The putative neuraminyllactose-binding hemagglutinin HpaA of Helicobacter pylori CCUG 17874 is a lipoprotein.
The ability of certain strains of Helicobacter pylori to cause sialic acid-sensitive agglutination of erythrocytes has been attributed to the HpaA protein (D.G. Evans, T.K. Karjalainen, D. J. Evans, Jr., D. Y. Graham, and C.H. Lee, J. Bacteriol. 175:674-683, 1993), the gene for which has been cloned and sequenced. On the basis of the hydropathy plot of HpaA and the presence of a potential lipoprotein signal sequence and modification site, and because of the similarities of these features with those of the cell envelope lipoprotein Lpp20 of H. pylori, we examined the possibility that HpaA was also a lipoprotein. Posttranslational processing of the HpaA protein expressed by the cloned gene was sensitive to globomycin, an inhibitor of the lipoprotein-specific signal peptidase II. Antibodies raised to the putative sialic acid-binding region of HpaA failed to bind to the surface of H. pylori cells in immunoelectron microscopy but instead were observed to have labeled the cytoplasm when thin sections were examined. This antibody recognized a 29,000-M(r) protein in Western blots (immunoblots) of cell extracts of H. pylori and Escherichia coli cells expressing the cloned hpaA gene. Determination of the sequence of hpaA from strain CCUG 17874 indicated significant differences from that determined by Evans and coworkers in the above-mentioned study, including extension of the gene into the open reading frame 3 downstream of hpaA to produce a protein with an M(r) of 26,414. Localization of HpaA indicated that it was predominantly located in the cytoplasmic fraction of the cell in both E. coli and H. pylori. HpaA was not observed in the sarkosyl-insoluble outer membrane fraction. An isogenic mutant generated by insertional inactivation of hpaA was unaffected in its ability to bind four different human cell lines as well as fixed sections of gastric tissue and had hemagglutination properties identical to those of the wild type. The data collectively suggest that HpaA is a nonessential lipoprotein internal to the H. pylori cell and that it is not involved in adhesion.


The stable isotope composition of nitrogen and carbon and elemental contents in modern and fossil seabird guano from Northern Chile - Marine sources and diagenetic effects.
Seabird excrements (guano) have been preserved in the arid climate of Northern Chile since at least the Pliocene. The deposits of marine organic material in coastal areas potentially open a window into the present and past composition of the coastal ocean and its food web. We use the stable isotope composition of nitrogen and carbon as well as element contents to compare the principal prey of the birds, the Peruvian anchovy, with the composition of modern guano. We also investigate the impact of diagenetic changes on the isotopic composition and elemental contents of the pure ornithogenic sediments, starting with modern stratified deposits and extending to fossil guano. Where possible, 14C systematics is used for age information. The nitrogen and carbon isotopic composition of the marine prey (Peruvian anchovy) of the birds is complex as it shows strong systematic variations with latitude. The detailed study of a modern profile that represents a few years of guano deposition up to present reveals systematic changes in nitrogen and carbon isotopic composition towards heavier values that increase with age, i.e. depth. Only the uppermost, youngest layers of modern guano show compositional affinity to the prey of the birds. In the profile, the simultaneous loss of nitrogen and carbon occurs by degassing, and non-volatile elements like phosphorous and calcium are passively enriched in the residual guano. Fossil guano deposits are very low in nitrogen and low in carbon contents, and show very heavy nitrogen isotopic compositions. One result of the study is that the use of guano for tracing nitrogen and carbon isotopic and elemental composition in the marine food web of the birds is restricted to fresh material. Despite systematic changes during diagenesis, there is little promise to retrieve reliable values of marine nitrogen and carbon signatures from older guano. However, the changes in isotopic composition from primary marine nitrogen isotopic signatures towards very heavy values generate a compositionally unique material. These compositions trace the presence of guano in natural ecosystems and its use as fertilizer in present and past agriculture.


Morbidity and Mortality Differences Between Hematopoietic Cell Transplantation Survivors and Other Cancer Survivors.
Purpose To compare the risks of serious health outcomes among hematopoietic cell transplantation (HCT) survivors versus a matched population of patients with cancer who did not undergo HCT, where the primary difference may be exposure to HCT. Methods Two-year HCT survivors treated at a comprehensive cancer center from 1992 through 2009 who were Washington State residents (n = 1,792; 52% allogeneic and 90% hematologic malignancies) were frequency matched by demographic characteristics and underlying cancer diagnosis (as applicable) to non-HCT 2-year cancer survivors, using the state cancer registry (n = 5,455) and the general population (n = 16,340) using driver's license files. Late outcomes for all three cohorts were ascertained from the state hospital discharge and death registries; subsequent cancers were ascertained from the state cancer registry. Results After median follow-up of 7.1 years, HCT survivors experienced significantly greater rates of hospitalization compared with matched non-HCT cancer survivors (280 v 173 episodes per 1,000 person-years, P < .001) and greater all-cause mortality (hazard ratio [HR], 1.1; 95% CI, 1.01 to 1.3). HCT survivors had more hospitalizations or death with infections (10-year cumulative incidence, 31% v 22%; HR, 1.4; 95% CI, 1.3 to 1.6) and respiratory complications (cumulative incidence, 27% v 20%; HR, 1.4; 95% CI, 1.2 to 1.5). Risks of digestive, skin, and musculoskeletal complications also were greater among HCT versus non-HCT cancer survivors. The two groups had similar risks of circulatory complications and second cancers. Both HCT and non-HCT cancer survivors had significantly greater 10-year cumulative incidences of all major organ-system outcomes versus the general population. Conclusion History of HCT was associated with late morbidity and mortality among cancer survivors. In particular, clinicians who care for HCT survivors should be aware of their high rates of late respiratory and infectious complications.


Lumbar disc degeneration: association between osteophytes, end-plate sclerosis and disc space narrowing.
Lumbar disc degeneration is characterised radiologically by the presence of osteophytes, end-plate sclerosis and disc space narrowing. To determine the strength of the association between increasing severity of combinations of these features in a population sample of men and women. Men and women aged >or=50 years were recruited from a primary care-based community health index in Aberdeen, UK. Participants had lateral spinal radiographs performed according to a standard protocol. The intervertebral disc spaces (L1/2-L4/5) were evaluated for the presence of anterior osteophytes, end-plate sclerosis and disc space narrowing using a graded semiquantitative score (grade 0-3). Log linear modelling was used to determine the associations (pairwise) between increasing severity of these features, with the results expressed as beta coefficients and 95% confidence intervals (CIs). There were 286 men (mean age 65.3 years) and 299 women (mean age 65.2 years) with spinal radiographs, yielding a total of 2340 assessable lumbar vertebral levels. In all, 73% of vertebral levels had evidence of osteophytes, 26% of sclerosis and 37% of disc space narrowing. Increasing severity of osteophyte grade was associated with an increasing severity both of sclerosis and of disc space narrowing, whereas the severity of sclerosis was associated with the severity of narrowing. This was true at all vertebral levels. The strongest association, however, was between osteophytes and sclerosis (beta coefficient = 2.7, 95% CI 2.4 to 3.1). For sclerosis and narrowing the beta coefficient was 1.9 (95% CI 1.7 to 2.1), whereas for osteophytes and narrowing the beta coefficient was much weaker at 1.2 (95% CI 1.1 to 1.3). There was no important influence of vertebral level on any of these associations. The association between increasing severity of osteophytes and end-plate sclerosis is stronger than for other combinations of radiographic features of lumbar disc degeneration.


Evaluation of Skin Colonisation And Placement of vascular access device Exit sites (ESCAPE Study).
Skin microorganisms may contribute to the development of vascular access device (VAD) infections. Baseline skin microorganism type and quantity vary between body sites, yet there is little evidence to inform choice of VAD site selection. To compare microorganisms present at different body sites used for VAD insertions and understand the effect of transparent dressings on skin microflora. The ESCAPE observational study consisted of three phases: (1) skin swabs of four sites (mid-neck, base neck, chest, upper arm) from 48 hospital patients; (2) skin swabs of five body sites (mid-neck, base neck, chest, upper arm, lower arm) from 10 healthy volunteers; and (3) paired skin swabs (n = 72) under and outside of transparent dressings from 36 hospital patients (16 mid/base neck, 10 chest, upper arm). Specimens were cultured for 72 h, species identified and colony-forming units (CFU) counted. Ordinal logistic regression compared CFU categories between variables of interest. The chest and upper arm were significantly associated with fewer microorganisms compared to neck or forearm (odds ratio [OR] = 0.40, 95% confidence interval [CI] = 0.25-0.65, P < 0.05). CFU levels under transparent dressings were not significantly different from outside (OR = 0.57, 95% CI = 0.22-1.45). Staphylococci were predominant at all sites. Other significant (P < 0.05) predictors of higher CFU count included prolonged hospitalisation and medical/surgical patient status. Skin microorganism load was significantly lower at the upper arm or chest, compared to the mid- or base neck. This may impact VAD site selection and subsequent infection risk.


Endothelial nitric oxide synthase immunoreactivity in early gestation and in trophoblastic disease.
To study the localisation of the endothelial nitric oxide synthase (eNOS) in the normal placenta, with special emphasis on the implantation site in the first trimester of pregnancy, and in the different subtypes of trophoblastic cells in gestational trophoblastic disease. The immunoperoxidase technique with an antibody directed against eNOS was applied to paraffin sections from first and second trimester placentas, placenta accreta, partial and complete hydatidiform moles, and choriocarcinoma. Immunoperoxidase staining for human placental lactogen (hPL) was performed on parallel sections. Prominent immunoreactivity for eNOS was found to be present in the intermediate trophoblastic cells of the cell columns of the anchoring villi and in trophoblastic cells at the implantation site. Staining was also present in the syncytiotrophoblast, most conspicuous at the apical cell border. In trophoblastic disease, proliferating large mononuclear cells, which were strongly positive for hPL, were found to be immunoreactive for eNOS. eNOS immunoreactivity is strongly positive in the extravillous trophoblastic cells and to a lesser extent in the syncytiotrophoblast. In the former it may play a role in implantation and vascular invasion. Cells with differentiation to intermediate trophoblast in complete hydatidiform mole and choriocarcinoma also show high levels of eNOS, which may be associated with the haematogenous mode of spread of trophoblastic disease.


