee, respectively [Kato, S., et al. (2002) J. Am. Chem. Soc. 124, 8506-8507]. On the contrary, the substitution of Val-68 in H64D Mb with an isoleucine residue alters the dominant sulfoxide product from the (R)- to the (S)-isomer. The crystal structures of H64D/V68A and H64D/V68S Mb elucidated in this study do not clearly indicate residues interacting with thioanisole. However, comparison of the active site structures provides the basis to interpret the changes in oxidation activity: (1) direct steric interactions between residue 68 and substrates (i.e., H(2)O(2), ABTS, thioanisole) and (2) the polar interactions between tightly hydrogen-bonded water molecules and substrates.


Linezolid versus vancomycin for skin and soft tissue infections.
The morbidity and treatment costs associated with skin and soft tissue infections (SSTIs) are high. Linezolid and vancomycin are antibiotics that are commonly used in treating skin and soft-tissue infections, specifically those infections due to methicillin-resistant Staphylococcus aureus (MRSA). To compare the effects and safety of linezolid and vancomycin for treating people with SSTIs. For this first update of this review we conducted searches of the following databases: Cochrane Wounds Group Specialised Register (searched 24 March 2015; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. We also contacted manufacturers for details of unpublished and ongoing trials. We scrutinised citations within all obtained trials and major review articles to identify any additional trials. We included all randomised controlled trials (RCTs) comparing linezolid with vancomycin in the treatment of SSTIs. Two review authors independently selected trials, assessed risk of bias and extracted data. The primary outcomes were clinical cure, microbiological cure, and SSTI-related and treatment-related mortality. We performed subgroup analyses according to age, and whether the infection was due to MRSA. No new trials were identified for this first update. We included nine RCTs (3144 participants). Linezolid was associated with a significantly better clinical (RR 1.09, 95% CI 1.03 to 1.16) and microbiological cure rate in adults (RR 1.08, 95% CI 1.01 to 1.16). For those infections due to MRSA, linezolid was significantly more effective than vancomycin in clinical (RR 1.09, 95% CI 1.03 to 1.17) and microbiological cure rates (RR 1.17, 95% CI 1.04 to 1.32). No RCT reported SSTI-related and treatment-related mortality. There was no significant difference in all-cause mortality between linezolid and vancomycin (RR 1.44, 95% CI 0.75 to 2.80). There were fewer incidents of red man syndrome (RR 0.04, 95% CI 0.01 to 0.29), pruritus (RR 0.36, 95% CI 0.17 to 0.75) and rash (RR 0.27, 95% CI 0.12 to 0.58) in the linezolid group compared with vancomycin, however, more people reported thrombocytopenia (RR 13.06, 95% CI 1.72 to 99.22), and nausea (RR 2.45, 95% CI 1.52 to 3.94) when treated with linezolid. It seems, from the available data, that length of stay in hospital was shorter for those in the linezolid group than the vancomycin group. The daily cost of outpatient therapy was less with oral linezolid than with intravenous vancomycin. Although inpatient treatment with linezolid cost more than inpatient treatment with vancomycin per day, the median length of hospital stay was three days shorter with linezolid. Thus, total hospital charges per patient were less with linezolid treatment than with vancomycin treatment. Linezolid seems to be more effective than vancomycin for treating people with SSTIs, including SSTIs caused by MRSA. The available evidence is at high risk of bias and is based on studies that were supported by the pharmaceutical company that makes linezolid. Further well-designed, independently-funded, RCTs are needed to confirm the available evidence.


Cost-utility analysis of dupilumab add on therapy versus standard therapy in adolescents and adults for severe asthma in Colombia.
Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits IL-4 and IL-13 signaling. This drug raises concerns about the economic impact in scenarios with constrained resources. This study aimed to estimate the cost-utility of dupilumab plus standard care (SoC) vs SoC alone in adolescents and adults with severe asthma and eosinophilic phenotype. A probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with uncontrolled allergic asthma in Colombia. Total costs and QALYs of standard therapy (ICS + LABA), add-on therapy with dupilumab, were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay (WTP) value of $19,000. The base-case analysis showed dupilumab was associated with higher annual annual per-patient costs (US$5,719 for dupilumab and US$1,214 for standard therapy) and higher QALYs than standard therapy (fe 4.06 QALYs vs 3.97 QALYs, respectively). . The incremental cost-effectiveness ratio estimated was US$50,160 per QALY gained. Dupilumab is not cost-effective using a WTP of US$19000 per QALY threshold in Colombia. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other middle-income countries.


Urban-Rural Differences in Hip Fracture Mortality: A Nationwide NOREPOS Study.
Higher hip fracture incidence in urban than in rural areas has been demonstrated, but urban-rural differences in posthip fracture mortality have been less investigated, and the results are disparate. Hence, the aims of the present register-based cohort study were to examine possible urban-rural differences in short- and long-term mortality in Norwegian hip fracture patients and their potential associations with sociodemographic variables, and to investigate possible urban-rural differences in excess mortality in hip fracture patients compared with the general population. Data were provided from the NOREPOS hip fracture database, the 2001 Population and Housing Census, and the National Registry. The urbanization degree in each municipality was determined by the proportion of inhabitants living in densely populated areas (rural: <1/3, semirural: 1/3 to 2/3, and urban: >2/3). Age-adjusted mortality rates and standardized mortality ratios were calculated for hip fracture patients living in rural, semirural, and urban municipalities. A flexible parametric model was used to estimate age-adjusted average and time-varying HRs by category of urbanization with the rural category as reference. Among 96,693 hip fracture patients, urban residents had higher mortality than their rural-dwelling counterparts. The HR of mortality in urban compared with rural areas peaked during the first 1 to 2 years postfracture with a maximum HR of 1.20 (95% CI, 1.10 to 1.30) in men and 1.15 (95% CI, 1.08 to 1.21) in women. The differences were significant during approximately 5 years after fracture. Adjusting for sociodemographic variables did not substantially change the results. However, absolute 30-day mortality was not significantly different between urban and rural residents, suggesting that health-care quality immediately postfracture does not vary by urbanization. The novel findings of a higher long-term mortality in urban hip fracture patients might reflect disparities in health status or lifestyle, differences in posthip fracture health care or rehabilitation, or a combination of several factors. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.


Sex Differences in Traditional and Nontraditional Risk Factors for Obstructive Coronary Artery Disease in Stable Symptomatic Patients.
There have been limited data on sex-specific risk factors for coronary artery disease (CAD) in patients with stable chest pain. This study was performed to investigate whether risk factors for CAD differ by sex in stable symptomatic patients. Data were obtained from a nation-wide registry, enrolling 1025 patients (age, 62.0 ± 11.0 years, 587 women) with chest pain who underwent elective invasive coronary angiography under the suspicion of CAD. A total of 373 patients (36.4%) had obstructive CAD (≥50% stenosis) (men vs. women: 33.8% vs. 38.3%, p = 0.135). In men, univariate analyses showed that age, renal function, total cholesterol, low-density lipoprotein cholesterol, triglyceride, C-reactive protein (CRP), left ventricular (LV) systolic function, and septal annular velocity of LV (e') were significantly associated with the presence of obstructive CAD. Among these factors, a high CRP level (≥0.50 mg/dL) was an independent predictor of CAD in multivariable analysis (odds ratio [OR], 2.93; 95% confidence interval [CI], 1.26-6.82; p = 0.012). In women, univariate analyses showed that age, waist circumference, heart rate, hypertension, diabetes mellitus, low high-density lipoprotein cholesterol, LV systolic function, LV mass index, e' velocity, E/e', and left atrial size were significantly associated with the presence of obstructive CAD. Among these factors, lower e' velocity (<6.35 cm/s) was an independent predictor of CAD in multivariable analysis (OR, 2.38; 95% CI, 1.21-4.70; p = 0.012). Among patients with stable chest pain, inflammation and LV diastolic dysfunction are independently associated with obstructive CAD in men and women, respectively.


