Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis.
The delivery of copper to specific sites within the cell is mediated by distinct intracellular carrier proteins termed copper chaperones. Previous studies in Saccharomyces cerevisiae suggested that the human copper chaperone HAH1 may play a role in copper trafficking to the secretory pathway of the cell. In this current study, HAH1 was detected in lysates from multiple human cell lines and tissues as a single-chain protein distributed throughout the cytoplasm and nucleus. Studies with a glutathione S-transferase-HAH1 fusion protein demonstrated direct protein-protein interaction between HAH1 and the Wilson disease protein, which required the cysteine copper ligands in the amino terminus of HAH1. Consistent with these in vitro observations, coimmunoprecipitation experiments revealed that HAH1 interacts with both the Wilson and Menkes proteins in vivo and that this interaction depends on available copper. When these studies were repeated utilizing three disease-associated mutations in the amino terminus of the Wilson protein, a marked diminution in HAH1 interaction was observed, suggesting that impaired copper delivery by HAH1 constitutes the molecular basis of Wilson disease in patients harboring these mutations. Taken together, these data provide a mechanism for the function of HAH1 as a copper chaperone in mammalian cells and demonstrate that this protein is essential for copper homeostasis.


NFKB1 insertion/deletion promoter polymorphism increases the risk of advanced ovarian cancer in a Chinese population.
Ovarian cancer is the leading cause of death among all gynecological cancers. This is mainly attributed to its frequent presentation at an advanced stage (International Federation of Gynecology and Obstetrics stage III-IV). Nuclear factor-kappaB (NF-κB) is critically involved in the carcinogenesis and development of ovarian cancer. A functional insertion/deletion polymorphism (-94 ins/del ATTG) in the promoter region of the NFKB1 gene, which encodes the p50 subunit of the NF-κB protein, has been recently identified and shown to increase the susceptibility to many diseases. The purpose of this study was to explore the association between this polymorphism and the risk of advanced ovarian cancer in a Chinese population. A total of 179 advanced ovarian cancer patients and 223 healthy controls were recruited into this study. Genotypes were determined using polymerase chain reaction-capillary electrophoresis method. The insertion increased the risk of advanced ovarian cancer (odds ratio = 2.111, 95% confidence intervals = 1.125-3.961, p = 0.019 for heterozygote insertion, and odds ratio = 2.656, 95% confidence intervals = 1.397-5.051, p = 0.002 for homozygote insertion) compared with homozygote deletion. Similar results were seen in age-adjusted analyses (p < 0.05). Our preliminary results suggest that NFKB1-94 ins/del ATTG promoter polymorphism may be associated with increased susceptibility to advanced ovarian cancer.


A "Roziah" by any other name: a simple Bayesian method for determining ethnicity from names.
Correct identification of ethnicity is central to many epidemiologic analyses. Unfortunately, ethnicity data are often missing. Successful classification typically relies on large databases (n > 500,000 names) of known name-ethnicity associations. We propose an alternative naïve Bayesian strategy that uses substrings of full names. Name and ethnicity data for Malays, Indians, and Chinese were provided by a health and demographic surveillance site operating in Malaysia from 2011-2013. The data comprised a training data set (n = 10,104) and a test data set (n = 9,992). Names were spliced into contiguous 3-letter substrings, and these were used as the basis for the Bayesian analysis. Performance was evaluated on both data sets using Cohen's κ and measures of sensitivity and specificity. There was little difference between the classification performance in the training and test data (κ = 0.93 and 0.94, respectively). For the test data, the sensitivity values for the Malay, Indian, and Chinese names were 0.997, 0.855, and 0.932, respectively, and the specificity values were 0.907, 0.998, and 0.997, respectively. A naïve Bayesian strategy for the classification of ethnicity is promising. It performs at least as well as more sophisticated approaches. The possible application to smaller data sets is particularly appealing. Further research examining other substring lengths and other ethnic groups is warranted.


Subpopulations of liver coated vesicles resolved by preparative agarose gel electrophoresis.
Rat liver clathrin coated vesicles (CVs) were separated into several distinct subpopulations using non-sieving concentrations of agarose, which allowed the separation of species differing primarily in surface charge. Using preparative agarose electrophoresis (Kedersha, N. L., and L. H. Rome, 1986, Anal. Biochem., in press), the CVs were recovered and analyzed for differences in morphology, coat protein composition, and stripped vesicle protein composition. Coat proteins from different populations appeared identical on SDS PAGE, and triskelions stripped from the different populations showed the same mobility on the agarose gel, suggesting that the mobility differences observed in intact CVs were due to differences in the surface charge of underlying vesicles rather than to variations in their clathrin coats. Several non-coat polypeptides appeared to segregate exclusively with different populations as resolved by two-dimensional electrophoresis. Stripped CVs also exhibited considerable heterogeneity when analyzed by Western blotting: the fast-migrating population was enriched in the mannose 6-phosphate receptor, secretory acetylcholine esterase, and an Mr 195,000 glycoprotein. The slow-migrating population of CVs was enriched in the asialoglycoprotein receptor, and it appeared to contain all detectable concanavalin A-binding polypeptides as well as the bulk of detectable WGA-binding proteins. When CVs were prepared from 125I-asialoorosomucoid-perfused rat liver, ligand was found in the slow-migrating CVs, suggesting that these were endocytic in origin. Morphological differences were also observed: the fast-migrating population was enriched in smaller CVs, whereas the slow-migrating population exhibited an enrichment in larger CVs. As liver consists largely of hepatocytes, these subpopulations appear to originate from the same cell type and probably represent CVs of different intracellular origin and destination.


Electrocardiogram, hemodynamics, and core body temperatures of the normal freely moving cynomolgus monkey by remote radiotelemetry.
The objectives of this study were to provide baseline normative values for circadian changes in the time-series data collected over the course of a normal day in laboratory-housed monkeys, and to assess the relative efficiency of standard correction formulas to correct for the variations in QT interval durations and heart rate functions. Ninety-nine cynomolgus monkeys (58 M, 41 F) were equipped with radiotelemetry transmitters and continuously monitored, while freely moving in their home cages. Electrocardiograms (ECGs), hemodynamic parameters (diastolic, systolic, and mean arterial pressures) as well as core body temperatures were recorded for 22 h from each of 99 monkeys. ECGs were measured by a computerized waveform analysis program and reported as RR, PR, QRS, and QT intervals. Blood pressures and core body temperatures demonstrated a normal circadian variation in their respective values over the 22 h monitoring period. Standard study-specific correction formulas failed to satisfactorily normalize the relationship between heart rate and QT intervals in the cynomolgus monkeys. In contrast, a subject-specific correction method based on analysis of covariance produced a linear function between heart rates and QT intervals and provided QTc values within the normal range of actual, recorded data. We believe these procedures represent the contemporary industry's preferred practice for measuring such parameters under the ICH guidelines, and are amenable to routine use in a variety of other relevant safety/efficacy studies.


Personality pattern and emotional stress in the genesis of gastric ulcer.
In a group of 181 persons with a past history of chronic gastric ulcer, a greatly increased incidence of domestic and financial stress has been found, when compared with age-and sex-matched persons with no previous history of gastric ulcer. The consumption of aspirin, alcohol, and cigarettes was also significantly increased. Persons with chronic gastric ulcer were characterized by a personality pattern of independence and self sufficiency, and they are prone to anxiety and depression. This pattern was three times as common as in matched individuals without chronic gastric ulcer. It is possible that internal conflict between a genetic and an environmentally induced sex role, together with an inability to externalize aggression, may be significant factors in the causation of chronic gastric ulcer.


Role of intracerebroventricular vasopressin in the development of stress-induced gastric lesions in rats.
We investigated whether arginine vasopressin (AVP) has a central influence on the development of gastric mucosal lesions evoked by restraint-cold stress in rats. AVP and vasopressin V1 receptor antagonist were injected intracerebroventricularly (i.c.v.) and the rats were exposed to restraint-cold stress for five hours. After decapitation the stomachs were examined for gastric mucosal lesions which were evaluated according to an ulcer score. Three different doses of AVP and V1 receptor antagonist were administered in order to investigate the effects of exogenous and endogenous AVP on stress-induced gastric mucosal lesions. The intensity of gastric mucosal lesions was reduced when exogenous AVP was injected intracerebroventricularly. On the other hand, vasopressin V1 receptor antagonist, which was administered by the same route, augmented gastric mucosal lesions. Our findings indicate that AVP, injected centrally, plays a role in preventing the formation of gastric mucosal lesions induced by stress via a central V1 receptor.


Descriptive epidemiology of Creutzfeldt-Jakob disease in six European countries, 1993-1995. EU Collaborative Study Group for CJD.
After the occurrence of bovine spongiform encephalopathy (BSE), there has been concern that transmission of BSE to the human population might result in a change in the epidemiological characteristics of Creutzfeldt-Jakob disease (CJD). A collaborative study of CJD in the European Union was performed from 1993 to 1995, to compare data from national registries for CJD in France, Germany, Italy, The Netherlands, Slovakia, and the United Kingdom. Five hundred seventy-five patients with definite or probable CJD died in the study period with an overall annual mortality rate of 0.71 cases per million. The incidence rates for CJD were similar in all participating countries despite variations in postmortem rates, and age-specific incidence rates were also relatively consistent, with the exception of an increased incidence of CJD in patients younger than 39 years of age in the United Kingdom. In relation to etiological subtypes of CJD, 87% of cases were sporadic, 8% genetic, and 5% iatrogenic. Genetic forms of CJD comprised 80% of all cases in Slovakia, and iatrogenic forms of CJD occurred most frequently in France and the United Kingdom. The statistical data reported here do not provide evidence of a causal link between BSE and CJD in Europe as a whole. However, the study has established baseline epidemiological parameters for CJD in participating European countries, which may be important in the assessment of any future change in the characteristics of CJD as a result of the epidemic of BSE.