Can attention selectively bias bistable perception? Differences between binocular rivalry and ambiguous figures.
It is debated whether different forms of bistable perception result from common or separate neural mechanisms. Binocular rivalry involves perceptual alternations between competing monocular images, whereas ambiguous figures such as the Necker cube lead to alternations between two possible pictorial interpretations. Previous studies have shown that observers can voluntarily control the alternation rate of both rivalry and Necker cube reversal, perhaps suggesting that bistable perception results from a common mechanism of top-down selection. However, according to the biased competition model of selective attention, attention should be able to enhance the attended percept and suppress the unattended percept. Here, we investigated selective attentional modulation of dominance durations in bistable perception. Observers consistently showed much weaker selective attentional control for rivalry than for Necker cube reversal, even for rivalry displays that maximized the opportunities for feature-, object-, or space-based attentional selection. In contrast, nonselective control of alternation rate was comparably strong for both forms of bistable perception and corresponded poorly with estimates of selective attentional control. Our results support the notion that binocular rivalry involves a more automatic, stimulus-driven form of visual competition than Necker cube reversal, and as a consequence, is less easily biased by selective attention.


Further evaluation of the reinforcing effects of the novel cocaine analog 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) in rhesus monkeys.
2Beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) is a cocaine analog which has been shown in rhesus monkeys to have cocaine-like discriminative stimulus effects and a long duration of action (>8 h), yet does not function as a reinforcer when substituted for cocaine in monkeys responding under a fixed-interval 5-min schedule (Nader et al. 1997). The purpose of the present study was to evaluate the reinforcing effects of PTT under a fixed-ratio (FR) schedule and to determine if decreasing the inter-injection interval would influence the reinforcing effects of PTT. Male rhesus monkeys (n=3) were trained to respond under a multiple FR 30 food-drug-food schedule. When responding was stable, cocaine (0.003-0.3 mg/kg per injection) or PTT (0.001-0.03 mg/kg per injection) was available during the drug component for at least five consecutive sessions and until stable responding was observed. To investigate whether the inter-injection interval would influence PTT-maintained response rates, the time-out (TO) following PTT injections was reduced from 180 or 300 s to 10 s for at least five consecutive sessions. Cocaine-maintained response rates were characterized as an inverted-U shaped function of dose, with peak rates maintained by 0.03 mg/kg per injection cocaine. PTT (0.001-0.03 mg/kg per injection) maintained response rates significantly higher than rates maintained by the PTT vehicle, but significantly lower than cocaine-maintained response rates; PTT intake increased with a dose. A reduction of the TO following PTT injections to 10 s did not alter PTT-maintained response rates or total session intake. Self-administered PTT was more potent than cocaine at decreasing food-maintained responding. These results suggest that for long-acting compounds like PTT, reinforcing effects are more likely to be observed when the drug is available under a ratio-based schedule, compared to an interval-based schedule.


Endosonography-related mortality and morbidity for pulmonary indications: a nationwide survey in the Netherlands.
Endosonography is being implemented rapidly in pulmonary medicine for the diagnosis and staging of lung cancer, the assessment of sarcoidosis, and the assessment of mediastinal lesions. Although serious adverse events (SAEs) have been described, safety data outside cohort studies are scarce. To assess the SAE and mortality rate of EUS-guided FNA (EUS-FNA) and endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for mediastinal and/or hilar analysis. Nationwide, retrospective survey by using questionnaires. All hospitals in the Netherlands. All patients undergoing EUS-FNA and EBUS-TBNA for intrathoracic analysis in the period 1999 to 2011. EUS-FNA and EBUS-TBNA. Occurrence of fatal outcomes and SAEs. Detailed information was obtained for each reported case, and all cases were reviewed independently by 2 investigators, including identification of risk factors. All 89 hospitals (100%) responded. An estimated 14,075 EUS-FNA and 2675 EBUS procedures were performed. Seven patients died after endosonography (5 EUS-FNA, 2 EBUS [mortality rate 0.04%]). All fatalities occurred in patients of poor performance status (American Society of Anesthesiologists Physical Status Classification System score of III/IV). Twenty-five SAEs were reported (22 EUS-FNA, 3 EBUS [SAE rate of 0.15%; EUS-FNA 0.16%, EBUS 0.11%]). SAEs were mostly (64%) of infectious origin. No specific risk factors for infectious adverse events could be identified. Retrospective study, possible recall bias, overrepresentation of EUS-FNA cases. Endosonography appears to be a safe technique for the analysis of mediastinal and/or hilar lesions. Poor performance status is a risk factor for fatal outcomes. Mediastinitis and/or mediastinal abscess formation is rare but is a potential and dangerous adverse event of endosonography.


Effect of Astaxanthin Supplementation on Salivary IgA, Oxidative Stress, and Inflammation in Young Soccer Players.
The physiologic stress induced by physical activity is reflected in immune system perturbations, oxidative stress, muscle injury, and inflammation. We investigated the effect of astaxanthin (Asx) supplementation on salivary IgA (sIgA) and oxidative stress status in plasma, along with changes in biochemical parameters and total/differential white cell counts. Forty trained male soccer players were randomly assigned to Asx and placebo groups. Asx group was supplemented with 4 mg of Asx. Saliva and blood samples were collected at the baseline and after 90 days of supplementation in preexercise conditions. We observed a rise of sIgA levels at rest after 90 days of Asx supplementation, which was accompanied with a decrease in prooxidant-antioxidant balance. The plasma muscle enzymes levels were reduced significantly by Asx supplementation and by regular training. The increase in neutrophil count and hs-CRP level was found only in placebo group, indicating a significant blunting of the systemic inflammatory response in the subjects taking Asx. This study indicates that Asx supplementation improves sIgA response and attenuates muscle damage, thus preventing inflammation induced by rigorous physical training. Our findings also point that Asx could show significant physiologic modulation in individuals with mucosal immunity impairment or under conditions of increased oxidative stress and inflammation.


The histidine kinase AHK5 integrates endogenous and environmental signals in Arabidopsis guard cells.
Stomatal guard cells monitor and respond to environmental and endogenous signals such that the stomatal aperture is continually optimised for water use efficiency. A key signalling molecule produced in guard cells in response to plant hormones, light, carbon dioxide and pathogen-derived signals is hydrogen peroxide (H(2)O(2)). The mechanisms by which H(2)O(2) integrates multiple signals via specific signalling pathways leading to stomatal closure is not known. Here, we identify a pathway by which H(2)O(2), derived from endogenous and environmental stimuli, is sensed and transduced to effect stomatal closure. Histidine kinases (HK) are part of two-component signal transduction systems that act to integrate environmental stimuli into a cellular response via a phosphotransfer relay mechanism. There is little known about the function of the HK AHK5 in Arabidopsis thaliana. Here we report that in addition to the predicted cytoplasmic localisation of this protein, AHK5 also appears to co-localise to the plasma membrane. Although AHK5 is expressed at low levels in guard cells, we identify a unique role for AHK5 in stomatal signalling. Arabidopsis mutants lacking AHK5 show reduced stomatal closure in response to H(2)O(2), which is reversed by complementation with the wild type gene. Over-expression of AHK5 results in constitutively less stomatal closure. Abiotic stimuli that generate endogenous H(2)O(2), such as darkness, nitric oxide and the phytohormone ethylene, also show reduced stomatal closure in the ahk5 mutants. However, ABA caused closure, dark adaptation induced H(2)O(2) production and H(2)O(2) induced NO synthesis in mutants. Treatment with the bacterial pathogen associated molecular pattern (PAMP) flagellin, but not elf peptide, also exhibited reduced stomatal closure and H(2)O(2) generation in ahk5 mutants. Our findings identify an integral signalling function for AHK5 that acts to integrate multiple signals via H(2)O(2) homeostasis and is independent of ABA signalling in guard cells.


Measuring campus sexual misconduct and its context: The Administrator-Researcher Campus Climate Consortium (ARC3) survey.
In response to The White House Task Force to Protect Students from Sexual Assault's recommendations, the Administrator-Researcher Campus Climate Collaborative (ARC3) has curated an empirically sound, no-cost campus climate survey for U.S. institutions of higher education. The ARC3 survey contains 19 modules that assess a range of Title IX violations, including sexual harassment, dating violence, and sexual misconduct victimization and perpetration; sexual misconduct prevention efforts, resources, and responses; and key predictors and possible outcomes of sexual misconduct. This article describes the ARC3 survey development and pilot test psychometric data. A total of 909 students attending one of three U.S. universities responded to the survey; 85% of students who began the survey completed it. Students completed the ARC3 survey in slightly less than 30 min, on average. The majority of measures produced evidence for at least acceptable internal consistency levels (α > .70), with only two short item sets having marginal reliability (α = .65-.70). Correlations among scales matched expectations set by the research literature. Students generally did not find the survey distressing; in fact, students viewed the climate assessment as important and personally meaningful. The survey performed sufficiently well in pilot testing to recommend its use with U.S. college populations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Impact of Coping Veneering Techniques on the Survival of Implant-Supported Zirconia-Based-Crowns Cemented to Hybrid-Abutments: An-In-Vitro Study.
The objective of this study is to investigate the influence of veneering technique (hand-layering vs. milling) on the fracture resistance of bi-layer implant-supported zirconia-based hybrid-abutment crowns. Mandibular molar copings were anatomically designed and milled. Copings were then veneered by hand-layering (HL) (n = 20) and milling using the Cad-On technique (LD) (n = 20). Crowns were cemented to zirconia hybrid-abutments. Ten samples of each group acted as a control while the remaining ten samples were subjected to fatigue in a chewing simulator. Crowns were loaded between 50 and 100 N for 1.2 million cycles under simultaneous temperature fluctuation between 5 and 55 °C. Crowns were then subjected to static load a to fracture test. Data were statistically analysed using the one-way ANOVA. Randomly selected crowns from each group were observed under scanning electron microscopy to view fractured surfaces. Study results indicate that during fatigue, LD crowns had a 100% survival rate; while HL crowns had a 50% failure rate. Fracture resistance of LD crowns was statistically significantly higher than that of HL crowns at the baseline and after fatigue (p ≤ 0.05). However, fatigue did not cause a statistically significant reduction in fracture resistance in both LD and HL groups (p > 0.05). Copings fractured in the LD crowns only and the fracture path was different in both LD and HL groups. According to the results, it was concluded that milled veneer implant-supported hybrid-abutment crowns exhibit significantly higher fracture resistance, and better withstand clinical masticatory loads in the posterior region compared to the hand-layered technique. Also, fatigue application and artificial aging caused no significant strength reduction in both techniques. Clinical significance: Different veneering techniques and materials (hand-layering or milling) act differently to clinical forces and environment and may be prone to early chipping during service. Therefore, practitioners are urged to consider the appropriate veneering protocol for posterior implant-supported hybrid-abutment restorations.