The Infrascanner, a handheld device for screening in situ for the presence of brain haematomas.
Early identification and treatment of intracranial haematomas in patients sustaining traumatic brain injury is fundamental to successful treatment. This pilot study evaluates the Infrascanner as a handheld medical screening tool for detection, in situ, of brain haematomas in patients with head injury. This study included 35 TBI patients aged 17-76 (M = 47.6), admitted to the neurosurgical intensive care unit and observation unit of a University Hospital in a Level 1 trauma centre. The Infrascanner NIRS device uses near infrared light measurements to calculate optical density in brain regions. Results show Infrascanner sensitivity at 89.5% and specificity at 81.2%. PPV was 85% and NPV 86.7%. The device detected 90% of extra-axial, 88.9% of intra-axial and 93.3% of non-surgical haematomas (less than 25 mL). PPV for this classification was 82.3%; 87.5% sensitivity was found when the Infrascanner exam was performed within 12 hours post-trauma, whereas after 12 hours post-trauma, exams had 90.1% sensitivity. This study demonstrates that the Infrascanner is useful in initial examinations and screenings of patients with head injury as an adjunct to a CT scan or when it is not available and may allow earlier treatment and reduce secondary injury caused by present and delayed haematomas.


TU-C-218-01: Effective Medical Imaging Physics Education.
A practical and applied knowledge of physics and the associated technology is required for the clinically effective and safe use of the various medical imaging modalities. This is needed by all involved in the imaging process, including radiologists, especially residents in training, technologists, and physicists who provide consultation on optimum and safe procedures and as educators for the other imaging professionals. This area of education is undergoing considerable change and evolution for three reasons: 1. Increasing capabilities and complexity of medical imaging technology and procedures, 2.Expanding scope and availability of educational resources, especially on the internet, and 3. A significant increase in our knowledge of the mental learning process and the design of learning activities to optimize effectiveness and efficiency, especially for clinically applied physics. This course will address those three issues by providing guidance on establishing appropriate clinically focused learning outcomes, a review of the brain function for enhancing clinically applied physics, and the design and delivery of effective learning activities beginning with the classroom and continuing through learning physics during the clinical practice of radiology. Characteristics of each type of learning activity will be considered with respect to effectiveness and efficiency in achieving appropriate learning outcomes. A variety of available resources will be identified and demonstrated for use in the different phases of learning process. A major focus is on enhancing the role of the medical physicist in clinical radiology both as a resource and educator with contemporary technology being the tool, but not the teacher. 1. Develop physics learning objectives that will support effective and safe medical imaging procedures. 2. Understand specific brain functions that are involved in learning and applying physics. 3. Describe the characteristics and development of mental knowledge structures for applied clinical physics. 4. List the established levels of learning and associate each with specific functions that can be performed. 5. Analyze the different types of learning activities (classroom, individual study, clinical, etc.) with respect to effectiveness and efficiency. 6. Design and Provide a comprehensive physics education program with each activity optimized with respect to outcomes and available resources.


Id gene expression as a key mediator of tumor cell biology.
Id genes encode members of the helix-loop-helix (HLH) family of transcription factors that inhibit transcription by forming inactive heterodimers with basic HLH (bHLH) proteins. There are four members of the Id gene family recognized in mammals, and the proteins they encode share homology primarily in their HLH domain. bHLH proteins typically form heterodimers with other bHLH proteins, and their basic domain binds to a DNA sequence element, the E-box, activating transcription. Products of Id genes lack the basic DNA binding domain of the bHLH transcription factors, and when they heterodimerize with bHLH proteins, the complexes are inactive. Generally, high levels of Id mRNA are detected in proliferative undifferentiated, embryonal cells and lower levels are detected in well-differentiated, mature, adult tissues. In vitro, these genes are generally expressed at lower levels in cells after the induction of differentiation. Recently, high levels of expression of Id genes have been identified in cell lines derived from a wide variety of different tumors and in tumor tissues as well. These findings suggest that not only the inappropriate proliferation of tumors but also the anaplastic characteristics that contribute to their malignant behavior may be regulated by Id gene expression.


Bullous Systemic Lupus Erythematosus as an Initial Manifestation of SLE.
Bullous systemic lupus erythematosus (BSLE) is a rare subset of systemic lupus erythematosus that is often associated with autoimmunity to type VII collagen. We describe a 45-year-old woman with BSLE who presented with vesiculobullous lesions as an initial manifestation of SLE. The patient first noticed a widespread urticarial, erythematous eruption associated with tense blisters, erosions, and crusting. She was diagnosed with bullous pemphigoid and underwent a one-month course of treatment with betamethazone. Because of the appearance of marked proteinuria, a subsequent renal biopsy, and serological tests, the patient was diagnosed with rapidly progressive glomerulonephritis and systemic lupus erythematosus. The patient's IgG circulating antibodies labeled the dermal floor of salt-split skin and recognized type VII collagen in immunoblot studies. Although methylprednisolone pulse therapy for glomerulonephritis did not alleviate the vesicullobullous eruption, treatment with dapsone resulted in dramatic disappearance of the lesions. Cessation of dapsone therapy due to hemolysis with Heinz-body formation did not aggravate the bullous disease. Our case illustrates that a generalized vesiculobullous eruption can be the sole presenting manifestation of SLE. It also emphasizes the close temporal relationship between BSLE and lupus nephritis.


Little League survey: the Houston study.
1. In a study of 595 Little League pitchers, approximately 17% had a history of elbow symptoms: only 1% had elbow symptoms which had ever excluded them from pitching. There was no correlation between the presence of symptoms and years of pitching experience. 2. Some limitation of active extension of the elbow was seen in 12% of the pitchers; however, there was no correlation between elbow flexion contractures and years of pitching experience, symptoms, or roentgenographic pathology. No normal child had an elbow flexion contracture greater than 15 degrees. 3. A slight valgus carrying angle is considered a normal anatomic variant in the dominant arm. There was no correlation between valgus carrying angle and years of pitching experience or symptoms or roentgenographic pathology. 4. No roentgenographic evidence of avascular necrosis of the capitellum, radial head, or both was seen in this population. 5. Roentgenographic findings such as bony hypertrophy, enlargement of the medial epicondyle, and secondary ossification centers are normal anatomic variants not related to symptoms. Undisplaced stress fractures of the medial epicondyle respond well to conservative treatment, with no functional residual.


