The body image and relationships scale: development and validation of a measure of body image in female breast cancer survivors.
A self-report measure of body image in female breast cancer survivors, the Body Image and Relationships Scale (BIRS), was developed to address attitudes about appearance, health, physical strength, sexuality, relationships, and social functioning following treatment. The 32-item measure, generated by expert consensus and revised based on focus group feedback, was administered to 95 female breast cancer participants twice within 1 to 2 weeks. Test-retest reliability, internal consistency, and validity of the measure were assessed using standard-scale construction techniques. The structure of the proposed measure was evaluated using exploratory factor analysis. Associations of the resulting factors and other variables were assessed using extreme groups analyses. The BIRS had satisfactory test-retest reliability and internal consistency. Principal axis factoring revealed three factors: (1) health and strength, (2) social barriers, and (3) appearance and sexuality. Correlations of the subscales with standardized measures of related constructs were significant and in the anticipated directions. Extreme groups analyses suggested associations between less physical activity and more impairment on factors 1 and 3, premenopausal status at first diagnosis and more impairment on factor 2, and younger age at the time of survey administration and more impairment on factor 3. The proposed scale demonstrated satisfactory reliability and internal consistency. Factor analysis revealed three subscales with coherent item content and differential associations with measures of activity level, menopause status, and age. Observed relationships with other measures support convergent and divergent validity. Results suggest that the proposed scale is useful for clinical and research applications.


Continuous preparation of polymer coated drug crystals by solid hollow fiber membrane-based cooling crystallization.
A facile way to continuously coat drug crystals with a polymer is needed in controlled drug release. Conventional polymer coating methods have disadvantages: high energy consumption, low productivity, batch processing. A novel method for continuous polymer coating of drug crystals based on solid hollow fiber cooling crystallization (SHFCC) is introduced here. The drug acting as the host particle and the polymer for coating are Griseofulvin (GF) and Eudragit RL100, respectively. The polymer's cloud point temperature in its acetone solution was determined by UV spectrophotometry. An acetone solution of the polymer containing the drug in solution as well as undissolved drug crystals in suspension were pumped through the tube side of the SHFCC device; a cold liquid was circulated in the shell side to rapidly cool down the feed solution-suspension in the hollow-fiber lumen. The polymer precipitated from the solution and coated the suspended crystals due to rapid temperature reduction and heterogeneous nucleation; crystals formed from the solution were also coated by the polymer. Characterizations by scanning electron microscopy, thermogravimetric analysis, laser diffraction spectroscopy, X-ray diffraction, Raman spectroscopy, and dissolution tests show that a uniformly coated, free-flowing drug/product can be obtained under appropriate operating conditions without losing the drug's pharmaceutical properties and controlled release characteristics.


Transcriptome profiling of a curdlan-producing Agrobacterium reveals conserved regulatory mechanisms of exopolysaccharide biosynthesis.
The ability to synthesize exopolysaccharides (EPS) is widespread among microorganisms, and microbial EPS play important roles in biofilm formation, pathogen persistence, and applications in the food and medical industries. Although it is well established that EPS synthesis is invariably in response to environmental cues, it remains largely unknown how various environmental signals trigger activation of the biochemical synthesis machinery. We report here the transcriptome profiling of Agrobacterium sp. ATCC 31749, a microorganism that produces large amounts of a glucose polymer known as curdlan under nitrogen starvation. Transcriptome analysis revealed a nearly 100-fold upregulation of the curdlan synthesis operon upon transition to nitrogen starvation, thus establishing the prominent role that transcriptional regulation plays in the EPS synthesis. In addition to known mechanisms of EPS regulation such as activation by c-di-GMP, we identify novel mechanisms of regulation in ATCC 31749, including RpoN-independent NtrC regulation and intracellular pH regulation by acidocalcisomes. Furthermore, we show evidence that curdlan synthesis is also regulated by conserved cell stress responses, including polyphosphate accumulation and the stringent response. In fact, the stringent response signal, pppGpp, appears to be indispensible for transcriptional activation of curdlan biosynthesis. This study identifies several mechanisms regulating the synthesis of curdlan, an EPS with numerous applications. These mechanisms are potential metabolic engineering targets for improving the industrial production of curdlan from Agrobacterium sp. ATCC 31749. Furthermore, many of the genes identified in this study are highly conserved across microbial genomes, and we propose that the molecular elements identified in this study may serve as universal regulators of microbial EPS synthesis.


Abiotic predictors and annual seasonal dynamics of Ixodes ricinus, the major disease vector of Central Europe.
Abiotic conditions provide cues that drive tick questing activity. Defining these cues is critical in predicting biting risk, and in forecasting climate change impacts on tick populations. This is particularly important for Ixodes ricinus nymphs, the vector of numerous pathogens affecting humans. A 6-year study of the questing activity of I. ricinus was conducted in Central Bohemia, Czech Republic, from 2001 to 2006. Tick numbers were determined by weekly flagging the vegetation in a defined 600 m(2) field site. After capture, ticks were released back to where they were found. Concurrent temperature data and relative humidity were collected in the microhabitat and at a nearby meteorological station. Data were analysed by regression methods. During 208 monitoring visits, a total of 21,623 ticks were recorded. Larvae, nymphs, and adults showed typical bimodal questing activity curves with major spring peaks and minor late summer or autumn peaks (mid-summer for males). Questing activity of nymphs and adults began with ~12 h of daylight and ceased at ~9 h daylight, at limiting temperatures close to freezing (in early spring and late autumn); questing occurred during ~70 % calendar year without cessation in summer. The co-occurrence of larvae and nymphs varied annually, ranging from 31 to 80 % of monitoring visits, and depended on the questing activity of larvae. Near-ground temperature, day length, and relative air humidity were all significant predictors of nymphal activity. For 70 % of records, near-ground temperatures measured in the microhabitat were 4-5 °C lower than those recorded by the nearby meteorological observatory, although they were strongly dependent. Inter-annual differences in seasonal numbers of nymphs reflected extreme weather events. Weather predictions (particularly for temperature) combined with daylight length, are good predictors of the initiation and cessation of I. ricinus nymph questing activity, and hence of the risk period to humans, in Central Europe. Co-occurrence data for larvae and nymphs support the notion of intrastadial rather than interstadial co-feeding pathogen transmission. Annual questing tick numbers recover quickly from the impact of extreme weather events.


[Hypertension after kidney transplantation].
Cardiovascular disease (CVD) is the leading cause of death among renal transplant recipients. The prevalence and severity of CVD in renal transplant recipients are related to numerous factors, most shared with the general population and others specific to transplant recipients, including effects of kidney dysfunction and immunosuppressive drugs. Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease and graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and sirolimus, are not nephrotoxic, do not have any hypertensive effect and may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation. Other metabolic disorders, such as post-transplant dyslipidemia and diabetes have to be closely monitored and treated as soon as possible. Incidence of arterial hypertension after kidney transplantation may be reduced by early detection, proper adjustment of immunosuppressive protocols and aggressive treatment with lifestyle modification and potent antihypertensive drugs.


Increased contribution of L-arginine-nitric oxide pathway in aorta of mice lacking the gene for vimentin.
Experiments were designed to investigate endothelial function in the aorta of mice lacking the gene for the cytoskeleton protein vimentin (vim -/- ). Rings with and without endothelium from wild-type (vim +/+ ), heterozygous (vim +/- ), and homozygous (vim -/- ) mice were suspended in organ chambers to record of changes in isometric tension. During phenylephrine contraction, acetylcholine evoked comparable endothelium-dependent relaxations in the three groups. In the presence of Nomega-nitro-L-arginine, acetylcholine caused endothelium-dependent contractions, which were greater in vim -/- than in vim +/+ and vim +/- aortas. Indomethacin did not affect relaxation to acetylcholine in vim +/+ or in vim +/-, but it significantly increased the maximal response in vim -/- (67 +/- 7 vs. 102 +/- 4%). Response to acetylcholine in vim -/- aortas was not affected by cyclooxygenase type 2 inhibitor NS-398, the thromboxane receptor antagonist SQ-29,548, or superoxide dismutase. Relaxations to sodium nitroprusside were not different between vim +/+ and vim -/- mice and were not affected by cyclooxygenase inhibition. Cyclic guanosine monophosphate levels, which were increased to a comparable level by acetylcholine in vim +/+ and vim -/-, were augmented by indomethacin in vim -/- aortas but not in vim +/+ aortas. Expression of endothelial nitric oxide synthase was not different between vim +/+ and vim -/- preparations. These results suggest that despite comparable endothelium-dependent responses to acetylcholine, endothelial cells from vim -/- mice release a cyclooxygenase product that compensates the augmented contribution of nitric oxide.


Recurrent Genetic Abnormalities in Human Pluripotent Stem Cells: Definition and Routine Detection in Culture Supernatant by Targeted Droplet Digital PCR.
Genomic integrity of human pluripotent stem cells (hPSCs) is essential for research and clinical applications. However, genetic abnormalities can accumulate during hPSC generation and routine culture and following gene editing. Their occurrence should be regularly monitored, but the current assays to assess hPSC genomic integrity are not fully suitable for such regular screening. To address this issue, we first carried out a large meta-analysis of all hPSC genetic abnormalities reported in more than 100 publications and identified 738 recurrent genetic abnormalities (i.e., overlapping abnormalities found in at least five distinct scientific publications). We then developed a test based on the droplet digital PCR technology that can potentially detect more than 90% of these hPSC recurrent genetic abnormalities in DNA extracted from culture supernatant samples. This test can be used to routinely screen genomic integrity in hPSCs.


Experimental evidence that parasites drive eco-evolutionary feedbacks.
Host resistance to parasites is a rapidly evolving trait that can influence how hosts modify ecosystems. Eco-evolutionary feedbacks may develop if the ecosystem effects of host resistance influence selection on subsequent host generations. In a mesocosm experiment, using a recently diverged (<100 generations) pair of lake and stream three-spined sticklebacks, we tested how experimental exposure to a common fish parasite (Gyrodactylus spp.) affects interactions between hosts and their ecosystems in two environmental conditions (low and high nutrients). In both environments, we found that stream sticklebacks were more resistant to Gyrodactylus and had different gene expression profiles than lake sticklebacks. This differential infection led to contrasting effects of sticklebacks on a broad range of ecosystem properties, including zooplankton community structure and nutrient cycling. These ecosystem modifications affected the survival, body condition, and gene expression profiles of a subsequent fish generation. In particular, lake juvenile fish suffered increased mortality in ecosystems previously modified by lake adults, whereas stream fish showed decreased body condition in stream fish-modified ecosystems. Parasites reinforced selection against lake juveniles in lake fish-modified ecosystems, but only under oligotrophic conditions. Overall, our results highlight the overlapping timescales and the interplay of host-parasite and host-ecosystem interactions. We provide experimental evidence that parasites influence host-mediated effects on ecosystems and, thereby, change the likelihood and strength of eco-evolutionary feedbacks.