Reconstruction of centennial-scale fluxes of chemical elements in the Australian coastal environment using seagrass archives.
The study of a Posidonia australis sedimentary archive has provided a record of changes in element concentrations (Al, Fe, Mn, Pb, Zn, Cr, Cd, Co, As, Cu, Ni and S) over the last 3000 years in the Australian marine environment. Human-derived contamination in Oyster Harbor (SW Australia) started ~100 years ago (AD ~1900) and exponentially increased until present. This appears to be related to European colonization of Australia and the subsequent impact of human activities, namely mining, coal and metal production, and extensive agriculture. Two contamination periods of different magnitude have been identified: Expansion period (EXP, AD ~1900-1970) and Establishment period (EST, AD ~1970 to present). Enrichments of chemical elements with respect to baseline concentrations (in samples older than ~115 cal years BP) were found for all elements studied in both periods, except for Ni, As and S. The highest enrichment factors were obtained for the EST period (ranging from 1.3-fold increase in Cu to 7.2-fold in Zn concentrations) compared to the EXP period (1.1-fold increase for Cu and Cr to 2.4-fold increase for Pb). Zinc, Pb, Mn and Co concentrations during both periods were 2- to 7-fold higher than baseline levels. This study demonstrates the value of Posidonia mats as long-term archives of element concentrations and trends in coastal ecosystems. We also provide preliminary evidence on the potential for Posidonia meadows to act as significant long-term biogeochemical sinks of chemical elements.


A clinical trial of anti-idiotype therapy for B cell malignancy.
Eleven patients with B lymphocytic malignancy were treated with mouse monoclonal anti-idiotype antibodies. All but one of the patients in this study had received extensive prior treatment with conventional lymphoma therapy. All antibodies were prepared against, and uniquely reactive with, the patient's own tumor. Ten patients were treated with a single antibody, but one patient received three antibodies concurrently. The treatment protocol initially used an escalating dose schedule that was intended to evaluate toxicity, pharmacokinetics and, eventually, to achieve appreciable levels of free mouse antibody in the circulation. The last two patients received substantial initial doses. Tumor sampling was performed before and during therapy to evaluate tissue penetration by antibody. None of the patients had serum paraproteins by routine clinical testing, but six had idiotype protein detectable by a sensitive immunoassay at levels greater than 1 microgram/mL, two of which were greater than 200 micrograms/mL. Plasmapheresis was capable of reducing these levels temporarily. However, the presence of serum idiotype increased the requirement for mouse antibody to achieve tumor penetration. Another obstacle to treatment was immune response to mouse Ig, which occurred in five of the 11 patients. Once an immune response had begun, further infusions of antibody were not capable of reaching the tumor or inducing tumor regression and were associated with toxicity. Our initial patient remains in an unmaintained complete remission 42 months after receiving antibody. Five of ten additional patients have had objective remissions that were also clinically significant. However, these remissions were not complete and were of relatively short duration. This therapy shows promise as an alternative modality for the treatment of B cell malignancy. Further study will be needed to determine the mechanisms of the antitumor effect and to improve the clinical results.


Efficacy of Deep Brain Stimulation in a Patient with Genetically Confirmed Chorea-Acanthocytosis.
Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disease due to mutation of the VPS13A gene encoding the protein chorein. ChAc is a slowly progressive disorder that typically presents in early adulthood, and whose clinical features include chorea and dystonia with involuntary lip, cheek, and tongue biting. Some patients also have seizures. Treatment for ChAc is symptomatic. A small number of ChAc patients have been treated with bilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi), and we now present an additional case. Patient chart, functional measures, and laboratory findings were reviewed from the time of ChAc diagnosis until 6 months after DBS surgery. Here, we present a case of ChAc in a 31-year-old male positive for VPS13A gene mutations who presented with chorea, tongue biting, dysarthria, weight loss, and mild cognitive dysfunction. DBS using monopolar stimulation with placement slightly lateral to the GPi was associated with significant improvement in chorea and dysarthria. This case adds to the current state of knowledge regarding the efficacy and safety of bilateral GPi-DBS for symptomatic control of drug-resistant hyperkinetic movements seen in ChAc. Controlled trials are needed to better assess the impact and ideal target of DBS in ChAc.


Identification and structure characterization of S-containing metabolites of 3-tert-butyl-4-hydroxyanisole in rat urine and liver microsomes.
After ip administration of 3-tert-butyl-4-hydroxyanisole (3-BHA) to rats, two previously undocumented metabolites 2-tert-butyl-5-methylthiohydroquinone (TBHQ-5-SMe) and 2-tert-butyl-6-methylthiohydroquinone (TBHQ-6-SMe) were identified in the urine by comparison with the authentic samples by GC/MS. In addition to these metabolites, 3-tert-butyl-4,5-dihydroxyanisole was also detected in the urine hydrolyzed by beta-glucuronidase/sulfatase. Administration of tert-butylhydroquinone (TBHQ), an O-demethylated metabolite of 3-BHA, also resulted in the formation of the S-containing metabolites, TBHQ-5-SMe and TBHQ-6-SMe. After incubation of TBHQ with rat liver microsomes in the presence of glutathione (GSH), two metabolites were isolated and purified by HPLC. The metabolites were identified as 2-tert-butyl-5-(glutathion-S-yl)hydroquinone and 2-tert-butyl-6-(glutathion-S-yl)hydroquinone by 1H- and 13C-NMR spectrometry and by fast atom bombardment-mass spectrometry. The formation of TBHQ-GSH conjugates required NADPH, molecular oxygen, and GSH. Cytochrome P-450 inhibitors such as SKF 525-A and metyrapone markedly inhibited the formation of TBHQ-GSH conjugates in vitro. These results suggest that TBHQ is converted by cytochrome P-450-mediated monooxygenases to a reactive metabolite, 2-tert-butyl-p-benzoquinone (TBQ), which then conjugates with GSH to form TBHQ-GSH conjugates. GSH S-transferase activities do not seem to play a role in GSH conjugation reaction to TBQ because cytosol fraction from rat liver homogenates did not enhance the microsome-mediated production of TBHQ-GSH conjugates.


Characterization of the "a" determinant region of the hepatitis B virus genome in Iranian patients at different clinical phases of chronic infection.
To determine the distribution of important mutations of the "a" determinant region in the HBV genome among patients in different clinical phases of HBV infection. Variations in Hepatitis B infection not only change the outcome of the disease but also the symptoms from which the chronic HBV patients are suffering. We have meticulously selected a total of 40 chronic HBV patients from four different subclasses of chronic HBV clinical phases including immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B e antigen (HBeAg)-negative (ENEG); 10 samples per each phase. Mutations of the "a" determinant region were identified using PCR-Direct sequencing method. 17 amino-acid substitutions at 12 positions inside the "a" determinant were identified in all forty samples; 3 mutations in the IT group, 6 mutations in the IA phase, 3 mutations in the IC patients and 5 mutations in the ENEG phase. Different substitutions were observed in all four clinical phases. The IA phase was the most variant group with the highest number of amino-acid substitutions. These results did not reveal a strong pattern to distinguish different clinical phases of Chronic HBV infection, but there are some obvious differences regarding the number and position of mutations between these four clinical phases.


Potential for drug interactions in seniors with osteoarthritis.
To document the potential for drug interactions in seniors with osteoarthritis and to consider the usefulness of computerized support for detecting clinically important interactions. Self-administered mailed survey. One question requested a list of all medications (prescribed drugs and self-care products, including herbal and "natural" health products) taken in the last 7 days. Interactions among all medications were assessed using an on-line software package. Three urban primary care practices in Nova Scotia. Questionnaires were sent to 244 patients aged 65 years and older with physician-confirmed osteoarthritis. Number of potential interactions and level of clinical significance associated with each. Response rate was 78% (n = 191); 174 respondents (92%) supplied information on medications. Respondents took an average of 4.7 products of which 2.8 were prescription medications and 1.9 were self-care products. A total of 214 potential interactions were identified; 30 (14%) of these were clinically significant. Most interactions involved nonprescription products, most frequently acetylsalicylic acid. Recommendations in 29 of these 30 clinically significant interactions were cautionary, advising such measures as closer monitoring of blood tests, observation for toxic effects, or making patients aware of side effects. Only 1 interaction prompted a recommendation for avoidance. Respondents reported use of 7 different herbal and natural health products; these products were associated with 5 clinically insignificant interactions. Risk of drug interactions in seniors might be high, but few interactions are clinically significant. Only 1 found in our study carried a recommendation for avoidance. The on-line program reported all significant interactions, but the high proportion of insignificant interactions (6 : 1) also reported could lead physicians to override computer-generated alerts.


Modularity and hormone sensitivity of the Drosophila melanogaster insulin receptor/target of rapamycin interaction proteome.
Genetic analysis in Drosophila melanogaster has been widely used to identify a system of genes that control cell growth in response to insulin and nutrients. Many of these genes encode components of the insulin receptor/target of rapamycin (InR/TOR) pathway. However, the biochemical context of this regulatory system is still poorly characterized in Drosophila. Here, we present the first quantitative study that systematically characterizes the modularity and hormone sensitivity of the interaction proteome underlying growth control by the dInR/TOR pathway. Applying quantitative affinity purification and mass spectrometry, we identified 97 high confidence protein interactions among 58 network components. In all, 22% of the detected interactions were regulated by insulin affecting membrane proximal as well as intracellular signaling complexes. Systematic functional analysis linked a subset of network components to the control of dTORC1 and dTORC2 activity. Furthermore, our data suggest the presence of three distinct dTOR kinase complexes, including the evolutionary conserved dTTT complex (Drosophila TOR, TELO2, TTI1). Subsequent genetic studies in flies suggest a role for dTTT in controlling cell growth via a dTORC1- and dTORC2-dependent mechanism.