Immunohistochemical localization of low density lipoprotein receptors in adrenal gland, liver, and intestine.
The localization of LDL receptors in adrenal gland, liver, and intestine was studied using immunohistochemistry. The anti-LDL receptor antibody used was shown to be monospecific and did not react with striated muscle, a tissue which has a very low level of LDL receptors. Similarly, cerebral cortex showed only faint reactivity and that was to an area previously demonstrated to have LDL receptors. Adrenal gland was intensely reactive with the zona fasciculata, having a greater density of receptors than the zona reticularis. In normal liver, LDL receptors were present on the sinusoidal membranes and were sparse in the areas of hepatocyte-to-hepatocyte contact without an obvious portal to central gradient. LDL receptors were present throughout the intestine. In jejunum, staining was most intense at the base of the villus and extended up toward the villus tip. At the base of the villus, the receptor was primarily at the basal lateral membrane, but toward the villus tip, there was appreciable intracellular staining. Staining in crypts was more faint; in duodenum, staining in crypts equaled that in the villus region in intensity. In colon, there was intense staining throughout the epithelial cells. These results provide new information about the cellular and subcellular localization of LDL receptors and raise the interesting possibility that there is a role for LDL-derived cholesterol in new lipoprotein formation.


Mitochondrial release of the NADH dehydrogenase Ndi1 induces apoptosis in yeast.
Saccharomyces cerevisiae NDI1 codes for the internal mitochondrial ubiquinone oxidoreductase, which transfers electrons from NADH to ubiquinone in the respiratory chain. Previously we found that Ndi1 is a yeast homologue of the protein apoptosis-inducing factor-homologous mitochondrion-associated inducer of death and displays potent proapoptotic activity. Here we show that S. cerevisiae NDI1 is involved in apoptosis induced by various stimuli tested, including H(2)O(2), Mn, and acetate acid, independent of Z-VAD-fmk (a caspase inhibitor) inhibition. Although Ndi1 also participates in respiration, its proapoptotic property is separable from the ubiquinone oxidoreductase activity. During apoptosis, the N-terminal of Ndi1 is cleaved off in the mitochondria, and this activated form then escapes out to execute its apoptotic function. The N-terminal cleavage appears to be essential for the manifestation of the full apoptotic activity, as the uncleaved form of Ndi1 exhibits much less growth-inhibitory activity. Our results thus indicate an important role of Ndi1 in the switch of life and death fates in yeast: during normal growth, Ndi1 assimilates electrons to the electron transport chain and initiates the respiration process to make ATP, whereas under stresses, it cleaves the toxicity-sequestering N-terminal cap, is released from the mitochondria, and becomes a cell killer.


Use of interpreters by physicians for hospitalized limited English proficient patients and its impact on patient outcomes.
Few studies have examined the impact of inpatient interpreter use for limited English proficient (LEP) patients on length of stay (LOS), 30-day post discharge emergency department (ED) visits and 30-day hospital readmission rates for LEP patients. A retrospective cohort analysis was conducted of all hospitalized patients admitted to the general medicine service at a large academic center. For patients self-reported as LEP, use of interpreters during each episode of hospitalization was categorized as: 1) interpreter used by non-MD (i.e., nurse); 2) interpreter used by a non-Hospitalist MD; 3) interpreter used by Hospitalist; and 4) no interpreter used during hospitalization. We examined the association of English proficiency and interpreter use on outcomes utilizing Poisson and logistic regression models. Of 4,224 patients, 564 (13 %) were LEP. Of these LEP patients, 65.8 % never had a documented interpreter visit, 16.8 % utilized an interpreter with a non-MD, 12.6 % utilized an interpreter with a non-Hospitalist MD and 4.8 % utilized an interpreter with a hospitalist present. In adjusted models, compared to English speakers, LEP patients with no interpreters had significantly shorter LOS. There were no differences in readmission rates and ED utilization between LEP and English-speaking patients. Compared to LEP patients with no interpreter use, those who had a physician use an interpreter had odds for a longer LOS, but there was no difference in odds of readmission or ED utilization. Academic hospital clinician use of interpreters remains highly variable and physicians may selectively be using interpreters for the sickest patients.


Correlation between pentraxin-3 and endothelial dysfunction in obstructive sleep apnea syndrome.
Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular disease. Recent studies showed endothelial dysfunction and pentraxin-3 both of an early marker for development of cardiovascular disease. The aim of the study was to evaluate the relationship between severity of OSAS and endothelial dysfunction and inflammatory markers including pentraxin-3 and high-sensitivity C-reactive protein (hs-CRP). This was a cross-sectional study in which patients who had undergone a polysomnographic study for diagnosis of OSAS were recruited. Included patients were grouped according to apnea-hypopnea index (AHI) as mild (AHI between 5 and 14.9) and moderate-severe OSAS (AHI ⩾ 15). Patients with AHI < 5 served as control group. Endothelial function was evaluated by flow-mediated dilatation (FMD). Serum pentraxin-3 and hs-CRP levels were measured. Eighty-three patients enrolled for the study. We found a significant increment in pentraxin-3 and hs-CRP levels and a significant decrement in FMD as the severity of OSAS increased. There was a negative correlation between FMD and AHI, pentraxin, and hs-CRP. OSAS patients have significantly elevated pentraxin-3 levels and endothelial dysfunction. Furthermore, both pentraxin-3 and endothelial dysfunction were independently associated with severity of OSAS defined by AHI.


Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.
In chronic liver disease, hepatic stellate cells (HSC) transdifferentiate into myofibroblasts, promoting extracellular matrix (ECM) synthesis and deposition. Stimulation of HSC by transforming growth factor-β (TGF-β) is a crucial event in liver fibrogenesis due to its impact on myofibroblastic transition and ECM induction. In contrast, hepatocyte growth factor (HGF), exerts antifibrotic activities. Recently, miR-29 has been reported to be involved in ECM synthesis. We therefore studied the influence of HGF and TGF-β on the miR-29 collagen axis in HSC. HSC, isolated from rats, were characterized for HGF and Met receptor expression by Real-Time PCR and Western blotting during culture induced myofibroblastic transition. Then, the levels of TGF-β, HGF, collagen-I and -IV mRNA, in addition to miR-29a and miR-29b were determined after HGF and TGF-β stimulation of HSC or after experimental fibrosis induced by bile-duct obstruction in rats. The interaction of miR-29 with 3'-untranslated mRNA regions (UTR) was analyzed by reporter assays. The repressive effect of miR-29 on collagen synthesis was studied in HSC treated with miR-29-mimicks by Real-Time PCR and immunoblotting. The 3'-UTR of the collagen-1 and -4 subtypes were identified to bind miR-29. Hence, miR-29a/b overexpression in HSC resulted in a marked reduction of collagen-I and -IV synthesis. Conversely, a decrease in miR-29 levels is observed during collagen accumulation upon experimental fibrosis, in vivo, and after TGF-β stimulation of HSC, in vitro. Finally, we show that during myofibroblastic transition and TGF-β exposure the HGF-receptor, Met, is upregulated in HSC. Thus, whereas TGF-β stimulation leads to a reduction in miR-29 expression and de-repression of collagen synthesis, stimulation with HGF was definitely associated with highly elevated miR-29 levels and markedly repressed collagen-I and -IV synthesis. Upregulation of miRNA-29 by HGF and downregulation by TGF-β take part in the anti- or profibrogenic response of HSC, respectively.