Etiology of UV-C-induced browning in var. Superior white table grapes.
White table grapes, var. Superior, were treated with UV-C light after harvest to increase stilbenes concentration, especially trans-resveratrol (RES), because this may be of relevance to the health-promoting properties assigned to these compounds. However, irradiated grapes also developed some browning on the surface on the third day of storage at 22 degrees C, with the subsequent detriment in the sensorial quality of the fruit. Possible causes for browning development during storage were investigated. The phenolic-related oxidative enzymes, polyphenol oxidase (PPO) and peroxidase (POD), were not specifically activated, and no new isoforms appeared upon UV-C treatment. UV-treated grapes had lower content of chlorophyll b than control grapes on the fourth day of storage, concomitant with the increase of pheophytins (chlorophyll degradation derived compounds). Microscopy data showed lower fluorescence emission in chloroplasts from the UV-treated samples, which may explain the decrease of chlorophylls content in the corresponding grape berries extracts. In addition, microscopy images showed cell wall thickening in the skin tissue of UV-treated grapes which could be considered as a general wound response in plant tissues. These results suggest that the development of browning in Superior white grapes after UV-C treatment is not closely related with the evolution of oxidative enzymes during storage and may be mainly due to the decrease of chlorophylls content.


Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial.
One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. clinicaltrials.gov Identifier: NCT01000441.


Radiomics-based nomogram using CT imaging for noninvasive preoperative prediction of early recurrence in patients with hepatocellular carcinoma.
The aim of this study was to develop and validate a radiomics nomogram based on radiomics features and clinical data for the non-invasive preoperative prediction of early recurrence (≤2 years) in patients with hepatocellular carcinoma (HCC). We enrolled 262 HCC patients who underwent preoperative contrast-enhanced computed tomography and curative resection (training cohort, n=214; validation cohort, n=48). We applied propensity score matching (PSM) to eliminate redundancy between clinical characteristics and image features, and the least absolute shrinkage and selection operator (LASSO) was used to prevent overfitting. Next, a radiomics signature, clinical nomogram, and combined clinical-radiomics nomogram were built to predict early recurrence, and we compared the performance and generalization of these models. The radiomics signature stratified patients into low-risk and high-risk, which show significantly difference in recurrence free survival and overall survival (P ≤ 0.01). Multivariable analysis identified dichotomised radiomics signature, alpha fetoprotein, and tumour number and size as key early recurrence indicators, which were incorporated into clinical and radiomics nomograms. The radiomics nomogram showed the highest area under the receiver operating characteristic curve (AUC), with significantly superior predictive performance over the clinical nomogram in the training cohort (0.800 vs 0.716, respectively; P = 0.001) and the validation cohort (0.785 vs 0.654, respectively; P = 0.039). The radiomics nomogram is a non-invasive preoperative biomarker for predicting early recurrence in patients with HCC. This model may be of clinical utility for guiding surveillance follow-ups and identifying optimal interventional strategies.


Improving acceleration and repeated sprint ability in well-trained adolescent handball players: speed versus sprint interval training.
The aim of the current study was to compare the effects of speed/agility (S/A) training with sprint interval training (SIT) on acceleration and repeated sprint ability (RSA) in well-trained male handball players. In addition to their normal training program, players performed either S/A (n = 7) or SIT (n = 7) training for 4 wk. Speed/agility sessions consisted of 3 to 4 series of 4 to 6 exercises (eg, agility drills, standing start and very short sprints, all of <5 s duration); each repetition and series was interspersed with 30 s and 3 min of passive recovery, respectively. Sprint interval training consisted of 3 to 5 repetitions of 30-s all-out shuttle sprints over 40 m, interspersed with 2 min of passive recovery. Pre- and posttests included a countermovement jump (CMJ), 10-m sprint (10m), RSA test and a graded intermittent aerobic test (30-15 Intermittent Fitness Test, V(IFT)). S/A training produced a very likely greater improvement in 10-m sprint (+4.6%, 90% CL 1.2 to 7.8), best (+2.7%, 90% CL 0.1 to 5.2) and mean (+2.2%, 90% CL -0.2 to 4.5) RSA times than SIT (all effect sizes [ES] greater than 0.79). In contrast, SIT resulted in an almost certain greater improvement in V(IFT) compared with S/A (+5.2%, 90% CL 3.5 to 6.9, with ES = -0.83). In well-trained handball players, 4 wk of SIT is likely to have a moderate impact on intermittent endurance capacity only, whereas S/A training is likely to improve acceleration and repeated sprint performance.


Effects of vibrations on gastrocnemius medialis tissue oxygenation.
Whole-body vibrations are known to affect muscle activity and tissue oxygenation, but some energetic aspects are still poorly understood. This study investigates the effects of whole-body vibration on gastrocnemius muscle oxygen utilization rate and tissue oxygenation dynamics during exercise. The effects of vibration on gastrocnemius medialis muscle oxygenation were investigated during a dynamic exercise on a sample of 16 active male subjects (age = 26.3 ± 5.1 yr, mass = 71.2 ± 4.8 kg (mean ± SD)). Both arterially occluded (AO) and nonoccluded (N/O) conditions were investigated. Tissue oxygenation was monitored with a near-infrared spectrometer. Oxygen utilization rate and tissue oxygenation recovery were computed as the slopes of the regression line of the oxygenation decay and recovery, respectively. A fast Fourier transform (FFT) was used to determine the frequency spectrum of the oxygen saturation data. EMG activity was monitored using bipolar EMG electrodes. A windowed root mean square analysis was used to monitor the amplitude of the EMG signal. A statistically significant increase of 15% (P < 0.05) in oxygen utilization rate was found for the vibration condition in the AO leg but not in the N/O leg. The oxygenation recovery rate for the vibration condition was 34% higher (P < 0.05) than that for the control condition. A low-frequency periodic oscillation (T ≈ 10 s) in the tissue oxygenation data was determined from the FFT spectrum. A statistically significant decrease in the oscillation frequency was noticed for the vibration condition compared with the control. Vibrations increased the oxygen utilization rate during a dynamic exercise. The oxygenation recovery rate increased with vibrations. The low-frequency oscillation of the oxygenation was attributed to the periodic changes in tissue blood flow, and this seems to be influenced by vibrations.


Emerging energy and environmental applications of vertically-oriented graphenes.
Graphene nanosheets arranged perpendicularly to the substrate surface, i.e., vertically-oriented graphenes (VGs), have many unique morphological and structural features that can lead to exciting properties. Plasma-enhanced chemical vapor deposition enables the growth of VGs on various substrates using gas, liquid, or solid precursors. Compared with conventional randomly-oriented graphenes, VGs' vertical orientation on the substrate, non-agglomerated morphology, controlled inter-sheet connectivity, as well as sharp and exposed edges make them very promising for a variety of applications. The focus of this tutorial review is on plasma-enabled simple yet efficient synthesis of VGs and their properties that lead to emerging energy and environmental applications, ranging from energy storage, energy conversion, sensing, to green corona discharges for pollution control.


[Immunosuppressive agents and infection (author's transl)].
Immunosuppressive agents often cause severe infection sometimes due to organisms rarely encountered in other circumstances. Virus and parasitic infections, together with tuberculosis and salmonella may be particularly frequent during treatments which depress. T lymphocytes. Gram positive bacterial infections are mainly caused by substances inducing cell B immune deficeincy. In the light of this data, verified both by animal experiments and clinical experience, it is important to determine the target cell of the main immunodepressive agents used in clinical medicine. Azathioprine and antilymphocyte serum act mainly on T lymphocytes whereas alkylating agent are at least as active on B lymphocytes as on T lymphocytes. The mode of action of corticosteroids is particularly obscure. T cells appear, on the whole, to be resistant to corticosteroids, whereas monocytes and macrophages are very sensitive.


Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages.
Agonism of the G protein-coupled free-fatty acid receptor-4 (FFA4) has been shown to promote numerous anti-inflammatory effects in macrophages that arise due to interaction with β-arrestin partner proteins. Humans express functionally distinct short and long FFA4 splice variants, such that FFA4-S signals through Gαq/11 and β-arrestin, while FFA4-L is intrinsically biased solely towards β-arrestin signaling. Recently, we and others have shown that phosphorylation of the FFA4 C-terminal tail is responsible for β-arrestin interactability and signaling. Given the significance of β-arrestin in the anti-inflammatory function of FFA4, the goal of this study was to examine the role of the C-terminal β-arrestin phosphosensor in FFA4 signaling induced by PMA and LPS in murine Raw 264.7 macrophages. Our data reveal for the first time that both FFA4 isoforms modulate PMA-induced ROS generation, and that abolishment of the FFA4-S, but not FFA4-L C-terminal phosphosensor, is detrimental to this effect. Furthermore, we show that while both isoforms reduce PMA-induced expression of COX-2, removal of the FFA4-S phosphosensor significantly decreases this response, suggesting that these effects of FFA4-S are β-arrestin mediated. On the contrary, FFA4-S, as well as the truncated C-terminal congener lacking the β-arrestin phosphosensor were both able to reduce LPS-induced NF-κB activity and ERK1/2 phosphorylation. However, FFA4-L and its corresponding mutant were incapable of modulating either, suggesting that these responses are mediated by G protein coupling. Taken together, our data reveal important structure-function and signaling differences between the two FFA4 isoforms, and for the first time link FFA4 to modulation of ROS in macrophages.


Amino acid sequence and comparative antigenicity of chicken metallothionein.
The complete amino acid sequence of metallothionein (MT) from chicken liver is reported. The primary structure was determined by automated sequence analysis of peptides produced by limited acid hydrolysis and by trypsin digestion. The comparative antigenicity of chicken MT was determined by radioimmunoassay using rabbit anti-rat MT polyclonal antibody. Chicken MT consists of 63 amino acids as compared to 61 found in MTs from mammals. One insertion (and two substitutions) occurs in the amino-terminal region, a region considered invariant among mammalian MTs. Eighteen of the 20 cysteines in chicken MT were aligned with cysteines from other mammalian sequences. Two cysteines near the carboxyl terminus are shifted by one residue due to the insertion of proline in that region. Overall, the chicken protein showed approximately equal to 68% sequence identity in a comparison with various mammalian MTs. The affinity of the polyclonal antibody for chicken MT was decreased by 2 orders of magnitude in comparison to that of a mammalian MT (rat MT isoforms). This reduced affinity is attributed to major substitutions in chicken MT in the regions of the principal determinants of mammalian MTs. Theoretical analysis of the primary structure predicted the secondary structure to consist of reverse turns and random coils with no stable beta or helix conformations. There is no evidence that chicken MT differs functionally from mammalian MTs.


Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice.
Pre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice.


Corticorelin, a synthetic human corticotropin-releasing factor analog, for the treatment of peritumoral brain edema.
Corticorelin is a synthetic analog of the naturally occurring human peptide corticotropin-releasing factor (CRF). Several studies have indicated the ability of CRF to reduce the brain edema caused by brain tumors. Peritumoral brain edema (PBE), caused by an intracerebral tumor, manifests several features of vasogenic edema, which is a type of edema characterized by disruption of the blood-brain barrier. Traditionally, PBE has been treated using corticosteroids, primarily dexamethasone. Introduced more than four decades ago, dexamethasone revolutionized the treatment of PBE, but the side effects and withdrawal symptoms associated with corticosteroids propelled the investigation of other drugs. Clinical trials with the synthetic human CRF (hCRF) corticorelin (Xerecept, NEU-3002; Celtic Pharmaceutical Holdings) have indicated that this drug has a distinct advantage over classical corticosteroids in the treatment of PBE. Fewer and/or milder side effects have been reported for corticorelin compared with dexamethasone, although at higher doses of corticorelin several side effects, including hypotension and transient flushing, have been reported. Nevertheless, corticorelin was reasonably well tolerated in patients and healthy volunteers, and may be a good candidate for reducing PBE and associated neural damage, as well as improving neurological symptoms.


[Evaluation of the efficacy of physical exercises in scoliotic disease].
Scoliotic disease manifests in the course of skeletal growth and requires long-term specialized treatment. Special literature does not present sound criteria of efficacy of exercise treatment of scoliosis in children and adolescents. The proposed comprehensive score assessment of body function of children and adolescents with scoliosis, objectively characterizes its dynamics, response to therapeutic procedure including exercise therapy.


Description and comparison of algorithms for correcting anisotropic magnification in cryo-EM images.
Single particle electron cryomicroscopy (cryo-EM) allows for structures of proteins and protein complexes to be determined from images of non-crystalline specimens. Cryo-EM data analysis requires electron microscope images of randomly oriented ice-embedded protein particles to be rotated and translated to allow for coherent averaging when calculating three-dimensional (3D) structures. Rotation of 2D images is usually done with the assumption that the magnification of the electron microscope is the same in all directions. However, due to electron optical aberrations, this condition is not met with some electron microscopes when used with the settings necessary for cryo-EM with a direct detector device (DDD) camera. Correction of images by linear interpolation in real space has allowed high-resolution structures to be calculated from cryo-EM images for symmetric particles. Here we describe and compare a simple real space method, a simple Fourier space method, and a somewhat more sophisticated Fourier space method to correct images for a measured anisotropy in magnification. Further, anisotropic magnification causes contrast transfer function (CTF) parameters estimated from image power spectra to have an apparent systematic astigmatism. To address this problem we develop an approach to adjust CTF parameters measured from distorted images so that they can be used with corrected images. The effect of anisotropic magnification on CTF parameters provides a simple way of detecting magnification anisotropy in cryo-EM datasets.


Climate change and avian influenza.
This paper discusses impacts of climate change on the ecology of avian influenza viruses (AI viruses), which presumably co-evolved with migratory water birds, with virus also persisting outside the host in subarctic water bodies. Climate change would almost certainly alter bird migration, influence the AI virus transmission cycle and directly affect virus survival outside the host. The joint, net effects of these changes are rather unpredictable, but it is likely that AI virus circulation in water bird populations will continue with endless adaptation and evolution. In domestic poultry, too little is known about the direct effect of environmental factors on highly pathogenic avian influenza transmission and persistence to allow inference about the possible effect of climate change. However, possible indirect links through changes in the distribution of duck-crop farming are discussed.


The ruminant parasite Haemonchus contortus expresses an alpha1,3-fucosyltransferase capable of synthesizing the Lewis x and sialyl Lewis x antigens.
Glycoproteins from the ruminant helminthic parasite Haemonchus contortus react with Lotus tetragonolobus agglutinin and Wisteria floribunda agglutinin, which are plant lectins that recognize alpha1,3-fucosylated GlcNAc and terminal beta-GalNAc residues, respectively. However, parasite glycoconjugates are not reactive with Ricinus communis agglutinin, which binds to terminal beta-Gal, and the glycoconjugates lack the Lewis x (Le(x)) antigen or other related fucose-containing antigens, such as sialylated Le(x), Le(a), Le(b) Le(y), or H-type 1. Direct assays of parasite extracts demonstrate the presence of an alpha1,3-fucosyltransferase (alpha1,3FT) and beta1,4-N-acetylgalactosaminyltransferase (beta1,4GalNAcT), but not beta1,4-galactosyltransferase. The H. contortus alpha1,3FT can fucosylate GlcNAc residues in both lacto-N-neotetraose (LNnT) Galalpha1-->4GlcNAcbeta1-->3Galbeta1-->4Glc to form lacto-N-fucopentaose III Galbeta1-->4[Fuca1-->3]GlcNAc beta1-->3Galbeta1-4GIc, which contains the Le(x) antigen, and the acceptor lacdiNAc (LDN) GalNAcbeta1-->4GlcNAc to form GalNAc beta1-->4[Fualpha1-->3]GlcNAc. The alpha1,3FT activity towards LNnT is dependent on time, protein, and GDP-Fuc concentration with a Km 50 microM and a Vmax of 10.8 nmol-mg(-1) h(-1). The enzyme is unusually resistant to inhibition by the sulfhydryl-modifying reagent N-ethylmaleimide. The alpha1,3FT acts best with type-2 glycan acceptors (Galbeta1-->4GlcNAcbeta1-R) and can use both sialylated and non-sialylated acceptors. Thus, although in vitro the H. contortus alpha1,3FT can synthesize the Le(x) antigen, in vivo the enzyme may instead participate in synthesis of fucosylated LDN or related structures, as found in other helminths.


Venom chemistry underlying the painful stings of velvet ants (Hymenoptera: Mutillidae).
Velvet ants (Hymenoptera: Mutillidae) are a family of solitary parasitoid wasps that are renowned for their painful stings. We explored the chemistry underlying the stings of mutillid wasps of the genus Dasymutilla Ashmead. Detailed analyses of the venom composition of five species revealed that they are composed primarily of peptides. We found that two kinds of mutillid venom peptide appear to be primarily responsible for the painful effects of envenomation. These same peptides also have defensive utility against invertebrates, since they were able to incapacitate and kill honeybees. Both act directly on cell membranes where they directly increase ion conductivity. The defensive venom peptides of Dasymutilla bear a striking similarity, in structure and mode of action, to those of the ant Myrmecia gulosa (Fabricius), suggesting either retention of ancestral toxins, or convergence driven by similar life histories and defensive selection pressures. Finally, we propose that other highly expressed Dasymutilla venom peptides may play a role in parasitisation, possible in delay or arrest of host development. This study represents the first detailed account of the composition and function of the venoms of the Mutillidae.


A computational approach for deciphering the organization of glycosaminoglycans.
Increasing evidence has revealed important roles for complex glycans as mediators of normal and pathological processes. Glycosaminoglycans are a class of glycans that bind and regulate the function of a wide array of proteins at the cell-extracellular matrix interface. The specific sequence and chemical organization of these polymers likely define function; however, identification of the structure-function relationships of glycosaminoglycans has been met with challenges associated with the unique level of complexity and the nontemplate-driven biosynthesis of these biopolymers. To address these challenges, we have devised a computational approach to predict fine structure and patterns of domain organization of the specific glycosaminoglycan, heparan sulfate (HS). Using chemical composition data obtained after complete and partial digestion of mixtures of HS chains with specific degradative enzymes, the computational analysis produces populations of theoretical HS chains with structures that meet both biosynthesis and enzyme degradation rules. The model performs these operations through a modular format consisting of input/output sections and three routines called chainmaker, chainbreaker, and chainsorter. We applied this methodology to analyze HS preparations isolated from pulmonary fibroblasts and epithelial cells. Significant differences in the general organization of these two HS preparations were observed, with HS from epithelial cells having a greater frequency of highly sulfated domains. Epithelial HS also showed a higher density of specific HS domains that have been associated with inhibition of neutrophil elastase. Experimental analysis of elastase inhibition was consistent with the model predictions and demonstrated that HS from epithelial cells had greater inhibitory activity than HS from fibroblasts. This model establishes the conceptual framework for a new class of computational tools to use to assess patterns of domain organization within glycosaminoglycans. These tools will provide a means to consider high-level chain organization in deciphering the structure-function relationships of polysaccharides in biology.


Ubiquitin-mediated response to microsporidia and virus infection in C. elegans.
Microsporidia comprise a phylum of over 1400 species of obligate intracellular pathogens that can infect almost all animals, but little is known about the host response to these parasites. Here we use the whole-animal host C. elegans to show an in vivo role for ubiquitin-mediated response to the microsporidian species Nematocida parisii, as well to the Orsay virus, another natural intracellular pathogen of C. elegans. We analyze gene expression of C. elegans in response to N. parisii, and find that it is similar to response to viral infection. Notably, we find an upregulation of SCF ubiquitin ligase components, such as the cullin ortholog cul-6, which we show is important for ubiquitin targeting of N. parisii cells in the intestine. We show that ubiquitylation components, the proteasome, and the autophagy pathway are all important for defense against N. parisii infection. We also find that SCF ligase components like cul-6 promote defense against viral infection, where they have a more robust role than against N. parisii infection. This difference may be due to suppression of the host ubiquitylation system by N. parisii: when N. parisii is crippled by anti-microsporidia drugs, the host can more effectively target pathogen cells for ubiquitylation. Intriguingly, inhibition of the ubiquitin-proteasome system (UPS) increases expression of infection-upregulated SCF ligase components, indicating that a trigger for transcriptional response to intracellular infection by N. parisii and virus may be perturbation of the UPS. Altogether, our results demonstrate an in vivo role for ubiquitin-mediated defense against microsporidian and viral infections in C. elegans.