Aberrant expression of tumor suppressor proteins in the Ewing family of tumors.
Deregulation of tumor suppressor gene function and abrogation of cell cycle control are common features of malignant neoplasms, but corresponding data on Ewing sarcomas and primitive neuroectodermal tumors are relatively scarce. We studied the expression of 4 tumor suppressor proteins in the Ewing family of tumors (EFTs). We examined a series of 20 pediatric EFTs for abnormal expression of p16(INK4a), p14(ARF), p21(WAF1), and pRB by immunohistochemical analysis of pretreatment, nondecalcified archival specimens. Clinical follow up was available in all cases (median, 21 months; range, 5-103 months). Five patients presented with metastatic disease, 8 had no evidence of disease at last follow up, and 12 had an adverse outcome (death or progressive tumor posttherapy). Twelve cases (60%) demonstrated abnormal expression of at least one tumor suppressor protein. There were 11 cases (55%) with loss of p21(WAF1) expression, 4 (20%) with down-regulation of p16(INK4a), 2 (10%) with absence of pRB, and one case (5%) with loss of p14(ARF) expression. Loss of p16(INK4a) expression correlated with metastatic disease at presentation (P =.026), and showed a trend toward shortened survival (P =.20). The p21(WAF1), p14(ARF), and pRB status was not significantly correlated with either metastatic disease at presentation or outcome. Abrogation of the G1 checkpoint was common in this series of EFTs, and down-regulation of p21(WAF1) and p16(INK4a) were the most frequent findings. Loss of p16(INK4a) expression may identify a subset of cases with a more aggressive phenotype.


Nebivolol ameliorates nitric oxide deficient hypertension.
Nebivolol is a new selective beta 1-adrenoceptor antagonist with nitric oxide (NO)-releasing properties. In the present study we have analyzed whether nebivolol affects the development of the arterial hypertension that follows the chronic inhibition of nitric oxide synthesis. Nebivolol (1 mg/kg/day, 14 days) was given concurrently with the NO synthesis inhibitor Nw-nitro-L-arginine methyl ester (L-NAME, 0.1, 1, and 10 mg/kg/day, 14 days) to several groups of rats. Blood pressure, renal function, plasma renin activity (PRA), and NO activity and metabolites were measured at the end of the treatment period. L-NAME treatment alone increased mean arterial pressure dose dependently (103.5 +/- 2.4, 110.9 +/- 2.0, and 125.8 +/- 2.2 mmHg, respectively). Nebivolol completely prevented the development of arterial hypertension in the groups treated with L-NAME at the doses of 0.1 and 1 mg/kg/day and reduced the increase achieved with the L-NAME dose of 10 mg/kg/day (110.3 +/- 2.7). There were no differences in glomerular filtration rate or natriuresis between nebivolol-treated and -untreated rats. Plasma nitrates+nitrites and calcium-dependent NO synthase activity in the kidney also decreased dose dependently with L-NAME treatment and nebivolol did not significantly modify it. However, PRA was lower in all groups treated with nebivolol and L-NAME as compared to the rats receiving only L-NAME. These data indicate that nebivolol prevents the development of the arterial hypertension associated with chronic NO deficit and this effect seems to be dependent on the inhibition of renin-angiotensin system.


Prognostic markers in smear preparations for pancreatic endocrine neoplasms: A cytomorphologic study and statistical analysis of 20 potential prognostic features.
Papanicolaou Society of Cytopathology guidelines place low- and intermediate-grade pancreatic endocrine tumors into the "neoplastic, other" category whereas high-grade pancreatic endocrine tumors are placed in the "malignant" category. No attempt was made to stratify pancreatic endocrine tumors in the "neoplastic, other" category by likelihood for metastases. Histologically, pancreatic endocrine tumors are divided into well, intermediate, and poorly differentiated examples based on mitotic count and Ki-67 proliferation index (PI). PI has been used in the evaluation of cytologic specimens utilizing cell block material. Unfortunately, cell block material may not always be available for analysis, and little data exists as to cytomorphologic features in smear preparations which might distinguish between low- and intermediate-grade endocrine neoplasms and predict metastases. We studied 36 cases of Diff-Quik stained smear preparations for 20 morphologic features to determine which best-classified cases into poor and not poor outcome categories. Hierarchical logistic regression analysis was used to determine associations between the morphologic features and outcomes. Absolute agreement between raters ranged from 51% to 97% across the 20 morphologic features. About 12 of the 20 morphologic features showed statistically significant associations with poor outcome. Mitoses, irregular nuclear membranes, and 3-fold variation in nuclear size are the best discriminators between poor and not poor outcomes. A scoring system was developed utilizing mitoses, irregular nuclear membranes, and 3-fold variation in nuclear size to divide smears of pancreatic endocrine tumors into poor and not poor outcome groups. The scoring system achieved 84% accuracy in separating cases into poor and not poor outcomes.


A serological survey of ruminant livestock in Kazakhstan during post-Soviet transitions in farming and disease control.
The results of a serological survey of livestock in Kazakhstan, carried out in 1997--1998, are reported. Serum samples from 958 animals (cattle, sheep and goats) were tested for antibodies to foot and mouth disease (FMD), bluetongue (BT), epizootic haemorrhagic disease (EHD), rinderpest (RP) and peste des petits ruminants (PPR) viruses, and to Brucella spp. We also investigated the vaccination status of livestock and related this to changes in veterinary provision since independence in 1991. For the 2 diseases under official surveillance (FMD and brucellosis) our results were similar to official data, although we found significantly higher brucellosis levels in 2 districts and widespread ignorance about FMD vaccination status. The seroprevalence for BT virus was 23%, and seropositive animals were widespread suggesting endemicity, despite the disease not having being previously reported. We found a few seropositives for EHDV and PPRV, which may suggest that these diseases are also present in Kazakhstan. An hierarchical model showed that seroprevalence to FMD and BT viruses were clustered at the farm/village level, rather than at a larger spatial scale. This was unexpected for FMD, which is subject to vaccination policies which vary at the raion (county) level.


Stigma, social reciprocity and exclusion of HIV/AIDS patients with illicit drug histories: a study of Thai nurses' attitudes.
Stigma is a key barrier for the delivery of care to patients living with HIV/AIDS (PLWHA). In the Asia region, the HIV/AIDS epidemic has disproportionately affected socially marginalised groups, in particular, injecting drug users. The effect of the stigmatising attitudes towards injecting drug users on perceptions of PLWHA within the health care contexts has not been thoroughly explored, and typically neglected in terms of stigma intervention. Semi-structured interviews were conducted with a group of twenty Thai trainee and qualified nurses. Drawing upon the idea of 'social reciprocity', this paper examines the constructions of injecting drug users and PLWHA by a group of Thai nurses. Narratives were explored with a focus on how participants' views concerning the high-risk behaviour of injecting drug use might influence their attitudes towards PLWHA. The analysis shows that active efforts were made by participants to separate their views of patients living with HIV/AIDS from injecting drug users. While the former were depicted as patients worthy of social support and inclusion, the latter were excluded on the basis that they were perceived as irresponsible 'social cheaters' who pose severe social and economic harm to the community. Absent in the narratives were references to wider socio-political and epidemiological factors related to drug use and needle sharing that expose injecting drug users to risk; these behaviours were constructed as individual choices, allowing HIV positive drug users to be blamed for their seropositive status. These attitudes could potentially have indirect negative implications on the nurses' opinions of patients living with HIV/AIDS more generally. Decreasing the stigma associated with illicit drugs might play crucial role in improving attitudes towards patients living with HIV/AIDS. Providing health workers with a broader understanding of risk behaviours and redirecting government injecting drug policy to harm reduction are discussed as some of the ways for stigma intervention to move forward.


Determination of macromolecular structures from anomalous diffraction of synchrotron radiation.
Resonance between beams of x-ray waves and electronic transitions from bound atomic orbitals leads to a phenomenon known as anomalous scattering. This effect can be exploited in x-ray crystallographic studies on biological macromolecules by making diffraction measurements at selected wavelengths associated with a particular resonant transition. In this manner the problem of determining the three-dimensional structure of thousands of atoms is reduced to that of initially solving for a few anomalous scattering centers that can then be used as a reference for developing the entire structure. This method of multiwavelength anomalous diffraction has now been applied in a number of structure determinations. Optimal experiments require appropriate synchrotron instrumentation, careful experimental design, and sophisticated analytical procedures. There are rich opportunities for future applications.


Fabrication of porous TiO2 nanorod array photoelectrodes with enhanced photoelectrochemical water splitting by helium ion implantation.
Porous photoelectrodes show high efficiency in hydrogen production by water splitting. However, fabrication of porous nanorods is usually difficult. Here, we report a simple approach to fabricate a kind of novel porous rutile titanium dioxide nanorod array by an advanced ion implantation method using multiple-energy helium ion implantation and subsequent annealing. The porous nanostructure enhances the photoelectrochemical performance of the titanium dioxide nanorod array photoelectrodes under Uv-visible light illumination, where the highest photocurrent density was relatively about 10 times higher than that of the pristine titanium dioxide nanorod array. The formation of nanocavities mainly contributes to the enhancement of the photocurrent density by trapping holes inside to separate the charge carriers. The study demonstrates that ion implantation could be an effective approach to develop novel porous nanostructural photoelectrodes for the application of hydrogen production.


Supercell lattice method for photonic crystal fibers.
A supercell lattice method, believed to be novel, deduced from the plane-wave expansion method and the localized basis function method, is presented for analyzing photonic crystal fibers (PCFs). The electric field is decomposed by use of Hermite-Gaussian functions, and the dielectric constant of PCFs missing a central air hole is considered as the sum of two virtual different periodic dielectric structures of perfect photonic crystals (PCs). The structures of both virtual PCs are expanded in cosine functions. From the wave equation and the orthonormality of the Hermite-Gaussian functions, the propagation characteristics of the PCFs, such as the mode field distribution, the effective area, and the dispersion property, are obtained. The accuracy of the novel method is demonstrated as we obtain the same results when the dielectric constant is split into two virtual ideal PCs in different ways.