Sex determination in insects: variations on a common theme.
Recent studies in a representative selection of holometabolous insects suggest that, despite diversity at the instructive level, the signal-relaying part of the sex-determining pathway is remarkably well conserved. In principle, it is composed of the transformer gene (tra), which acts as a common binary switch that transduces the selected sexual fate, female when ON, male when OFF, to the downstream effector doublesex(dsx) that controls overt sexual differentiation. An interesting recurrent feature is that tra is switched ON in the early zygote by maternally provisioned tra activity. Different male-determining signals evolved, which prevent maternal activation of zygotic tra to allow for male development. In some species, where lack of maternal activation leaves tra in the OFF state, novel female-determining signals were deployed to activate zygotic tra. It appears that both the instructive end of the pathway upstream of tra as well as the executive end downstream of dsx are primary targets of evolutionary divergence, while the transduction part seems less prone to changes. We propose that this is a feature shared with many other signaling cascades that regulate developmental fates.


SegNet: A Deep Convolutional Encoder-Decoder Architecture for Image Segmentation.
We present a novel and practical deep fully convolutional neural network architecture for semantic pixel-wise segmentation termed SegNet. This core trainable segmentation engine consists of an encoder network, a corresponding decoder network followed by a pixel-wise classification layer. The architecture of the encoder network is topologically identical to the 13 convolutional layers in the VGG16 network [1] . The role of the decoder network is to map the low resolution encoder feature maps to full input resolution feature maps for pixel-wise classification. The novelty of SegNet lies is in the manner in which the decoder upsamples its lower resolution input feature map(s). Specifically, the decoder uses pooling indices computed in the max-pooling step of the corresponding encoder to perform non-linear upsampling. This eliminates the need for learning to upsample. The upsampled maps are sparse and are then convolved with trainable filters to produce dense feature maps. We compare our proposed architecture with the widely adopted FCN [2] and also with the well known DeepLab-LargeFOV [3] , DeconvNet [4] architectures. This comparison reveals the memory versus accuracy trade-off involved in achieving good segmentation performance. SegNet was primarily motivated by scene understanding applications. Hence, it is designed to be efficient both in terms of memory and computational time during inference. It is also significantly smaller in the number of trainable parameters than other competing architectures and can be trained end-to-end using stochastic gradient descent. We also performed a controlled benchmark of SegNet and other architectures on both road scenes and SUN RGB-D indoor scene segmentation tasks. These quantitative assessments show that SegNet provides good performance with competitive inference time and most efficient inference memory-wise as compared to other architectures. We also provide a Caffe implementation of SegNet and a web demo at http://mi.eng.cam.ac.uk/projects/segnet.


Treatment decisions and the impact of adverse events before and during extended endocrine therapy in postmenopausal early breast cancer.
Extended endocrine therapy beyond 5 years for postmenopausal breast cancer has been studied within multiple phase III trials. Treatment compliance in these trials is generally poor. In this analysis, we aimed to determine factors that were associated with participation in the phase III Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial and with early treatment discontinuation, and how this influenced survival outcome. In the IDEAL trial, postmenopausal patients were randomised between 2.5 or 5 years of extended letrozole, after completing 5 years of endocrine therapy for hormone receptor-positive early breast cancer. A subgroup of this population participated earlier in the Tamoxifen Exemestane Adjuvant Multinational trial (5 years of exemestane or 2.5 years of tamoxifen followed by exemestane as primary adjuvant therapy) in which we explored which factors were determinative for enrolment in the IDEAL study. In the IDEAL cohort, we evaluated which factors predicted for early treatment discontinuation and the effect of early treatment discontinuation on disease-free survival (DFS). Nodal status, younger age and adjuvant chemotherapy were significantly associated with higher enrolment in the IDEAL trial. In the IDEAL cohort, adverse events (AEs), the type of primary endocrine therapy and the interval between primary and extended therapy were associated with early treatment discontinuation. Among the reported AEs, depressive feelings (56%) were most frequently associated with early treatment discontinuation. Early treatment discontinuation was not associated with worse DFS (hazard ratio [HR] = 1.02, 95% confidence interval = 0.76-1.37). In this analysis, we found that risk factors were most strongly associated enrolment in the IDEAL trial. In contrast, patient experiences were the most significant factors leading to early treatment discontinuation, with no effect on DFS.


Long-term follow-up of the ileoanal anastomosis in children and young adults.
The purpose of this study was to carry out a long-term study of the ileoanal anastomosis (IAA) in children and young adults, comparing the straight IAA to the J pouch. One hundred twenty-one young people who had undergone IAA were studied, with 114 available for long-term follow-up. One hundred one were 18 years and under. Forty-nine patients had a straight IAA and 72 had a J-pouch reservoir. There were no deaths. After surgery, three children had intraabdominal sepsis and one had pelvic sepsis, but it did not lead to excision of the IAA. The mean stool frequency in all 114 patients was 5.0 +/- 2.5 per day and 1.2 +/- 1.1 at night. The mean number of stools for the straight IAA was 6 per day and 2.1 at night. The mean number of stools for the straight IAA with balloon dilations was 5.8 per day and 1.2 at night, and for the J pouch it was 4 per day and 1 at night. Patients with both the J pouch and straight IAA had good to excellent sensation, with patients with the J pouch always able to distinguish flatus from stool in 87% of patients and almost always in 13%. Daytime continence was very good in both groups. Moderate nighttime loss of stool occurred in 10 patients, 6 with a straight IAA and 4 with a J pouch. Ninety-five percent of the 114 patients were satisfied or very satisfied, with most children with a J pouch very satisfied. The J pouch remains the procedure of choice in young people.


History, ethics, advantages and limitations of experimental models for hepatic ablation.
Numerous techniques developed in medicine require careful evaluation to determine their indications, limitations and potential side effects prior to their clinical use. At present this generally involves the use of animal models which is undesirable from an ethical standpoint, requires complex and time-consuming authorization, and is very expensive. This process is exemplified in the development of hepatic ablation techniques, starting experiments on explanted livers and progressing to safety and efficacy studies in living animals prior to clinical studies. The two main approaches used are ex vivo isolated non-perfused liver models and in vivo animal models. Ex vivo non perfused models are less expensive, easier to obtain but not suitable to study the heat sink effect or experiments requiring several hours. In vivo animal models closely resemble clinical subjects but often are expensive and have small sample sizes due to ethical guidelines. Isolated perfused ex vivo liver models have been used to study drug toxicity, liver failure, organ transplantation and hepatic ablation and combine advantages of both previous models.


Is the alcohol industry doing well by 'doing good'? Findings from a content analysis of the alcohol industry's actions to reduce harmful drinking.
The aims of this study were to: (1) describe alcohol industry corporate social responsibility (CSR) actions conducted across six global geographic regions; (2) identify the benefits accruing to the industry ('doing well'); and (3) estimate the public health impact of the actions ('doing good'). Actions from six global geographic regions. A web-based compendium of 3551 industry actions, representing the efforts of the alcohol industry to reduce harmful alcohol use, was issued in 2012. The compendium consisted of short descriptions of each action, plus other information about the sponsorship, content and evaluation of the activities. Public health professionals (n=19) rated a sample (n=1046) of the actions using a reliable content rating procedure. WHO Global strategy target area, estimated population reach, risk of harm, advertising potential, policy impact potential and other aspects of the activity. The industry actions were conducted disproportionately in regions with high-income countries (Europe and North America), with lower proportions in Latin America, Africa and Asia. Only 27% conformed to recommended WHO target areas for global action to reduce the harmful use of alcohol. The overwhelming majority (96.8%) of industry actions lacked scientific support (p<0.01) and 11.0% had the potential for doing harm. The benefits accruing to the industry ('doing well') included brand marketing and the use of CSR to manage risk and achieve strategic goals. Alcohol industry CSR activities are unlikely to reduce harmful alcohol use but they do provide commercial strategic advantage while at the same time appearing to have a public health purpose.