Understanding minimum and ideal factor levels for participation in physical activities by people with haemophilia: An expert elicitation exercise.
The benefits of physical activity (PA) for people with haemophilia (PWH) may include improvements in joint, bone and muscle health. However, the factor VIII activity level required to avoid a bleeding episode associated with PA is unknown. To elicit the opinion of clinical experts on the minimum level and ideal factor VIII activity ('level') required to avoid a bleeding episode during participation in different types of PA for PWH. Based on the 2017 National Hemophilia Foundation PA descriptions, clinical experts estimated a minimally acceptable and an ideal factor level at which a bleed could be avoided. The uncertainty around estimates was quantified using an approach to construct a probability distribution to represent expert opinion. Minimum and ideal factor level increased with higher risk PA, whether or not joint morbidity was present, as did the experts' uncertainty in their estimates (ie the range between lowest and highest estimates for minimum and ideal levels). Mean minimum levels ranged from 4% to 48% for low to high risk for people without joint morbidity, and from 7% to 47% for those with joint morbidity. For ideal factor levels, corresponding figures were 9%-52% and 12%-64%, respectively. To support a patient-centric outcome, expert opinion indicates that the clinical norm of 0.01 IU/mL (1%) trough level is insufficient. It is anticipated that introducing a more targeted approach to meet the needs of patients who are increasingly physically active will benefit patients further in addition to recent treatment advances.


Emergence of NK Cell Hyporesponsiveness after Two IL-15 Stimulation Cycles.
IL-15 is a cytokine playing a crucial role in the function of immune cells, including NK and CD8 T cells. In this study, we demonstrated that in vivo, in mice, IL-15-prestimulated NK cells were no longer able to respond to a second cycle of IL-15 stimulation. This was illustrated by defects in cell maturation, proliferation, and activation, seemingly linked to the environment surrounding NK cells but not related to the presence of CD4 regulatory T cells, TGF-β, or IL-10. Moreover, NK cells from immunodeficient mice could respond to two cycles of IL-15 stimulation, whereas an adoptive transfer of CD44+CD8+ cells impaired their responsiveness to the second cycle. Conversely, in immunocompetent mice, NK cell responsiveness to a second IL-15 stimulation was restored by the depletion of CD8+ cells. These biological findings refine our understanding of the complex mode of action of NK cells in vivo, and they should be taken into consideration for IL-15-based therapy.


Susceptibility of two karyotypic forms of Anopheles aconitus (Diptera: Culicidae) to Plasmodium falciparum and P. vivax.
Four laboratory-raised colonies of two karyotypic forms of Anopheles aconitus, i.e., Form B (Chiang Mai and Phet Buri strains) and C (Chiang Mai and Mae Hong Son strains), were experimentally infected with Plasmodium falciparum and P. vivax using an artificial membrane feeding technique and dissected eight and 12 days after feeding for oocyst and sporozoite rates, respectively. The results revealed that An. aconitus Form B and C were susceptible to P. falciparum and P. vivax, i.e., Form B (Chiang Mai and Phet Buri strains/P. falciparum and P. vivax) and Form C (Chiang Mai and Mae Hong Son strains/P. vivax). Comparative statistical analyses of the oocyst rates, average number of oocysts per infected midgut and sporozoite rates among all strains of An. aconitus Form B and C to the ingroup control vectors, An. minimus A and C, exhibited mostly no significant differences, confirming the high potential vector of the two Plasmodium species. The sporozoite-like crystals found in the median lobe of the salivary glands, which could be a misleading factor in the identification of true sporozoites in salivary glands were found in both An. aconitus Form B and C.


Early availability of laboratory results increases same day ward discharge rates.
Delayed discharge reduces hospital efficiency and inconveniences patients. Most hospitals discharge in the afternoon, whereas the most common admission time is mid-morning. Consequently, new patients wait for the beds of patients who are fit to be discharged. Earlier discharge may, therefore, improve patient flow. We investigated the impact of early phlebotomy with early availability of laboratory results on patient discharge rates and discharge time. Discharge rates, discharge time and sample turnaround time were assessed before (1 October 2014 to 31 December 2014) and after (1 October 2015 to 31 December 2015) introduction of earlier phlebotomy with availability of laboratory results prior to the ward rounds on two surgical wards. Following the intervention, over 95% of results were available before 8:30 am in 2015 as compared to less than 1% in 2014. Specimen turnaround times were similar in both study periods. Even after adjustment for age, gender, admission type and length of admission, the same day discharge rate was higher in 2015 compared to 2014 (60% vs. 52%; p<0.002), but time of discharge was unchanged. Early availability of blood results prior to ward rounds increased ward discharges but did not affect discharge time.


Access to specialist gastroenterology care in Canada: comparison of wait times and consensus targets.
Monitoring wait times and defining targets for care have been advocated to improve health care delivery related to cancer, heart, diagnostic imaging, joint replacements and sight restoration. There are few data on access to care for digestive diseases, although they pose a greater economic burden than cancer or heart disease in Canada. The present study compared wait times for specialist gastroenterology care with recent, evidence-based, consensus-defined benchmark wait times for a range of digestive diseases. Total wait times from primary care referral to investigation were measured for seven digestive disease indications by using the Practice Audit in Gastroenterology program, and were benchmarked against consensus recommendations. Total wait times for 1903 patients who were undergoing investigation exceeded targets for those with probable cancer (median 26 days [25th to 75th percentiles eight to 56 days] versus target of two weeks); probable inflammatory bowel disease (101 days [35 to 209 days] versus two weeks); documented iron deficiency anemia (71 days [19 to 142 days] versus two months); positive fecal occult blood test (73 days [36 to 148 days] versus two months); dyspepsia with alarm symptoms (60 days [23 to 140 days] versus two months); refractory dyspepsia without alarm symptoms (126 days [42 to 225 days] versus two months); and chronic constipation and diarrhea (141 days [68 to 264 days] versus two months). A minority of patients were seen within target times: probable cancer (33% [95% CI 20% to 47%]); probable inflammatory bowel disease (12% [95% CI 1% to 23%]); iron deficiency anemia (46% [95% CI 37% to 55%]); positive occult blood test (41% [95% CI 28% to 54%]); dyspepsia with alarm symptoms (51% [95% CI 41% to 60%]); refractory dyspepsia without alarm symptoms (33% [95% CI 19% to 47%]); and chronic constipation and diarrhea (21% [95% CI 14% to 29%]). Total wait times for the seven indications exceeded the consensus targets; 51% to 88% of patients were not seen within the target wait time. Multiple interventions, including adoption of evidence-based management guidelines and provision of economic and human resources, are needed to ensure appropriate access to digestive health care in Canada. Outcomes can be evaluated by the 'point-of-care', practice audit methodology used for the present study.


entla, a novel epileptic and ataxic Cacna2d2 mutant of the mouse.
entla (ent) is a novel recessive phenotype of mice. The underlying mutation was mapped to chromosome 9 (60.1 centimorgans) and identified as an allele of the Cacna2d2 gene encoding the alpha2delta-2 subunit of voltage-gated calcium channels. The Cacna2d2entla allele harbors a 38-kb duplication comprising the 117 nucleotides of exon 3. The predicted duplication of 39 amino acid residues near the subunit's N terminus results in the expression of a full-length, membrane-associated protein. Western blot data were consistent with correct cleavage of the alpha2delta-2entla precursor into alpha2entla and delta2 proteins but indicated loss of the disulfide linkage between the two proteins. ent/ent mice develop ataxia by postnatal day 13-15, followed by paroxysmal dyskinesia a few days later. Two distinct types of cortical and hippocampal epileptic activity at 2 and 4 Hz were recorded, indicative of absence epilepsy. Homozygotes display reduced size and weight, increased mortality before weaning, and female infertility. No overt neuroanatomical abnormalities were detected. Ca2+ current densities recorded from acutely dissociated Purkinje cells of homozygous entla animals were reduced by 50% compared with wild type. Ligand binding assays using the antiepileptic drug [3H]gabapentin, a specific ligand of the alpha2delta-1 and alpha2delta-2 subunits, revealed a >60% reduced maximum binding to cerebellar membranes of ent/ent compared with unaffected littermates. entla is allelic to ducky and ducky2J, representing the third murine Cacna2d2 allele identified and so far the only one encoding an untruncated protein that is incorporated into membranes.


[Influence of lactose rate on calcium fixation in bones. Study in rats].
This investigation was performed to study the effect of lactose on the fixation of calcium in bones of rats. Lactose 3% and 10% concentration was used and the action was compared to that obtained by 67 U.I. of vitamin D in 100 g diet. The data obtained indicated very definitely that the presence of lactose in the diet favorably influences the fixation of Ca in bone, when the amount is 10%; at 3% concentration lactose don't seem influence Ca fixation in bone.


Associated analysis of DNA methylation for cancer detection using CCP-based FRET technique.
This paper describes an associated analysis method of DNA methylation for the detection of cancer using an optically amplifying cationic conjugated polymer (CCP, poly{(1,4-phenylene)-2,7-[9,9-bis(6'-N,N,N-trimethyl ammonium)-hexyl fluorene] dibromide)}. Genomic DNA is digested by methylation-sensitive restriction endonuclease, followed by PCR amplification to incorporate fluorescein-labeled dNTP. Only methylated DNA can be amplified by PCR, and the methylation level is detected through fluorescence resonance energy transfer (FRET) between CCP and fluorescein that is incorporated into the PCR product. The methylation levels of RASSF1A, OPCML, and HOXA9 promoters of 35 ovarian cancer samples and 11 normal samples were assayed. In accordance with the degree of methylation levels, they are clustered to three sections and assigned a value. Through an associated analysis, we acquired a threshold for cancer detection with a sensitivity of 85.7%. The assay takes about 20 h to obtain the detection results and shows great potential as a useful tool for diagnostic and screening of cancer.


