A new small-angle X-ray scattering set-up on the crystallography beamline I711 at MAX-lab.
A small-angle X-ray scattering (SAXS) set-up has recently been developed at beamline I711 at the MAX II storage ring in Lund (Sweden). An overview of the required modifications is presented here together with a number of application examples. The accessible q range in a SAXS experiment is 0.009-0.3 A(-1) for the standard set-up but depends on the sample-to-detector distance, detector offset, beamstop size and wavelength. The SAXS camera has been designed to have a low background and has three collinear slit sets for collimating the incident beam. The standard beam size is about 0.37 mm x 0.37 mm (full width at half-maximum) at the sample position, with a flux of 4 x 10(10) photons s(-1) and lambda = 1.1 A. The vacuum is of the order of 0.05 mbar in the unbroken beam path from the first slits until the exit window in front of the detector. A large sample chamber with a number of lead-throughs allows different sample environments to be mounted. This station is used for measurements on weakly scattering proteins in solutions and also for colloids, polymers and other nanoscale structures. A special application supported by the beamline is the effort to establish a micro-fluidic sample environment for structural analysis of samples that are only available in limited quantities. Overall, this work demonstrates how a cost-effective SAXS station can be constructed on a multipurpose beamline.


Automated localization and segmentation of lung tumor from PET-CT thorax volumes based on image feature analysis.
Positron emission tomography - computed tomography (PET-CT) plays an essential role in early tumor detection, diagnosis, staging and treatment. Automated and more accurate lung tumor detection and delineation from PET-CT is challenging. In this paper, on the basis of quantitative analysis of contrast feature of PET volume in SUV (standardized uptake value), our method firstly automatically localized the lung tumor. Then based on analysing the surrounding CT features of the initial tumor definition, our decision strategy determines the tumor segmentation from CT or from PET. The algorithm has been validated on 20 PET-CT studies involving non-small cell lung cancer (NSCLC). Experimental results demonstrated that our method was able to segment the tumor when adjacent to mediastinum or chest wall, and the algorithm outperformed the other five lung segmentation methods in terms of overlapping measure.


JNK and decapentaplegic signaling control adhesiveness and cytoskeleton dynamics during thorax closure in Drosophila.
One of the fundamental events in metamorphosis in insects is the replacement of larval tissues by imaginal tissues. Shortly after pupariation the imaginal discs evaginate to assume their positions at the surface of the prepupal animal. This is a very precise process that is only beginning to be understood. In Drosophila, during embryonic dorsal closure, the epithelial cells push the amnioserosa cells, which contract and eventually invaginate in the body cavity. In contrast, we find that during pupariation the imaginal cells crawl over the passive larval tissue following a very accurate temporal and spatial pattern. Spreading is driven by filopodia and actin bridges that, protruding from the leading edge, mediate the stretching of the imaginal epithelia. Although interfering with JNK (Jun N-terminal kinase) and dpp (decapentaplegic) produces similar phenotypic effects suppressing closure, their effects at the cellular level are different. The loss of JNK activity alters the adhesion properties of larval cells and leads to the detachment of the imaginal and larval tissues. The absence of dpp signaling affects the actin cytoskeleton, blocks the emission of filopodia, and promotes the collapse of the leading edge of the imaginal tissues. Interestingly, these effects are very similar to those observed after interfering with JNK and dpp signaling during embryonic dorsal closure.


[Collective action and veto players in public policy: the sanitation policy in Brazil (1998-2002)].
In 1999, the federal government has committed itself to the IMF with the privatization of the sanitation and other public services, seeking resources to address the fiscal crisis. He proposed the bill 4147/01 as the regulatory framework that would provide the necessary security for investors interested in acquiring the state-owned sanitation enterprises. Against this initiative, a coalition of industry interests mobilized in order to veto the adoption of privatization: the National Front for Environmental Sanitation (FNSA). This paper identifies the actors, the agenda and the interests involved in this political coalition. It shows that the coalition acted decisively as an instance of veto, limiting the effects of the agreement with the IMF on the public policy of sanitation in Brazil this time.


Genetic fine structure of the Y chromosome of Drosophila hydei.
A genetic map of the Y chromosome of Drosophila hydei has been constructed from deletion/complementation experiments, with the aid of male sterile mutants of the Y chromosome. A central conclusion of our experiments is that not more than a single complementation group can be detected in each of the lampbrush loop forming sites. Additional complementation groups, functionally independent of lampbrush loops, reside between these loci. Six complementation groups have been defined by several methods of mapping. An additional ten complementation groups are indicated, but their exact definition requires further investigation. The "synthetic sterility" of mutations in these ten loci contributes to the difficulty in unequivocally establishing their individual boundaries. Mapping problems also arise from the instability of certain mutants.


Multiple Morphologies of "Crew-Cut" Aggregates of Polystyrene-b-poly(acrylic acid) Block Copolymers.
The observation by transmission electron microscopy of six different stable aggregate morphologies is reported for the same family of highly asymmetric polystyrene-poly-(acrylic acid) block copolymers prepared in a low molecular weight solvent system. Four of the morphologies consist of spheres, rods, lamellae, and vesicles in aqueous solution, whereas the fifth consists of simple reverse micelle-like aggregates. The sixth consists of up to micrometer-size spheres in aqueous solution that have hydrophilic surfaces and are filled with the reverse micelle-like aggregates. In addition, a needle-like solid, which is highly birefringent, is obtained on drying of aqueous solutions of the spherical micelles. This range of morphologies is believed to be unprecedented for a block copolymer system.


Prevalence and pathogenicity of Aeromonas hydrophila.
A field survey to determine the prevalence of Aeromonas hydrophila revealed a recovery rate of 8% in 141 specimens derived from a range of live, companion, and exotic avian species. The prevalence rate was similar in 240 sequential postmortem submissions during 1984. Studies on the pathogenicity of A. hydrophila showed that 2-to-4-day-old chicks and turkey poults were highly susceptible to exposure via the subcutaneous, yolk-sac, and intracerebral routes, and mortality of 80-100% occurred within 48 hours of inoculation. Ducklings aged 4 days were generally refractory to exposure.


IgE receptor-mediated depolarization of rat basophilic leukemia cells measured with the fluorescent probe bis-oxonol.
Receptor-mediated changes in plasma membrane potential were recorded in rat basophilic leukemia (RBL) cells with the potential-sensitive fluorescent indicator bis-oxonol. Depolarization of the mitochondria with metabolic inhibitors was not detected by bis-oxonol, suggesting that only potential changes across the plasma membrane were being measured. The resting membrane potential of RBL cells was largely generated by the equilibrium distribution of K+ and not through electrogenic activity of the sodium pump. Depolarization was maintained as long as IgE receptors remained aggregated. We believe that at physiologic calcium concentrations a large portion of the measured potential change may be due to calcium influx across the plasma membrane. Prevention of calcium influx by lanthanum, disruption of aggregated receptors, or prior depolarization in a high K+ saline solution completely inhibited the antigen-induced depolarization. The time course of the antigen-stimulated increase in bis-oxonol fluorescence was similar, but not identical, to the antigen-stimulated rise in cytoplasmic free ionized calcium measured with fura-2. Antigen-stimulated depolarization was inhibited by removing both calcium and sodium and could be restored by the addition of either ion. Reduction of total cellular adenosine triphosphate inhibited depolarization in response to antigen stimulation.


Intracellular calcium modulates the nuclear translocation of calsenilin.
Calsenilin, which was originally identified as a presenilin interacting protein, has since been shown to be involved in the processing of presenilin(s), the modulation of amyloid beta-peptide (Abeta) levels and apoptosis. Subsequent to its original identification, calsenilin was shown to act as a downstream regulatory element antagonist modulator (and termed DREAM), as well as to interact with and modulate A-type potassium channels (and termed KChIP3). Calsenilin is primarily a cytoplasmic protein that must translocate to the nucleus to perform its function as a transcriptional repressor. This study was designed to determine the cellular events that modulate the translocation of calsenilin from the cytoplasm to the nucleus. The nuclear translocation of calsenilin was found to be enhanced following serum deprivation. A similar effect was observed when cells were treated with pharmacological agents that directly manipulate the levels of intracellular calcium (caffeine and the calcium ionophore A23187), suggesting that the increased levels of calsenilin in the nucleus are mediated by changes in intracellular calcium. A calsenilin mutant that was incapable of binding calcium retained the ability to translocate to the nucleus. Taken together, these findings indicate that the level of intracellular calcium can modulate the nuclear translocation of calsenilin and that this process does not involve the direct binding of calcium to calsenilin.