Underway spectrophotometry in the Fram Strait (European Arctic Ocean): a highly resolved chlorophyll a data source for complementing satellite ocean color.
Satellite remote sensing of chlorophyll a concentration (Chl-a) in the Arctic Ocean is spatially and temporally limited and needs to be supplemented and validated with substantial volumes of in situ observations. Here, we evaluated the capability of obtaining highly resolved in situ surface Chl-a using underway spectrophotometry operated during two summer cruises in 2015 and 2016 in the Fram Strait. Results showed that Chl-a measured using high pressure liquid chromatography (HPLC) was well related (R2 = 0.90) to the collocated particulate absorption line height at 676 nm obtained from the underway spectrophotometry system. This enabled continuous surface Chl-a estimation along the cruise tracks. When used to validate Chl-a operational products as well as to assess the Chl-a algorithms of the aqua moderate resolution imaging spectroradiometer (MODIS-A) and Sentinel-3 Ocean Land Color Imager (OLCI) Level 2 Chl-a operational products, and from OLCI Level 2 products processed with Polymer atmospheric correction algorithm (version 4.1), the underway spectrophotometry based Chl-a data sets proved to be a much more sufficient data source by generating over one order of magnitude more match-ups than those obtained from discrete water samples. Overall, the band ratio (OCI, OC4) Chl-a operational products from MODIS-A and OLCI as well as OLCI C2RCC products showed acceptable results. The OLCI Polymer standard output provided the most reliable Chl-a estimates, and nearly as good results were obtained from the OCI algorithm with Polymer atmospheric correction method. This work confirms the great advantage of the underway spectrophotometry in enlarging in situ Chl-a data sets for the Fram Strait and improving satellite Chl-a validation and Chl-a algorithm assessment over discrete water sample analysis in the laboratory.


Long-term cardiovascular outcome following fetal anaemia and intrauterine transfusion: a cohort study.
To compare long-term cardiovascular outcomes in survivors of fetal anaemia and intrauterine transfusion with those of non-anaemic siblings. Retrospective cohort study. Auckland, New Zealand. Adults who received intrauterine transfusion for anaemia due to rhesus disease (exposed) and their unexposed sibling(s). Fetal anaemia requiring intrauterine transfusion. Anthropometry, blood pressure, lipids, heart rate variability and cardiac MRI, including myocardial perfusion. Exposed participants (n=95) were younger than unexposed (n=92, mean±SD 33.7±9.3 vs 40.1±10.9 years) and born at earlier gestation (34.3±1.7 vs 39.5±2.1 weeks). Exposed participants had smaller left ventricular volumes (end-diastolic volume/body surface area, difference between adjusted means -6.1, 95% CI -9.7 to -2.4 mL/m2), increased relative left ventricular wall thickness (difference between adjusted means 0.007, 95% CI 0.001 to 0.012 mm.m2/mL) and decreased myocardial perfusion at rest (ratio of geometric means 0.86, 95% CI 0.80 to 0.94). Exposed participants also had increased low frequency-to-high frequency ratio on assessment of heart rate variability (ratio of geometric means 1.53, 95% CI 1.04 to 2.25) and reduced high-density lipoprotein concentration (difference between adjusted means -0.12, 95% CI -0.24 to 0.00 mmol/L). This study provides the first evidence in humans that cardiovascular development is altered following exposure to fetal anaemia and intrauterine transfusion, with persistence of these changes into adulthood potentially indicating increased risk of cardiovascular disease. These findings are relevant to the long-term health of intrauterine transfusion recipients, and may potentially also have implications for adults born preterm who were exposed to anaemia at a similar postconceptual age.


PGC-1α transcriptional response and mitochondrial adaptation to acute exercise is maintained in skeletal muscle of sedentary elderly males.
The aim of the present study was to examine the effects of ageing and training status on (1) markers of skeletal muscle mitochondrial content and (2) the ability to activate the acute signalling pathways associated with regulating exercise-induced mitochondrial biogenesis. Muscle biopsies were obtained from the vastus lateralis muscle of young untrained (24 ± 4 years, n = 6; YU), young trained (22 ± 3 years, n = 6; YT), old untrained (65 ± 6 years, n = 6; OU) and old trained (64 ± 3 years, n = 6; OT) healthy males before and after (3 h and 3 days post-exercise) completion of high-intensity interval cycling exercise. In resting muscle, lifelong training preserved mtDNA, PGC-1α and COXIV protein content such that muscles from OT individuals were comparable to muscles from both YU and YT individuals, whereas lifelong sedentary behaviour reduced such markers of mitochondrial content. Regardless of age or training status, acute exercise induced comparable increases in p38MAPK phosphorylation immediately post-exercise, PGC-1α and COXIV mRNA expression at 3 h post-exercise and COXIV protein at 3 days post-exercise. Data demonstrate that lifelong endurance training preserves skeletal muscle PGC-1α content and that despite the mitochondrial dysfunction typically observed with sedentary ageing, muscles from sedentary elderly individuals retain the capacity to activate the acute signalling pathways associated with regulating the early processes of mitochondrial biogenesis. We consider our data to have immediate translational potential as they highlight the potential therapeutic effects of exercise to induce skeletal muscle mitochondrial biogenesis persist late in adulthood, even after a lifetime of physical inactivity.


Retrospective analysis of the natural history and management of serpiginous choroiditis in Australia and New Zealand.
To examine the prevalence of serpiginous choroidopathy in a predominantly Caucasian community, to examine associations between serpiginous choroiditis and other systemic diseases, and to report on the effect of immunosuppression on the long-term course of serpiginous choroiditis. Retrospective cohort study with patients from tertiary care centres and private practices. 18 patients, mean age 48 years at baseline. One patient was seen only once. Median follow-up was 69 months (5.8 years, range 0.4-29.7 years). Patients were identified using the Australian and New Zealand Ophthalmic Surveillance Unit. A chart analysis was performed for all patients. Three treatment groups were identified: no treatment, prednisolone monotherapy, or combination of prednisolone and immunosuppression. Negative binomial regression was used to calculate incidence rate ratios for patient relapse. Patient demographics, clinical features, associated systemic diseases, treatments administered and dates of relapse. The disease prevalence in Australia and New Zealand is 1 case per 1.5 million people. Five cases (28%) had a positive QuantiFERON. A total of 32 relapses were observed: 14 while receiving no treatment, 11 on prednisolone and 7 on combination therapy. Compared with the no treatment group, the incidence rate ratio for prednisolone monotherapy and combination therapy was 1.29 and 2.92, respectively (95% confidence interval 0.40-4.14 and 0.96-8.88). Although the confidence intervals indicate that the difference in incidence rate ratios are not significant, these results suggest that there is a group of patients who have a benign course without long-term immunosuppression or corticosteroid treatment.


Development of a hybrid ozonation biofilm-membrane filatration process for the production of drinking water.
Drinking water sources in Norway are characterized by high concentrations of natural organic matter (NOM), low alkalinity and low turbidity. The removal of NOM is therefore a general requirement in producing potable water. Drinking water treatment plants are commonly designed with coagulation direct filtration or NF spiral wound membrane processes. This study has investigated the feasibility and potential of a hybrid process combining ozonation and biofiltration with a rotating disk membrane for treating drinking water with high NOM concentrations. Ozonation will oxidize the NOM content removing colour and form biodegradable organic compounds, which can be removed in biological filters. A constructed water was used in this study which is representative of ozonated NOM-containing water. A rotating membrane disk bioreactor downstream the ozonation process was used to carry out both the biodegradation as well as biomass separation in the same reactor. Maintenance of biodegradation of the organic matter while controlling biofouling of the membrane and acceptable water production rates was the focus in the study. Three operating modes were investigated. Removal of the biodegradable organics was consistent throughout the study indicating that sufficient biomass was maintained in the reactor for all operating conditions tested. Biofouling control was not achieved through shear-induced cleaning by periodically rotating the membrane disks at high speed. By adding a small amount of sponges in the membrane chamber the biofouling could be controlled by mechanical cleaning of the membrane surface during disk rotation. The overall results indicate that the system can favorably be used in an ozonation/biofiltration process by carrying out both biodegradation as well as biomass separation in the same reactor.


A survey of spinal collateral actions of feline ventral spinocerebellar tract neurons.
The aim of this study was to identify spinal target cells of spinocerebellar neurons, in particular the ventral spinocerebellar tract (VSCT) neurons, giving off axon collaterals terminating within the lumbosacral enlargement. Axons of spinocerebellar neurons were stimulated within the cerebellum while searching for most direct synaptic actions on intracellularly recorded hindlimb motoneurons and interneurons. In motoneurons the dominating effects were inhibitory [inhibitory postsynaptic potentials (IPSPs) in 67% and excitatory postsynaptic potentials (EPSPs) in 17% of motoneurons]. Latencies of most IPSPs indicated that they were evoked disynaptically and mutual facilitation between these IPSPs and disynaptic IPSPs evoked by group Ia afferents from antagonist muscles and group Ib and II afferents from synergists indicated that they were relayed by premotor interneurons in reflex pathways from muscle afferents. Monosynaptic EPSPs from the cerebellum were accordingly found in Ia inhibitory interneurons and intermediate zone interneurons with input from group I and II afferents but only oligosynaptic EPSPs in motoneurons. Monosynaptic EPSPs following cerebellar stimulation were also found in some VSCT neurons, indicating coupling between various spinocerebellar neurons. The results are in keeping with the previously demonstrated projections of VSCT neurons to the contralateral ventral horn, showing that VSCT neurons might contribute to motor control at a spinal level. They might thus play a role in modulating spinal activity in advance of any control exerted via the cerebellar loop.


Why replication is important in landscape genetics: American black bear in the Rocky Mountains.
We investigated how landscape features influence gene flow of black bears by testing the relative support for 36 alternative landscape resistance hypotheses, including isolation by distance (IBD) in each of 12 study areas in the north central U.S. Rocky Mountains. The study areas all contained the same basic elements, but differed in extent of forest fragmentation, altitude, variation in elevation and road coverage. In all but one of the study areas, isolation by landscape resistance was more supported than IBD suggesting gene flow is likely influenced by elevation, forest cover, and roads. However, the landscape features influencing gene flow varied among study areas. Using subsets of loci usually gave models with the very similar landscape features influencing gene flow as with all loci, suggesting the landscape features influencing gene flow were correctly identified. To test if the cause of the variability of supported landscape features in study areas resulted from landscape differences among study areas, we conducted a limiting factor analysis. We found that features were supported in landscape models only when the features were highly variable. This is perhaps not surprising but suggests an important cautionary note - that if landscape features are not found to influence gene flow, researchers should not automatically conclude that the features are unimportant to the species' movement and gene flow. Failure to investigate multiple study areas that have a range of variability in landscape features could cause misleading inferences about which landscape features generally limit gene flow. This could lead to potentially erroneous identification of corridors and barriers if models are transferred between areas with different landscape characteristics.