Qigong exercise for chronic fatigue syndrome.
Chronic fatigue syndrome (CFS) is often overlooked, has unclear etiology and no effective cure except some symptomatic treatments. Additionally, most people with CFS do not seek medical attention. Qigong exercise, an ancient Eastern body-mind-spirit practice, has been long practiced in Chinese communities and may powerfully trigger the self-healing process. Using full baseline data (n=1409), the average Hong Kong CFS respondent was found to be female, married, 42.5yo, highly educated and employed full-time, experiencing sleep disturbance (~95%), anxiety (>80%), and depressive symptoms (68%). Here, we summarized our previous studies to evaluate the potential of Qigong as a complementary and alternative therapy for CFS. Two randomized controlled trials were conducted (RCT1 n1=137, RCT2 n2=150). In both trials, extensive online questionnaires allowed individuals with CFS-like illness (i.e., symptoms match CFS, yet without clinical confirmation) to be identified. RCT1 included a 5-week intervention. The intervention in RCT2 was 8weeks. In RCT1 Qigong group had reduced fatigue (P<0.001) and depressive symptoms (P=0.002), and improved telomerase activity (P=0.029). An effective practice regimen was identified (≥3 days/week, at ≥30min/session). Methods were slightly adjusted for RCT2, which replicated RCT1 findings, and further documented improved subjective sleep quality (P=0.008) and adiponectin levels (P<0.05). A significant dose-response relationship was founded. Thus, Qigong exercise should be recognized as a possible standalone therapy and self-management skill in CFS. Strategies are needed to increase motivation for regular practice and to explore its possibility of self-management skill in brain health. Further clarity would come from studies comparing Qigong with other physical exercises.


beta-MHC transgene expression in suspended and mechanically overloaded/suspended soleus muscle of transgenic mice.
Non-weight-bearing (NWB) activity [space flight and hindlimb suspension (HS)] results in the loss of soleus muscle mass, a slow-to-fast fiber-type conversion, and decreased beta-myosin heavy chain (beta-MHC) protein and mRNA expression. To identify beta-MHC promoter sequences required for decreased beta-MHC expression in response to HS, we have modified an existing noninvasive hindlimb unweighting model to accommodate the use of (transgenic) mice. After 2 wk of HS, body and muscle (soleus > gastrocnemius > plantaris) weights were decreased as was the proportion of histochemically classified type I fibers in HS soleus muscle. Northern blot analysis revealed decreases in endogenous mRNA representing beta-MHC, slow myosin light chain 1 and 2, and cardiac/slow troponin C, whereas those representing skeletal troponin C, muscle creatine kinase, and glyceraldehyde-3-phosphate dehydrogenase increased. Protein extracts prepared from HS soleus (SS) muscle of mice harboring transgenes comprised of 5.6 or 0.6 kilobase of wild type (wt) mouse beta-MHC promoter (beta 5.6 wt, beta 0.6wt) and those carrying the simultaneous mutation (mut) of the MCAT, C-rich, and beta e3 subregions (beta 5.6mut3, beta 0.6mut3) revealed decreases in chloramphenicol acetyltransferase (CAT) specific activity relative to respective controls. Decreased CAT mRNA was observed for transgene beta 5.6mut3, line 85. Two weeks of the simultaneous imposition of mechanical overload (synergist ablation) and HS (MOV/HS) countermanded the loss in absolute and normalized SS weight but did not decrease beta 0.6wt transgene expression. These transgenic results demonstrate that regulatory sequences within a 600-base pair beta-MHC promoter are sufficient to direct decreased transcription of beta-MHC transgenes after 2 wk of HS.


Curcumin and other dietary polyphenols: potential mechanisms of metabolic actions and therapy for diabetes and obesity.
Recent controversy regarding the therapeutic potential of curcumin indicates the challenges to research in this field. Here, we highlight the investigations of curcumin and other plant-derived polyphenols that demonstrate their application to metabolic diseases, in particular, obesity and diabetes. Thus, a number of preclinical and clinical investigations have shown the beneficial effect of curcumin (and other dietary polyphenols) in attenuating body weight gain, improving insulin sensitivity, and preventing diabetes development in rodent models and prediabetic subjects. Other intervention studies with dietary polyphenols have also found improvements in insulin resistance. Recent studies suggest that the metabolic effects of curcumin/polyphenols are linked to changes in the gut microbiota. Thus, research into curcumin continues to provide novel insights into metabolic regulation that may ultimately translate into effective therapy.


Quality control initiative on the evaluation of the dysmegakaryopoiesis in myeloid neoplasms: Difficulties in the assessment of dysplasia.
Evaluation of megakaryocyte morphology is difficult but can be essential for the diagnosis of myelodysplastic syndromes (MDS) and other myeloid neoplasms. We agreed upon descriptions and provided images of megakaryoblasts and of normal and dysplastic megakaryocytes, which were used as a basis for assessing the concordance of expert morphologists in their recognition. We showed a high rate of concordance for the recognition of micromegakaryocytes and confirmed their strong association with hematologic neoplasia, including MDS. Concordance was also found to be good for the recognition of multinucleated megakaryocytes, which showed a significant association with MDS. However cytoplasmic abnormalities were found not to be useful in MDS recognition. The occurrence of appreciable numbers of nonlobulated and hypolobulated megakaryocytes in individuals without a myeloid neoplasm was confirmed. We demonstrated that subjects without a myeloid neoplasm can have some megakaryocytes that are assessed as 'dysplastic' or 'possibly dysplastic' and that to avoid over diagnosis of dysplasia, 'possibly dysplastic' forms should be excluded from the count of dysplastic cells. Our results demonstrate that the nature as well as the presence of megakaryocyte dysplasia is important in the diagnosis of MDS; although evaluation of 30 megakaryocytes is strongly recommended, it may be possible to recognize diagnostically important dysplasia when fewer megakaryocytes are present but highly diagnostic forms are seen.


Sports-related dental injuries: knowledge of first aid and mouthguard use in a sample of Italian children and youngsters.
The purpose of this study was to evaluate the awareness of sports as risk factor of dental injuries, the emergency management when a tooth avulsion occurs and the compliance about mouthguards. Two hundred children and youngsters 8- to 15-year-old (147 boys and 53 girls) attending Sports Societies in Isernia, a town in Southern Italy, participated to the investigation. The sports involved were soccer, martial arts, tennis, swimming, volleyball, basketball and cycling. The questionnaire was structured into three parts: 1) questions about age, sex, type and time of sports practice; 2) questions about dental injuries, particularly personal experience, awareness of first aid and procedure about tooth avulsion; 3) questions about knowledge and use of mouthguards. Sixty-five per cent of the athletes were aware of the possibility of oral injuries during sports practice and 8.5% referred an experience of dental trauma; 71.5% of the participants think that the immediate management of dental injuries by a dentist is very important to increase the rate of success; 31% know that the avulsed tooth may be reimplanted: 33.9% would reimplant the tooth within an hour and 62.9% would keep it in a wet storage medium. Finally, 80.5% of the athletes knew about mouthguards as protective devices, but only 5% actually used them; eight out of ten were provided by the dentist. Educational programs organized by the sports dentistry community are needed to inform coaches, teachers, athletes and parents about dental injuries and to promote the mouthguards use, especially in contact sports practice.


This study evaluates up to which degree physicians of Hospital Dr. Dario Contreras of Dominican Republic know, respect, inform and apply the General Health Law in relation to the right of Jehovah witness patients to refuse being blood transfused (respect to their autonomy). It also evaluates whether Jehovah witnesses know General Health Law and in which degree they have been benefited by putting it into practice. The study reveals that Jehovah Witnesses do not know the law.


Clinical survival of indirect, anterior 3-unit surface-retained fibre-reinforced composite fixed dental prosthesis: Up to 7.5-years follow-up.
This prospective clinical study evaluated the performance of indirect, anterior, surface-retained, fibre-reinforced-composite restorations (ISFRCR). Between June-2003 and January-2011, a total of 134 patients (83 females, 51 males, 16-68 years old) received 175 ISFRCRs (local ethical registration number: 14/9/4). All restorations were made indirectly on a plaster model using unidirectional E-glass fibres (everStick C&B, StickTech) in combination with a laboratory resin composite (Dialogue, Schütz Dental) and cemented according to the instructions of 4 resin cements [(RelyX ARC, 3M-ESPE, n=61), Bifix DC, VOCO, n=45), Variolink II (Ivoclar Vivadent, n=32) and Multilink (Ivoclar Vivadent, n=37)]. After baseline recordings, patients were followed at 6 months and thereafter annually up to 7.5 years. The evaluation protocol involved technical (chipping, debonding or fracture of tooth/restoration) and biological failures (caries). Mean observation period was 58 months. Altogether, 13 failures were observed [survival rate: 97.7%] (Kaplan-Meier). One catastrophic fracture [(cement: RelyX ARC), eight partial debonding (cement: Bifix DC (5), Multilink (1), RelyX ARC (1), Variolink II (1)] and four delaminations of veneering composite [(cement: Bifix DC (2), RelyX ARC (1), Multilink (1)] were observed. Except one replacement, all defective restorations were repaired or recemented. Annual failure rate of ISFRCRs was 1.73%. The survival rates with the four resin cements did not show significant differences (RelyX ARC: 98.3%; Bifix DC: 93.5%; Variolink 2: 100%; Multilink: 100%) (p=0.114). Secondary caries did not occur in any of the teeth. The 3-unit anterior indirect surface-retained resin-bonded FRC FDPs showed similar clinical survival rate when cemented with the resin cements tested. Experienced failures in general were due to debonding of the restoration or delamination of the veneering composite. 3-unit surface retained resin-bonded FRC FDPs could be considered minimal invasive and cost-effective alternatives to conventional tooth- or implant-borne FDPs. Failures were mainly repairable in the form of chipping or debonding depending on the resin cement type.