In vitro growth versus inhibition of growth of Malassezia pachydermatis in the presence of the antibacterial drug gentamicin.
Malassezia pachydermatis is part of the normal cutaneous microbiota of most warm-blooded vertebrates and is associated with otitis externa and seborrhoeic dermatitis in dogs and cats. In this study, we evaluated the growth capacity of nine M. pachydermatis strains on Sabouraud medium in the presence of a high concentration of gentamicin. Strains of M. pachydermatis cultured on Sabouraud medium in the presence of 50 and 100 µg gentamicin ml(-1) displayed different growth patterns such as growth or lack of growth. We hypothesized that this difference in growth of M. pachydermatis strains was correlated with the different genotypes of the strains. Random amplification of polymorphic DNA (RAPD) was applied for genetic typing of M. pachydermatis isolates, derived from the external ears of house pet cats suffering from otitis externa. The M. pachydermatis strains were cultured on commercial or home-made Sabouraud medium supplemented or not with gentamicin. RAPD analysis demonstrated a genetic heterogeneity between each strain. In particular, five out of nine strains tested were able to form colonies in the presence of gentamicin. However, a correlation between M. pachydermatis genotype and growth capacity in the presence of gentamicin was not widely demonstrated.


Optimising screening for cognitive dysfunction in bipolar disorder: Validation and evaluation of objective and subjective tools.
Cognitive impairment is common in bipolar disorder and contributes to socio-occupational difficulties. The objective was to validate and evaluate instruments to screen for and monitor cognitive impairments, and improve the understanding of the association between cognitive measures and socio-occupational capacity. Patients with bipolar disorder in partial or full remission (n=84) and healthy controls (n=68) were assessed with the Screen for Cognitive Impairment in Psychiatry (SCIP), Cognitive Complaints in Bipolar Disorder Rating Scale (COBRA), and established neuropsychological tests and subjective rating scales. Socio-occupational function and affective symptoms were evaluated with the Functional Assessment Short Test, and the Hamilton Depression Rating Scale 17-items and Young Mania Rating Scale, respectively. Concurrent validity of the SCIP and COBRA were assessed by correlation with established objective and subjective cognitive measures, and decision validity was determined with Receiver-Operating-Characteristic analyses. Correlations and linear regression analyses were conducted to determine the associations between objective and subjective cognitive impairment, and socio-occupational difficulties. The SCIP and COBRA correlated strongly with established objective and subjective cognitive measures, respectively. The SCIP yielded higher sensitivity and specificity for detection of cognitive dysfunction than the COBRA or a combined SCIP-COBRA measure. Correlations between objective and subjective cognitive impairment were weak but both were associated with socio-occupational difficulties. Influence of ageing was not investigated. The SCIP and COBRA are valid for detection of objective and subjective cognitive impairment in bipolar disorder. Screening for cognitive dysfunction should be conducted with an objective measure like the SCIP.


Enhanced expression of c-Ha-ras p21 in human stomach adenocarcinomas defined by immunoassays using monoclonal antibodies and in situ hybridization.
Using c-Ha-, c-Ki-, and c-N-ras-specific probes in a RNA-RNA hybridization assay we found enhanced expression of c-Ha-ras protooncogene in stomach adenocarcinomas relative to nonneoplastic epithelium, whereas little or no transcription of either c-Ki- or c-N-ras was detected. Enhanced levels of c-Ha-ras RNA expression were detected in all of the adenocarcinomas examined. Hybridization with c-Ha-ras was also detected in nonneoplastic gastric epithelium adjacent to carcinoma, although the labeling was less intense than that of carcinoma cells. More extensive analysis of the c-Ha-ras p21 expression was then carried out in formalin-fixed, paraffin-embedded tissue sections and extracts from surgically resected stomach tissues using monoclonal antibodies (MAbs) RAP-5 and Y13-259. The data obtained from the immunohistochemical studies were consistent with the results of in situ hybridization assay. Adenocarcinomas were much more reactive with MAb RAP-5 than benign and normal tissues, and the majority of carcinomas demonstrated increased expression of c-Ha-ras p21. Quantitative liquid competition radioimmunoassays using MAb Y13-259 also demonstrated significantly higher levels of c-Ha-ras p21 in extracts from stomach adenocarcinomas than those from normal mucosae. No strict correlation was found between ras p21 expression and the degree of tumor differentiation or histological type. Although advanced carcinomas generally demonstrated higher levels of ras p21 than early carcinomas, no correlation among advanced carcinomas and ras p21 levels was observed in relation to depth of tumor invasion to the muscularis propria, subserosa, or serosa. Benign lesions, in comparison, were much less reactive with MAb RAP-5 than carcinomas. Among the benign lesions tested, dysplastic lesions were more reactive than nondysplastic lesions. Normal stomach mucosa was generally nonreactive with the exception of parietal cells. Our results indicate that transformation of the stomach mucosa from benign to malignant phenotype is associated with an increase in c-Ha-ras p21 expression.


Remote ischaemic pre- and delayed postconditioning - similar degree of cardioprotection but distinct mechanisms.
Myocardial ischaemia-reperfusion injury can be significantly reduced by an episode(s) of ischaemia-reperfusion applied prior to or during myocardial ischaemia (MI) to peripheral tissue located at a distance from the heart; this phenomenon is called remote ischaemic conditioning (RIc). Here, we compared the efficacy of RIc in protecting the heart when the RIc stimulus is applied prior to, during and at different time points after MI. A rat model of myocardial ischaemia-reperfusion injury involved 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Remote ischaemic conditioning was induced by 15 min occlusion of femoral arteries and conferred a similar degree of cardioprotection when applied 25 min prior to MI, 10 or 25 min after the onset of MI, or starting 10 min after the onset of reperfusion. These RIc stimuli reduced infarct size by 54, 56, 56 and 48% (all P < 0.001), respectively. Remote ischaemic conditioning applied 30 min into the reperfusion period was ineffective. Activation of sensory nerves by application of capsaicin was effective in establishing cardioprotection only when elicited prior to MI. Vagotomy or denervation of the peripheral ischaemic tissue both completely abolished cardioprotection induced by RIc applied prior to MI. Cardioprotection conferred by delayed remote postconditioning was not affected by either vagotomy or peripheral denervation. These results indicate that RIc confers potent cardioprotection even if applied with a significant delay after the onset of myocardial reperfusion. Cardioprotection by remote preconditioning is critically dependent on afferent innervation of the remote organ and intact parasympathetic activity, while delayed remote postconditioning appears to rely on a different signalling pathway(s).


Effect of Addition of Green Coffee Parchment on Structural, Qualitative and Chemical Properties of Gluten-Free Bread.
Green coffee parchment (GCP) is becoming interesting, due to the diffusion of wet processing in which coffee parchment is collected separately; it is one of the less studied coffee by-products, but it is reported to be rich in phenolic compounds and dietary fiber. The addition of GCP (355-500 μm) at 2 % to gluten-free breads was investigated in terms of physical properties (volume, moisture content, water activity, crumb grain, texture, and color), total antioxidant capacity (TAC) and total phenol content during three days of storage. Moreover, the effects of GCP on sensorial characteristics, 5-hydroxymethylfurfural (HMF), and oxidative stability was evaluated. From the sensorial analysis, bread with 2% addition resulted in being acceptable for consumers with no significant differences from the control, while 4% of GCP was discarded by consumers, as it resulted in being too bitter. Moreover, GCP at 2% addition did not modify volume, moisture content, and water activity. On the contrary, GCP deeply affected the color with a darker aspect that was appreciated by consumers. Regarding texture, 2% of GCP did not affect hardness, cohesiveness, and staling process during storage. Interestingly, 2% of GCP significantly improved the TAC and oxidative stability of the bread; in accordance with these results, 2% of GCP reduced the HMF content, thanks to its antioxidant compounds.


Disintegrated experience: the dissociative disorders revisited.
We present proposed changes to the dissociative disorders section of the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders and review the concept of pathological and nonpathological dissociation, including empirical findings on the relations between trauma and dissociative phenomenology and between dissociation and hypnosis. The most important proposals include the creation of two new diagnostic entities, brief reactive dissociative disorder and transient dissociative disturbance, and the readoption of the criterion of amnesia for a multiple personality disorder diagnosis. We conclude that further work on dissociative processes will provide an important link between clinical and experimental approaches to human cognition, emotion, and personality.


Evolutionary dynamics and genomic features of the Elizabethkingia anophelis 2015 to 2016 Wisconsin outbreak strain.
An atypically large outbreak of Elizabethkingia anophelis infections occurred in Wisconsin. Here we show that it was caused by a single strain with thirteen characteristic genomic regions. Strikingly, the outbreak isolates show an accelerated evolutionary rate and an atypical mutational spectrum. Six phylogenetic sub-clusters with distinctive temporal and geographic dynamics are revealed, and their last common ancestor existed approximately one year before the first recognized human infection. Unlike other E. anophelis, the outbreak strain had a disrupted DNA repair mutY gene caused by insertion of an integrative and conjugative element. This genomic change probably contributed to the high evolutionary rate of the outbreak strain and may have increased its adaptability, as many mutations in protein-coding genes occurred during the outbreak. This unique discovery of an outbreak caused by a naturally occurring mutator bacterial pathogen provides a dramatic example of the potential impact of pathogen evolutionary dynamics on infectious disease epidemiology.