Trends in Discharge Prescription of Digoxin After Norwood Operation: An Analysis of Data from the Pediatric Health Information System (PHIS) Database.
Quality improvement efforts have focused on reducing interstage mortality for infants with hypoplastic left heart syndrome (HLHS). In 1/2016, two publications reported that use of digoxin was associated with reduced interstage mortality. The degree to which these findings have affected real world practice has not been evaluated. The discharge medications of neonates with HLHS undergoing Norwood operation between 1/2007 and 12/2018 at Pediatric Health Information Systems Database hospitals were studied. Mixed effects models were calculated to evaluate the hypothesis that the likelihood of digoxin prescription increased after 1/2016, adjusting for measurable confounders with furosemide and aspirin prescription measured as falsification tests. Interhospital practice variation was measured using the median odds ratio. Over the study period, 6091 subjects from 45 hospitals were included. After adjusting for measurable covariates, discharge after 1/2016 was associated with increased odds of receiving digoxin (OR 3.9, p < 0.001). No association was seen between date of discharge and furosemide (p = 0.26) or aspirin (p = 0.12). Prior to 1/2016, the likelihood of receiving digoxin was decreasing (OR 0.9 per year, p < 0.001), while after 1/2016 the rate has increased (OR 1.4 per year, p < 0.001). However, there remains significant interhospital variation in the likelihood of receiving digoxin even after adjusting for known confounders (median odds ratio = 3.5, p < 0.0001). Following publication of studies describing an association between digoxin and improved interstage survival, the likelihood of receiving digoxin at discharge increased without similar changes for furosemide or aspirin. Despite concerted efforts to standardize interstage care, interhospital variation in pharmacotherapy in this vulnerable population persists.


Pattern and scale: evaluating generalities in crab distributions and marsh dynamics from small plots to a national scale.
The generality of ecological patterns depends inextricably on the scale at which they are examined. We investigated patterns of crab distribution and the relationship between crabs and vegetation in salt marshes at multiple scales. By using consistent monitoring protocols across 15 U.S. National Estuarine Research Reserves, we were able to synthesize patterns from the scale of quadrats to the entire marsh landscape to regional and national scales. Some generalities emerged across marshes from our overall models, and these are useful for informing broad coastal management policy. We found that crab burrow distribution within a marsh could be predicted by marsh elevation, distance to creek and soil compressibility. While these physical factors also affected marsh vegetation cover, we did not find a strong or consistent overall effect of crabs at a broad scale in our multivariate model, though regressions conducted separately for each site revealed that crab burrows were negatively correlated with vegetation cover at 4 out of 15 sites. This contrasts with recent smaller-scale studies and meta-analyses synthesizing such studies that detected strong negative effects of crabs on marshes, likely because we sampled across the entire marsh landscape, while targeted studies are typically limited to low-lying areas near creeks, where crab burrow densities are highest. Our results suggest that sea-level rise generally poses a bigger threat to marshes than crabs, but there will likely be interactions between these physical and biological factors. Beyond these generalities across marshes, we detected some regional differences in crab community composition, richness, and abundance. However, we found striking differences among sites within regions, and within sites, in terms of crab abundance and relationships to marsh integrity. Although generalities are broadly useful, our findings indicate that local managers cannot rely on data from other nearby systems, but rather need local information for developing salt marsh management strategies.


First Report of Alfalfa mosaic virus in Lavandula officinalis.
For several years, in ornamental nurseries in the Mediterranean area of Spain, stunting and yellow leaf spotting have been observed in young plants of Lavandula officinalis. Symptoms eventually disappeared as the plants matured. During the summer of 2003, the number of plantlets affected and the intensity of symptoms increased significantly. Symptomatic plants tested positive using enzyme-linked immunosorbent assay (ELISA) (Phyto-Diagnostics, INRA, France) for the presence of Alfalfa mosaic virus (AMV). ELISA results were verified using reverse transcription-polymerase chain reaction (RT-PCR). Total RNA extracts from symptomatic plants were analyzed using primers designed specifically for the coat protein region of AMV utilizing sequence data from GenBank Accession No. AF215664: AMVcoat-F: GT GGT GGG AAA GCT GGT AAA and AMVcoat-R: CAC CCA GTG GAG GTC AGC ATT. The thermocycling schedule was as follows: reverse transcriptase step at 50°C for 30 min, first PCR cycle at 94°C for 2 min, 35 cycles each of 30 s at 94°C, 30 s at 54°C, 30 s at 72°C, followed by a final extension at 72°C for 10 min. A 700-pb PCR product of the expected size was obtained from plants that were positive for AMV using ELISA. The two systems provide for rapid detection of AMV in L. officinalis. A regular screening program will assist in providing virus-free plants to ornamental nurseries. These results demonstrate the presence of AMV in L. officinalis. Alfalfa (Medicago sativa L.) is a typical source of AMV. However, because the nurseries where L. officinalis is grown are not in the vicinity of alfalfa fields, we suggest the source of the infection originated in the propagation material. AMV has currently been reported in L. officinalis only in Italy and France (1). To our knowledge, this is the first report of AMV in L. officinalis in Spain. Reference: (1): A. Garibaldi et al. Ed. Edagricole-Edisioni Agricole della Calderini s.r.l., Bologna, 2000.


Single-molecule measurements in microwells for clinical applications.
The ability to detect and analyze proteins, nucleic acids, and other biomolecules is critical for clinical diagnostics and for understanding the underlying mechanisms of disease. Current detection methods in clinical and research laboratories rely upon bulk measurement techniques such as immunoassays, polymerase chain reaction, and mass spectrometry to detect these biomarkers. However, many potentially useful protein or nucleic acid biomarkers in blood, saliva, or other biofluids exist at concentrations well below the detection limits of current methods, necessitating the development of more sensitive technologies. Single-molecule measurements are poised to address this challenge, vastly improving sensitivity for detecting low abundance biomarkers and rare events within a population. Microwell arrays have emerged as a powerful tool for single-molecule measurements, enabling ultrasensitive detection of disease-relevant biomolecules in easily accessible biofluids. This review discusses the development, fundamentals, and clinical applications of microwell-based single-molecule methods, as well as challenges and future directions for translating these methods to the clinic.