The lived experiences of oropharyngeal dysphagia in adults living with fibromyalgia.
Fibromyalgia is a chronic pain condition which has recently been linked with eating, drinking and swallowing difficulties (dysphagia). However, to date, sample sizes within completed research are small and study designs heterogeneous, and therefore, little is known about the lived experiences of dysphagia among people with fibromyalgia. To go some way towards addressing this gap in the literature, this study collected and analysed the first-hand experiences of the physical symptoms, the psychosocial impacts and environmental factors that influenced the lived experience of a sample of people living with fibromyalgia-associated dysphagia. Qualitative semi-structured interviews were conducted with adults with dysphagia and fibromyalgia. Reflexive thematic analysis was employed and themes were identified regarding the reported experience and impact of swallowing problems. The same researcher conducted the interviews and extracted all data, and a second researcher analysed a random sample of 5% of the data for accuracy, with no disagreements arising between the two researchers. All participants (n = 8) reported the negative psychosocial impact of their dysphagia. Participants reported managing their dysphagia independently, primarily using compensatory strategies. Participants discussed feeling unsupported in healthcare interactions due to clinicians not understanding the occurrence, nature or impact of eating, drinking and swallowing difficulties. Participants also reported that they did not have access to evidence-based management strategies that adequately addressed their fibromyalgia-related swallowing problems. Despite minimal previous research in this area, findings here highlight the impact that dysphagia has on people with fibromyalgia. A broad range of physical symptoms were reported to have negative consequences across both social and emotional domains. The reported symptoms often required complex coping strategies and sometimes impeded participants from seeking suitable medical intervention from healthcare providers. There are both broad-ranging implications of fibromyalgia-associated dysphagia and reported poor perceptions of medical interactions for this cohort of patients. Therefore, there is evidently a need for clinical research into the management of this condition to develop patient-centred care delivery options and to equip healthcare professionals with the knowledge and skills necessary to provide efficacious management to this group. Before initiation of the qualitative interviews, the interview schedule was piloted with an individual living with fibromyalgia and dysphagia, with feedback provided on the appropriate wording and format of semi-structured questioning.


Monoclonal antibodies specific for hepatitis B e antigen and hepatitis B core antigen.
Despite effective vaccination programs in many countries, HBV infection is still a serious health problem throughout the world; more than 2 billion people have been infected with Hepatitis B virus (HBV). The serologic markers are crucial indicators in clinical diagnosis of HBV infection. The persistent presence of anti-HBc is associated with chronicity, and anti-HBe is an indicator for active viral replication. In the present study, two different hybridoma clones, 12E5 and 16F8, secreting anti-HBeAg and anti-HBc antibody were developed using hybridoma technology. BALB/c mice were immunized with HBe antigen (HBeAg), and monoclonal antibodies were generated from the spleen and lymph nodes of mice. Immunoglobulin types of antibodies were found to be IgG2a and IgG1, respectively. Monoclonal antibodies (MAbs) were produced in large scale, purified with affinity chromatography, and epitope analysis was performed. The results have shown that 12E5 and 16F8 monoclonal antibodies can be used for detection of HBcAg and HBeAg, indicating that they have the potential for use in clinical diagnosis.


Long-term risk of recurrence in patients with a first unprovoked venous thromboembolism managed according to d-dimer results; A cohort study.
Essentials Long-term recurrence risk after a first unprovoked VTE with negative d-dimer levels is uncertain. Anticoagulation was stopped if d-dimer was negative, and was continued if d-dimer was positive. Five years after stopping anticoagulants, recurrent VTE was 30% in men and 17% in women. Negative d-dimers do not justify stopping anticoagulants in most men but appear to in most women. The long-term risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative d-dimer results is uncertain. To determine this risk, including in subgroups based on sex. ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if d-dimer was negative on therapy and 1 month after stopping therapy. Other patients remained on anticoagulant therapy. We previously reported findings after a mean of 2.2 years. The current report includes 3 years of additional follow-up in 293 of these patients. During a median follow-up of 5.0 years, recurrent VTE after stopping therapy in response to negative d-dimer testing was 5.1% (95% confidence interval [CI], 3.6-6.5) per patient-year overall, 7.5% (95% CI, 5.5-10.0) in men, 3.8% (95% CI, 2.0-6.6) in women with VTE not associated with estrogens, and 0.4% (95% CI, 0.0-2.3) in women with VTE associated with estrogens (P < 0.001 for three-group comparison). Risk of recurrence at 5 years was 21.5% (95% CI, 16.4-26.5) overall, 29.7% (95% CI, 22.1-37.3) in men, 17.0% (95% CI, 8.1-25.9) in non-estrogen women, and 2.3% (95% CI, 0.0-6.8) in estrogen women. The long-term risk of recurrence in patients with a first unprovoked VTE who have negative d-dimer results is not low enough to justify stopping anticoagulant therapy in men, but appears to be low enough in women for many to choose stopping therapy (ClinicalTrials.gov; NCT00720915).


Electro-optic sampling based characterization of broad-band high efficiency THz-FEL.
Extremely high beam-to-radiation energy conversion efficiencies can be obtained in a THz FEL using a strongly tapered helical undulator at the zero-slippage resonant condition, where a circular waveguide is used to match the radiation group velocity to the electron beam longitudinal velocity. In this paper we report on the first electro-optic sampling (EOS) based measurements of the broadband THz FEL radiation pulses emitted in this regime. The THz field waveforms are reconstructed in the spatial and temporal domains using multi-shot and single-shot EOS schemes respectively. The measurements are performed varying the input electron beam energy in the undulator providing insights on the complex dynamics in a waveguide FEL.


Prognostic power of anaerobic threshold parameters in patients with transposition of the great arteries and systemic right ventricle.
Both transposition of the great arteries (TGA) previously submitted to a Senning/Mustard procedure and congenitally corrected TGA (cc-TGA) have the systemic circulation supported by the morphological right ventricle, thereby rendering these patients to heart failure events risk. The aim of this study was to evaluate cardiopulmonary exercise test parameters for stratifying the risk of heart failure events in TGA patients. Retrospective evaluation of adult TGA patients with systemic circulation supported by the morphological right ventricle submitted to cardiopulmonary exercise test in a tertiary centre. Patients were followed up for at least 1 year for the primary endpoint of cardiac death or heart failure hospitalisation. Several cardiopulmonary exercise test parameters were analysed as potential predictors of the combined endpoint and their predictive power were compared (area under the curve). Cardiopulmonary exercise test was performed in 44 TGA patients (8 cc-TGA), with a mean age of 35.1 ± 8.4 years. The primary endpoint was reached by 10 (22.7%) patients, with a mean follow-up of 36.7 ± 26.8 months. Heart rate at anaerobic threshold had the highest area under the curve value (0.864), followed by peak oxygen consumption (pVO2) (0.838). Heart rate at anaerobic threshold ≤95 bpm and pVO2 ≤20 ml/kg/min had a sensitivity of 87.5 and 80.0% and a specificity of 82.4 and 76.5%, respectively, for the primary outcome. Heart rate at anaerobic threshold ≤95 bpm had the highest predictive power of all cardiopulmonary exercise test parameters analysed for heart failure events in TGA patients with systemic circulation supported by the morphological right ventricle.


A review of drug delivery systems based on nanotechnology and green chemistry: green nanomedicine.
This review discusses the impact of green and environmentally safe chemistry on the field of nanotechnology-driven drug delivery in a new field termed "green nanomedicine". Studies have shown that among many examples of green nanotechnology-driven drug delivery systems, those receiving the greatest amount of attention include nanometal particles, polymers, and biological materials. Furthermore, green nanodrug delivery systems based on environmentally safe chemical reactions or using natural biomaterials (such as plant extracts and microorganisms) are now producing innovative materials revolutionizing the field. In this review, the use of green chemistry design, synthesis, and application principles and eco-friendly synthesis techniques with low side effects are discussed. The review ends with a description of key future efforts that must ensue for this field to continue to grow.


Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK.
Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours. Rapamycin (0.25 mg/kg) or DMSO (7.5%) was injected intracardially at the onset of reperfusion. Post-I/R survival (87%) and cardiac function (fractional shortening, FS: 28.63 ± 3.01%) were improved in Rapamycin-treated mice compared to DMSO (survival: 63%, FS: 17.4 ± 2.6%). Rapamycin caused significant reduction in myocardial infarct size (IS: 26.2 ± 2.2%) and apoptosis (2.87 ± 0.64%) as compared to DMSO-treated mice (IS: 47.0 ± 2.3%; apoptosis: 7.39 ± 0.81%). Rapamycin induced phosphorylation of AKT S473 (target of mTORC2) but abolished ribosomal protein S6 phosphorylation (target of mTORC1) after I/R. Rapamycin induced phosphorylation of ERK1/2 but inhibited p38 phosphorylation. Infarct-limiting effect of Rapamycin was abolished with ERK inhibitor, PD98059. Rapamycin also attenuated Bax and increased Bcl-2/Bax ratio. These results suggest that reperfusion therapy with Rapamycin protects the heart against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38.


Design and synthesis of theranostic antibiotic nanodrugs that display enhanced antibacterial activity and luminescence.
We report the modular formulation of ciprofloxacin-based pure theranostic nanodrugs that display enhanced antibacterial activities, as well as aggregation-induced emission (AIE) enhancement that was successfully used to image bacteria. The drug derivatives, consisting of ciprofloxacin, a perfluoroaryl ring, and a phenyl ring linked by an amidine bond, were efficiently synthesized by a straightforward protocol from a perfluoroaryl azide, ciprofloxacin, and an aldehyde in acetone at room temperature. These compounds are propeller-shaped, and upon precipitation into water, readily assembled into stable nanoaggregates that transformed ciprofloxacin derivatives into AIE-active luminogens. The nanoaggregates displayed increased luminescence and were successfully used to image bacteria. In addition, these nanodrugs showed enhanced antibacterial activities, lowering the minimum inhibitory concentration (MIC) by more than one order of magnitude against both sensitive and resistant Escherichia coli The study represents a strategy in the design and development of pure theranostic nanodrugs for combating drug-resistant bacterial infections.