Hypothalamic CART is a new anorectic peptide regulated by leptin.
The mammalian hypothalamus strongly influences ingestive behaviour through several different signalling molecules and receptor systems. Here we show that CART (cocaine- and amphetamine-regulated transcript), a brain-located peptide, is a satiety factor and is closely associated with the actions of two important regulators of food intake, leptin and neuropeptide Y. Food-deprived animals show a pronounced decrease in expression of CART messenger RNA in the arcuate nucleus. In animal models of obesity with disrupted leptin signalling, CART mRNA is almost absent from the arcuate nucleus. Peripheral administration of leptin to obese mice stimulates CART mRNA expression. When injected intracerebroventricularly into rats, recombinant CART peptide inhibits both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. An antiserum against CART increases feeding in normal rats, indicating that CART may be an endogenous inhibitor of food intake in normal animals.


Thiosemicarbazone(s)-anchored water soluble mono- and bimetallic Cu(ii) complexes: enzyme-like activities, biomolecular interactions, anticancer property and real-time live cytotoxicity.
The reactions of CuCl2·2H2O with chromone thiosemicarbazone ligands containing a -H or -CH3 substituent on terminal N yielded monometallic Cu(ii) complexes [Cu(HL1)Cl2] (1) and [Cu(HL2)Cl2] (2), whereas bimetallic Cu(ii) complexes [Cu(μ-Cl)(HL3)]2Cl2 (3), [Cu(μ-Cl)(HL4)]2Cl2 (4) and [Cu(μ-Cl)(L5)]2 (5) were obtained when a -C2H5, -C6H11 or -C6H5 substituent was present, respectively, in the ligands. The complexes were characterized using elemental analyses, UV-Vis, FT-IR, EPR, mass and TGA studies. The structures of neutral monometallic and dicationic bimetallic complexes were confirmed by single crystal X-ray diffraction, and they exhibited a distorted square pyramidal geometry around Cu(ii) ions. The catecholase-mimicking activity of complexes 1-5 was examined spectrophotometrically, and the results revealed that all the complexes except 5 had the ability to oxidize 3,5-di-tert-butylcatechol (3,5-DTBC) to 3,5-di-tert-butylquinone (3,5-DTBQ) under aerobic conditions with moderate turnover numbers. In order to find the possible complex-substrate intermediates, a mass spectrometry study was carried out for complexes 1-4 in the presence of 3,5-DTBC. The phosphatase-like activity of 1-5 was also investigated using 4-nitrophenylphosphate (4-NPP) as a model substrate. All the complexes exhibited excellent phosphatase activity in DMF-H2O medium. The complexes displayed significant biomolecular interactions and antioxidant potential. Complex 3 showed good interaction with apoptotic CASP3 protein, VEGFR2 and PIM-1 kinase receptors as revealed by a molecular docking study. Complexes (3-5) exhibited promising cytotoxicity against HeLa-cervical cancer cells with IC50 values of 2.24 (3), 2.25 (4) and 3.77 (5) μM, respectively, and showed a two-fold higher activity than cisplatin. The active complex 3 showed complete inhibition of colony formation at 10 μM concentration. In addition, the acridine orange (AO)/ethidium bromide (EB) staining and real-time live cell imaging results confirmed that complex 3 induced cell death in HeLa cells.


Does eating local food reduce the environmental impact of food production and enhance consumer health?
The concept of local food has gained traction in the media, engaged consumers and offered farmers a new marketing tool. Positive claims about the benefits of local food are probably not harmful when made by small-scale producers at the local level; however, greater concern would arise should such claims be echoed in policy circles. This review examines the evidence base supporting claims about the environmental and health benefits of local food. The results do not offer any support for claims that local food is universally superior to non-local food in terms of its impact on the climate or the health of consumers. Indeed several examples are presented that demonstrate that local food can on occasions be inferior to non-local food. The analysis also considers the impact on greenhouse gas emissions of moving the UK towards self-sufficiency. Quantitative evidence is absent on the changes in overall emissions that would occur if the UK switched to self-sufficiency. A qualitative assessment suggests the emissions per item of food would probably be greater under a scenario of self-sufficiency than under the current food system. The review does not identify any generalisable or systematic benefits to the environment or human health that arise from the consumption of local food in preference to non-local food.


Genistein alleviates lead-induced neurotoxicity in vitro and in vivo: Involvement of multiple signaling pathways.
Lead (Pb) is a ubiquitous environmental and industrial pollutant. It induces neurotoxicity and cell death by disrupting the pro- and anti-oxidative balance; however, the mechanisms of its toxicity have yet to be fully understood. The soy-derived isoflavonoid, genistein (GEN), was reported to possess neuroprotective and antioxidative properties. The present study investigated the molecular mechanisms of Pb-induced neurotoxicity in vivo and in vitro, addressing the efficacy of GEN in protecting against Pb-induced toxicity. Pb exposure was associated with reduction of cell viability and cell apoptosis, concomitant with reactive oxygen species (ROS) generation in vitro, and pre-treatment with GEN markedly ameliorated the Pb-induced oxidative injury by increasing the expression of key antioxidant enzymes and the antioxidant transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2). Next, PKC-α activation was found after Pb exposure in vitro and pretreatment with GEN attenuated Pb-induced ROS generation by PKC-α inhibition. MAPK-NF-κB activation triggered by Pb was also inhibited by GEN. In summary, our study establishes that GEN alleviates Pb-induced impairment in spatial memory, and reduces cell apoptosis caused by Pb exposure and GEN protects neurons from Pb-induced neurotoxicity by downstream activation of antioxidant and anti-apoptotic pathways via regulation of Nrf2 and MAPK-NF-κB signaling.


Exosomes: immune properties and potential clinical implementations.
To communicate, cells are known to release in their environment proteins which bind to receptors on surrounding cells. But cells also secrete more complex structures, called membrane vesicles, composed of a lipid bilayer with inserted transmembrane proteins, enclosing an internal content of hydrophilic components. Exosomes represent a specific subclass of such secreted membrane vesicles, which, despite having been described more than 20 years ago by two groups studying reticulocyte maturation, have only recently received attention from the scientific community. This renewed interest originated first from the description of exosome secretion by antigen-presenting cells, suggesting a potential role in immune responses, and very recently by the identification of the presence of RNA (both messenger and microRNA) in exosomes, suggesting a potential transfer of genetic information between cells. In this review, we will describe the conclusions of 20 years of studies on the immune properties of exosomes and the most recent advances on their roles and potential uses as markers or as therapeutic tools during pathologies, especially in cancer.


Experience with concurrent chemoradiotherapy treatment in advanced cervical cancer: results from a hospital in Argentina.
To describe our experience with concurrent chemoradiotherapy using three-dimensional conformal radiotherapy (3D-CRT) and high-dose-rate intracavitary brachytherapy with weekly cisplatin in the treatment of patients with locally advanced cervical cancer. Forty-three patients were identified between January 2009 and December 2015. Their medical records were retrospectively reviewed, and data on patient characteristics, tumour, treatment and toxicities were collected and analysed. The median age was 45 years (interquartile range (IQR): 26) The median tumour size was 45 mm (IQR: 20). Thirty-eight patients (88%) had a cervical tumour with a size of ≥ 40 mm. The median cervical tumour size evaluated by magnetic resonance imaging (MRI) was 52 mm (IQR: 17). Twenty-two patients (51%) had enlarged lymph nodes on MRI (≥ 10 mm). MRI demonstrated the involvement of the parametrium in 29 patients (67%). Fifteen patients had positive para-aortic nodes (36%). The median total treatment time was 58 days (IQR: 20). Sixteen patients (39%) received extended-field radiotherapy. Cisplatin was administered simultaneously for a median of five courses. The median follow-up period was 32 months (IQR: 28 months). Grade 3 acute toxicity was observed at the gastrointestinal level in seven patients (16%). Late grade 3/4 toxicity was observed in 14 patients (33%). Seven patients (16%) persisted with the disease and five died. The local relapse rate was 9%. Eleven patients underwent a hysterectomy after treatment. The disease-free interval was 24.2 months. The 2-year global survival rate was 82.9%. Concurrent chemo-radiotherapy appears to be an effective regimen, with acceptable toxicity, for patients with locally advanced cervical cancer.


Cystic fibrosis in Austria.
Registry data for patients with cystic fibrosis (CF) are increasingly used to evaluate the natural history, for benchmarking of therapy and in order to identify eligible patients for clinical studies. So far, no data on frequency and clinical status of CF patients have been available for Austria on a national level. We collected data of CF patients treated 2014 in Austrian CF outpatient clinics by means of a European CF registry and on an individual search basis. A total of 773 CF patients with a median age of 18.9 years (SD 11.8 years) were seen in 13 centers (18-151 patients/center). Homozygous F508del mutation being the most common genotype was observed in 48.8% of patients. Mean age at diagnosis was 27 days. In 59% of all patients FEV1% predicted (Forced Exspiratory Volume in 1 second) was <80% and in 20% <50%. An average FEV1 predicted decline per year of 1.9% was observed between 6-18 years of age. Colonisation with Pseudomonas aeruginosa ranged between 12% and 69% in adult patients and in 0-16% in children with CF. Burkholderia cepacia complex species were present in a total of 29 samples (3.8%). Insulin therapy for diabetes was given in 14.5%. Liver involvement was reported in 36.3%. A wide variation of prescribed CF therapy was observed between centers. Data on CF patients living in Austria are now available and form a basis for clinical benchmarking as well as analyses from a public health perspective.


Elucidation of myricetin biosynthesis in Morella rubra of the Myricaceae.
Flavonols are health-promoting bioactive compounds important for plant defense and human nutrition. Quercetin (Q) and kaempferol (K) biosynthesis have been studied extensively while little is known about myricetin (M) biosynthesis. The roles of flavonol synthases (FLSs) and flavonoid 3',5'-hydroxylase (F3'5'H) in M biosynthesis in Morella rubra, a member of the Myricaceae rich in M-based flavonols, were investigated. The level of MrFLS transcripts alone did not correlate well with the accumulation of M-based flavonols. However, combined transcript data for MrFLS1 and MrF3'5'H showed a good correlation with the accumulation of M-based flavonols in different tissues of M. rubra. Recombinant MrFLS1 and MrFLS2 proteins showed strong activity with dihydroquercetin (DHQ), dihydrokaempferol (DHK), and dihydromyricetin (DHM) as substrates, while recombinant MrF3'5'H protein preferred converting K to M, amongst a range of substrates. Tobacco (Nicotiana tabacum) overexpressing 35S::MrFLSs produced elevated levels of K-based and Q-based flavonols without affecting M-based flavonol levels, while tobacco overexpressing 35S::MrF3'5'H accumulated significantly higher levels of M-based flavonols. We conclude that M accumulation in M. rubra is affected by gene expression and enzyme specificity of FLS and F3'5'H as well as substrate availability. In the metabolic grid of flavonol biosynthesis, the strong activity of MrF3'5'H with K as substrate additionally promotes metabolic flux towards M in M. rubra.