Predictors for the 5-year risk of serious infections in patients with rheumatoid arthritis treated with anti-tumour necrosis factor therapy: a cohort study in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry.
The use of TNF inhibitors leads to an increased risk of serious infections in RA. Predicting this risk would facilitate the prevention of serious infections. The objective of this study was to identify which factors are predictive of the increased risk of serious infections in RA patients treated with TNF inhibiting therapy. Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry of 2044 patients with RA were used for the analyses. Data were censored at stopping TNF inhibitors or end of observation time up to 5 years. Univariate and multivariate analysis of baseline variables was performed using Cox regression with time to the first serious infection as dependent variable. During a follow-up time of 5 years, 128 of 2044 (6.3%) patients developed a first serious infection with a total of 141 serious infections. The incidence rate in the first year after start of TNF inhibiting therapy was 4.57 first serious infections per 100 patient-years and 2.91 per 100 patient-years over 5 years. Age, corticosteroid use, visual analogue scale (VAS) pain, HAQ, tender joint count 28 joints (TJC28) and the presence of comorbidities were significant predictors for developing a serious infection during TNF inhibiting therapy in the multivariate model. Age, corticosteroid use, VAS pain, HAQ, TJC28 and the presence of comorbidities all at baseline were significant predictors for developing a serious infection during TNF inhibiting therapy in RA patients.


Increasing detection of significant prostate cancer in younger men - ten year trends in prostate cancer risk profile in the Mid-West of Ireland.
Although PSA (prostate specific antigen) based screening for prostate cancer (PCa) is controversial, an increasing number of men are undergoing Transrectal Ultrasound Guided prostate biopsy (TRUSPB) through primary care-based PSA testing and referral to hospitals. The aim of our study was to investigate presenting risk profiles of PCa over the last decade in a cohort of men in Ireland and to examine any change in the same over this time period. The hospital patient administration system was analysed for patients who underwent TRUSPB from January 2005 to December 2015. Clinically significant PCa was defined as Gleason score of 7 or above. Complete data was available on 2391 TRUSPB patients: number of biopsies increased by 53%, median age decreased by 0.9%, median PSA decreased by 6% (p = 0.001, ANOVA) and abnormal DRE increased by 9% (p = 0.001, chi square). Overall positive biopsy was 44% and significant cancer rate was 21%. There was a significant change in trend of detection (p = 0.02) with average annual increase in significant cancer of 3%. The median age of the significant cancer cohort reduced by 1% and the PSA at diagnosis reduced by 9%. In younger men (<50 years), the rate of significant cancer detection increased by 18%. Significant PCa detection increased across all age groups but recently, a younger patient profile was diagnosed with high-grade disease. This paves the way for future research on early-onset PCa. Younger patients with significant disease would result in increasing number of patients being eligible for radical treatment with implications on health resource planning and provision.


Systemic adeno-associated virus-mediated gene therapy preserves retinal ganglion cells and visual function in DBA/2J glaucomatous mice.
A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.


Neurofibroma of the palate.
Neurofibroma is a benign peripheral nerve sheath tumor comprising variable mixture of Schwann cells, perineurial-like cells, and fibroblasts. Neurofibroma may occur as solitary lesion or as part of a generalised syndrome of neurofibromatosis or very rarely as multiple neurofibromas without any associated syndrome. There are two distinct variants of neurofibromatosis type I and type II. We present a case of neurofibroma of the hard palate associated with neurofibromatosis type I. The diagnosis of the lesion was made based on the clinical findings, family history, histopathology, and immunohistochemistry. Literature was reviewed and different types of neurofibroma, their incidence and frequency in the oral cavity, its association with neurofibromatosis, clinical manifestations, histopathologic characteristics, immunohistochemical analysis, behaviour, treatment, and recurrence are discussed.


Natural selection on synonymous sites is correlated with gene length and recombination in Drosophila.
Evolutionary analysis of codon bias in Drosophila indicates that synonymous mutations are not neutral, but rather are subject to weak selection at the translation level. Here we show that the effectiveness of natural selection on synonymous sites is strongly correlated with the rate of recombination, in accord with the nearly neutral hypothesis. This correlation, however, is apparent only in genes encoding short proteins. Long coding regions have both a lower codon bias and higher synonymous substitution rates, suggesting that they are affected less efficiently by selection. Therefore, both the length of the coding region and the recombination rate modulate codon bias. In addition, the data indicate that selection coefficients for synonymous mutations must vary by a minimum of one or two orders of magnitude. Two hypotheses are proposed to explain the relationship among the coding region length, the codon bias, and the synonymous divergence and polymorphism levels across the range of recombination rates in Drosophila. The first hypothesis is that selection coefficients on synonymous mutations are inversely related to the total length of the coding region. The second hypothesis proposes that interference among synonymous mutations reduces the efficacy of selection on these mutations. We investigated this second hypothesis by carrying out forward simulations of weakly selected mutations in model populations. These simulations show that even with realistic recombination rates, this interference, which we call the "small-scale" Hill-Robertson effect, can have a moderately strong influence on codon bias.


Elevated Strain and Structural Disarray Occur at the Right Ventricular Apex.
The right ventricular apex (RVA) is a potential hot spot for development of cardiac rhythm anomalies. Many conditions, including arrhythmogenic right ventricular cardiomyopathy and Brugada's syndrome affect the RVA, and further, the RVA remains an incompletely characterized pacing region. Whether there are structural reasons underlying these conduction properties remains unsettled. In the current study, we characterize the mechanical strains and structural attributes of the right ventricular wall, and test the hypothesis that the right ventricular apex experiences heterogeneous strain distributions and altered fiber organization, and is thus susceptible to conduction alterations. Electromechanical wave imaging (EWI), or elastography, of hearts was used to quantify mechanical strains occurring through a cardiac cycle. Histological and immunofluorescence imaging techniques were used to examine cardiac wall structure and arrangement of junctional proteins. Right ventricular mechanical strains were elevated and sustained throughout systole, compared to the left ventricle and septum. Heterogeneous strain distributions, myocardial fiber disarray, and altered junctional protein localization occured at the RVA. Disarray and altered strain distributions suggest decreased structural strength at the right ventricular apex in particular and increased mechanical impositions in the right ventricle, respectively. Thus, these data demonstrate why the right ventricular apex may be particularly vulnerable to conduction abnormalities.


Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.
The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.


Serum thyroglobulin autoantibody titres and immunoglobulin concentrations in Nigerians with goitre.
Using the tanned turkey red blood cell haemaglutination test, blood samples from 327 Nigerians with goitre were screened for the presence of thyroglobulin autoantibody. 15 (4.6%) were found to have significantly positive autoantibody titres while none of the 50 age and sex-matched normal controls and autoantibody. Of the 15 with significantly positive thyroglobulin autoantibody titres, only 2 were males, giving a male:female ratio of 1 to 6.5. The mean serum concentration of IgG in the positive cases (4,163 +/- 53.5 mg/100 ml) was significantly higher than either that of normal controls (3,044 +/- 147.6 mg/100 ml) of goiterous subjects with no thyroglobulin autoantibody (2,196 +/- 116.5mg/100ml). It was found that thyroglobulin autoantibody is an IgG immunoglobulin. It is concluded that autoimmune thyroid disease occurs in Nigerians with goitre and that females are affected more than males.


Differential proteome analysis of bone marrow mesenchymal stem cells from adolescent idiopathic scoliosis patients.
Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine. The cause and pathogenesis of scoliosis and the accompanying generalized osteopenia remain unclear despite decades of extensive research. In this study, we utilized two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS) to analyze the differential proteome of bone marrow mesenchymal stem cells (BM-MSCs) from AIS patients. In total, 41 significantly altered protein spots were detected, of which 34 spots were identified by MALDI-TOF/TOF analysis and found to represent 25 distinct gene products. Among these proteins, five related to bone growth and development, including pyruvate kinase M2, annexin A2, heat shock 27 kDa protein, γ-actin, and β-actin, were found to be dysregulated and therefore selected for further validation by Western blot analysis. At the protein level, our results supported the previous hypothesis that decreased osteogenic differentiation ability of MSCs is one of the mechanisms leading to osteopenia in AIS. In summary, we analyzed the differential BM-MSCs proteome of AIS patients for the first time, which may help to elucidate the underlying molecular mechanisms of bone loss in AIS and also increase understanding of the etiology and pathogenesis of AIS.


Field survey of Glycyrrhiza plants in Central Asia (3). Chemical characterization of G. glabra collected in Uzbekistan.
The chemical characteristics of Glycyrrhiza glabra L. were investigated at a habitat in Uzbekistan. HPLC analysis of the underground parts indicated that glycyrrhizin contents varied from 3.3 to 6.1% of dry weight, and that glabridin, a species-specific flavonoid for G. glabra, was detected in all underground samples (0.08-0.35% of dry weight). HPLC analysis of the leaves indicated that G. glabra plants collected in the present study could be divided into two types, RT-type and IQ-type, according to their major flavonol glycosides, rutin or isoquercitrin, respectively.


Butyrate Decreases ICAM-1 Expression in Human Oral Squamous Cell Carcinoma Cells.
Short-chain fatty acids (SCFA) are bacterial metabolites that can be found in periodontal pockets. The expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) within the epithelium pocket is considered to be a key event for the selective transmigration of leucocytes towards the gingival sulcus. However, the impact of SCFA on ICAM-1 expression by oral epithelial cells remains unclear. We therefore exposed the oral squamous carcinoma cell line HSC-2, primary oral epithelial cells and human gingival fibroblasts to SCFA, namely acetate, propionate and butyrate, and stimulated with known inducers of ICAM-1 such as interleukin-1-beta (IL1β) and tumor necrosis factor-alfa (TNFα). We report here that butyrate but not acetate or propionate significantly suppressed the cytokine-induced ICAM-1 expression in HSC-2 epithelial cells and primary epithelial cells. The G-protein coupled receptor-43 (GPR43/ FFAR2) agonist but not the histone deacetylase inhibitor, trichostatin A, mimicked the butyrate effects. Butyrate also attenuated the nuclear translocation of p65 into the nucleus on HSC-2 cells. The decrease of ICAM-1 was independent of Nrf2/HO-1 signaling and phosphorylation of JNK and p38. Nevertheless, butyrate could not reverse an ongoing cytokine-induced ICAM-1 expression in HSC-2 cells. Overall, these observations suggest that butyrate can attenuate cytokine-induced ICAM-1 expression in cells with epithelial origin.