Origin of anomalous slip in tungsten.
Low-temperature deformation of body-centered cubic metals shows a significant amount of plastic slip on planes with low shear stresses, a phenomenon called anomalous slip. Despite progress in atomistic modeling of the consequences of complex stress states on dislocation mobility, the phenomenon of anomalous slip remained elusive. Using in situ Laue microdiffraction and discrete dislocation dynamics in micrometer sized tungsten single crystals, we demonstrate the occurrence of significant anomalous slip. It occurs as a consequence of cross kinks, topological configurations generated by prior dislocation interactions. This clearly identifies anomalous slip as a multidislocation process and not a property of isolated dislocations. The cross-kink mechanism also explains the ambiguous reporting of anomalous slip traces in the past and directs us to ways of including anomalous slip in continuum crystal plasticity formulations.


A Sox10 expression screen identifies an amino acid essential for Erbb3 function.
The neural crest (NC) is a population of embryonic stem cells that gives rise to numerous cell types, including the glia and neurons of the peripheral and enteric nervous systems and the melanocytes of the skin and hair. Mutations in genes and genetic pathways regulating NC development lead to a wide spectrum of human developmental disorders collectively called neurocristopathies. To identify molecular pathways regulating NC development and to understand how alterations in these processes lead to disease, we established an N-ethyl-N-nitrosourea (ENU) mutagenesis screen utilizing a mouse model sensitized for NC defects, Sox10(LacZ/+). Out of 71 pedigrees analyzed, we identified and mapped four heritable loci, called modifier of Sox10 expression pattern 1-4 (msp1-4), which show altered NC patterning. In homozygous msp1 embryos, Sox10(LacZ) expression is absent in cranial ganglia, cranial nerves, and the sympathetic chain; however, the development of other Sox10-expressing cells appears unaffected by the mutation. Linkage analysis, sequencing, and complementation testing confirmed that msp1 is a new allele of the receptor tyrosine kinase Erbb3, Erbb3(msp1), that carries a single amino acid substitution in the extracellular region of the protein. The ENU-induced mutation does not alter protein expression, however, it is sufficient to impair ERBB3 signaling such that the embryonic defects observed in msp1 resemble those of Erbb3 null alleles. Biochemical analysis of the mutant protein showed that ERBB3 is expressed on the cell surface, but its ligand-induced phosphorylation is dramatically reduced by the msp1 mutation. These findings highlight the importance of the mutated residue for ERBB3 receptor function and activation. This study underscores the utility of using an ENU mutagenesis to identify genetic pathways regulating NC development and to dissect the roles of discrete protein domains, both of which contribute to a better understanding of gene function in a cellular and developmental setting.


Lighting Up DNA with the Environment-Sensitive Bright Adenine Analogue qAN4.
The fluorescent adenine analogue qAN4 was recently shown to possess promising photophysical properties, including a high brightness as a monomer. Here we report the synthesis of the phosphoramidite of qAN4 and its successful incorporation into DNA oligonucleotides using standard solid-phase synthesis. Circular dichroism and thermal melting studies indicate that the qAN4-modification has a stabilizing effect on the B-form of DNA. Moreover, qAN4 base-pairs selectively with thymine with mismatch penalties similar to those of mismatches of adenine. The low energy absorption band of qAN4 inside DNA has its peak around 358 nm and the emission in duplex DNA is partly quenched and blue-shifted (ca. 410 nm), compared to the monomeric form. The spectral properties of the fluorophore also show sensitivity to pH; a property that may find biological applications. Quantum yields in single-stranded DNA range from 1-29 % and in duplex DNA from 1-7 %. In combination with the absorptive properties, this gives an average brightness inside duplex DNA of 275 M-1 cm-1 , more than five times higher than the most used environment-sensitive fluorescent base analogue, 2-aminopurine. Finally, we show that qAN4 can be used to advantage as a donor for interbase FRET applications in combination with adenine analogue qAnitro as an acceptor.


Phagocytosis mediated by three distinct Fc gamma receptor classes on human leukocytes.
We have evaluated the capacity of the three major classes of human Fc gamma R to mediate phagocytosis by measuring the ability of adherent phagocytes to internalize erythrocytes coated with anti-Fc gamma R mAb. Five different cell types were studied, freshly purified monocytes, cultured monocytes, alveolar macrophages, freshly purified polymorphonuclear neutrophilic leukocytes, and PMNs cultured in IFN-gamma. Fc gamma RI and Fc gamma RII on whichever cells they were expressed were capable of phagocytosing anti-Fc gamma R mAb-coated erythrocytes. Furthermore, Fc gamma RIII on mononuclear phagocytes, which appears to be a conventional integral membrane protein that spans the lipid bilayer, was capable of phagocytosing anti-Fc gamma RIII-coated erythrocytes. However, Fc gamma RIII on neutrophils, a molecule linked to the membrane by a phosphatidylinositol-glycan moiety, although binding anti-Fc gamma RIII-coated erythrocytes vigorously was incapable of mounting a phagocytic response. This deficiency correlates with the limited capacity of Fc gamma RIII on neutrophils to mediate superoxide generation and antibody-dependent cell-mediated cytotoxicity and it may be related to the unique structural features of Fc gamma RIII.


An automated in vitro motility assay for high-throughput studies of molecular motors.
Molecular motors, essential to force-generation and cargo transport within cells, are invaluable tools for powering nanobiotechnological lab-on-a-chip devices. These devices are based on in vitro motility assays that reconstitute molecular transport with purified motor proteins, requiring a deep understanding of the biophysical properties of motor proteins and thorough optimization to enable motility under varying environmental conditions. Until now, these assays have been prepared manually, severely limiting throughput. To overcome this limitation, we developed an in vitro motility assay where sample preparation, imaging and data evaluation are fully automated, enabling the processing of a 384-well plate within less than three hours. We demonstrate the automated assay for the analysis of peptide inhibitors for kinesin-1 at a wide range of concentrations, revealing that the IAK domain responsible for kinesin-1 auto-inhibition is both necessary and sufficient to decrease the affinity of the motor protein for microtubules, an aspect that was hidden in previous experiments due to scarcity of data.


Bypassing the pump: changing practices in coronary artery surgery.
Improvements in techniques in coronary revascularization over the past decade have led to a revival of interest in off-pump coronary artery surgery. A fifth of coronary revascularization procedures are now performed off-pump. Randomized trials comparing off-pump surgery with conventional coronary artery bypass grafting using cardiopulmonary bypass (CPB) mainly included low-risk patients and were therefore underpowered to detect a difference in mortality. Current evidence, however, suggests a significant reduction in morbidity with off-pump surgery. The avoidance of CPB and the elimination of any aortic manipulation may significantly reduce the risk of stroke. Those benefits are likely to be most marked in older, sicker patients, who represent an increasing proportion of the surgical population.


Mechanical properties of the fetal ductus venosus and umbilical vein.
During fetal circulatory compromise, velocity pulsations in the precordial veins increase and are commonly transmitted through the ductus venosus into the umbilical vein, indicating a serious prognosis. The nature of the pulsations and their transmission into the periphery, specifically the umbilical vein, is poorly understood. We present information on the mechanical properties of fetal veins as a basis for describing the pulse wave propagation. Five fetal sheep livers with connecting veins (gestational age 0.8-0.9) were studied in vitro. The transmural pressure, obtained with a fluid-filled catheter, was reduced stepwise from 10.3 to 0 mmHg, and the diameter determined by ultrasonography. Each data set was fitted to an exponential function to determine the stiffness parameter and the area at a standard pressure, which we proposed to be 5 mmHg for the fetal venous circulation. The stiffness parameter was 6.2+/-1.8 at the ductus venosus outlet, 3.4+/-1.3 at the ductus venosus inlet, and 4.0+/-1.0 in the umbilical vein. Correspondingly, values for compliance and pulse wave velocity for the three venous sections were established for a physiological pressure range. The estimated pulse wave velocity of 1-3m/s is comparable with values estimated for veins in adults. The mechanical properties of fetal veins are comparable with those described for veins later in life. The stiffness parameter represents the elastic properties at all pressure levels and conveniently permits inference of compliance and pulse wave velocity.


Testing messages about comparative risk of electronic cigarettes and combusted cigarettes.
Health agencies are grappling with communicating risks of electronic cigarettes (e-cigarettes) compared with combusted cigarettes. This study examined smokers' responses to two types of comparative risk messages with one type incorporating more negative antismoking elements in the design. In an online experiment, 1400 US adult (18+ years) current smokers and recent quitters were randomised to view one of three comparative risk messages about e-cigarettes (CR messages), one of three comparative risk messages that included more negative antismoking elements in the design (CR- messages) or a control message. Selection of outcomes was guided by the antismoking message impact framework. Multivariate analyses of covariance and logistic regression models analysed effects of messages on message evaluations, e-cigarette-related and cigarette-related beliefs and behavioural intentions. Both CR and CR- messages decreased smokers' intentions to smoke cigarettes, increased intentions to switch to e-cigarettes completely and increased perceptions that e-cigarettes are less harmful than combusted cigarettes. Neither message type increased dual use intentions relative to exclusive e-cigarettes use or smoking cessation. CR messages decreased perceived absolute risks of e-cigarettes and self-exempting beliefs about smoking, whereas CR- versus CR messages produced higher self-efficacy to quit smoking. Comparative risk communication might encourage smokers to switch to lower-harm tobacco products. Comparative risk messages with more negative antismoking elements in the design might be particularly effective, because they led to higher self-efficacy to quit smoking. Regulatory agencies may consider using comparative risk messages with more negative antismoking elements to educate the public about lower risk of e-cigarettes.


P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases.
A novel neuroprotective small molecule was discovered using a target-agnostic in vivo screen in living mice. This aminopropyl carbazole, named P7C3, is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose. The potency and drug-like properties of P7C3 were optimized through a medicinal chemistry campaign, providing analogues for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders.