Innovation Pathways for Age-Friendly Homes in Europe.
A variety of innovative pilot projects are being implemented to improve the life-course resilience of existing and newly built home environments. We refer to these projects as "socio-technical experiments" that embody different kinds of promising futures and provide direction to current developments in the emerging domain of age-friendly homes. To take stock of this diversity within Europe; this paper provides an overview of 53 ongoing socio-technical experiments that are being conducted in the Netherlands, France, Ireland and Poland. We find that, besides the variation between European countries, there is a more important type variation in terms of the character of the experiments themselves and the differences in development direction that they propose. Our findings suggest that most of the innovations tested in these experiments are not primarily material or technical but primarily social or conceptual in character (i.e., new organizational modes or everyday practices that re-arrange social relations or new housing concepts that bridge the divide between ageing in place individually and a nursing home). This variety of innovations tested in the experiments can be categorized into seven distinct innovation pathways: (1) Showcasing Technology, (2) Innovation Ecosystem, (3) Sheltered Elite, (4) Specific Community, (5) Conscious Retrofitting, (6) Home Sharing and (7) Retrovation Challenge.


Autophagy is important to the acidogenic metabolism of Aspergillus niger.
Significant phenotypic overlaps exist between autophagy and acidogenesis in Aspergillus niger. The possible role of autophagy in the acidogenic growth and metabolism of this fungus was therefore examined and the movement of cytosolic EGFP to vacuoles served to monitor this phenomenon. An autophagy response to typical as well as a metabolic inhibitor-induced nitrogen starvation was observed in A. niger mycelia. The vacuolar re-localization of cytosolic EGFP was not observed upon nitrogen starvation in the A. niger Δatg1 strain. The acidogenic growth of the fungus consisted of a brief log phase followed by an extended autophagy-like state throughout the idiophase of fermentation. Mycelia in the idiophase were highly vacuolated and EGFP was localized to the vacuoles but no autolysis was observed. Both autophagy and acidogenesis are compromised in Δatg1 and Δatg8 strains of A. niger. The acidogenic growth of the fungus thus appears to mimic a condition of nutrient limitation and is associated with an extended autophagy-like state. This crucial role of autophagy in acidogenic A. niger physiology could be of value in improving citric acid fermentation.


Association of cigarette smoking and metabolic syndrome in a puerto rican adult population.
Metabolic syndrome (MetSyn) is related to an increased risk for type 2 diabetes and cardiovascular disease. Smokers are at greater risk than nonsmokers of becoming insulin resistant and to develop cardiovascular disease. This study aimed to explore the association between cigarette smoking, MetSyn, and its components among Puerto Rican adults. A representative sample of 856 persons aged 21-79 years from the San Juan Metropolitan area participated in this study. Demographic and lifestyle characteristics, including smoking habits, were gathered from a self-reported questionnaire. MetSyn was defined according to the revised NCEP-ATP III criteria and measured using biochemical measurements and anthropometric indices. Logistic regression models were used to estimate prevalence odds ratios (POR) and its 95% confidence intervals (CI). MetSyn was significantly (P < 0.001) more prevalent in former smokers (48.4%) as compared to current (42.7%) and never smokers (40.0%). However, after adjusting for possible confounders, current smokers who used more than 20 cigarettes per day were 2.24 (95% CI = 1.00-4.99) times more likely to have MetSyn as compared to never smokers. Heavy smokers were also more likely to have high triglyceride levels (POR = 2.22, 95% CI = 1.12-4.38) and low HDL-cholesterol levels (POR = 2.49, 95% CI = 1.28-4.86) as compared to never smokers. This study supports previous reports of an increased risk of MetSyn among current smokers, particularly those with a heavier consumption. Tobacco control strategies, such as preventing smoking initiation and disseminating evidence-based cessation programs, are necessary to reduce the burden of MetSyn in Puerto Rico.


Nuclear translocation of jacob in hippocampal neurons after stimuli inducing long-term potentiation but not long-term depression.
In recent years a number of potential synapto-nuclear protein messengers have been characterized that are thought to be involved in plasticity-related gene expression, and that have the capacity of importin- mediated and activity-dependent nuclear import. However, there is a surprising paucity of data showing the nuclear import of such proteins in cellular models of learning and memory. Only recently it was found that the transcription factor cyclic AMP response element binding protein 2 (CREB2) transits to the nucleus during long-term depression (LTD), but not during long-term potentiation (LTP) of synaptic transmission in hippocampal primary neurons. Jacob is another messenger that couples NMDA-receptor-activity to nuclear gene expression. We therefore aimed to study whether Jacob accumulates in the nucleus in physiological relevant models of activity-dependent synaptic plasticity. We have analyzed the dynamics of Jacob's nuclear import following induction of NMDA-receptor dependent LTP or LTD at Schaffer collateral-CA1 synapses in rat hippocampal slices. Using time-lapse imaging of neurons expressing a Jacob-Green-Fluorescent-Protein we found that Jacob rapidly translocates from dendrites to the nucleus already during the tetanization period of LTP, but not after induction of LTD. Immunocytochemical stainings confirmed the nuclear accumulation of endogenous Jacob in comparison to apical dendrites after induction of LTP but not LTD. Complementary findings were obtained after induction of NMDA-receptor dependent chemical LTP and LTD in hippocampal primary neurons. However, in accordance with previous studies, high concentrations of NMDA and glycine as well as specific activation of extrasynaptic NMDA-receptors resembling pathological conditions induce an even more profound increase of nuclear Jacob levels. Taken together, these findings suggest that the two major forms of NMDA-receptor dependent synaptic plasticity, LTP and LTD, elicit the transition of different synapto-nuclear messengers albeit in both cases importin-mediated retrograde transport and NMDA-receptor activation is required.


Aligning conservation priorities across taxa in Madagascar with high-resolution planning tools.
Globally, priority areas for biodiversity are relatively well known, yet few detailed plans exist to direct conservation action within them, despite urgent need. Madagascar, like other globally recognized biodiversity hot spots, has complex spatial patterns of endemism that differ among taxonomic groups, creating challenges for the selection of within-country priorities. We show, in an analysis of wide taxonomic and geographic breadth and high spatial resolution, that multitaxonomic rather than single-taxon approaches are critical for identifying areas likely to promote the persistence of most species. Our conservation prioritization, facilitated by newly available techniques, identifies optimal expansion sites for the Madagascar government's current goal of tripling the land area under protection. Our findings further suggest that high-resolution multitaxonomic approaches to prioritization may be necessary to ensure protection for biodiversity in other global hot spots.


Hymenobacter nivis sp. nov., isolated from red snow in Antarctica.
A novel aerobic bacterial strain, P3T, was isolated from a red snow obtained from Antarctica. Cells of strain P3T were rod-shaped, non-motile, catalase-negative, oxidase-positive and Gram-stain-negative. Growth was observed at temperatures ranging from 0 to 25 °C, with optimum growth at 15 °C. The pH range for growth was pH 5.3-7.8. The G+C content of the genomic DNA was 55.0 mol%. The major components in the fatty acid profile were iso-C15 : 0, summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B), anteiso-C15 : 0 and summed feature 3 (iso-C16 : 1ω7c and/or iso-C16 : 1ω6c). The predominant isoprenoid quinone was MK-7. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that the novel isolate was a member of the genus Hymenobacter, and the strain showed highest sequence similarity (94 %) with H.ymenpbacter glaciei VUG-A130T, Hymenobacter. soli PB17T and Hymenobacter. antarcticus VUG-A42aaT. On the basis of phylogenetic and phenotypic properties strain P3T represents a novel species of the genus Hymenobacter (for which the name Hymenobacter nivis sp. nov. is proposed. The types strain is P3T (=DSM 101755T=NBRC 111535T).


Accurate macromolecular structures using minimal measurements from X-ray free-electron lasers.
X-ray free-electron laser (XFEL) sources enable the use of crystallography to solve three-dimensional macromolecular structures under native conditions and without radiation damage. Results to date, however, have been limited by the challenge of deriving accurate Bragg intensities from a heterogeneous population of microcrystals, while at the same time modeling the X-ray spectrum and detector geometry. Here we present a computational approach designed to extract meaningful high-resolution signals from fewer diffraction measurements.


A rapid and reliable alternative to ISO 21528-1:2004 for detection of Enterobacteriaceae.
Current legislation in Europe uses the Enterobacteriaceae as a parameter in process hygiene criteria for various food products and refers to the corresponding ISO standard (ISO 21528-1:2004) as mandatory analytical method for this purpose. The ISO procedure includes an enrichment step in EE ("Enterobacteriaceae Enrichment") broth, but it has been reported recently that some isolates of Enterobacteriaceae do not grow well or will even die off in this broth, which could lead to false negative results. To determine if this trait is common among the Enterobacteriaceae, a collection of 95 strains was screened for growth in EE broth. Inhibition was observed with 9 strains (7 Cronobacter sakazakii, 1 Cronobacter malonaticus and 1 Enterobacter amnigenus). Factors affecting cell death were found to be related mainly to the inclusion of bile salts and dyes in this medium. In a second step, an alternative method omitting the EE broth was evaluated using 326 samples, comprising 8 different food matrices and environmental samples from the corresponding manufacturing sites. Positive results were obtained for 235 samples using the ISO standard method and 232 samples using the alternative shortened method. No significant difference was found between the results for the two methods. It is proposed that the standard method for detection of Enterobacteriaceae is revised accordingly.