Chronic ethanol consumption induces global hepatic protein hyperacetylation.
Although the clinical manifestations of alcoholic liver disease are well described, little is known about the molecular basis for liver injury. Recent studies have indicated that chronic alcohol consumption leads to the lysine-hyperacetylation of several hepatic proteins, and this list is growing quickly. To identify other hyperacetylated proteins in ethanol-fed livers, we chose a proteomics approach. Cytosolic and membrane proteins (excluding nuclei) were separated on 2D gels, transferred to PVDF and immunoblotted with antibodies specific for acetylated lysine residues. Hyperacetylated proteins were selected for trypsin digestion and mass spectrometric analysis. In all, 40 proteins were identified, 11 of which are known acetylated proteins. Remarkably, the vast majority of hyperacetylated membrane proteins were mitochondrial residents. Hyperacetylated cytosolic proteins ranged in function from metabolism to cytoskeletal support. Notably, 3 key anti-oxidant proteins were identified whose activities are impaired in ethanol-treated cells. We confirmed that the anti-oxidant enzyme, glutathione peroxidase 1, actin and cortactin are hyperacetylated in ethanol-treated livers. Alcohol-induced hyperacetylation of multiple proteins may contribute to the development of liver injury. The abundance of acetylated mitochondrial proteins further suggests that this modification is important in regulating liver metabolism and when perturbed, may contribute to the progression of a variety of metabolic diseases.


Interdisciplinary perspectives on privacy awareness in lifelogging technology development.
Population aging resulting from demographic changes requires some challenging decisions and necessary steps to be taken by different stakeholders to manage current and future demand for assistance and support. The consequences of population aging can be mitigated to some extent by assisting technologies that can support the autonomous living of older individuals and persons in need of care in their private environments as long as possible. A variety of technical solutions are already available on the market, but privacy protection is a serious, often neglected, issue when using such (assisting) technology. Thus, privacy needs to be thoroughly taken under consideration in this context. In a three-year project PAAL ('Privacy-Aware and Acceptable Lifelogging Services for Older and Frail People'), researchers from different disciplines, such as law, rehabilitation, human-computer interaction, and computer science, investigated the phenomenon of privacy when using assistive lifelogging technologies. In concrete terms, the concept of Privacy by Design was realized using two exemplary lifelogging applications in private and professional environments. A user-centered empirical approach was applied to the lifelogging technologies, investigating the perceptions and attitudes of (older) users with different health-related and biographical profiles. The knowledge gained through the interdisciplinary collaboration can improve the implementation and optimization of assistive applications. In this paper, partners of the PAAL project present insights gained from their cross-national, interdisciplinary work regarding privacy-aware and acceptable lifelogging technologies.


A nationwide study of molecular epidemiology and antimicrobial susceptibility of Clostridioides difficile in South Korea.
The molecular epidemiology and antimicrobial resistance of Clostridioides difficile were studied in South Korea in 2017 as part of a National Surveillance System. From February to May 2017, all non-duplicate isolates of C. difficile were recovered from patients who were suspected to have C. difficile infection and collected from 6 referral hospitals representing the 6 regions in South Korea. We performed PCRs for the toxin gene, PCR ribotyping, multilocus sequence typing (MLST), antimicrobial susceptibility testing by agar dilution according to the recommendations of the CLSI and detection of antimicrobial resistance genes such as ermB, catD, tetM, vanZ and nimR by PCR. Of 331 C. difficile isolates, 257 (77.6%) were toxigenic and the prevalence of strains producing binary toxin (CDT) was 5.1% (13/257). A total of 52 different ribotype (RT) patterns were found. RT018 was the most common (25.1% of all isolates), and RT014/020, RT002 and RT012 were also common. RT010 was most common non-toxigenic strain. MLST analysis of randomly selected 72 C. difficile isolates identified 46 sequence types (STs), of which three were new and not in the PubMLST library. There was a good correlation between MLST and RT as following: ST1 (RT027), ST8 (RT002), ST11 (RT078), ST17 (RT018), ST35 (RT046), ST37 (RT017), ST42 (RT106), ST53 (RT103), ST81 (RT369), and ST99 (RT070). All toxigenic isolates were susceptible to metronidazole and vancomycin (MIC ≤ 2 mg/L). For rifaximin, 24% of toxigenic isolates were resistant. Of randomly selected 106 toxigenic isolates, resistance rates for ampicillin, cefotetan, clindamycin, imipenem, chloramphenicol, tetracycline, and moxifloxacin were 48%, 46%, 64%, 54%, 0%, 6% and 52% respectively and frequencies of various resistance genes were 62.3% for ermB, 0.9% catD and 10.4% tetM. RTs018, 002, 017 and 369 showed high MICs to various antimicrobial agents and multi-drug resistance was common also.


The constitutive expression of galectin-3 is downregulated in the intestinal epithelia of Crohn's disease patients, and tumour necrosis factor alpha decreases the level of galectin-3-specific mRNA in HCT-8 cells.
Galectin-3, a lectin with specificity for beta galactoside, is expressed by a variety of cells, including intestinal epithelial cells. Among other functions, galectin-3 mediates cell adhesion and is involved in inflammatory processes. In this study, we assessed the expression of galectin-3 in intestinal epithelial cells from Crohn's disease patients (n = 10), ileum adjacent to resected colon carcinoma (n = 9), unspecific bowel inflammation (n = 1), diverticulosis (n = 1), ulcerative colitis (n = 3) and healthy jejunum used for interposition in larynx carcinoma (n = 1). The role of cytokines on galectin-3 expression was a further aim of our study. The galectin-3 distribution in intestinal epithelia was analysed by immunohistochemistry, immunoblotting, immunofluorescence and reverse transcriptase polymerase chain reaction (RT-PCR). Human intestinal epithelial cell line (HCT-8) and primary cultured intestinal epithelial cells were treated with cytokines, and the effects on galectin-3 expression were determined by RT-PCR. Galectin-3 showed a homogeneous distribution in epithelia from control patients. In contrast, in epithelial cells from Crohn's disease lesions, galectin-3 staining was strongly spotted and heterogeneous. In inflamed and reorganized tissue, galectin-3 expression was markedly reduced, and was associated with disintegration of epithelia. Primary cultured epithelial cells as well as HCT-8 cells expressed galectin-3 protein and mRNA. Incubation of HCT-8 cells with tumour necrosis factor alpha (TNF-alpha), but not with other cytokines, substantially reduced galectin-3 expression as shown by semiquantitative RT-PCR. Downregulation of galectin-3 in the intestinal epithelium of Crohn's disease patients may be a consequence of enhanced TNF-alpha production by inflammatory cells, thereby contributing to the pathophysiology of the disease.


Circulatory impairment induced by exercise in the lizard Iguana iguana.
Mechanical integration of the cardiac, muscular and ventilatory pumps enables mammals to vary cardiac output over a wide range to match metabolic demands. We have found this integration lacking in a lizard (Iguana iguana) that differs from mammals because blood flow from the caudal body and ventilation are maximal after, rather than during, exercise. Because Iguana iguana are constrained from ventilation during intense locomotion, they appear to be unable to recruit the abdomen and thorax as a pump for venous return. This constraint on simultaneous running and costal breathing arises from their musculoskeletal design, which is similar to that of basal tetrapods, and so a constraint on venous return during exercise may be ancestral for tetrapods. We suggest that mechanical coupling of the pulmonary and cardiac pumps may have been important for the evolution of high-speed locomotor stamina in terrestrial vertebrates.


Extraction of strategically important elements from brines: Constraints and opportunities.
Strategically important elements are those that are vital to advanced manufacturing, low carbon technologies and other growing industries. Ongoing depletion and supply risks to these elements are a critical concern, and thus, recovery of these elements from low-grade ores and brines has generated significant interest worldwide. Among the strategically important elements, this paper focuses on rare earth elements (REEs), the platinum-group metals and lithium due to their wide application in the advanced industrial economics. We critically review the current methods such as precipitation, ion exchange and solvent extraction for extracting these elements from low-grade ores and brines and provide insight into the technical challenges to the practical realisation of metal extraction from these low-grade sources. The challenges include the low concentration of the target elements in brines and inadequate selectivity of the existing methods. This review also critically analyzes the potential applicability of an integrated clean water production and metal extraction process based on conventional pressure-driven membrane and emerging membrane technologies (e.g., membrane distillation). Such a process can first enrich the strategically important elements in solution for their subsequent recovery along with clean water production.