Graphitic carbon nitride nano sheets functionalized with selected transition metal dopants: an efficient way to store CO2.
Proficient capture of carbon dioxide (CO2) is considered to be a backbone for environment protection through countering the climate change caused by mounting carbon content. Here we present a comprehensive mechanism to design novel functional nanostructures capable of capturing a large amount of CO2 efficiently. By means of van der Waals corrected density functional theory calculations, we have studied the structural, electronic and CO2 storage properties of carbon nitride (g-C6N8) nano sheets functionalized with a range of transition metal (TM) dopants ranging from Sc to Zn. The considered TMs bind strongly to the nano sheets with binding energies exceeding their respective cohesive energies, thus abolishing the possibility of metal cluster formation. Uniformly dispersed TMs change the electronic properties of semiconducting g-C6N8 through the transfer of valence charges from the former to the latter. This leaves all the TM dopants with significant positive charges, which are beneficial for CO2 adsorption. We have found that each TM's dopants anchor a maximum of four CO2 molecules with suitable adsorption energies (-0.15 to -1.0 eV) for ambient condition applications. Thus g-C6N8 nano sheets functionalized with selected TMs could serve as an ideal sorbent for CO2 capture.


Polypharmacy in patients with schizophrenia.
Polypharmacy in patients with schizophrenia is a common practice with little basis in well-controlled studies. The objective of this report is to describe the changes in prescription practices with psychotropic medications for patients diagnosed with schizophrenia in 1995 and 2000. The medical records of patients who were discharged from our facility in 1995 and 2000 with the diagnosis of schizophrenia (DSM-IV criteria) were reviewed. The psychotropic medications at discharge were compared. The incidence of adverse drug reactions and indicators of patient outcome were also compared. 459 records were reviewed for 1995 and 584 were reviewed for 2000. Patients discharged in 2000 were significantly more likely to receive antidepressants, mood stabilizers, anxiolytics, and multiple antipsychotics than patients discharged in 1995 (p < .0001). Patients discharged in 2000 were given significantly fewer anticholinergics (p < .0001). There was a large increase in the use of divalproex. No patients were discharged on treatment with more than 1 antipsychotic in 1995, whereas in 2000, 15.9% of patients were. The most common antipsychotic combination was haloperidol and olanzapine. Paralleling the increased use of polypharmacy, there were significantly fewer adverse drug reactions in 2000 than in 1995 (p = .002). In addition, patients with schizophrenia who were discharged in 2000 had significantly shorter lengths of stay (p < .0001) and were significantly more likely to be discharged to the community than to a state hospital (p = .0001). This study found that acutely ill hospitalized patients with schizophrenia are being treated with more psychotropic medications, including more than 1 antipsychotic. These changes are coincidental with a decrease in adverse drug reactions and an improvement in indicators of patient outcome.


Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination.
In meiotic DNA recombination, the Hop2-Mnd1 complex promotes Dmc1-mediated single-stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2-Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra α-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle-like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2-Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasion.


Efficacy and safety of simeprevir and sofosbuvir with and without ribavirin in subjects with recurrent genotype 1 hepatitis C postorthotopic liver transplant: the randomized GALAXY study.
This prospective, randomized, phase 2 study in subjects with recurrent hepatitis C virus (HCV) genotype 1 postorthotopic liver transplant evaluated once-daily simeprevir 150 mg + sofosbuvir 400 mg, with and without ribavirin 1000 mg. Primary endpoint was proportion of subjects with week 12 sustained virologic response (SVR12). Thirty-three subjects without cirrhosis were randomized 1:1:1 into three arms (stratified by genotype/subtype and Q80K): Arm 1, simeprevir + sofosbuvir + ribavirin, 12 weeks; Arm 2, simeprevir + sofosbuvir, 12 weeks; Arm 3, simeprevir + sofosbuvir, 24 weeks; 13 additional subjects (two with cirrhosis, 11 without cirrhosis) entered Arm 3. All 46 subjects received at least one dose of study drug; median age, 60 years; 73.9% male; 80.4% White; 71.7% genotype/subtype 1a [12 (36.4%) of these had Q80K]; median 4.5 years post-transplant. Among randomized subjects, SVR12 was achieved by 81.8% in Arm 1, 100% in Arm 2, and 93.9% in Arm 3; two subjects did not achieve SVR12: one viral relapse (follow-up week 4; Arm 1) and one missing follow-up week 12 data. In total, five subjects had a serious adverse event, considered unrelated to treatment per investigator. Simeprevir exposure was increased relative to the nontransplant setting, but not considered clinically relevant. Simeprevir + sofosbuvir treatment, with or without ribavirin, was efficacious and well tolerated (ClinicalTrials.gov Identifier: NCT02165189).


Prevalence and risk factors for nosocomial infections in four university hospitals in Switzerland.
To determine the prevalence and risk factors for nosocomial infections (NIs) in four Swiss university hospitals. A 1-week period-prevalence survey conducted in May 1996 in medical, surgical, and intensive-care wards of four Swiss university hospitals (900-1,500 beds). Centers for Disease Control and Prevention definitions were used, except that asymptomatic bacteriuria was not categorized as NI. Study variables included patient demographics, primary diagnosis, comorbidities, exposure to medical and surgical risk factors, and use of antimicrobials. Risk factors for NIs were determined using logistic regression with adjustment for length of hospital stay, study center, device use, and patients' comorbidities. 176 NI were recorded in 156 of 1,349 screened patients (11.6%; interhospital range, 9.8%-13.5%). The most frequent NI was surgical-site infection (53; 30%), followed by urinary tract infection (39; 22%), lower respiratory tract infection (27; 15%), and bloodstream infection (23; 13%). Prevalence of NI was higher in critical-care units (25%) than in medical (9%) and surgical wards (12%). Overall, 65% of NIs were culture-proven; the leading pathogens were Enterobacteriaceae (44; 28%), Staphylococcus aureus (20; 13%), Pseudomonas aeruginosa (17; 11%), and Candida species (16; 10%). Independent risk factors for NI were central venous catheter (CVC) use (odds ratio [OR], 3.35; 95% confidence interval [CI95], 2.91-3.80), admission to intensive care (OR, 1.75; CI95, 1.30-2.21), emergency admission (OR, 1.57; CI95, 1.15-2.00), impaired functional status (Karnofsky index 1-4: OR, 2.56; CI95, 1.953.17), and McCabe classification of ultimately fatal (OR, 2.50; CI95, 2.04-2.96) or rapidly fatal (OR, 2.25; CI95, 1.52-2.98) underlying condition. According to the results of this survey, NIs are frequent in Swiss university hospitals. This investigation confirms the importance of CVCs as a major risk factor for NI. Patient comorbidities must be taken into account to adjust for case mix in any study comparing interhospital or intrahospital infection rates.


Alcohol sale status and homicide victimization in Kentucky, 2005-2012: Is there a spatial association?
To date, the association between the alcohol sale status of decedents' residence and alcohol-related homicide victimization have not been studied as far as we know. The current study aims to: i) determine whether homicide victims who were residents of wet counties had higher odds of testing positive for alcohol than their counterparts in moist or dry counties after adjusting for confounders; ii) determine whether homicides and alcohol-related homicides tend to cluster spatially; iii) determine whether the aforementioned associations exist only in highly-populated counties. A multilevel logistic regression analysis was used to analyze the data on homicide victims in the Kentucky Violent Death Reporting System from 2005 to 2012. Spatial statistics were used to determine the spatial autocorrelation in rates of homicides and alcohol-related homicides. Overall, 944 homicide victims were included. The male to female ratio was 3:1. About 32.8% of homicide victims tested positive for alcohol. About 33.0% of homicide decedents who were residents in wet counties tested positive for alcohol compared to 32.5% of their counterparts in moist/dry counties. Residence in wet counties was associated with a statistically insignificant increase in the unadjusted odds ratio (OR) of alcohol-related homicide victimization (OR=1.20, 95% CI=0.81-1.77) as well as the adjusted odds (aOR=1.33, 95% CI=0.83-2.12). There was no association between population size and alcohol-related homicide rate.


Occurrence of Ochratoxin a in Animal Tissues and Feeds in Poland in 2014-2016.
Ochratoxin A (OTA) is a toxic metabolite mainly produced by Aspergillus spp. and Penicillum spp. fungi. Research on the contamination of cereals, complete feeds, and tissues with this mycotoxin has indicated that it can be a toxicological problem impacting animal health and food safety in temperate climes. OTA contamination mainly besets the global pig industry, necessitating the monitoring of feeds and animal tissues. The aim of the study was to present the results of the official monitoring of OTA in animal tissues and feeds in Poland in 2014-2016 and determine the possible correlation between the presence of OTA in different types of samples. The presence of ochratoxin A was determined using accepted procedures based on liquid chromatography with fluorescence detection after immunoaffinity column clean-up. Determination of OTA was afforded in the range of 0.3 µg/kg to 300 µg/kg in complete feeds and from 0.2 µg/kg to 150 µg/kg in the kidneys, liver, and muscles. Over the three year span, about 23.5% of the animal tissues samples were contaminated by ochratoxin A. In the 2014 survey, 10% of the sample tissues contained 5-10 µg/kg (only one sample above 10 μg/kg), and in 2015 and 2016, 24% of samples showed levels above the limit of quantification 0.2 μg/kg, while none of the samples exceeded the established provisional action level of 5 μg/kg for animal tissues. The animal feed analysis showed that 9% was contaminated with ochratoxin A above the limit of quantification of 0.3μg/kg. In 2% of feed samples the OTA concentration was greater than 50 μg/kg. The results confirm the appropriacy of OTA contamination monitoring and help to increase food safety.