Equid Assessment, Research and Scoping (EARS): The Development and Implementation of a New Equid Welfare Assessment and Monitoring Tool.
The assessment of animal welfare poses numerous challenges, yet an emerging approach is the consolidation of existing knowledge into new frameworks which can offer standardised approaches to welfare assessment across a variety of contexts. Multiple tools exist for measuring the welfare of equids, but such tools have typically been developed for specific contexts. There is no 'one size fits all' which means that resulting datasets are generally non-comparable, creating a barrier to knowledge-sharing and collaboration between the many organisations working to improve equid welfare around the globe. To address this, we developed the Equid Assessment, Research and Scoping (EARS) tool, which incorporates pre-existing validated welfare assessment methods alongside new welfare indicators to deliver a larger and more comprehensive series of welfare indicators than currently exists, creating a single resource that can be used to assess equid welfare in any context. We field-trialled three welfare assessment protocols within the EARS tool, and applied these to welfare assessment of equids in a variety of contexts across nineteen countries. The EARS tool proved a useful, versatile and rapid method for collecting welfare assessment data and we collected 7464 welfare assessments in a period of fifteen months. We evaluate the EARS tool and provide ideas for future development.


Ethanol consumption by rat dams during gestation, lactation and weaning increases ethanol consumption by their adolescent young.
In two experiments, we examined effects of ethanol consumption in rat dams during gestation, lactation, and weaning on voluntary ethanol consumption by their adolescent young. We found that exposure to an ethanol-ingesting dam throughout gestation, lactation, and weaning enhanced voluntary ethanol consumption by 26- to 33-day-old adolescents. We systematically examined effects on adolescent ethanol intake or requiring dams to drink ethanol during various periods in their pups' development. We found that exposure to an ethanol-consuming dam during weaning enhanced adolescent ethanol consumption and exposure to a dam drinking ethanol during either gestation or while nursing enhanced adolescents' ethanol consumption only if pups also had access to ethanol during the weaning period.


Human blue-opsin promoter preferentially targets reporter gene expression to rat s-cone photoreceptors.
To develop a gene therapy system that specifically targets transgene expression to S-cones of the mammalian retina, the authors coupled recombinant AAV-mediated delivery with the use of a human blue-opsin (HB) promoter to drive expression. Two regions of the HB promoter sequence, HB569 and HB996, were amplified from human DNA, cloned into an AAV vector cassette upstream of the green fluorescent protein (GFP) gene, and packaged into AAV2 and AAV5 capsids. Eyes of postnatal day (P) 40 to P48 Sprague-Dawley rats were subretinally injected with 2 muL vector. Animals were humanely killed 2 to 3 weeks or 20 months after injection, and the pattern and persistence of GFP expression were analyzed in the treated retinas by immunohistochemistry, Western blotting, and RT-PCR. AAV5.HB.GFP vectors targeted photoreceptor transduction with an efficiency 20-fold higher than analogous serotype 2 vector. Both AAV5.HB.GFP vectors exhibited similar transduction efficiencies with patterns of GFP expression that did not vary depending on the size of the HB promoter used. Transgene expression was exclusively localized to photoreceptors of retinas treated with either vector. Furthermore, GFP expression was observed for at least 20 months. Dual GFP immunostaining with S- or M-opsin antibodies and GFP/PNA labeling revealed that cones coexpressing S-opsin/GFP or M-opsin/GFP constituted 37.5% +/- 8% and 13.5% +/- 3% of the GFP-positive photoreceptors, respectively, whereas rods constituted 49% +/- 5% of the GFP-positive photoreceptors. Because cones constitute approximately 1% of adult rat retinal photoreceptors, it was estimated that the relative transduction efficiency of AAV5.HB.GFP vectors was approximately 100:1 for cones versus rods. AAV5.HB.GFP vector injected into the subretinal space of Sprague-Dawley rats targeted gene expression to photoreceptor cells with an efficiency approximately 20-fold higher than that for AAV2.HB.GFP. Transgene expression regulated by the human blue cone-promoter persisted at least for 20 months. Cones coexpressing S-opsin and the GFP transgene appeared to prevail, confirming that in addition to having properties of the AAV serotype, the promoter choice is key to fine-tuning transgene delivery and expression in specific retinal cells. The system described here may be effective in a therapeutic setting in which strong S-cone transgene expression is required.


Uridine diphosphate glucuronic acid production and utilization in various tissues actively synthesizing glycosaminoglycans.
1. UDP-glucose dehydrogenase has been partially purified from sheep nasal septum cartilage, neonatal rat skin and bovine corneal epithelium. 2. The pH profile, K(m) values for NAD(+) and UDP-glucose, activation energy and molecular weight have been determined for the enzyme from several of the tissues. 3. The sugar nucleotide concentrations in each of the tissues have been related to the spectrum of glycosaminoglycans produced by each tissue. 4. The presence of an allosteric UDP-xylose-binding site distinct from the active site(s) in sheep nasal septum UDP-glucose dehydrogenase has been demonstrated. 5. An active UDP-glucuronic acid nucleotidase has been demonstrated in sheep nasal cartilage. 6. Tissue-space experiments have shown the cell water content of sheep nasal septum cartilage to be 14% of the wet weight. 7. Glucuronic acid 1-phosphate does not occur in measurable amounts in sheep nasal septum cartilage and no UDP-glucuronic acid pyrophosphorylase activity could be detected in this tissue. 8. The inhibition by UDP-xylose with respect to both substrates, UDP-glucose and NAD(+), has been examined, and shown to be allosteric.


Testosterone-induced suppression of autoimmune disease in lacrimal tissue of a mouse model (NZB/NZW F1) of Sjögren's syndrome.
The current investigation was designed to examine whether androgen administration might suppress autoimmune disease in lacrimal glands of a mouse model (NZB/NZW F1) of Sjögren's syndrome. Autoimmune, female mice were treated with vehicle or varying concentrations of testosterone for 0, 17, 34, or 51 days, and tears, lacrimal glands, as well as submandibular tissue, were collected from killed mice after androgen exposure. Glands were histologically processed and evaluated with a computer-assisted image analysis system. Results showed that testosterone administration induced a significant, time-dependent decrease in the extent of lymphocytic accumulation in the lacrimal gland. After 34-51 days of androgen therapy, the magnitude of lymphocyte infiltration had been suppressed 22- to 46-fold, compared with that in placebo-treated tissue. This hormone effect was associated with significant reductions in the number of focal infiltrates, the area of individual foci, and the total quantity of lymphocyte infiltration per lacrimal section. Testosterone exposure also stimulated an increase in lacrimal gland weight and a rise in tear volumes, relative to those measured in the same mice before treatment. In addition, androgens significantly diminished the extent of lymphocyte accumulation in submandibular tissue. In summary, our results demonstrate that androgen administration may inhibit the progression of autoimmune disease in lacrimal and submandibular glands of NZB/NZW F1 mice.


18-year change in serum intact fibroblast growth factor 23 from midlife to late life and risk of mortality: the ARIC Study.
Fibroblast growth factor 23 (FGF23) concentration increases in response to declining kidney function to preserve normal phosphate concentrations. However, the etiological association of change in FGF23 concentration with mortality has not been examined in the general population. We analyzed 5458 participants of the Atherosclerosis Risk in Communities Study who had intact FGF23 and estimated glomerular filtration rate (eGFR) assessed during midlife (visit 3, 1993-1995, mean age: 58 years) and late life (visit 5, 2011-2013, 76 years) to examine the association of FGF23 change over 18 years from mid-life to late life with the subsequent risk of mortality in late life using Cox regression models. The median 18-year change in intact FGF23 was +17.3 pg/mL. During a median follow-up of 7.2 years following visit 5, 1176 participants died. In multivariable Cox models, elevated mortality was seen in the highest quartile of FGF23 change (ΔFGF23: ≥31.3 pg/mL) (adjusted hazard ratio (aHR): 1.61 (95%CI: 1.36-1.90), or 1.37 (1.15-1.64) after additionally adjusting for eGFR change, compared with the lowest quartile (≤6.4 pg/mL)). When both FGF23 change and FGF23 in late life were simultaneously entered into the Cox model, FGF23 in late life, but not FGF23 change, was an independent predictor of mortality; however, we observed a high correlation between FGF23 change from midlife to late life and FGF23 in late life (r = 0.77). Serum intact FGF23 change from midlife to late life was associated with subsequent risk of mortality independent of decline in kidney function. Our findings further support the implications of FGF23 beyond its association with kidney function.


[Monitoring and evaluation platform for HEARTS in the Americas: improving population-based hypertension control programs in primary health carePlataforma de monitoramento e avaliação do programa HEARTS nas Américas: melhoria dos programas de controle da hipertensão de base populacional na atenção primária à saúde].
HEARTS in the Americas is the Pan American Health Organization flagship program to accelerate the reduction of the cardiovascular disease (CVD) burden by improving hypertension control and CVD secondary prevention in primary health care. A monitoring and evaluation (M&E) platform is needed for program implementation, benchmarking, and informing policy-makers. This paper describes the conceptual bases of the HEARTS M&E platform including software design principles, contextualization of data collection modules, data structure, reporting, and visualization. The District Health Information Software 2 (DHIS2) web-based platform was chosen to implement aggregate data entry of CVD outcome, process, and structural risk factor indicators. In addition, PowerBI was chosen for data visualization and dashboarding for the analysis of performance and trends above the health care facility level. The development of this new information platform was focused on primary health care facility data entry, timely data reporting, visualizations, and ultimately active use of data to drive decision-making for equitable program implementation and improved quality of care. Additionally, lessons learnt and programmatic considerations were assessed through the experience of the M&E software development. Building political will and support is essential to developing and deploying a flexible platform in multiple countries which is contextually specific to the needs of various stakeholders and levels of the health care system. The HEARTS M&E platform supports program implementation and reveals structural and managerial limitations and care gaps. The HEARTS M&E platform will be central to monitoring and driving further population-level improvements in CVD and other noncommunicable disease-related health.