Emergency Organization of Child Psychiatric Care Following the Terrorist Attack on July 14, 2016, in Nice, France.
In the actual context of terrorism targeting children and families, it seems essential to describe different experiences of pediatric psychological emergency devices after such unexpected mass trauma. Here we testify our experience of the psychological emergency care setup dedicated to children and families during the first 48 hours after the terrorist attack of Nice, France, on July 14, 2016. Activated within the hour following the attack, the device included two child psychiatry teams turning over each day, receiving at least 163 individuals (99 children and 64 adults) within the first 2 days. (Disaster Med Public Health Preparedness. 2019;13:144-146).


Management and control of varicella on cruise ships: a collaborative approach to promoting public health.
In most years varicella is the vaccine-preventable disease most frequently reported to Centers for Disease Control and Prevention (CDC) by cruise ships. Since 2005, CDC has received numerous isolated case reports of varicella among crew members and has investigated varicella outbreaks aboard vessels sailing into and from US seaports. CDC investigators reviewed electronic varicella case reports from 2005 to 2009 and outbreak reports from 2009 to characterize the response and control efforts implemented by cruise ships in accordance with CDC protocols. Outbreak reports from 2009 were manually reviewed for details of case identification, contact investigations, isolation and restriction of cases and contacts, respectively, and number of contacts administered varicella vaccine post-exposure by cruise lines. During 2005 to 2009, cruise ships reported 278 cases of varicella to CDC among predominantly male (80%) crew members, three-quarters of whom were residents of Caribbean countries, Indonesia, the Philippines, or India, and whose median age was 29 years. Cases were more commonly reported during spring and winter months. During 2009, cruise ships reported 94 varicella cases among crew members of which 66 (70%) were associated with 18 reported varicella outbreaks. Outbreak response included isolation of 66 (100%) of 66 cases, restriction of 66 (26%) of 255 crew-contacts, and administration of post-exposure vaccine to 522 close contacts and other susceptible crew members per standard CDC recommendations. Most cases reported to CDC during 2005 to 2009 were among non-US resident crew members. Overall, cruise lines sailing into North America have the onboard capability to manage varicella cases and outbreaks and appear responsive to CDC recommendations. Cruise lines should continue to implement CDC-recommended response protocols to curtail outbreaks rapidly and should consider whether pre-placement varicella immunity screening and vaccination of crew members is a cost-effective option for their respective fleet operations.


The feasibility and construct validity of graduate and supervisor surveys in a pulmonary fellowship training program.
The purpose of this study was to determine the feasibility and construct validity of our graduate and employer survey and its potential use in programmatic evaluation. An identical survey instrument was sent to fellowship graduates from our institution and their employers. We estimated feasibility through determining our survey response rate. Construct validity was assessed by comparing graduate self-ratings and employer ratings and through comparing survey ratings with passing board-certification examinations and referrals to the National Practitioner Databank. Eleven years of graduates were included (n = 38 graduates). Response rates were 84% and 82% for graduates and their employers, respectively. Mean supervisor ratings were greater than graduate self-ratings on all questions. The lowest rating consistently across survey years was in graduates' self-perception of their ability to direct a PFT lab. One fellow failed his pulmonary boards and 1 failed his critical care boards on the first attempt. No graduates were referred to the National Practitioner Databank during our study period. This fellowship survey appears to be feasible and have construct validity. The consistency in the relatively low self-rating of graduates in directing a PFT lab has led to important areas for curriculum reform.


Interactive effects of central leptin and peripheral fuel oxidation on estrous cyclicity.
A 48-h period of fasting inhibits estrous cycles in Syrian hamsters, and fasting-induced anestrus can be prevented by intracerebroventricular treatment with leptin during the fasting period. In the present experiment, the effects of intracerebroventricular leptin were blocked by systemic treatment with inhibitors of metabolic fuel oxidation. Leptin was infused continuously into the lateral ventricles (1 microgram/day) during fasting on days 1 and 2 of the estrous cycle. Intraperitoneal injection of 2-deoxy-D-glucose (2DG) was used to block both central and peripheral glucose oxidation, and intragastric treatment with methyl palmoxirate (MP) was used to inhibit peripheral long-chain fatty acid oxidation during the fasting and leptin-treatment period. 2DG or MP were administered at doses that did not induce anestrus in ad libitum-fed hamsters. Despite elevated central levels of leptin, fasting-induced anestrus occurred in hamsters treated with either 2DG or MP. Thus an elevated intracerebroventricular leptin concentration is not a sufficient condition for normal estrous cycles when fuel oxidation is inhibited. These results raise the possibility that central leptin influences reproduction by indirect effects on peripheral fuel metabolism.


A review of issues of nomenclature and taxonomy of Hypericum perforatum L. and Kew's Medicinal Plant Names Services.
To review which names are used to refer to Hypericum perforatum L. in health regulation and medicinal plant references, and the potential for ambiguity or imprecision. Structured searches of Kew's Medicinal Plant Names Services Resource, supplemented with other online bibliographic resources, found that the scientific name Hypericum perforatum L. is used consistently in the literature, but variation between subspecies is rarely considered by researchers. Research is still published using only the common name 'St John's wort' despite it being imprecise; at least 80 other common names are also used for this plant in multiple languages. Ambiguous and alternative plant names can lead to ineffective regulation, misinterpretation of literature, substitution of raw material or the failure to locate all published research. Kew's Medicinal Plant Names Services (MPNS) maps all names used for each plant in medicinal plant references onto current taxonomy, thereby providing for disambiguation and comprehensive access to the regulations and references that cite that plant, regardless of the name used. MPNS also supplies the controlled vocabulary for plant names now required for compliance with a new standard (Identification of Medicinal Products, IDMP) adopted by medicines regulators worldwide.


Induction of cystine transport and other stress proteins by disulfiram: effects on glutathione levels in cultured cells.
Disulfiram (Antabuse) (DSF) has been reported to protect rats and other animals from the effects of hyperbaric hyperoxia at 4 to 6 ATA (atmospheres). In contrast, DSF and diethyldithiocarbamate (DDC), its metabolite, accelerate the toxic effects in rats of 100% oxygen at 1 to 2 ATA. We have examined the effects of DSF and DDC on glutathione (GSH) levels in bovine pulmonary artery endothelial cells and Chinese hamster ovary cells. Increases in intracellular GSH occurred 8 to 24 h after addition of DSF to the culture media. These increases in intracellular GSH were associated with increases in the rate of uptake of cystine into the cells. DDC was a less effective inducer of cystine uptake and increased intracellular GSH levels than was DSF. At the concentrations used, neither DDC nor DSF caused significant decreases in intracellular superoxide dismutase levels. Exogenous sulfhydryl compounds including GSH and cysteine partially blocked the induction of cystine transport by DSF or DDC, suggesting that the induction might be mediated through a sulfhydryl reaction between DSF and some cellular components. The increases in GSH in the cultured cells were not significant by 4 h of exposure. In contrast, other stress proteins including heme oxygenase are induced by 2 to 4 h after DSF addition. In previously reported in vivo studies, DSF treatment protected against hyperbaric oxygen damage after as little as 1 to 4 h pre-exposure. This suggests that effects of DSF exposure other than GSH augmentation may be responsible for the protective effects seen in vivo.


Evaluation of fluticasone (flixonase) nasal spray versus beclomethasone (beconase) nasal spray in the treatment of allergic rhinitis.
Although response to intranasal steroid therapy has been reported in patients with allergic rhinitis, efficacy of some nasal steroids is noteworthy.This study was undertaken to evaluate the efficacy of a two-week course of Fluticasone (Flixonase) nasal spray vs. Beclomethasone (beconase) nasal spray in patients with symptoms of allergic rhinitis referred to our clinic. This study reviewed sixty randomized studies with symptoms of allergic rhinitis which supported common aeroallergens with skin prick test. Patients received a total daily dose of nasal spray of Fluticasone (Flixonase) 100 mcg bid (N=30) compared with patients with allergic rhinitis who received a total daily dose of Beclomethasone (Beconase) 50mcg 2 puffs bid (N=30). Patients were visited before and after therapy, and efficacy of Flixonase and Beconase was evaluated by the change in nasal symptoms including: nasal discharge, nasal obstruction, nasal itching, and sneezing. After two weeks of treatment nasal symptoms of blockage, discharge, sneezing and itching were significantly better in the group treated with Fluticasone nasal spray (65%, 82%, 67%, 79% respectively (p<0.001) but after treatment with beconase nasal spray lower benefits in the nasal symptoms includes: 50%, 71%, 51%, 57% respectively. After two weeks of treatment no deleterious changes consequent to therapy were observed in nasal symptoms. 100 mcg bid Flixonase (Fluticasone) intranasal spray is more effective than 50 mcg 2 puffs bid Beconase (Beclomethasone) intranasal spray. Like asthma, allergic rhinitis is an inflammatory disease and should be managed with anti-inflammatory medication.