Role of the sodium pump in pacemaker generation in dog colonic smooth muscle.
1. The role of the Na+ pump in the generation of slow wave activity in circular muscle of the dog colon was investigated using a partitioned 'Abe-Tomita' type chamber for voltage control. 2. Blockade of the Na+ pump by omission of extracellular K+, by ouabain, or the combination of 0 mM-Na+ and ouabain, depolarized the membrane up to approximately -40 mV and abolished the slow wave activity. Repolarization back to the control membrane potential by hyperpolarizing current restored the slow wave activity. 3. Slow waves continued to be present in 0 Na+, Li+ HEPES solution. 4. The depolarization induced by the procedures to block Na+ pump activity was associated with an increase in input membrane resistance. 5. Voltage-current relationships show the presence of an inward rectification. 6. Reduction of temperature depolarized the membrane, and decreased the slow wave frequency and amplitude. The slow wave amplitude was restored by repolarization of the membrane. 7. Brief depolarizing pulses evoked premature slow waves. Brief hyperpolarizing pulses terminated the slow waves. 8. We conclude that abolition of slow wave activity by Na+ pump blockade is a direct effect of membrane depolarization and that the Na+ pump is not responsible for the generation of the slow wave. 9. Our results are consistent with the hypothesis that pacemaker activity in smooth muscle is a consequence of membrane conductance changes which are metabolically dependent.


A Novel g.55040074delT in ALAS2 Gene Resulting in a Monomeric Protein and Severe Sideroblastic Anemia Phenotype.
Sideroblastic anemias are a rare group of disorders resulting from defective iron incorporation during heme synthesis and hence characterized by anemia and presence of ringed sideroblasts in bone marrow. The most common form is an X-linked disorder caused by mutations in ALAS2 gene. In the current paper, a case of X-linked sideroblastic anemia caused by a novel homozygous deletional mutation in exon 10 of ALAS2 gene is presented. The female infant developed moderately severe anemia at 6 months of age, which did not improve despite adequate nutritional support. The diagnosis was suspected considering a high plasma ferritin of 740.9 μg/L. The protein structure as predicted by SWISS model was a monomeric form rather than wild-type homodimer, resulting in marked loss of function and protein instability.


Scientific triumphalism and learning from facts: bacteriology and the "Spanish flu" challenge of 1918.
The devastating influenza pandemic known as 'Spanish flu', which killed at least 20 million people all over the world in 1918, was responsible for the first bitter blow inflicted on triumphant bacteriology, fortified by the series of resounding successes achieved in identifying the pathogenic agents of terrible diseases such as anthrax, cholera, tuberculosis, plague, and syphilis. Over-confidence and the idea, born of the Pasteur revolution, that every infectious disease was caused by a bacterium, had led the scientific community to accept the theory put forward by the German bacteriologist, Richard Pfeiffer, who, in 1892, believed he had identified the pathogenic influenza agent in a bacterium, Haemophilus influenzae. But, while the most appalling epidemic ever to sweep through the world since the 'Black Death' of the 1300s was still raging, the scientific community had to admit that influenza originated not from a microbe, but from a virus. This article aims to reconstruct the enlightening and little-known cultured/scientific events and issues of the dramatic crisis that bacteriology experienced in the autumn of 1918, with the consequent simultaneous collapse of both the 'Pfeiffer doctrine' on the microbial origin of influenza and the illusion of a world free of infectious diseases. This was an illusion destined to surface again at the end of the century and collapse with the advent of AIDS.


3DMorph Automatic Analysis of Microglial Morphology in Three Dimensions from Ex Vivo and In Vivo Imaging.
Microglia are dynamic immune cells of the central nervous system, and their morphology is commonly used as a readout of cellular function. However, current morphological analysis techniques rely on either tracing of cells or two-dimensional projection analysis, which are time-consuming, subject to bias, and may ignore important three-dimensional (3D) information. Therefore, we have created 3DMorph, a MATLAB-based script that analyzes microglial morphology from 3D data. The program initially requires input of threshold levels, cell size expectations, and preferred methods of skeletonization. This makes 3DMorph easily scalable and adaptable to different imaging parameters or cell types. After these settings are defined, the program is completely automatic and can batch process files without user input. Output data includes cell volume, territorial volume, branch length, number of endpoints and branch points, and average distance between cells. We show that 3DMorph is accurate compared to manual tracing, with significantly decreased user input time. Importantly, 3DMorph is capable of processing in vivo microglial morphology, as well as other 3D branching cell types, from mouse cranial windows or acute hippocampal slices. Therefore, we present a novel, user-friendly, scalable, and semiautomatic method of analyzing cell morphology in 3 dimensions. This method should improve the accuracy of cell measurements, remove user bias between conditions, increase reproducibility between experimenters and labs, and reduce user input time. We provide this open source code on GitHub so that it is free and accessible to all investigators.


Oocyst shedding by cats fed isolated bradyzoites and comparison of infectivity of bradyzoites of the VEG strain Toxoplasma gondii to cats and mice.
Infectivity of bradyzoites of the VEG strain of Toxoplasma gondii was compared in cats and mice. For this, tissue cysts were separated from brains of infected mice using a Percoll gradient, and bradyzoites were released by incubation in acidic pepsin solution. After filtration through a 3-microm filter, bradyzoites were counted and diluted 10-fold in RPMI tissue culture medium. Dilutions estimated to have 1, 10, 100, and 1,000 bradyzoites were fed to cats and inoculated into mice, orally or subcutaneously (s.c.). Three experiments were performed. In experiment 1, 2 of 2 cats fed 1,000 bradyzoites, 1 of 2 cats fed 100 bradyzoites, 1 of 4 cats fed 10 bradyzoites, and 1 of 4 cats fed 1 bradyzoite shed millions of oocysts; 1,000 bradyzoites were infective to all 4 inoculated mice s.c. but not to 4 mice inoculated orally, and 100 bradyzoites were infective to 2 of 4 mice injected s.c. but not to 4 mice inoculated orally. All 16 mice (8 oral, 8 s.c.) injected with 1 or 10 bradyzoites were negative for T. gondii. In experiment 2, 1 of 4 cats fed 10 counted bradyzoites shed oocysts; the same inocula were not infective to 4 mice injected s.c. In experiment 3, 3 of 4 cats fed 1,000 bradyzoites shed oocysts and the inocula were infective to 10 of 10 mice s.c. and 4 of 10 mice orally; 4 of 4 cats fed 100 bradyzoites shed oocysts and the inocula were infective to 6 of 10 mice s.c. and 0 of 10 mice orally; 10 bradyzoites were not infective to cats and mice. Results indicate that bradyzoites are more infective to cats than to mice, and cats can shed millions of oocysts after ingesting just a few bradyzoites.


[Flavonolignans - compounds not only for liver treatment].
Flavonolignans are the major bioactive components presented in the Milk thistle (Silybum marianum) standarized extract - silymarin. S. marianum is a medicinal plant, which has been using for thousands of years as a remedy for a variety of ailments. Since the 70s of the last century flavonolignans presented in silymarin have been regarded to the official medicine as substances having an hepatoprotective properties. Structurally, flavonolignans are composed of a flavonoid unit (taxifolin) and a phenylpropane unit (coniferyl alcohol), linked together by an oxeran ring. Many studies which have been conducted in recent years demonstrated that flavonolignans posses a various healthy properties. Flavonolignans modulate of a variety cell-signaling pathways as well as inhibit arachidonic acid metabolism, resulting in the reduction of pro-inflammatory mediators formation. The researches performed in last year's demonstrated that the major flavonolignan - silybin is able to inhibit two blood coagulation factors: thrombin and FXa. Flavonolignans have been also studied as a potential anticancer agents. This review article presents flavonolignans health benefits effects not only for the liver.


Deep functional immunophenotyping predicts risk of cytomegalovirus reactivation after hematopoietic cell transplantation.
Cytomegalovirus (CMV) is the most common viral infection in hematopoietic cell transplantation (HCT) recipients. We performed deep phenotyping of CMV-specific T cells to predict CMV outcomes following allogeneic HCT. By using 13-color flow cytometry, we studied ex vivo CD8+ T-cell cytokine production in response to CMV-pp65 peptides in 3 clinically distinct subgroups of CMV-seropositive HCT patients: (1) Elite Controllers (n = 19): did not have evidence of CMV DNAemia on surveillance testing; (2) Spontaneous Controllers (n = 16): spontaneously resolved low-grade CMV DNAemia without antiviral therapy; and (3) Noncontrollers (NC; n = 21): experienced clinically significant CMV. Two CMV-specific CD8+ T-cell functional subsets were strongly associated with risk of CMV: (i) the nonprotective signature (NPS; IL-2-IFN-γ+TNF-α-MIP-1β+), found at increased levels among NC; and (ii) the protective signature (PS; IL-2+IFN-γ+TNF-α+MIP-1β+) found at low levels among NC. High levels of the NPS and low levels of PS were associated with an increased 100-day cumulative incidence of clinically significant CMV infection (35% vs 5%; P = .02; and 40% vs 12%; P = .05, respectively). The highest predictive value was observed when these signatures were combined into a composite biomarker consisting of low levels of the PS and high levels of the NPS (67% vs 10%; P < .001). After adjusting for steroid use or donor type, this composite biomarker remained associated with a fivefold increase in the risk of clinically significant CMV infection. CMV-specific CD8+ T-cell cytokine signatures with robust predictive value for risk of CMV reactivation should prove useful in guiding clinical decision making in HCT recipients.


Practice patterns of mitochondrial disease physicians in North America. Part 1: diagnostic and clinical challenges.
Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.


[Current status of schistosomiasis in Santchou health area, (Santchou Health District, Cameroon western region)].
Schistosomiasis, the second endemic parasitic infection in the world, is a parasitosis caused by trematodes from the genus Schistosoma. Our study aims to assess the prevalence of different species of schistosomes (Schistosoma mansoni, haematobium and intercalatum) among schoolchildren and to identify risk factors, clinical signs of schistosomiasis, and schistosomiasis intermediate host snails in stagnant water. We conducted a cross sectional study over a three months period. The study consisted of sociodemographic and clinical data recording, collection of stool samples and urine, molluscan research and treatment of positive students for other helminths. Laboratory tests were performed at the Medical Research Institute and the study of Medicinal Plants in Yaounde where stool samples and urine were examined using KATO KATZ and centrifugation technique respectively, and shellfish species were determined by a malacologist. A total of 400 students aged between 8-16 years, 223 (55.7%) girls and 177 (44.3%) boys attending 4 elementary school were enrolled in the study. The social survey revealed that 154 students out of 400 (or 38.5%) were in contact with the river water at least once a week, 58% from around noon. All students had at least one symptom of schistosomiasis although nonspecific and dominated by abdominal pain in 72% of cases (n = 288 of 400). Biologically, no schistosomiasis eggs were detected. Cercaria releasing rate was negative in the 100 watery species found. The Santchou health area is not an active outbreak of schistosomiasis, but remains a risk area because of rice cultivation and stagnant water. The intensification of health education campaigns among the general population would delay the onset of this infection in the locality.