Potential of brown adipose tissue type II thyroxine 5'-deiodinase as a local and systemic source of triiodothyronine in rats.
Previous reports suggest that a type II iodothyronine 5'-deiodinase may become the main enzymatic pathway for extrathyroidal triiodothyronine (T3) generation when the enzyme levels are sufficiently elevated and/or liver and kidney type I 5'-deiodinase activity is depressed. The present studies assessed the potential of brown adipose tissue (BAT) type II 5'-deiodinase to generate T3 for the plasma pool. BAT 5'-deiodination (BAT 5'D) was stimulated by either short- (4 h) or long-term (7 wk) cold exposure (4 degrees C). Long-term cold exposure increased thyroxine (T4) secretion 40-60% and extrathyroidal T3 production three-fold. In cold-adapted rats treated with propylthiouracil (PTU), extrathyroidal T3 production was 10-fold higher than in PTU-treated rats maintained at room temperature. Cold did not stimulate liver or kidney 5'D, but the cold-adapted rats showed a six- to eightfold higher BAT 5'D content. PTU caused greater than 95% inhibition of liver and kidney 5'D, but did not affect BAT 5'D. Thyroidectomized rats maintained on 0.8 micrograms of T4/100 g of body weight (BW) per day were acutely exposed to 4 degrees C. In rats given 10 mg of PTU/100 g of BW, 4 h of cold exposure still caused a 12-fold increase in BAT 5'D, a 2.3-fold increase in plasma T3 production, and a 4.8-fold increment in the locally produced T3 in BAT itself. All these responses were abolished by pretreatment with the alpha 1-antiadrenergic drug prazosin. Regardless of the ambient temperature, liver 5'D activity was greater than 90% inhibited by PTU. These results indicate that BAT can be a major source of plasma T3 under suitable circumstances such as acute or chronic exposure to cold. Furthermore, BAT 5'D activity affects BAT T3 content itself, suggesting that thyroid hormone may have a previously unrecognized role in augmenting the thermogenic response of this tissue to sympathetic stimulation. Such interactions may be especially important during the early neonatal period in humans, a time of marked thermogenic stress.


The Current State of Deep Brain Stimulation for Chronic Pain and Its Context in Other Forms of Neuromodulation.
Chronic intractable pain is debilitating for those touched, affecting 5% of the population. Deep brain stimulation (DBS) has fallen out of favour as the centrally implantable neurostimulation of choice for chronic pain since the 1970⁻1980s, with some neurosurgeons favouring motor cortex stimulation as the 'last chance saloon'. This article reviews the available data and professional opinion of the current state of DBS as a treatment for chronic pain, placing it in the context of other neuromodulation therapies. We suggest DBS, with its newer target, namely anterior cingulate cortex (ACC), should not be blacklisted on the basis of a lack of good quality study data, which often fails to capture the merits of the treatment.


Relationship between coffee consumption and stroke risk in Korean population: the Health Examinees (HEXA) Study.
Although coffee consumption is increasing rapidly, the results of previous studies regarding the association between coffee consumption and stroke risk have been conflicting. This was a multi-center cross-sectional study that aimed to evaluate the relationship between coffee consumption and stroke risk in Korean population. Data were obtained from the Health Examinees (HEXA) Study, which involved 146,830 individuals aged 40-69 years. Coffee consumption was categorized as none, < 1 cup/day, 1 to < 3 cups/day, and ≥ 3 cups/day. We used logistic regression models to examine the association between coffee consumption and the risk of stroke while controlling for potential confounders and performed subgroup analyses. After adjusting for age and various possible confounders, high coffee consumption was associated with a 38% lower odds ratio for stroke in women (none vs. ≥ 3 cups/day: OR, 0.62; 95% CI 0.47-0.81; P for trend < 0.0001). No significant association was found in men (none vs. ≥ 3 cups/day: OR, 0.84; 95% CI, 0.66-1.07; P for trend = 0.1515). In analyses stratified by covariates, an inverse association between coffee consumption and stroke risk was most evident among healthy women who were younger, non-obese, non-hypertensive, non-diabetic, non-smokers, and non-alcohol drinkers. Our results suggest that higher coffee consumption may have protective benefits with regards to stroke risk in middle-aged Korean women.


Functional connectivity correlates of attentional networks in insomnia disorder: A pilot study.
Insomnia disorder has been associated with poor executive functioning. Functional imaging studies of executive functioning in insomnia are scarce and inconclusive. Because the Attentional Network Test relies on well-defined cortical networks and sensitively distinguishes different aspects of executive function, it might reveal brain functional alterations in relatively small samples of patients. The current pilot study assessed functional connectivity during the Attentional Network Test performed using magnetic resonance imaging in 12 participants with insomnia and 13 self-defined good sleepers. ANCOVAs were used to evaluate group differences in performance and functional connectivity in the regions of interest representing the attentional networks (i.e. alerting, orienting and executive control) at p < 0.05, uncorrected. During the orienting part, participants with insomnia showed weaker connectivity of the precentral gyrus with the superior parietal lobe (false discovery rate-corrected), while they showed stronger connectivity between premotor and visual regions. Individual differences in connectivity between premotor and visual regions correlated inversely with reaction time. Reaction times suggested more efficient executive control in participants with insomnia compared with good sleepers. During the executive control part, participants with insomnia showed stronger connectivity of thalamic parts of the arousal circuit with the middle frontal and the occipital gyri. Conversely, connectivity between the inferior and superior frontal gyri was weaker. Participants with insomnia seem to recruit more cortical resources in visuo-motor regions to orient attention than good sleepers do, and seem to have enhanced executive control that relates to stronger connectivity of arousal-related thalamic areas. This latter result should be treated with caution and requires confirmation.


Interaction between hypertension, apoE, and cerebral white matter lesions.
Cerebral white matter lesions (WMLs) are frequently found on magnetic resonance imaging scans in both cognitively intact and demented elderly persons. Vascular risk factors, especially hypertension, are related to their presence. However, not every person with vascular risk factors has WMLs, which suggests interaction with other determinants, eg, genetic factors. The epsilon4 allele of the apolipoprotein E gene (apoE) may be a candidate because this allele is associated with both the vascular risk factors and the consequences (cognitive impairment, dementia) of WMLs. We investigated apoE genotype, blood pressure levels, and their interaction in relation to subcortical and periventricular WMLs in 971 participants in the Rotterdam Scan Study. ApoE epsilon4 carriers had a significantly higher subcortical WML volume than did apoE epsilon3epsilon3 carriers (adjusted mean difference, 0.5; 95% confidence interval, 0.2 to 0.8), irrespective of hypertension. This was not found for periventricular WMLs. Participants with both hypertension and at least 1 apoE epsilon4 allele had the highest degree of both types of WML; the interaction was statistically significant for subcortical WMLs (P=0.016). apoE epsilon4 carriers are at increased risk for WMLs if they suffer from hypertension as well. This may reflect a diminished capacity for neuronal repair in apoE epsilon4 carriers.


SU(3) spin-orbit coupling in systems of ultracold atoms.
Motivated by the recent experimental success in realizing synthetic spin-orbit coupling in ultracold atomic systems, we consider N-component atoms coupled to a non-Abelian SU(N) gauge field. More specifically, we focus on the case, referred to here as "SU(3) spin-orbit-coupling," where the internal states of three-component atoms are coupled to their momenta via a matrix structure that involves the Gell-Mann matrices (in contrast to the Pauli matrices in conventional SU(2) spin-orbit-coupled systems). It is shown that the SU(3) spin-orbit-coupling gives rise to qualitatively different phenomena and in particular we find that even a homogeneous SU(3) field on a simple square lattice enables a topologically nontrivial state to exist, while such SU(2) systems always have trivial topology. In deriving this result, we first establish an equivalence between the Hofstadter model with a 1/N Abelian flux per plaquette and a homogeneous SU(N) non-Abelian model. The former is known to have a topological spectrum for N>2, which is thus inherited by the latter. It is explicitly verified by an exact calculation for N=3, where we develop and use a new algebraic method to calculate topological indices in the SU(3) case. Finally, we consider a strip geometry and establish the existence of three gapless edge states-the hallmark feature of such an SU(3) topological insulator.


How do doctors experience the interactions among professional fulfilment, organisational factors and quality of patient care? A qualitative study in a Norwegian hospital.
Doctors increasingly experience high levels of burnout and loss of engagement. To address this, there is a need to better understand doctors' work situation. This study explores how doctors experience the interactions among professional fulfilment, organisational factors and quality of patient care. An exploratory qualitative study design with semistructured individual interviews was chosen. Interviews were transcribed verbatim and analysed by a transdisciplinary research group. The study focused on a surgical department of a mid-sized hospital in Norway. Seven doctors were interviewed. A purposeful sampling was used with gender and seniority as selection criteria. Three senior doctors (two female, one male) and four in training (three male, one female) were interviewed. We found that in order to provide quality care to the patients, individual doctors described 'stretching themselves', that is, handling the tensions between quantity and quality, to overcome organisational shortcomings. Experiencing a workplace emphasis on production numbers and budget concerns led to feelings of estrangement among the doctors. Participants reported a shift from serving as trustworthy, autonomous professionals to becoming production workers, where professional identity was threatened. They felt less aligned with workplace values, in addition to experiencing limited management recognition for quality of patient care. Management initiatives to include doctors in development of organisational policies, processes and systems were sparse. The interviewed doctors described their struggle to balance the inherent tension among professional fulfilment, organisational factors and quality of patient care in their everyday work. They communicated how 'stretching themselves', to overcome organisational shortcomings, is no longer a feasible strategy without compromising both professional fulfilment and quality of patient care. Managers need to ensure that doctors are involved when developing organisational policies, processes and systems. This is likely to be beneficial for both professional fulfilment and quality of patient care.


Safe insulin use in the hospital setting.
Inpatients have a high rate of diabetes (12%-26%) and hyperglycemia (~38%). All patients should have their glycosylated hemoglobin (A1C) checked on admission to help differentiate between long-term and new-onset hyperglycemia. Good glycemic control throughout the hospital stay is associated with decreases in short- and long-term risk of mortality, inpatient complications, length of hospital stay, and health care costs. Insulin is first-line therapy for hyperglycemia; patients with hyperglycemia should be managed using either intravenous (IV) or subcutaneous (SC) insulin algorithms. A hypoglycemia management protocol should be in place at the hospital for safety purposes. For successful glycemic control, insulin algorithms should have dynamic scales, require frequent glucose monitoring, and be simple and easy to use. The algorithm should address transitioning patients from IV to SC insulin and a discharge plan. Insulin analogues are preferred for basal, mealtime, and correction doses instead of human insulins (regular and NPH) because analogues have a more predictable absorption and action profile and less pharmacokinetic fluctuation. Institutions can increase safe insulin use by utilizing insulin algorithms, preprinted order sets, and hypoglycemia protocols; by supporting patient and health care provider education; and by implementing needle-stick prevention techniques.