Pea and Broad Bean Pods as a Natural Source of Dietary Fiber: The Impact on Texture and Sensory Properties of Cake.
Attention has focused on bakery products such as cake which is one of the most common bakery products consumed by people in the world. Legume by-products, pea pods (PPs) (Pisum sativum L.) and broad bean pods (BBPs) (Vicia faba L.) mediterranean (Tunisian), has been studied for its high dietary fiber content (PP: 43.87 g/100 g; BBP: 53.01 g/100 g). Protein content was also a considerable component for both by-products. We investigated the effect of substituted of 5%, 10%, 15%, 20%, 25%, and 30% of PP and BBP flours on the sensory and technological properties in cake. Cakes hardness increased whereas L* and a* color values decreased. The overall acceptability rate showed that a maximum of 15% of PP and BBP flours can be added to prepare acceptable quality cakes.


Opioids: the role in headache pharmacotherapy.
Optimal acute opioid management involves a continual awareness of the potential for development of MOH. Both the clinician and patient should be aware of the IHS MOH diagnostic criteria. Prophylactic medications should be initiated for patients having two headache days per week. Reduction in headache risk factors should include behavioral modification approaches to headache control earlier in the natural history of migraine. DSO therapy may provide significant long-term relief to a small percentage of patients suffering from intractable chronic daily headaches. A one-month DSO trial may provide a fair indication whether long-term DSO will be of benefit in the otherwise intractable cases.


The World (of Warcraft) through the eyes of an expert.
Negative correlations between pupil size and the tendency to look at salient locations were found in recent studies (e.g., Mathôt et al., 2015). It is hypothesized that this negative correlation might be explained by the mental effort put by participants in the task that leads in return to pupil dilation. Here we present an exploratory study on the effect of expertise on eye-movement behavior. Because there is no available standard tool to evaluate WoW players' expertise, we built an off-game questionnaire testing players' knowledge about WoW and acquired skills through completed raids, highest rated battlegrounds, Skill Points, etc. Experts (N = 4) and novices (N = 4) in the massively multiplayer online role-playing game World of Warcraft (WoW) viewed 24 designed video segments from the game that differ in regards with their content (i.e, informative locations) and visual complexity (i.e, salient locations). Consistent with previous studies, we found a negative correlation between pupil size and the tendency to look at salient locations (experts, r = - .17, p < .0001, and novices, r = - .09, p < .0001). This correlation has been interpreted in terms of mental effort: People are inherently biased to look at salient locations (sharp corners, bright lights, etc.), but are able (i.e., experts) to overcome this bias if they invest sufficient mental effort. Crucially, we observed that this correlation was stronger for expert WoW players than novice players (Z = - 3.3, p = .0011). This suggests that experts learned to improve control over eye-movement behavior by guiding their eyes towards informative, but potentially low-salient areas of the screen. These findings may contribute to our understanding of what makes an expert an expert.


Spheres growing on a sphere: a model to predict the morphology yields of colloidal molecules obtained through a heterogeneous nucleation route.
Through the heterogeneous nucleation of polymer nodules on a surface-modified silica particle, the high-yield achievement of hybrid colloidal molecules with a well-controlled multipod-like morphology was recently demonstrated. However, as the formation mechanism of these colloidal molecules has not been completely understood yet, some opportunities remain to reduce the tedious empirical process needed to optimize the chemical recipes. In this work, we propose a model to help understand the formation mechanism of almost pure suspensions of well-defined colloidal molecules. The outcomes of the model allow proposing probable nucleation growth scenario able to explain the experimental results. Such a model should make easier the determination of the optimal recipe parameters for a targeted morphology. The reasonably good agreements between the model and the experimental results show that the most important processes have been captured. It is thus a first step toward the rational design of large quantities of chemically prepared colloidal molecules.


Radiocontrast-induced acute renal failure.
The intravascular administration of iodinated radiocontrast media can lead to acute renal dysfunction. Even small changes in renal function have been associated with increased morbidity and mortality, making the prevention of radiocontrast nephropathy of paramount importance. This review summarizes the principal risk factors for radiocontrast nephropathy and evidence-based preventive strategies that should be used to limit its occurrence. Risk factors for radiocontrast nephropathy include preexistent kidney disease, diabetes mellitus, dose of radiocontrast used, advanced congestive heart failure, and intravascular volume depletion. Proven preventive measures include volume expansion with intravenous saline or sodium bicarbonate and the use of low-osmolar or iso-osmolar radiocontrast media. Studies evaluating N-acetylcysteine have been conflicting, with meta-analyses suggesting a small beneficial effect. Studies of other pharmacologic agents have not demonstrated clinical benefit.


Rich topologies of monolayer ices via unconventional electrowetting.
Accurate manipulation of a substance on the nanoscale and ultimately down to the level of a single atom or molecule is an ongoing subject of frontier research. Herein, we show that topologies of water monolayers on substrates, in the complete wetting condition, can be manipulated into rich forms of ordered structures via electrowetting. Notably, two new topologies of monolayer ices were identified from our molecular dynamics simulations: one stable below room temperature and the other one having the ability to be stable at room temperature. Moreover, the wettability of the substrate can be tuned from superhydrophobic to superhydrophilic by uniformly changing the charge of each atomic site of the dipole or quadrupole distributed in an orderly manner on the model substrate. At a certain threshold value of the atomic charge, water droplets on the substrate can spread out spontaneously, achieving a complete electrowetting. Importantly, unlike the conventional electrowetting, which involves application of a uniform external electric field, we proposed non-conventional electrowetting, for the first time, by invoking the electric field of dipoles and quadrupoles embedded in the substrate. Moreover, different topologies of water monolayers can be achieved by using the non-conventional electrowetting. A major advantage of the non-conventional electrowetting is that the contact-angle saturation, a long-standing and known limitation in the field of electrowetting, can be overcome by tuning uniformly the lattice atomic charge at the surface, thereby offering a new way to mitigate the contact-angle saturation for various electrowetting applications.


Modifiable risk factors for subsequent lethal prostate cancer among men with an initially negative prostate biopsy.
Previously suggested modifiable risk factors for prostate cancer could have resulted from detection bias because diagnosis requires a biopsy. We investigated modifiable risk factors for a subsequent cancer diagnosis among men with an initially negative prostate biopsy. In total, 10,396 participants of the Health Professionals Follow-up Study with an initial negative prostate biopsy after 1994 were followed for incident prostate cancer until 2017. Potential risk factors were based on previous studies in the general population. Outcomes included localised, advanced, and lethal prostate cancer. With 1851 prostate cancer cases (168 lethal) diagnosed over 23 years of follow-up, the 20-year risk of any prostate cancer diagnosis was 18.5% (95% CI: 17.7-19.3). Higher BMI and lower alcohol intake tended to be associated with lower rates of localised disease. Coffee, lycopene intake and statin use tended to be associated with lower rates of lethal prostate cancer. Results for other risk factors were less precise but compatible with and of similar direction as for men in the overall cohort. Risk factors for future prostate cancer among men with a negative biopsy were generally consistent with those for the general population, supporting their validity given reduced detection bias, and could be actionable, if confirmed.


Direct interaction of garcinol and related polyisoprenylated benzophenones of Garcinia cambogia fruits with the transcription factor STAT-1 as a likely mechanism of their inhibitory effect on cytokine signaling pathways.
Garcinol (1), a polyisoprenylated benzophenone occurring in Garcinia species, has been reported to exert anti-inflammatory activity in LPS-stimulated macrophages, through inhibition of NF-κB and/or JAK/STAT-1 activation. In order to provide deeper insight into its effects on the cytokine signaling pathway and to clarify the underlying molecular mechanisms, 1 was isolated from the fruits of Garcinia cambogia along with two other polyisoprenylated benzophenones, guttiferones K (2) and guttiferone M (3), differing from each other in their isoprenyl moieties and their positions on the benzophenone core. The affinities of 1-3 for the STAT-1 protein have been evaluated by surface plasmon resonance and molecular docking studies and resulted in KD values in the micromolar range. Consistent with the observed high affinity toward the STAT-1 protein, garcinol and guttiferones K and M were able to modulate cytokine signaling in different cultured cell lines, mainly by inhibiting STAT-1 nuclear transfer and DNA binding, as assessed by an electrophorectic mobility shift assay.


Collaborative mentoring for effective medical research groups.
This article was migrated. The article was marked as recommended. Research benefits professors and students, mentors and mentees, however, many Universities lack formal programs, especially in basic sciences such as anatomy. Faculty, many times, lack the time, resources, and a well-structured program. Mentoring and collaborative work, have played an important role in creating an effective environment that inspires its members into scientific production, enhances research skills, while gaining experience. The authors presented a student anatomy research group (Grupo de Investigación en Anatomía [GIA]) model that integrates faculty from basic and clinical fields through a collaborative mentoring and tightly organized structure that increases training, experience, and scientific output. The transformation stages described shows the progress, reporting the fundamental elements for integration of the model, with results presented at 16 years of experience of the group in the Anatomy department. Results evidence a steady increase in student/professor involvement, scientific publishing, presentations in meetings (national/international), and cites.


Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial.
Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa compared with placebo or entacapone in patients with Parkinson's disease and motor fluctuations. We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinson's disease with end-of-dose motor fluctuations. Patients aged 30-83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14-15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov, NCT01568073. Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was -56·0 min (SE 13·4; 95% CI -82·3 to -29·7) for placebo, -96·3 min (13·4; -122·6 to -70·0) for entacapone, -91·3 min (13·5; -117·7 to -64·8) for opicapone 5 mg, -85·9 min (13·7; -112·8 to -59·1) for opicapone 25 mg, and -116·8 min (14·0; -144·2 to -89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline -60·8 min, 95% CI -97·2 to -24·4; p=0·0015) and non-inferior to entacapone (-26·2 min, -63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group. The addition of opicapone 50 mg to levodopa treatment in patients with Parkinson's disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit. BIAL.


Assessment of the Role of Endothelial and Vascular Smooth Muscle EGFR for Acute Blood Pressure Effects of Angiotensin II and Adrenergic Stimulation in Obese Mice.
(1) Background: Obesity is associated with hypertension because of endocrine dysregulation of the adrenergic and the renin-angiotensin-aldosterone systems. The epidermal growth factor receptor (EGFR) is an important signaling hub in the cardiovascular system. In this study, we investigate the role of smooth muscle cell (VSMC) and endothelial cell (EC) EGFRs for blood pressure homeostasis and acute vascular reactivity in vivo. (2) Methods: Mice with deletion of the EGFR in the respective cell type received either a high-fat (HFD) or standard-fat diet (SFD) for 18 weeks. Intravascular blood pressure was measured via a Millar catheter in anesthetized animals upon vehicle load, angiotensin II (AII) and phenylephrine (PE) stimulation. (3) Results: We confirmed that deletion of the EGFR in VSMCs leads to reduced blood pressure and a most probably compensatory heart rate increase. EC-EGFR and VSMC-EGFR had only a minor impact on volume-load-induced blood pressure changes in lean as well as in obese wild-type animals. Regarding vasoactive substances, EC-EGFR seems to have no importance for angiotensin II action and counteracting HFD-induced prolonged blood pressure increase upon PE stimulation. VSMC-EGFR supports the blood pressure response to adrenergic and angiotensin II stimulation in lean animals. The responsiveness to AII and alpha-adrenergic stimulation was similar in lean and obese animals despite the known enhanced activity of the RAAS and the sympathetic nervous system under a high-fat diet. (4) Conclusions: We demonstrate that EGFRs in VSMCs and to a lesser extent in ECs modulate short-term vascular reactivity to AII, catecholamines and volume load in lean and obese animals.


Comparison of budesonide Turbuhaler with budesonide aqua in the treatment of seasonal allergic rhinitis. Rhinocort Study Group.
To compare the effect of budesonide Turbuhaler 400 microg/day with budesonide aqua 256 microg/day in the treatment of seasonal allergic rhinitis (SAR). Secondarily to ascertain patients' preferences for the two nasal devices and to assess quality of life. Randomized, multicentre, double-blind, double- dummy, parallel groups study. Private practices and hospital clinics in Ontario, Quebec and Manitoba. Two hundred and eighty-four out-patients with SAR, who were symptomatic during the ragweed season, volunteered for enrolment (243 randomized). Mean daily nasal symptom scores were significantly reduced with treatment. There were no statistically significant changes from baseline for eye symptoms. Most patients (more than 80%) achieved substantial control of their symptoms with budesonide. The most common nasal and non-nasal adverse events for both groups were epistaxis and headache. Turbuhaler was easier to use and more convenient to carry, had less of an unpleasant taste, and caused less nasal irritation than the aqua spray. More than twice as many patients preferred Turbuhaler to the aqua spray (69% versus 31%). Improvement in quality of life from baseline to clinic visits was statistically significant in both groups. Once daily use of 256 mg of budesonide aqua and 400 mg of budesonide Turbuhaler are equally safe and efficacious in the treatment of SAR. Patients preferred the budesonide powder formulation delivered via Turbuhaler two to one over the aqua formulation.


Attentional prioritization reconfigures novel instructions into action-oriented task sets.
An astonishing aspect of human cognitive flexibility concerns the ability to efficiently convert complex symbolic instructions into novel behaviors. In such ability, the rapid transformation of relevant content into action plans is particularly crucial as it allows for reflexive, automatic-like execution of merely instructed task sets. However, little is known about the mechanisms that give rise to this transformation. In the current study, we test the hypothesis that novel instructions held in working memory are reformatted into action-oriented representations when selective attention prioritizes their content. To do so, we devised a paradigm in which participants first encoded 4 S-R mappings and later, a retro-cue selected two of them. We first found that participants can benefit from retro-cues during the implementation of novel task-sets. Then, across two preregistered experiments, we observed that cued mappings (but not uncued ones) induced intention-based reflexivity, suggesting that only these entered an action-oriented state. Altogether, our results reveal that selective attention prioritizes relevant novel instructed content, playing an important role in its prospective reformatting into an action-bound task set.


Genome-wide association mapping for seedling and adult plant resistance to stripe rust in synthetic hexaploid wheat.
Use of genetic diversity from related wild and domesticated species has made a significant contribution to improving wheat productivity. Synthetic hexaploid wheats (SHWs) exhibit natural genetic variation for resistance and/or tolerance to biotic and abiotic stresses. Stripe rust caused by (Puccinia striiformis f. sp. tritici; Pst), is an important disease of wheat worldwide. To characterise loci conferring resistance to stripe rust in SHWs, we conducted a genome-wide association study (GWAS) with a panel of 181 SHWs using the wheat 9 K SNP iSelect array. The SHWs were evaluated for their response to the prevailing races of Pst at the seedling and adult plant stages, the latter in replicated field trials at two sites in Ethiopia in 2011. About 28% of the SHWs exhibited immunity at the seedling stage while 56% and 83% were resistant to Pst at the adult plant stage at Meraro and Arsi Robe, respectively. A total of 27 SNPs in nine genomic regions (1 BS, 2 AS, 2 BL, 3 BL, 3 DL, 5A, 5 BL, 6DS and 7A) were linked with resistance to Pst at the seedling stage, while 38 SNPs on 18 genomic regions were associated with resistance at the adult plant stage. Six genomic regions were commonly detected at both locations using a mixed linear model corrected for population structure, kinship relatedness and adjusted for false discovery rate (FDR). The loci on chromosome regions 1 AS, 3 DL, 6 DS and 7 AL appeared to be novel QTL; our results confirm that resynthesized wheat involving its progenitor species is a rich source of new stripe (yellow) rust resistance that may be useful in choosing SHWs and incorporating diverse yellow rust (YR) resistance loci into locally adapted wheat cultivars.


Disinfection efficacy of green synthesized gold nanoparticles for medical disinfection applications.
In recent times, biosyntheses of metal nanoparticles were used for several life rescue applications. In this study, Dillenia indica leaf aqueous extract was utilized for the synthesis of gold nanoparticles. To test anti-microbial properties of biologically fabricated gold nanoparticles. Gold nanoparticles were efficiently prepared by making use of aqueous leaf extract of Dillenia indica. The excitation of formed AuNPs was confirmed using UV-Vis spectrophotometer. In particular, absorption spectra of AuNPs exhibited a well-defined SPR band centered at around 530 nm. The high-resolution Scanning Electron Microscope (SEM) results of the obtained AuNPs confirmed the formation of particles with a size range of 5-50 nm. The ultra-high resolution TEM (UHRTEM) images displayed clear lattice fringes on the particle surfaces. Single crystalline nature of the biosynthesized AuNPs was represented by means of selected-area electron diffraction pattern. The antibacterial activity of AuNPs revealed significant activity towards both gram negative and gram positive bacteria signifying their potential disinfection related applications in medicine and biology.


Evaluation of taeniasis prevalence in the area supervised by the Provincial Sanitary-Epidemiological Unit in Szczecin between 1994 and 1998.
The aim of the study was to investigate the prevalence of taeniasis in population supervised by the Provincial Sanitary-Epidemiological Unit in Szczecin between 1994 and 1998. The prevalence of intestinal taeniasis in population of Szczecin Province was evaluated basing on data from the selection charts available in the Provincial and Field Sanitary-Epidemiological Units between 1994 and 1998. The following parameters were analyzed: environment (urban, rural), sex and age groups of patients. Basing on these data the prevalence of taeniasis per 100,000 of citizens was calculated. The study presents also the prevalence of taeniasis according to the species. In the studied period 337 cases of infestation of tapeworms were registered. The incidence of taeniasis in the consecutive years tended to be decreasing. The incidence of taeniasis decreased from 10.33 cases per 100.000 of population in 1994 to 3.52/100.000 in 1998. The incidence rate was higher in urban residents than in rural residents. In the whole analyzed period 82% of cases were noted in patients aged 20-59; however, the highest incidence of taeniasis (30%) was observed in patients aged 40-49 years. Taenia saginata turned out to be the prevalent species. The percentage of unclassified taeniasis (Taenia species) was only 3.3% in the analyzed period of time. It is necessary to improve the accessibility of efficient health care units in the rural environment to make the evaluation of incidence of taeniasis reliable. Taeniasis, despite its lower prevalence in the consecutive years, is still an epidemiological problem. Better access to effective health care institutions in the rural area is extremely important for reliable evaluation of prevalence of tapeworm infestation.