Microbial diversity in bovine papillomatous digital dermatitis in Holstein dairy cows from upstate New York.
Papillomatous digital dermatitis (PDD) is one of the most prevalent diseases of cattle, adversely affecting the dairy industry by its negative effect on milk production and reproductive performance. Our objective was to use culture-independent methods to determine the microbial diversity in different strata of PDD lesions of three Holstein dairy cows, analyzing whether major differences exist compared to foot skin of three non-infected cows. Both group-specific 16S rRNA gene PCR-denaturing gradient gel electrophoresis and clone library sequencing of broad-range 16S rRNA gene showed differences between the microbial composition of healthy dairy cows and the different strata of the lesion. The predominant bacterial community in the lesion, regardless of the stratum, consisted of 166 specific phylotypes belonging to seven bacterial phyla. Spirochetes (particularly, treponemes) was the most prominent group detected in PDD deep biopsies and was only found in samples from the lesion. Additionally, one phylotype phylogenetically affiliated with uncultured Euryarchaeota was detected in two strata of the lesion. Sequences from healthy foot skin samples revealed 86 specific phylotypes that were affiliated with Firmicutes and Proteobacteria. Our study corroborates the theory that treponemes are involved in PDD disease etiology and suggests, for the first time, the presence of archaeal members in this particular bovine infection.


ReCodLiver0.9: Overcoming Challenges in Genome-Scale Metabolic Reconstruction of a Non-model Species.
The availability of genome sequences, annotations, and knowledge of the biochemistry underlying metabolic transformations has led to the generation of metabolic network reconstructions for a wide range of organisms in bacteria, archaea, and eukaryotes. When modeled using mathematical representations, a reconstruction can simulate underlying genotype-phenotype relationships. Accordingly, genome-scale metabolic models (GEMs) can be used to predict the response of organisms to genetic and environmental variations. A bottom-up reconstruction procedure typically starts by generating a draft model from existing annotation data on a target organism. For model species, this part of the process can be straightforward, due to the abundant organism-specific biochemical data. However, the process becomes complicated for non-model less-annotated species. In this paper, we present a draft liver reconstruction, ReCodLiver0.9, of Atlantic cod (Gadus morhua), a non-model teleost fish, as a practicable guide for cases with comparably few resources. Although the reconstruction is considered a draft version, we show that it already has utility in elucidating metabolic response mechanisms to environmental toxicants by mapping gene expression data of exposure experiments to the resulting model.


High-dose cytosine arabinoside plus etoposide as initial treatment for acute myeloid leukaemia: a single centre study.
In a single centre, 52 newly diagnosed patients with acute myeloid leukemia (AML) under the age of 56 years received induction chemotherapy commencing with high-dose cytosine arabinoside (Ara-C) and etoposide (Protocol BF11), followed by Ara-C, 6 thioguanine (6TG). A total of 67% of patients entered remission using these drugs. An anthracycline was added for those patients not in remission. The overall remission rate (CR) was 86.5% (45/52), with a minimum follow-up of 90 days. Patients are hospitalised for relatively short periods, and consequently require less blood product and antibiotic support. Patients in continuing first remission following induction with Ara-C and etoposide are similar in number to those in continuing first remission who initially received an anthracycline. This would imply that the efficiency of Ara-C and etoposide in inducing long-term disease-term survival is comparable with anthracycline-containing regimens. We conclude that high-dose Ara-C and etoposide used in the first induction cycle for treating AML have good antileukaemic effect with acceptable toxicity.


Associations between residential treatment length, PTSD, and outpatient healthcare utilization among veterans.
Premature discontinuation of posttraumatic stress disorder (PTSD) treatment is generally associated with poorer outcomes for veterans with PTSD. What is less clear is whether treatment benefits, as a function of treatment length, persist, as well as predict less future mental health care utilization. We sought to determine whether length of stay (LOS) in residential PTSD treatment predicted discharge PTSD symptom severity and outpatient mental health care utilization. We hypothesized discharge PTSD Checklist (PCL) scores would mediate the relations between LOS in residential treatment and outpatient mental health care utilization. The current study included 740 veterans who received residential PTSD treatment within 5 VA hospitals and completed intake and discharge assessments, including the PTSD Checklist (PCL). Information about LOS in residential treatment and outpatient mental health care utilization was obtained from the National Patient Care Database. We examined the relations between residential LOS, discharge Posttraumatic Stress Disorder Checklist (PCL), and outpatient mental health care utilization. Nonparametric bootstrapping was utilized to test for the significance of the indirect effect. Veterans who stayed in residential treatment longer had lower PCL scores at discharge (est. = -2.50, SE = .51, p < .001), and veterans with lower PCL scores at discharge sought fewer outpatient mental health visits (est. = .31, SE = .14, p = .03). A bias-corrected bootstrap confidence interval for the indirect effect (ab = -.77) based on 10,000 bootstrap samples was entirely below zero (-1.72 to -.05). This indicates discharge PCL mediated the relations between LOS and outpatient mental health care utilization, such that individuals with a longer LOS in residential PTSD treatment had lower PCL scores at discharge and thus utilized less outpatient mental health care. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats.
Acceptance of cannabis use is growing. However, prolonged use is associated with diminished psychosocial outcomes, potentially mediated by drug-induced cognitive impairments. Δ9-Tetrahydrocannabinol (THC) is the main psychoactive ingredient in cannabis, yet other phytocannabinoids in the plant, such as cannabidiol (CBD), have unique properties. Given that CBD can modulate the undesirable effects of THC, therapeutic agents, such as nabiximols, contain higher CBD:THC ratios than illicit marijuana. We tested the hypothesis that THC impairs a relevant cognitive function for long-term success, namely willingness to exert cognitive effort for greater rewards, and that CBD could attenuate such decision-making impairments. Male Long-Evans rats (n = 29) performing the rat cognitive effort task (rCET) received acute THC and CBD, independently and concurrently, in addition to other cannabinoids. Rats chose between 2 options differing in reward magnitude, but also in the cognitive effort (attentional load) required to obtain them. We found that THC decreased choice of hard trials without impairing the animals' ability to accurately complete them. Strikingly, this impairment was correlated with CB1 receptor density in the medial prefrontal cortex - an area previously implicated in effortful decision-making. In contrast, CBD did not affect choice. Coadministration of 1:1 CBD:THC matching that in nabiximols modestly attenuated the deleterious effects of THC in "slacker" rats. Only male rats were investigated, and the THC/CBD coadministration experiment was carried out in a subset of individuals. These findings confirm that THC, but not CBD, selectively impairs decision-making involving cognitive effort costs. However, coadministration of CBD only partially ameliorates such THC-induced dysfunction.


Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome.
To identify cytogenetic risk factors predicting outcome in children with advanced myelodysplastic syndrome, overall survival of 192 children prospectively enrolled in European Working Group of Myelodysplastic Syndrome in Childhood studies was evaluated with regard to karyotypic complexity. Structurally complex constitutes a new definition of complex karyotype characterized by more than or equal to 3 chromosomal aberrations, including at least one structural aberration. Five-year overall survival in patients with more than or equal to 3 clonal aberrations, which were not structurally complex, did not differ from that observed in patients with normal karyotype. Cox regression analysis revealed the presence of a monosomal and structurally complex karyotype to be strongly associated with poor prognosis (hazard ratio = 4.6, P < .01). Notably, a structurally complex karyotype without a monosomy was associated with a very short 2-year overall survival probability of only 14% (hazard ratio = 14.5; P < .01). The presence of a structurally complex karyotype was the strongest independent prognostic marker predicting poor outcome in children with advanced myelodysplastic syndrome.