Waterborne diseases of bacterial origin in relation to quality of water in a suburb of Uttar Pradesh.
Waterborne disorders of bacterial origin, e.g. typhoid, bacillary dysentery and diarrhea are one of the major global health problems, especially in developing countries like India. The prevalence of these diseases is largely dependent on the quality of water consumed by people. The quality of water in India is still below the WHO recommendation of zero fecal coliform/100 ml of water. The present study was conducted in a suburb of Aligarh District of U.P. (India). A total of 1270 persons were selected by paying home visits and followed up for a period of one year. The study revealed that morbidity was higher in standpost group, i.e., 88.3% while in piped water group it was 51.8%. The average episode of typhoid for both source of water was one while dysentery had 3 average episodes. The average episodes of diarrhea was 4 in stand post and 3 in piped water group. In standpost group the majority of people, (87.6%) were using unsatisfactory water as compared to 74.4% for piped water supply. The frequency of typhoid was 1.4% bacillary dysentery 3.4% and diarrhea 7.7%. The occurrence of waterborne disorders of bacterial origin was common for typhoid in the 5-12 years age group bacillary dysentery for the 1-5 years, and diarrhea for the 0-5 years age group. The morbidity rate in standpost group was comparatively higher, i.e., 79.6%. The frequency for the standpost group and piped water group for different diseases were, typhoid 1.1% and 0.7%, bacillary dysentery 2.7% and 2.2%, and diarrhea 6.1% and 5.1%, respectively.


Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies.
Previous studies have reported inconsistent findings regarding the association between the use of acid-suppressive drugs such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H(2)RAs) and fracture risk. We investigated this association using meta-analysis. We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 using common key words. We included case-control, nested case-control, and cohort studies. Two evaluators independently reviewed and selected articles. We determined pooled effect estimates by using random-effects meta-analysis, because of heterogeneity. Of 1,809 articles meeting our initial inclusion criteria, 5 case-control studies, 3 nested case-control studies, and 3 cohort studies were included in the final analyses. The pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18-1.41) with use of PPIs and 1.10 (95% CI, 0.99-1.23) with use of H(2)RAs when compared with nonuse of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30; 95% CI, 1.15-1.48) and hip fracture risk (adjusted OR = 1.34; 95% CI, 1.09-1.66), whereas long-term H(2)RA use was not significantly associated with fracture risk. We found possible evidence linking PPI use to an increased risk of fracture, but no association between H(2)RA use and fracture risk. Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors.


Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG).
Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.


A zwitterionic aluminabenzene-alkylzirconium complex having half-zirconocene structure: synthesis and application for additive-free ethylene polymerization.
An aluminabenzene-alkylzirconium complex having a half-zirconocene structure was synthesized. X-ray crystallographic analysis of this complex revealed a zwitterionic structure consisting of cationic alkylzirconium chloride and four-coordinated aluminate. In the presence of a catalytic amount of this complex, ethylene polymerization could proceed without any additives to form ultra-high molecular weight polyethylene.


Risk for colon adenomas in patients with rectosigmoid hyperplastic polyps.
To determine whether hyperplastic polyps found in the rectosigmoid area of the colon are associated with proximal adenomas, and to judge whether patients with distal hyperplastic polyps found during sigmoidoscopy might benefit from full colonoscopy. Data on patients having colonoscopy collected prospectively according to a set protocol. The size and location of all polyps were noted, and all polyps were biopsied. Two university hospitals. One thousand eight hundred and thirty-six consecutive patients referred for colonoscopy between 31 December 1987 and 31 August 1989. Of the 970 patients who met eligibility requirements, 274 (28.3%) had adenomas and 108 (11.1%) had hyperplastic polyps. The proportion of patients with distal hyperplastic polyps and proximal adenomas (31.9%) was similar to the proportion of those without distal hyperplastic polyps (23.0%) (crude odds ratio, 1.57; 95% CI, 0.77 to 3.06). After adjusting for age and sex, the results were unchanged (adjusted odds ratio, 1.53; CI, 0.82 to 2.88). Patients with distal adenomas, on the other hand, were three times more likely to have proximal adenomas than those without distal adenomas (adjusted odds ratio, 3.42; CI, 1.99 to 5.88). Distal hyperplastic polyps are not strong predictors of risk for proximal adenomas. Based on the magnitude of the risk difference, we do not believe that finding a hyperplastic polyp during sigmoidoscopy justifies doing a full colonoscopy to search for proximal adenomas. Because rectosigmoid adenomas are associated with proximal adenomas, however, small polyps seen during sigmoidoscopy should be biopsied to determine their type. Colonoscopy should be reserved for patients who are proved to have adenomas.


Characterization of the yeast ionome: a genome-wide analysis of nutrient mineral and trace element homeostasis in Saccharomyces cerevisiae.
Nutrient minerals are essential yet potentially toxic, and homeostatic mechanisms are required to regulate their intracellular levels. We describe here a genome-wide screen for genes involved in the homeostasis of minerals in Saccharomyces cerevisiae. Using inductively coupled plasma-atomic emission spectroscopy (ICP-AES), we assayed 4,385 mutant strains for the accumulation of 13 elements (calcium, cobalt, copper, iron, potassium, magnesium, manganese, nickel, phosphorus, selenium, sodium, sulfur, and zinc). We refer to the resulting accumulation profile as the yeast 'ionome'. We identified 212 strains that showed altered ionome profiles when grown on a rich growth medium. Surprisingly few of these mutants (four strains) were affected for only one element. Rather, levels of multiple elements were altered in most mutants. It was also remarkable that only six genes previously shown to be involved in the uptake and utilization of minerals were identified here, indicating that homeostasis is robust under these replete conditions. Many mutants identified affected either mitochondrial or vacuolar function and these groups showed similar effects on the accumulation of many different elements. In addition, intriguing positive and negative correlations among different elements were observed. Finally, ionome profile data allowed us to correctly predict a function for a previously uncharacterized gene, YDR065W. We show that this gene is required for vacuolar acidification. Our results indicate the power of ionomics to identify new aspects of mineral homeostasis and how these data can be used to develop hypotheses regarding the functions of previously uncharacterized genes.


Metabolic and inflammatory markers: associations with individual depressive symptoms.
Literature has shown that obesity, metabolic syndrome and inflammation are associated with depression, however, evidence suggests that these associations are specific to atypical depression. Which of the atypical symptoms are driving associations with obesity-related outcomes and inflammation is unknown. We evaluated associations between individual symptoms of depression (both atypical and non-atypical) and body mass index (BMI), metabolic syndrome components and inflammatory markers. We included 808 persons with a current diagnosis of depression participating in the Netherlands Study of Depression and Anxiety (67% female, mean age 41.6 years). Depressive symptoms were derived from the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology. Univariable and multivariable regression analyses adjusting for sex, age, educational level, depression severity, current smoking, physical activity, anti-inflammatory medication use, and statin use were performed. Increased appetite was positively associated with BMI, number of metabolic syndrome components, waist circumference, C-reactive protein and tumor necrosis factor-α. Decreased appetite was negatively associated with BMI and waist circumference. Psychomotor retardation was positively associated with BMI, high-density lipoprotein cholesterol and triglycerides, and insomnia with number of metabolic syndrome components. Increased appetite - in the context of a depressive episode - was the only symptom that was associated with both metabolic as well as inflammatory markers, and could be a key feature of an immuno-metabolic form of depression. This immuno-metabolic depression should be considered in clinical trials evaluating effectiveness of compounds targeting metabolic and inflammatory pathways or lifestyle interventions.


Adoptive cell transfer as personalized immunotherapy for human cancer.
Adoptive cell therapy (ACT) is a highly personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity. ACT using naturally occurring tumor-reactive lymphocytes has mediated durable, complete regressions in patients with melanoma, probably by targeting somatic mutations exclusive to each cancer. These results have expanded the reach of ACT to the treatment of common epithelial cancers. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment.