Air travel-related outbreak of multiple SARS-CoV-2 variants.
A large cluster of 59 cases were linked to a single flight with 146 passengers from New Delhi to Hong Kong in April 2021. This outbreak coincided with early reports of exponential pandemic growth in New Delhi, which reached a peak of > 400 000 newly confirmed cases on 7 May 2021. Epidemiological information including date of symptom onset, date of positive-sample detection and travel and contact history for individual cases from this flight were collected. Whole genome sequencing was performed, and sequences were classified based on the dynamic Pango nomenclature system. Maximum-likelihood phylogenetic analysis compared sequences from this flight alongside other cases imported from India to Hong Kong on 26 flights between June 2020 and April 2021, as well as sequences from India or associated with India-related travel from February to April 2021 and 1217 reference sequences. Sequence analysis identified six lineages of SARS-CoV-2 belonging to two variants of concern (Alpha and Delta) and one variant of public health interest (Kappa) involved in this outbreak. Phylogenetic analysis confirmed at least three independent sub-lineages of Alpha with limited onward transmission, a superspreading event comprising 37 cases of Kappa and transmission of Delta to only one passenger. Additional analysis of another 26 flights from India to Hong Kong confirmed widespread circulation of all three variants in India since early March 2021. The broad spectrum of disease severity and long incubation period of SARS-CoV-2 pose a challenge for surveillance and control. As illustrated by this particular outbreak, opportunistic infections of SARS-CoV-2 can occur irrespective of variant lineage, and requiring a nucleic acid test within 72 hours of departure may be insufficient to prevent importation or in-flight transmission.


Down-regulation of apurinic/apyrimidinic endonuclease 1/redox factor-1 expression by soy isoflavones enhances prostate cancer radiotherapy in vitro and in vivo.
We previously showed that genistein, the major bioactive component of soy isoflavones, acts as a radiosensitizer and potentiates prostate tumor cell killing by radiation in vitro and in animal tumor models in vivo. However, when given alone in vivo, pure genistein promoted increased lymph node metastasis, which was not observed with a soy isoflavone mixture consisting of genistein, daidzein, and glycitein. In this study, we show that soy inhibit tumor cell growth and potentiates radiation-induced cell killing in vitro like pure genistein. In an orthotopic model, combining soy isoflavones with tumor irradiation inhibited prostate tumor growth. To determine the molecular mechanisms by which soy isoflavones potentiate radiotherapy, we investigated apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) and nuclear factor kappaB (NF-kappaB), two signaling molecules involved in survival pathways. Soy isoflavones decreased APE1/Ref-1 expression in vitro, whereas radiation up-regulated it. Pretreatment with soy isoflavones followed by radiation inhibited APE1/Ref-1 expression. APE1/Ref-1 decrease correlated with decreased DNA-binding activity of NF-kappaB mediated by soy isoflavones and radiation, thus promoting cell killing. In vivo treatment of prostate tumors with soy isoflavones and radiation down-regulated APE1/Ref-1 protein expression and NF-kappaB activity, confirming the molecular alterations observed in vitro. The down-regulation of APE1/Ref-1 and NF-kappaB by isoflavones, in vitro and in vivo, supports our hypothesis that these markers represent biological targets of isoflavones. Indeed, a 2-fold increase in APE1/Ref-1 expression, obtained by cDNA transfection, resulted in a 2-fold increase in NF-kappaB DNA-binding activity, and both of which were down-regulated by soy isoflavones, confirming the cross-talk between these molecules and, in turn, causing radiosensitization.


Malignant pleural mesothelioma in the southwestern part of The Netherlands.
This report is the result of an analysis of the medical records of 124 patients presenting with a malignant pleural mesothelioma. Information about asbestos exposure was available in 104 of them, which appeared to be positive in 95 (91%). The median duration of exposure was 34 yrs. The median latent period was 41 yrs. The median survival was 11 months while different ways of treatment could not prolong survival. The most common radiologic findings were pleural effusions, while in some patients contralateral effusions or pleural thickening was found. Pleural plaques or asbestosis were seen in a minority of the patients. In this series a relatively high percentage of mixed type mesotheliomas was found (56%). Large biopsies will often show both epithelial and connective tissue type elements. Concerning diagnostic procedures we recommend beginning with cytology of pleural fluid, which can easily be obtained together with an Abrams biopsy. If this does not give a definite diagnosis thoracoscopy or thoracotomy will be indicated.


Inter- and intraindividual variation in dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells.
The activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in fluorouracil catabolism, has been reported to vary according to time of day. We wished to determine whether peak and trough DPD activities occurred at uniform times in six subjects, whether individual patterns fit a discernible profile, and whether such patterns were consistent and reproducible over time. Mononuclear cells were isolated from peripheral blood at 3-h intervals over a 24-h period on three different dates over a 6-month period. DPD activity was determined by incubating cellular lysates with [3H]FUra and measuring [3H]dihydrofluorouracil formation over time. When the data were averaged by study date for each subject, the median value for the average DPD activity (11.0 pmol/min per 10(6) cells) was significantly different from both the median peak (21.1 pmol/min per 10(6) cells, P = 0.004) and median trough activities (4.0 pmol/min per 10(6) cells, P = 0.002). Within the six subjects, the average DPD activity for the three study dates differed by a median of 2.4-fold (range 1.2- to 4.8-fold). The time at which peak and trough DPD activities occurred varied between subjects: 8 of the 17 peaks (47%) occurred between 10:00 p.m. and 6:00 a.m., 6 (35%) occurred between 8:00 a.m. and 3:00 p.m., and 3 (18%) occurred between 5:00 p.m. and 8:15 p.m. Thus, the time of day when the peak occurred was essentially randomly distributed over the 24-h period of observation (P = 0.68). Ten (59%) of the trough DPD activities occurred between 7:00 a.m. and 3:00 p.m. The median interval between the peak and trough was 6.5 h. The data were also expressed as percent of the mean for each individual's 24-h sampling period, and reordered as time from peak rather than as the actual time of day. When the combined data for all cycles was considered, the trough occurred 6-9 h after the peak, and the DPD levels subsequent to the peak did not display merely random variation (P = 0.0055). DPD activity levels and the times at which peak and trough DPD activities occurred varied both between and within subjects. If fluctuations in DPD activity influence the tolerability of fixed-rate infusions of FUra, these data suggest that a single variable-rate infusion regimen may not be suitable for all patients nor for a given individual treated over several months.


A constant conversation: tuning into and harmonizing the needs and priorities of the body and mind.
Individuals rely upon many types of information to manage an illness, including information provided by their own bodies. This study investigated how people tune into and manage the flow of information from their bodies to manage their health. We developed a platform for participants to share and collaboratively reflect on how they engaged in this dialogic process, in which participants contributed to a discussion on topics relating to body listening and body awareness. Though the study was open to anyone interested in or wanting to contribute to knowledge on "body listening," the social media recruitment focused on chronic conditions requiring self-care and having overlapping symptomatology, with chronic pain as the primary characteristic. A qualitative analysis method based on grounded theory was used to analyse the data. Six main themes emerged: learning the language, recognizing and heeding limits, experiencing emotional fatigue and despair, regulating the channel, moving from conflict to communication, and settling into an uneasy acceptance. The monitoring and filtering of information from one's body, and the appeasement of conflicting demands and voices, is difficult work. Knowledge of this process can be used in patient education and in the development of tools to support body listening.


Lanthanoid element recognition on surface-imprinted polymers containing dioleylphosphoric acid as a functional host.
Surface-imprinted polymers have been newly developed for the separation of lanthanoid elements: i.e. La(III), Ce(III), and Dy(III). The imprinted polymers were prepared by surface template polymerization with dioleylphosphoric acid, which exhibits a high affinity to lanthanoids, as a functional host molecule. Separation behavior of La(III), Ce(III) and Dy(III) was investigated with the imprinted polymers, and the imprinting effect of the polymers was evaluated in comparison with that of the unimprinted polymers and also with a conventional solvent extraction method for the same lanthanoid ions. The results indicate that the increase of selectivity for Dy(III) compared to the rest of the ions by the surface-imprinted polymers originated from a synergistic effect of both the affinity with the functional host molecule in nature and the size exclusion by the cavity formed on the polymer surface.


Modeling micelle formation and interfacial properties with iSAFT classical density functional theory.
Surfactants reduce the interfacial tension between phases, making them an important additive in a number of industrial and commercial applications from enhanced oil recovery to personal care products (e.g., shampoo and detergents). To help obtain a better understanding of the dependence of surfactantproperties on molecular structure, a classical density functional theory, also known as interfacial statistical associating fluid theory, has been applied to study the effects of surfactant architecture on micelle formation and interfacial properties for model nonionic surfactant/water/oil systems. In this approach, hydrogen bonding is explicitly included. To minimize the free energy, the system minimizes interactions between hydrophobic components and hydrophilic components with water molecules hydrating the surfactant head group. The theory predicts micellar structure, effects of surfactant architecture on critical micelle concentration, aggregation number, and interfacial tension isotherm of surfactant/water systems in qualitative agreement with experimental data. Furthermore, this model is applied to study swollen micelles and reverse swollen micelles that are necessary to understand the formation of a middle-phase microemulsion.