A nocturnal atmospheric loss of CH2I2 in the remote marine boundary layer.
Ocean emissions of inorganic and organic iodine compounds drive the biogeochemical cycle of iodine and produce reactive ozone-destroying iodine radicals that influence the oxidizing capacity of the atmosphere. Di-iodomethane (CH2I2) and chloro-iodomethane (CH2ICl) are the two most important organic iodine precursors in the marine boundary layer. Ship-borne measurements made during the TORERO (Tropical Ocean tRoposphere Exchange of Reactive halogens and Oxygenated VOC) field campaign in the east tropical Pacific Ocean in January/February 2012 revealed strong diurnal cycles of CH2I2 and CH2ICl in air and of CH2I2 in seawater. Both compounds are known to undergo rapid photolysis during the day, but models assume no night-time atmospheric losses. Surprisingly, the diurnal cycle of CH2I2 was lower in amplitude than that of CH2ICl, despite its faster photolysis rate. We speculate that night-time loss of CH2I2 occurs due to reaction with NO3 radicals. Indirect results from a laboratory study under ambient atmospheric boundary layer conditions indicate a k CH2I2+NO3 of ≤4 × 10-13 cm3 molecule-1 s-1; a previous kinetic study carried out at ≤100 Torr found k CH2I2+NO3 of 4 × 10-13 cm3 molecule-1 s-1. Using the 1-dimensional atmospheric THAMO model driven by sea-air fluxes calculated from the seawater and air measurements (averaging 1.8 +/- 0.8 nmol m-2 d-1 for CH2I2 and 3.7 +/- 0.8 nmol m-2 d-1 for CH2ICl), we show that the model overestimates night-time CH2I2 by >60 % but reaches good agreement with the measurements when the CH2I2 + NO3 reaction is included at 2-4 × 10-13 cm3 molecule-1 s-1. We conclude that the reaction has a significant effect on CH2I2 and helps reconcile observed and modeled concentrations. We recommend further direct measurements of this reaction under atmospheric conditions, including of product branching ratios.


Geriatric rehabilitation. 3. Mid- and late-life effects of early-life disabilities.
This self-directed learning module highlights mid- and late-life effects of early-life disabilities. It is part of the chapter on geriatric rehabilitation in the Self-Directed Medical Knowledge Program for practitioners and trainees in physical medicine and rehabilitation. This article contains information on how to evaluate, prevent, and manage late complications seen in adults and older adults with cerebral palsy, spina bifida, spinal cord injury, multiple sclerosis, juvenile rheumatoid arthritis, and early-life amputations, including psychosocial and other quality-of-life issues. New advances in post-polio syndrome are also covered.


Complications of cosmetic wide conjunctivectomy combined with postsurgical mitomycin C application.
To raise awareness among clinicians about the risk of severe complications after cosmetic conjunctivectomy plus postsurgical topical mitomycin C (MMC) treatment. We retrospectively reviewed the medical records of 48 consecutive patients who received cosmetic wide conjunctivectomy plus postsurgical topical MMC treatment to eliminate conjunctival injection and visited our outpatient clinic between January 2009 and January 2011. Forty-four patients (91.67%) developed complications after cosmetic wide conjunctivectomy plus postsurgical topical MMC treatment. Complications included chronic conjunctival epithelial defects (22 patients), scleral thinning with (19 patients) or without (2 patients) calcified plaques, fibrovascular conjunctival adhesion at the muscle insertion site (15 patients), chronic dysfunctional tear syndrome (11 patients), avascular zones (10 patients), abnormal vessel growth (5 patients), lymphangiectasis (3 patients), adhesions of Tenon capsule and the conjunctiva at the extraocular muscle insertion site (1 patient), extraocular muscle fiber exposure (1 patient), and diplopia (9 patients). The mean time between surgery and the onset of diplopia was 1.67 months (range, 1-3 months), and the mean deviation was 11.0 prism diopters (range, 0-25 prism diopters) in the primary position. Three patients underwent strabismus surgery due to incomitant esotropia. Eight patients underwent calcified plaque removal because of severe progression of the calcification. Five patients underwent conjunctival flap operation because of severe progressive scleral thinning. Cosmetic wide conjunctivectomy, which has been advertised as a simple and effective surgical option for the treatment of conjunctival injection, has caused disruption in the normal physiology of the ocular surface, which leads to various devastating complications.


Changes in family variables among normal and overweight preschoolers.
The purpose of this study was to examine differences in the weight and height of normal and overweight children in variables relating to the individual, home/family and community across a six month time period. RESEARCH QUESTIONS/HYPOTHESES: What are the ecological factors that influence the body mass index (BMI) of preschool children? The rate of overweight preschool children aged 2 to 5 years has more than doubled in the past 30 years. Low socioeconomic and ethnic minority groups have higher rates. Research shows a strong correlation between a child's size (height, weight, and BMI) and the ecological factors present in the family's environment. This study is a secondary data analysis from a cross sectional study of 200 Mexican American children ages 2-3 years old receiving WIC services. The sample consisted of 100 children with a BMI > 95% for age and 100 children with a BMI of <85% for age. Variables and measurements included: host/child (BMI percentile, diet, TV watching hours); agent/food (feeding assistance); microsystem/parent (parental BMI, acculturation level, employment, physical activities); microsystem/home (stimulation, TV hours); and microsystem/mother-child relationship (NCAST Teaching Scale).This study is limited to populations with similar characteristics. Both overweight and normal weight children showed decreases in BMI, but maintained their between group differences even while slimming down (p = .000). Overweight children consumed significantly more fruit, bread and other carbohydrates, and total calories, than did normal weight children. Both groups of children increased significantly in their consumption of water, fruit juice and juice drinks, as well as meat and other protein. Maternal BMIs for overweight children were higher than those for the mothers of the normal weight children and increased across time. More overweight children ate in the presence of another person. The interaction patterns between mothers and overweight children were significantly more positive and responsive than were the interaction patterns of mothers and normal weight children. multiple ecological factors influence the BMI of the preschooler leading to obesity. Nurses can use these findings to teach parents about the importance managing the environmental factors that contribute to childhood obesity and growth.


The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases.
A20 is a Cys2/Cys2 zinc finger protein which is induced by a variety of inflammatory stimuli and which has been characterized as an inhibitor of cell death by a yet unknown mechanism. In order to clarify its molecular mechanism of action, we used the yeast two-hybrid system to screen for proteins that interact with A20. A cDNA fragment was isolated which encoded a portion of a novel protein (TXBP151), which was recently found to be a human T-cell leukemia virus type-I (HTLV-I) Tax-binding protein. The full-length 2386 bp TXBP151 mRNA encodes a protein of 86 kDa. Like A20, overexpression of TXBP151 could inhibit apoptosis induced by tumour necrosis factor (TNF) in NIH3T3 cells. Moreover, transfection of antisense TXBP151 partially abolished the anti-apoptotic effect of A20. Furthermore, apoptosis induced by TNF or CD95 (Fas/APO-1) was associated with proteolysis of TXBP151. This degradation could be inhibited by the broad-spectrum caspase inhibitor zVAD-fmk or by expression of the cowpox virus-derived inhibitor CrmA, suggesting that TXBP151 is a novel substrate for caspase family members. TXBP151 was indeed found to be specifically cleaved in vitro by members of the caspase-3-like subfamily, viz. caspase-3, caspase-6 and caspase-7. Thus TXBP151 appears to be a novel A20-binding protein which might mediate the anti-apoptotic activity of A20, and which can be processed by specific caspases.