Time for a change: patterns of sex expression, health and mortality in a sex-changing tree.
The ability of individuals to change sex during their lifetime is known as environmental sex determination (ESD). This represents a unique life history trait, allowing plants to allocate resources differentially to male and female functions across lifetimes, potentially maximizing fitness in response to changing environmental or internal cues. In this study, Acer pensylvanicum, a species with an unconfirmed sex determination system, was investigated to see what patterns in sex expression existed across multiple years, if there were sex-based differences in growth and mortality, and whether this species conformed to theoretical predictions that females are larger and in better condition. Patterns of sex expression were documented over 4 years in a phenotypically subdioecious A. pensylvanicum population located in New Jersey, USA, and data on size, mortality, health and growth were collected. A machine-learning algorithm known as a boosted classification tree was used to develop a model to predict the sex of a tree based on its condition, size and previous sex. In this study, 54 % of the trees switched sex expression during a 4-year period, with 26 % of those trees switching sex at least twice. Consistently monoecious trees could change relative sex expression by as much as 95 %. Both size and condition were influential in predicting sex, with condition exerting three times more relative influence than size on expressed sex. Contrary to theoretical predictions, the model showed that full female sex expression did not increase with size. Healthy trees were more likely to be male; predicted female sex expression increased with deteriorating health. Growth rate negatively correlated with multiple years of female sex expression. Populations maintained similar male-skewed sex ratios across years and locations and may result from differential mortality: 75 % of dead trees flowered female immediately before death. This study shows conclusively that A. pensylvanicum exhibits ESD and that femaleness correlates with decreased health, in contrast to prevailing theory. The mortality findings advance our understanding of puzzling non-equilibrium sex ratios and life history trade-offs resulting from male and female sex expression.


Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study.
The clinical features of idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis can be indistinguishable; the need to eliminate occult environmental factors known to cause pulmonary fibrosis in patients suspected to have IPF during diagnostic evaluation is evident. We aimed to investigate occult, putative causes in the environments of patients diagnosed with IPF using tests beyond those conventionally used. In this case-cohort study, 60 consecutive patients diagnosed with IPF on the basis of the 2000 American Thoracic Society (ATS) and the European Respiratory Society (ERS) criteria were prospectively followed up every 4 months for 6 years between Jan 1, 2004, and Dec 31, 2009. At each visit a uniformly applied questionnaire was administered to these 60 patients to identify occult antigen exposure known to cause hypersensitivity pneumonitis. Patients underwent specific IgG determination, bronchoalveolar lavage, bronchial challenge testing with suspected antigens, and re-review of histopathological features in existing and subsequently obtained surgical lung biopsy samples and from lung explants. Specimens obtained from suspected sources from the patient's environment were subjected to cultures in microbiology laboratory. These clinical data and discussions among pulmonologists and radiologists familiar with IPF were used to confirm the diagnosis in accordance with 2011 ATS, ERS, Japanese Respiratory Society, and Latin American Thoracic Association guidelines; 46 of the 60 patients had IPF according to the 2011 guidelines, and our analyses in this study were focused on these 46 patients. 20 of the 46 (43%, 95% CI 29-58) patients with IPF according to 2011 guidelines had a subsequent diagnosis of chronic hypersensitivity pneumonitis: nine patients had positive bronchial challenge testing (eight of whom were also IgG positive and six of these patients also had surgical lung biopsy showing a pattern consistent with chronic hypersensitivity pneumonitis); seven were IgG positive plus had histopathology on surgical lung biopsy that was consistent with hypersensitivity pneumonitis; one was IgG positive plus had greater than 20% lymphocytes in bronchoalveolar lavage fluid; and three had findings on surgical lung biopsy that were consistent with subacute hypersensitivity pneumonitis (and IgG positive). Altogether, 29 of 46 patients diagnosed with IPF who had met the 2011 criteria had lung tissue available for histopathology (surgical lung biopsy in 28 patients and explanted lung in two patients, one of whom also had surgical biopsy) during the study period, and 16 of the 20 patients with chronic hypersensitivity pneumonitis had histopathological features on surgical lung biopsy that were consistent with this diagnosis. 26 of the 46 patients remained with a diagnosis of IPF. Almost half of patients diagnosed with IPF on the basis of 2011 criteria were subsequently diagnosed with chronic hypersensitivity pneumonitis, and most of these cases were attributed to exposure of occult avian antigens from commonly used feather bedding. Our results reflect findings in one centre with recognised expertise in chronic hypersensitivity pneumonitis, and further research and studies at other centres are warranted. Fondo de Investigaciones Sanitarias; Fundació Privada Cellex; SEPAR 2010.


Waxy corn starch: a potent cofiller in pellets produced by extrusion-spheronization.
The purpose of this study was to assess the usefulness of waxy corn (maize) starch as a cofiller and diluent in pellets produced by aqueous extrusion-spheronization. Waxy corn starch was combined with microcrystalline cellulose (MCC) in the range of 20-50% of the entire composition. Pellets containing ordinary corn starch or lactose with MCC were used as reference. The shape of pellets was characterized using an optical microscopic image analysis system. The surface and cross-sectional structure were investigated by means of scanning electron microscopy (SEM). The replacement of ordinary corn starch by waxy corn starch made it possible to increase the amount of starch from 20 to 40%. The pellets containing 50% waxy corn starch were of poorer quality but superior to those containing 30% corn starch. The surface structure became slightly more irregular with respect to the amount of either starch, and a cavity was formed inside the pellet during the spheronization. The origin of starch did not affect the surface structure of the pellets. Waxy corn starch is a potential cofiller: the amount of MCC can be reduced in pellets produced by extrusion-spheronization by using waxy corn starch as a cofiller. This enables the reduction of the manufacturing cost of pellets with low drug load.


High-dose cisplatin combination chemotherapy in the treatment of advanced epithelial ovarian carcinoma.
We treated 25 newly diagnosed patients with advanced epithelial ovarian cancer with an intensive induction chemotherapy regimen using high-dose cisplatin in combination with cyclophosphamide and doxorubicin. All patients had either stage IIIC or stage IV disease. Two intensive induction courses of chemotherapy were administered at 28-day intervals, which consisted of cisplatin 40 mg/m2 daily for 5 days, cyclophosphamide 500 mg/m2 day 1, and doxorubicin 40 mg/m2 day 1. Four courses of chemotherapy using cisplatin 60 mg/m2, doxorubicin 40 mg/m2, and cyclophosphamide 500 mg/m2 followed the high-dose induction therapy. Two of the first six patients died during high-dose induction therapy (one died of neutropenia and sepsis, one of intercurrent intracerebral hemorrhage). Doxorubicin was subsequently omitted from the induction therapy due to unacceptable myelosuppression; no deaths occurred in the remaining 19 patients, and myelosuppression was manageable. Peripheral neuropathy was the most severe side effect with this regimen. This complication was unpredictable, developed during the third or fourth month of treatment, and was disabling in five patients. Other toxicity included prolonged nausea and vomiting (eight patients), ototoxicity (five patients), and nephrotoxicity (two patients), but these did not compromise therapy. All 23 assessable patients had objective response to therapy. Four of 12 patients who underwent second-look laparotomy had pathologic complete response, while four additional patients had only microscopic residual disease. The median survival for the entire group was 25 months. Four patients remain continuously disease-free 23 to 48 months following completion of therapy. Although this regimen was tolerated by most patients, the unpredictable occurrence of disabling neuropathy may limit its usefulness.(ABSTRACT TRUNCATED AT 250 WORDS)


Identification of the biologically active form of sulindac.
In five animal species, the only quantitatively significant biotransformations undergone by cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene]indene-3-acetic acid (sulindac) are oxidation of its sulfinyl substituent to sulfone, and reduction to sulfide. The former metabolite is eliminated unchanged and elicits no pharmacological response. The sulfide, on the other hand, is readily reoxidized in vivo to sulindac. In each of seven in vivo models of inflammation, sulfide administered as such is more active than sulindac. The inference that the activity of sulindac might be attributed in whole or in part to the sulfide was tested directly by comparison of responses with concentrations of each reduction oxidation species in appropriate biological fluids. Regression analyses of circulation levels of sunlindac and sulfide vs. inhibition of rat paw edema, and of their levels in synovial fluid vs. response in the dog knee joint assay, show highly significant correlations only for sulfide. Sulindac thus appears to be a "latentiated" or "pro-drug," oral dosage with chich may circumvent the gastrointestinal side effects commonly associated with nonsteriod anti-inflammatory agents.


A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5.
To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation for eyes with vision loss associated with macular edema secondary to perfused central retinal vein occlusion (CRVO). Multicenter, randomized, clinical trial of 271 participants. Gain in visual acuity letter score of 15 or more from baseline to month 12. Seven percent, 27%, and 26% of participants achieved the primary outcome in the observation, 1-mg, and 4-mg groups, respectively. The odds of achieving the primary outcome were 5.0 times greater in the 1-mg group than the observation group (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.8-14.1; P = .001) and 5.0 times greater in 4-mg group than the observation group (OR, 5.0; 95% CI, 1.8-14.4; P = .001); there was no difference identified between the 1-mg and 4-mg groups (OR, 1.0; 95% CI, 0.5-2.1; P = .97). The rates of elevated intraocular pressure and cataract were similar for the observation and 1-mg groups, but higher in the 4-mg group. Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema secondary to CRVO in patients who have characteristics similar to those in the SCORE-CRVO trial. The 1-mg dose has a safety profile superior to that of the 4-mg dose. Application to Clinical Practice Intravitreal triamcinolone in a 1-mg dose, following the retreatment criteria applied in the SCORE Study, should be considered for up to 1 year, and possibly 2 years, for patients with characteristics similar to those in the SCORE-CRVO trial. Trial Registration clinicaltrials.gov Identifier: NCT00105027.


Managing myelofibrosis (MF) that "blasts" through: advancements in the treatment of relapsed/refractory and blast-phase MF.
Myelofibrosis (MF) is the most aggressive form of Philadelphia chromosome-negative myeloproliferative neoplasm, and it is complicated by severe symptom burden, thrombotic events, infections, cytopenias, and transformation to acute myeloid leukemia (AML). Ruxolitinib, the first-line therapy for symptomatic or intermediate- and high-prognostic risk MF, has improved overall survival for this population. However, approximately one-half of MF patients will discontinue ruxolitinib by the first few years of therapy due to a spectrum of resistance, intolerance, relapse, or progression to blast phase disease. Danazol, erythropoietin-stimulating agents, and spleen-directed therapies can be useful in the ruxolitinib-resistant setting. In the ruxolitinib-refractory or -intolerant setting, commercial and novel therapies, either alone or in combination with ruxolitinib, have shown clinical utility. For blast-phase MF, the recent advancements in available AML therapies have increased the options with targeted and more tolerable therapies. In this article, we will discuss our paradigm for the management of relapsed/refractory and blast-phase MF in the context of therapeutic advancements in both AML and MF.