Risperidone (depot) for schizophrenia.
Risperidone is the first new generation antipsychotic drug made available in a long-acting injection formulation. To examine the effects of depot risperidone for treatment of schizophrenia or related psychoses in comparison with placebo, no treatment or other antipsychotic medication.To critically appraise and summarise current evidence on the resource use, cost and cost-effectiveness of risperidone (depot) for schizophrenia. We searched the Cochrane Schizophrenia Group's Register (December 2002, 2012, and October 28, 2015). We also checked the references of all included studies, and contacted industry and authors of included studies. Randomised clinical trials comparing depot risperidone with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. Two review authors independently selected trials, assessed trial quality and extracted data. For dichotomous data, we calculated the risk ratio (RR), with 95% confidence interval (CI). For continuous data, we calculated mean differences (MD). We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. Twelve studies, with a total of 5723 participants were randomised to the following comparison treatments: Risperidone depot versus placebo Outcomes of relapse and improvement in mental state were neither measured or reported. In terms of other primary outcomes, more people receiving placebo left the study early by 12 weeks (1 RCT, n=400, RR 0.74 95% CI 0.63 to 0.88, very low quality evidence), experienced severe adverse events in short term (1 RCT, n=400, RR 0.59 95% CI 0.38 to 0.93, very low quality evidence). There was however, no difference in levels of weight gain between groups (1 RCT, n=400, RR 2.11 95% CI 0.48 to 9.18, very low quality evidence). Risperidone depot versus general oral antipsychotics The outcome of improvement in mental state was not presented due to high levels of attrition, nor were levels of severe adverse events explicitly reported. Most primary outcomes of interest showed no difference between treatment groups. However, more people receiving depot risperidone experienced nervous system disorders (long-term:1 RCT, n=369, RR 1.34 95% CI 1.13 to 1.58, very-low quality evidence). Risperidone depot versus oral risperidoneData for relapse and severe adverse events were not reported. All outcomes of interest were rated as moderate quality evidence. Main results showed no differences between treatment groups with equivocal data for change in mental state, numbers leaving the study early, any extrapyramidal symptoms, weight increase and prolactin-related adverse events. Risperidone depot versus oral quetiapine Relapse rates and improvement in mental state were not reported. Fewer people receiving risperidone depot left the study early (long-term: 1 RCT, n=666, RR 0.84 95% CI 0.74 to 0.95, moderate quality evidence). Experience of serious adverse events was similar between groups (low quality evidence), but more people receiving depot risperidone experienced EPS (1 RCT, n=666, RR 1.83 95% CI 1.07 to 3.15, low quality evidence), had greater weight gain (1 RCT, n=666, RR 1.25 95% CI 0.25 to 2.25, low quality evidence) and more prolactin-related adverse events (1 RCT, n=666, RR 3.07 95% CI 1.13 to 8.36, very low quality evidence). Risperidone depot versus oral aripiprazoleRelapse rates, mental state using PANSS, leaving the study early, serious adverse events and weight increase were similar between groups. However more people receiving depot risperidone experienced prolactin-related adverse events compared to those receiving oral aripiprazole (2 RCTs, n=729, RR 9.91 95% CI 2.78 to 35.29, very low quality of evidence). Risperidone depot versus oral olanzapineRelapse rates were not reported in any of the included studies for this comparison. Improvement in mental state using PANSS and instances of severe adverse events were similar between groups. More people receiving depot risperidone left the study early than those receiving oral olanzapine (1 RCT, n=618, RR 1.32 95% CI 1.10 to 1.58, low quality evidence) with those receiving risperidone depot also experiencing more extrapyramidal symptoms (1 RCT, n=547, RR 1.67 95% CI 1.19 to 2.36, low quality evidence). However, more people receiving oral olanzapine experienced weight increase (1 RCT, n=547, RR 0.56 95% CI 0.42 to 0.75, low quality evidence). Risperidone depot versus atypical depot antipsychotics (specifically paliperidone palmitate)Relapse rates were not reported and rates of response using PANSS, weight increase, prolactin-related adverse events and glucose-related adverse events were similar between groups. Fewer people left the study early due to lack of efficacy from the risperidone depot group (long term: 1 RCT, n=749, RR 0.60 95% CI 0.45 to 0.81, low quality evidence), but more people receiving depot risperidone required use of EPS-medication (2 RCTs, n=1666, RR 1.46 95% CI 1.18 to 1.8, moderate quality evidence). Risperidone depot versus typical depot antipsychoticsOutcomes of relapse, severe adverse events or movement disorders were not reported. Outcomes relating to improvement in mental state demonstrated no difference between groups (low quality evidence). However, more people receiving depot risperidone compared to other typical depots left the study early (long-term:1 RCT, n=62, RR 3.05 95% CI 1.12 to 8.31, low quality evidence). Depot risperidone may be more acceptable than placebo injection but it is hard to know if it is any more effective in controlling the symptoms of schizophrenia. The active drug, especially higher doses, may be associated with more movement disorders than placebo. People already stabilised on oral risperidone may continue to maintain benefit if treated with depot risperidone and avoid the need to take tablets, at least in the short term. In people who are happy to take oral medication the depot risperidone is approximately equal to oral risperidone. It is possible that the depot formulation, however, can bring a second-generation antipsychotic to people who do not reliably adhere to treatment. People with schizophrenia who have difficulty adhering to treatment, however, are unlikely to volunteer for a clinical trial. Such people may gain benefit from the depot risperidone with no increased risk of extrapyramidal side effects.


Evaluation of xenoestrogenic potential of propylparaben in zebrafish (Danio rerio).
Xenoestrogenic potential of propylparaben (PP), one of the most commonly used preservatives in drugs, cosmetics and food, was investigated in vivo using zebrafish (Danio rerio). Juvenile zebrafish (20 days post hatching) were exposed to three different concentrations of propylparaben (PP) dissolved in ethanol and added into the water. After 20 days of exposure the fish were euthanized and vitellogenin concentrations in their whole body homogenates were measured by the method of direct sandwich ELISA. Simultaneously, vitellogenin concentrations in either fish from the control group (exposed to solvent without the substance tested) and in fish from the positive control group (exposed to natural estrogen 17beta-estradiol) were measured. Vitellogenin concentration in whole body homogenates of control fish was 400 (396-540) ng/ml(-1) (geometric mean (95% CI)). Zebrafish exposure to propylparaben at the concentrations of 0.1; 0.4 and 0.9 mg/l(-1) elicited statistically significant decline (P<0.001) of vitellogenin production, i.e. geometric means of vitellogenin concentrations in whole body homogenates were 240 (186-311); 218 (175-270) and 270 (234-311) ng/ml(-1), respectively. Conversely, the geometric mean of vitellogenin concentration in whole body homogenates of zebrafish exposed to 100 ng/ml(-1) of 17beta-estradiol (positive control) was significantly higher (P<0.001) than values in all other groups, i.e. 35,553 (16,860-74,968) ng/ml(-1). Our results suggest an antiestrogenic potential of propylparaben tested in vivo in juvenile zebrafish (Danio rerio). The estrogenic effect of 17beta-estradiol was confirmed.


Whole cell hybridisation for monitoring harmful marine microalgae.
Fluorescence in situ hybridisation (FISH) is a powerful molecular biological tool to detect and enumerate harmful microorganism in the marine environment. Different FISH methods are available, and especially in combination with automated counting techniques, the potential for a routine monitoring of harmful marine microalgae is attainable. Various oligonucleotide probes are developed for detecting harmful microalgae. However, FISH-based methods are not yet regularly included in monitoring programmes tracking the presence of harmful marine microalgae. A limitation factor of the FISH technique is the currently available number of suited fluorochromes attached to the FISH probes to detect various harmful species in one environmental sample at a time. However, coupled automated techniques, like flow cytometry or solid-phase cytometry, can facilitate the analysis of numerous field samples and help to overcome this drawback. A great benefit of FISH in contrast to other molecular biological detection methods for harmful marine microalgae is the direct visualisation of the hybridised target cells, which are not permitted in cell free formats, like DNA depending analysis methods. Therefore, an additional validation of the FISH-generated results is simultaneously given.


RNA Sequencing of the In Vivo Human Herpesvirus 6B Transcriptome To Identify Targets for Clinical Assays Distinguishing between Latent and Active Infections.
Human herpesvirus 6B (HHV-6B) DNA is frequently detected in human samples. Diagnostic assays distinguishing HHV-6B reactivation from latency are limited. This has impaired strategies to diagnose and treat HHV-6B-associated diseases. We used RNA sequencing to characterize and compare the HHV-6B transcriptome in multiple sample types, including (i) whole blood from hematopoietic cell transplant (HCT) recipients with and without HHV-6B plasma viremia, (ii) tumor tissue samples from subjects with large B cell lymphoma infected with HHV-6B, (iii) lymphoblastoid cell lines (LCLs) from subjects with inherited chromosomally integrated HHV-6B or latent infection with HHV-6B, and (iv) HHV-6B Z29 infected SupT1 CD4+ T cells. We demonstrated substantial overlap in the HHV-6B transcriptome observed in in vivo and in vitro samples, although there was variability in the breadth and quantity of gene expression across samples. The HHV-6B viral polymerase gene U38 was the only HHV-6B transcript detected in all next-generation RNA sequencing (RNA-seq) data sets and was one of the most highly expressed genes. We developed a novel reverse transcription-PCR assay targeting HHV-6B U38, which identified U38 mRNA in all tested whole-blood samples from patients with concurrent HHV-6B viremia. No HHV-6B U38 transcripts were detected by RNA-seq or reverse transcription-real-time quantitative PCR (RT-qPCR) in whole-blood samples from subjects without HHV-6B plasma detection or from latently infected LCLs. A RT-qPCR assay for HHV-6B U38 may be useful to identify lytic HHV-6B infection in nonplasma samples and samples from individuals with inherited chromosomally integrated HHV-6B. This study also demonstrates the feasibility of transcriptomic analyses for HCT recipients.IMPORTANCE Human herpesvirus 6B (HHV-6B) is a DNA virus that infects most children within the first few years of life. After primary infection, HHV-6B persists as a chronic, latent infection in many cell types. Additionally, HHV-6B can integrate into germ line chromosomes, resulting in individuals with viral DNA in every nucleated cell. Given that PCR to detect viral DNA is the mainstay for diagnosing HHV-6B infection, the characteristics of HHV-6B infection complicate efforts to distinguish between latent and active viral infection, particularly in immunocompromised patients who have frequent HHV-6B reactivation. In this study, we used RNA sequencing to characterize the HHV-6B gene expression profile in multiple sample types, and our findings identified evidence-based targets for diagnostic tests that distinguish between latent and active viral infection.


Esophageal cancer in Canada: trends according to morphology and anatomical location.
Esophageal adenocarcinoma has one of the fastest rising incidence rates and one of the lowest survival rates of any cancer type in the Western world. However, in many countries, trends in esophageal cancer differ according to tumour morphology and anatomical location. In Canada, incidence and survival trends for esophageal cancer subtypes are poorly known. Cancer incidence and mortality rates were obtained from the Canadian Cancer Registry, the National Cancer Incidence Reporting System and the Canadian Vital Statistics Death databases for the period from 1986 to 2006. Observed trends (annual per cent change) and five-year relative survival ratios were estimated separately for esophageal adenocarcinoma and squamous cell carcinoma, and according to location (upper, middle, or lower one-third of the esophagus). Incidence rates were projected up to the year 2026. Annual age-standardized incidence rates for esophageal cancer in 2004 to 2006 were 6.1 and 1.7 per 100,000 for males and females, respectively. Esophageal adenocarcinoma incidence rose by 3.9% (males) and 3.6% (females) per year for the period 1986 to 2006, with the steepest increase in the lower one-third of the esophagus (4.8% and 5.0% per year among males and females, respectively). In contrast, squamous cell carcinoma incidence declined by 3.3% (males) and 3.2% (females) per year since the early 1990s. The five-year relative survival ratio for esophageal cancer was 13% between 2004 and 2006, approximately a 3% increase since the period from 1992 to 1994. Projected incidence rates showed increases of 40% to 50% for esophageal adenocarcinoma and decreases of 30% for squamous cell carcinoma by 2026. Although esophageal cancer is rare in Canada, the incidence of esophageal adenocarcinoma has doubled in the past 20 years, which may reflect the increasing prevalence of obesity and gastroesophageal reflux disease. Declines in squamous cell carcinoma may be the result of the decreases in the prevalence of smoking in Canada. Given the low survival rates and the potential for further increases in incidence, esophageal adenocarcinoma warrants close attention.