The endobronchial ultrasound-guided transbronchial lung biopsy in peripheral pulmonary lesions.
Peripheral pulmonary lesions are technically challenging with conventional bronchoscopy in obtaining tissue diagnosis. The recently developed small-caliber ultrasonographic probe can be introduced via the working channel of a flexible bronchoscope to localize peripheral pulmonary lesions (PPLs) prior to transbronchial lung biopsy (TBLB). The endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) is a new diagnostic method for the diagnosis of pulmonary lesions in our center. To evaluate the diagnostic yield of EBUS-TBLB in pulmonary lesions. A prospective cross-sectional study. We enrolled 152 patients with pulmonary lesions that were beyond the segmental bronchus and had no evidence of endobronchial lesion, who underwent bronchoscopy in our center. With EBUS assisted, transbronchial lung biopsy was performed after localizing and measuring distance from the tip of bronchoscope to the lesion. The diagnostic yield was calculated. The pulmonary lesions were visible on EBUS image in 98.7% of cases. The overall diagnostic yield of EBUS-TBLB was 66.4%. The diagnostic yield in the infiltrative and mass lesions were 86.4% and 63.1%, respectively. The lesions which EBUS probe located within it were diagnosed by EBUS-TBLB about 74.8%. The benign and malignant lesions were diagnosed by EBUS-TBLB about 81.1% and 58.6%, respectively. The average EBUS time was 3.55 +/- 2.29 minutes. No complication of EBUS and transbronchial lung biopsy were observed in this study. EBUS-TBLB is a safe procedure for diagnosing pulmonary lesions. Our results indicate that the EBUS-TBLB improves the diagnostic yield compared to conventional brochoscopy.


Neuropsychiatric and Behavioral Involvement in AAS Abusers. A Literature Review.
Background and Objectives: Anabolic androgenic steroids (AASs) are a complex group of molecules that include both steroidal androgens and synthetic compounds, derived from testosterone. AASs are commonly used to support pharmacological therapy in cases of primary or secondary hypogonadism, major burns, and neoplastic cachexia. Their prolonged and supra-physiological consumption can provoke several adverse effects on various organs and systems. Among these, the physiopathological mechanisms that induce neuropsychiatric disorders related to AAS abuse are poorly known. For this reason, the proposed review aims to retrace the pathway of action of testosterone to focus on the effects on the central nervous system and specifically highlight the effects of AASs on neuropsychiatric and behavioral functions, as well as on lifestyle. Materials and Methods: This review was conducted using PubMed and Google Scholar databases. On these database websites, we searched for articles from 1 January 1980 to March 2019 using the key terms: "AAS," "Anabolic Androgenic Steroids," "brain," and "neurology." Results: The use of AASs through self-administration yields circulating androgens levels, inducing neuron apoptosis, which is linked to thinner cortex and, in general, less cortical volume. The same alterations affect the putamen. These differences were more evident when correlated with longer use. From a functional point of view, prolonged AAS consumption seemed to be related to lower connectivity between amygdala and frontal, striatal, limbic, hippocampal and visual cortical areas. On the other hand, AAS use seems to negatively condition the positive effects of the sport exercise, reducing its important anti-apoptotic and pro-proliferative functions on the hippocampus, implicated in anxiolytic control. Conclusion: This review clarifies the major aspects of the side effects related to AAS use/abuse highlighting the complex mechanisms on neuropsychiatric and cognitive pathological alterations and also the emotional and behavioral dysfunctions.


E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia.
Transgenic mice with lymphoid-restricted overexpression of the double bromodomain protein bromodomain-containing 2 (Brd2) develop splenic B-cell lymphoma and, upon transplantation, B-cell leukemia with leukemic infiltrates in liver and lung. Brd2 is a nuclear-localized transcription factor kinase that is most closely related to TATA box binding protein-associated factor, 250 kDa (TAF(II)250) and the Drosophila developmental protein female sterile homeotic. Constitutive expression of BRD2 in the lymphoid compartment increases cyclin A transcription, "priming" transgenic B cells for proliferation. Mice stochastically develop an aggressive B-cell lymphoma with the features of B-1 cells, including CD5 and surface IgM expression. The B-cell lymphoma is monoclonal for immunoglobulin gene rearrangement and is phenotypically stable. The lymphoblasts are very large and express a transcriptome that is similar to human non-Hodgkin lymphomas. Both a wild-type BRD2 transgene and a kinase-null point mutant drive lymphomagenesis; therefore we propose that, rather than kinase activity, Brd2-mediated recruitment of E2 promoter binding factors (E2Fs) and a specific histone acetyltransferase to the cyclin A promoter by both types of transgene is a mechanistic basis for neoplasia. This report is the first to describe a transgenic mouse model for constitutive expression of a protein with more than one bromodomain.


SB203580 increases G-CSF production via a stem-loop destabilizing element in the 3' untranslated region in macrophages independently of its effect on p38 MAPK activity.
Granulocyte-colony stimulating factor (G-CSF) is a major regulator of the production and survival of neutrophils. Regulation of G-CSF expression is complex and occurs at both transcription and post-transcription levels. Two distinct types of cis-acting elements in the 3' untranslated region (3'UTR) of G-CSF mRNA have been identified as destabilizing elements; these consist of adenylate uridylate-rich elements (AUREs) and a stem-loop destabilizing element (SLDE). Regulation of the stability of mRNA by p38 mitogen-activated protein kinase (MAPK) has been indicated to be linked to AUREs in the 3'UTR. However, whether p38 MAPK is involved in the regulation of the stability of G-CSF mRNA has not been elucidated. This study investigated the effect of SB203580, an inhibitor of p38 MAPK, on the lipopolysaccharide-induced G-CSF expression in macrophages at the post-transcription level. Our study showed surprising results that SB203580 augmented the lipopolysaccharide-induced increase in the G-CSF mRNA levels in RAW264.7 mouse macrophages, mouse bone marrow-derived macrophages and in THP-1 human macrophages. This effect was also seen in p38α MAPK knockdown RAW264.7 cells, showing that it was not due to inhibition of p38 MAPK activity. In the presence of actinomycin D, the decay of G-CSF mRNA was slower in SB203580-treated cells than in control cells, showing that SB203580 increased the stability of G-CSF mRNA. Reporter genes containing luciferase with or without the 3'UTR of G-CSF were constructed and transfected into RAW264.7 cells and the results showed that the presence of the 3'UTR reduced the luciferase mRNA levels and luciferase activity. Furthermore, SB203580 increased the luciferase mRNA levels and activity in RAW264.7 cells transfected with the luciferase reporter containing the 3'UTR, but not in cells transfected with the luciferase reporter without the 3'UTR. Mutations of the highly conserved SLDE in the 3'UTR abolished these effects, showing that the SLDE was essential for the SB203580-induced increase in the stability of mRNA. SB203580 increases G-CSF expression in macrophages by increasing the stability of G-CSF mRNA via its 3'UTR, and the effect was not due to its inhibition of p38 MAPK activity. The results of this study also highlight a potential target for boosting endogenous production of G-CSF during neutropenia.