MimoPro: a more efficient Web-based tool for epitope prediction using phage display libraries.
A B-cell epitope is a group of residues on the surface of an antigen which stimulates humoral responses. Locating these epitopes on antigens is important for the purpose of effective vaccine design. In recent years, mapping affinity-selected peptides screened from a random phage display library to the native epitope has become popular in epitope prediction. These peptides, also known as mimotopes, share the similar structure and function with the corresponding native epitopes. Great effort has been made in using this similarity between such mimotopes and native epitopes in prediction, which has resulted in better outcomes than statistics-based methods can. However, it cannot maintain a high degree of satisfaction in various circumstances. In this study, we propose a new method that maps a group of mimotopes back to a source antigen so as to locate the interacting epitope on the antigen. The core of this method is a searching algorithm that is incorporated with both dynamic programming (DP) and branch and bound (BB) optimization and operated on a series of overlapping patches on the surface of a protein. These patches are then transformed to a number of graphs using an adaptable distance threshold (ADT) regulated by an appropriate compactness factor (CF), a novel parameter proposed in this study. Compared with both Pep-3D-Search and PepSurf, two leading graph-based search tools, on average from the results of 18 test cases, MimoPro, the Web-based implementation of our proposed method, performed better in sensitivity, precision, and Matthews correlation coefficient (MCC) than both did in epitope prediction. In addition, MimoPro is significantly faster than both Pep-3D-Search and PepSurf in processing. Our search algorithm designed for processing well constructed graphs using an ADT regulated by CF is more sensitive and significantly faster than other graph-based approaches in epitope prediction. MimoPro is a viable alternative to both PepSurf and Pep-3D-Search for epitope prediction in the same kind, and freely accessible through the MimoPro server located at http://informatics.nenu.edu.cn/MimoPro.


Ethanol- and cocaine-induced locomotion are genetically related to increases in accumbal dopamine.
Neuroanatomical research suggests that interactions between dopamine and glutamate within the mesolimbic dopamine system are involved in both drug-induced locomotor stimulation and addiction. Therefore, genetically determined differences in the locomotor responses to ethanol and cocaine may be related to differences in the effects of these drugs on this system. To test this, we measured drug-induced changes in dopamine and glutamate within the nucleus accumbens (NAcc), a major target of mesolimbic dopamine neurons, using in vivo microdialysis in selectively bred FAST and SLOW mouse lines, which were bred for extreme sensitivity (FAST) and insensitivity (SLOW) to the locomotor stimulant effects of ethanol. These mice also show a genetically correlated difference in stimulant response to cocaine (FAST > SLOW). Single injections of ethanol (2 g/kg) or cocaine (40 mg/kg) resulted in larger increases in dopamine within the NAcc in FAST compared with SLOW mice. There was no effect of either drug on NAcc glutamate levels. These experiments indicate that response of the mesolimbic dopamine system is genetically correlated with sensitivity to ethanol- and cocaine-induced locomotion. Because increased sensitivity to the stimulating effects of ethanol appears to be associated with greater risk for alcohol abuse, genetically determined differences in the mesolimbic dopamine response to ethanol may represent a critical underlying mechanism for increased genetic risk for alcoholism.


Spatial and temporal analysis of scanned systems.
An analysis of input-output characteristics of scanned systems is presented from the input camera to the output reproducer. The system characteristics are developed in terms of both spatial coordinates and spatial frequency responses in both dimensions. These include the effects of the scanning apertures of both the camera and the reproducer, in addition to the electrical filter on the resultant signal. The effects of time varying input patterns are also considered in terms of the temporal responses of the camera and the phosphor characteristic of the reproducer.


Control of malabsorption in cystic fibrosis.
Intestinal malabsorption is severe and of early onset in virtually all people who have cystic fibrosis. The main cause is deficiency of pancreatic enzymes, but bicarbonate deficiency, abnormalities of bile salts, mucosal transport and motility, and anatomical structural changes are other contributory factors. Appropriate pancreatic replacement therapy will achieve normal or near normal absorption in many patients. It is important to identify both malabsorption and evidence of a pancreatic lesion in all patients who are to receive pancreatic enzymes. All who have evidence of fat malabsorption are deemed pancreatic insufficient and candidates for enzyme replacement therapy. Effective treatment should allow a normal diet to be taken, control symptoms, correct malabsorption and achieve a normal nutritional state and growth. The occurrence of fibrosing colonopathy in some patients receiving very high doses of those enzymes that have the copolymer Eudragit L30 D55 in their covering has resulted in guidelines in the UK to avoid dosages greater than the equivalent of 10,000 IU lipase/kg/day for all patients and also to avoid preparations containing this copolymer in children and adolescents. For patients not responding to 10,000 IU lipase/kg/day, review of adherence to treatment, change of enzyme preparation, variation of the time of administration and reduction in gastric acid may improve absorption. The importance of excluding other gastrointestinal disorders as a cause of the patient's symptoms and the need for early investigations, rather than merely increasing the dosage of enzymes, is stressed. With modern enzymes, adequate control of gastrointestinal symptoms and absorption can be achieved at dosages of 10,000 IU lipase/kg/day or only slightly more, and a normal nutritional state and growth rate maintained in most patients with cystic fibrosis.


Propolis and Herba Epimedii extracts enhance the non-specific immune response and disease resistance of Chinese sucker, Myxocyprinus asiaticus.
The effect of traditional Chinese medicine (TCM) formulated from propolis and Herba Epimedii extracts at the ratio of 3:1 (w/w) on non-specific immune response of Chinese sucker (Myxocyprinus asiaticus) was investigated. Fish were fed diets containing 0 (control), 0.1%, 0.5% or 1.0% TCM extracts for five weeks. The respiratory burst and phagocytic activities of blood leukocytes, lysozyme and natural haemolytic complement activities in plasma were measured weekly. After five weeks of feeding, fish were infected with Aeromonas hydrophila and mortalities were recorded. Results of this study showed that feeding Chinese sucker with different dosage of TCM extracts stimulated respiratory burst activity, phagocytosis of phagocytic cells in blood and lysozyme activity in plasma. They had no effect on plasma natural haemolytic complement activity. All dosage of treated groups showed reduced mortality following A. hydrophila infection. Feed containing 0.5% TCM extracts was the most effective with the mortality of the fish significantly reduced by 35% compared to the control. The results indicate that propolis and Herba Epimedii extracts in combination enhances the non-specific immune response and disease resistance of Chinese sucker against A. hydrophila.


New labor management guidelines and changes in cesarean delivery patterns.
In 2010 the Consortium on Safe Labor published labor curves. It was proposed that the rate of cesarean delivery could be lowered by avoiding the diagnosis of arrest of dilation before 6 cm. However, there is little information on the uptake of the guidelines and on changes in cesarean delivery rates that may have occurred. The objective of the study was to test the following hypotheses: (1) among patients laboring at term, rates of arrest of dilation disorders have decreased, leading to a decrease in the rate of cesarean delivery; (2) in the second stage, pushing duration prior to diagnosis of arrest of descent has increased, also leading to a reduction in the rate of cesarean delivery for this indication. As a secondary aim, we investigated changes in maternal and neonatal morbidity. This was a secondary analysis of a prospective cohort study of all patients presenting at ≥37 weeks' gestation from 2010 through 2014 with a nonanomalous vertex singleton and no prior history of cesarean delivery. Rates of cesarean delivery, arrest of dilation, and changes in rates of maternal and neonatal morbidity were calculated in crude and adjusted models. Cervical dilation at diagnosis of the arrest of dilation, time spent at the maximal dilation prior to diagnosis of arrest of dilation, and time in the second stage prior to the diagnosis of arrest of descent were compared over the study period. There were 7845 eligible patients. The cesarean delivery rate in 2010 was 15.8% and, in 2014, 17.7% (P trend = .51). In patients undergoing cesarean delivery for the arrest of dilation, the median cervical dilation at the time of cesarean delivery was at 5.5 cm in 2010 and 6.0 cm in 2014 (P trend = .94). In these patients, there was an increase in the time spent at last dilation: 3.8 hours in 2010 to 5.2 hours in 2014 (P trend = .02). There was no change in the frequency of patients diagnosed with the arrest of dilation at <6 cm: 51.4% in 2010 and 48.6% in 2014 (P trend = .56). However, in these patients, the median time spent at the last cervical dilation was 4.0 hours in 2010 and 6.7 hours in 2014 (P trend = .046). There were 206 cesarean deliveries for the arrest of descent. The median pushing time in these patients increased in multiparous patients from 1.1 hours in 2010 to 3.4 hours in 2014 (P trend = .009); in nulliparous patients these times were 2.7 hours in 2010 and 3.8 hours in 2014 (P trend = .09). There was a significant trend toward increasing adverse neonatal and maternal outcomes (P < .001 for each). The adjusted odds ratio for adverse maternal outcome for 2014 compared with 2010 was 1.66 (95% confidence interval, 1.27-2.17); however, considering only transfusion, hemorrhage, or infection, there was no difference (P trend = .96). The adjusted odds ratio of adverse neonatal outcome in 2014 compared with 2010 was 1.80 (95% confidence interval, 1.36-2.36). Despite significant changes in labor management that have occurred over the initial years since publication of the new labor curves and associated guidelines, the primary cesarean delivery rate was not reduced and there has been an increase in maternal and neonatal morbidity in our institution. A randomized controlled trial is needed.