The 100 most influential publications in paracetamol poisoning treatment: a bibliometric analysis of human studies.
Analysis of the most influential publications within paracetamol poisoning treatment can be helpful in recognizing main and novel treatment issues within the field of toxicology. The current study was performed to recognize and describe the most highly cited articles related to paracetamol poisoning treatment. The 100 most highly cited articles in paracetamol poisoning treatment were identified from the Scopus database in November 2015. All eligible articles were read for basic information, including total number of citations, average citations per year, authors' names, journal name, impact factors, document types and countries of authors of publications. The median number of citations was 75 (interquartile range 56-137). These publications were published between 1974 and 2013. The average number of years since publication was 17.6 years, and 45 of the publications were from the 2000s. A significant, modest positive correlation was found between years since publication and the number of citations among the top 100 cited articles (r = 0.316; p = 0.001). A total of 55 journals published these 100 most cited articles. Nine documents were published in Clinical Toxicology, whereas eight documents were published in Annals of Emergency Medicine. Citations per year since publication for the top 100 most-cited articles ranged from 1.5 to 42.6 and had a mean of 8.5 citations per year and a median of 5.9 with an interquartile range of 3.75-10.35. In relation to the origin of the research publications, they were from 8 countries. The USA had the largest number of articles, 47, followed by the UK and Australia with 38 and nine articles respectively. This study is the first bibliometric assessment of the top 100 cited articles in toxicology literature. Interest in paracetamol poisoning as a serious clinical problem continues to grow. Research published in high-impact journals and from high income countries is most likely to be cited in published paracetamol research.


Interactions between L-arginine/L-arginine derivatives and lysozyme and implications to their inhibition effects on protein aggregation.
L-arginine (Arg), L-homoarginine (HArg), L-arginine ethylester (ArgEE), and L-arginine methylester (ArgME) were found effective in inhibiting protein aggregation, but the molecular mechanisms are not clear. Herein, stopped-flow fluorescence spectroscopy, isothermal titration calorimetry, and mass spectroscopy were used to investigate the folding kinetics of lysozyme and the interactions of the additives with lysozyme. It was found that the interactions of ArgME and ArgEE with lysozyme were similar to that of guanidine hydrochloride and were much stronger than those of Arg and HArg. The binding forces were all mainly hydrogen bonding and cation-π interaction from the guanidinium group, but their differences in molecular states led to the significantly different binding strengths. The additives formed molecular clusters in an increasing order of ArgEE, ArgME, HArg, and Arg. Arg and HArg mainly formed annular clusters with head-to-tail bonding, while ArgME and ArgEE formed linear clusters with guanidinium groups stacking. The interactions between the additives and lysozyme were positively related to the monomer contents. That is, the monomers were the primary species that participated in the direct interactions due to their intact guanidinium groups and small sizes, while the clusters performed as barriers to crowd out the protein-protein interactions for aggregation. Thus, it is concluded that the effects of Arg and its derivatives on protein aggregation stemmed from the direct interactions by the monomers and the crowding effects by the clusters. Interplay of the two effects led to the differences in their inhibition effects on protein aggregation.


The development of modulated, quasi-isothermal and ultraslow thermal methods as a means of characterizing the α to γ indomethacin polymorphic transformation.
While polymorphism remains a key issue within the pharmaceutical and related industries, the understanding of the transformation process itself remains relatively poorly understood. In this study we use a combination of conventional and modulated temperature differential scanning calorimetry (MTDSC), quasi-isothermal MTDSC (Qi-MTDSC) and ultraslow heating rate MTDSC as a novel means of investigating the temperature-induced α to γ transformation in indomethacin, using hot stage microscopy and variable temperature attenuated total reflectance FTIR spectroscopy as supportive techniques. In particular, we utilize the ability of MTDSC to measure subtle heat capacity changes through the transformation, we examine the use of Lissajous analysis of the modulated heating signal itself (both scanning and quasi-isothermal) and finally we investigate the use of ultraslow heating rates (down to 0.04 °C/min) so as to facilitate examination of the melt-crystallization process at a scanning rate whereby kinetic hindrance becomes negligible. Indomethacin was prepared in the metastable α and stable γ forms using standard approaches. Samples were studied using conventional DSC, Qi-MTDSC (involving holding and modulating the sample at a series of incremental temperature steps) and ultraslow MTDSC. All studies were conducted using a Q-1000 MTDSC using crimped pans, following standard calibration procedures. Conventional DSC at 10 °C/min showed the expected single melting responses for the α and γ forms, while MTDSC at slower rates indicated the presence of a melt-crystallization process. Quasi-isothermal studies allowed the heat capacity to be estimated as a function of time, while the associated Lissajous analysis demonstrated distortion of the elliptical response as a result of the kinetic events involved. Ultraslow heating resulted in superimposition of the melting and crystallization processes, resulting in a discrete thermal event that was enthalpically equivalent to the difference between the two processes. It is suggested that these combined thermal methods allow the conversion to be profiled in a manner which facilitates both kinetic and thermodynamic analysis of the transformation.


Neuromyelitis Optica: Pathogenesis Overlap with Other Autoimmune Diseases.
Neuromyelitis optica (NMO) is an auto-immune disease essentially depicted by optic neuritis and transverse myelitis. Per se, NMO was initially believed to be a sub-type of multiple sclerosis with typical demyelinating cerebral lesions and optic nerve inflammation. More recently, corroborating lignes of evidence have strengthened the concept of the spectrum of diseases associated with NMO and more specifically with the role of anti-aquaporin-4 antibodies in the pathogenesis of disease. In this article, we review the recent pathogenic findings in NMO and more interestingly the newly discovered role of anti-aquaporin-4 antibodies as key players in triggering cerebral lesions. The concept of spectrum of diseases associated with NMO is also discussed. These recent findings have paved in the further understanding of the pathogenesis underlying NMO and new treatments are currently being developed targeting anti-aquaporin-4 antibodies.


N-Acetylcysteine Prevents Retrograde Motor Neuron Death after Neonatal Peripheral Nerve Injury.
Neuronal death may be an overlooked and unaddressed component of disability following neonatal nerve injuries, such as obstetric brachial plexus injury. N-acetylcysteine and acetyl-L-carnitine improve survival of neurons after adult nerve injury, but it is unknown whether they improve survival after neonatal injury, when neurons are most susceptible to retrograde neuronal death. The authors' objective was to examine whether N-acetylcysteine or acetyl-L-carnitine treatment improves survival of neonatal motor or sensory neurons in a rat model of neonatal nerve injury. Rat pups received either a sciatic nerve crush or transection injury at postnatal day 3 and were then randomized to receive either intraperitoneal vehicle (5% dextrose), N-acetylcysteine (750 mg/kg), or acetyl-L-carnitine (300 mg/kg) once or twice daily. Four weeks after injury, surviving neurons were retrograde-labeled with 4% Fluoro-Gold. The lumbar spinal cord and L4/L5 dorsal root ganglia were then harvested and sectioned to count surviving motor and sensory neurons. Transection and crush injuries resulted in significant motor and sensory neuron loss, with transection injury resulting in significantly less neuron survival. High-dose N-acetylcysteine (750 mg/kg twice daily) significantly increased motor neuron survival after neonatal sciatic nerve crush and transection injury. Neither N-acetylcysteine nor acetyl-L-carnitine treatment improved sensory neuron survival. Proximal neonatal nerve injuries, such as obstetric brachial plexus injury, produce significant retrograde neuronal death after injury. High-dose N-acetylcysteine significantly increases motor neuron survival, which may improve functional outcomes after obstetrical brachial plexus injury.


Studies on Aspirin Crystals Generated by a Modified Vapor Diffusion Method.
The objectives of the current investigation were (1) to study the influence of selected two different non-solvents (diethylether and dichloromethane) on the drug crystal formation of a model drug, aspirin (ASP-I) by the modified vapor diffusion method and (2) to characterize and compare the generated crystals (ASP-II and ASP-III) using different analytical techniques with that of unprocessed ASP-I. When compared to the classical vapor diffusion method which consumes about 15 days to generate drug crystals, the modified method needs only 12 h to get the same. Fourier transform-infrared spectroscopy (FT-IR) reveals that the internal structures of ASP-II and ASP-III crystals were identical when compared with ASP-I. Although the drug crystals showed a close similarity in X-ray diffraction patterns, the difference in the relative intensities of some of the diffraction peaks (especially at 2θ values of around 7.7 and 15.5) could be attributed to the crystal habit or crystal size modification. Similarly, the differential scanning calorimetry (DSC) study speculates that only the crystal habit modifications might occur but without involving any change in internal structure of the generated drug polymorphic form I. This is further substantiated from the scanning electron microscopy (SEM) pictures that indicated the formation of platy shape for the ASP-II crystals and needle shape for the ASP-III crystals. In addition, the observed slow dissolution of ASP crystals should indicate polymorph form I formation. Thus, the modified vapor diffusion method could routinely be used to screen and legally secure all possible forms of other drug entities too.


Synchronization matters for motor coordination.
Using electroencephalography and electromyography recordings from healthy participants during a visual-depended bimanual coordination task, de Vries and colleagues showed that functional synchronization is important in motor coordination. The authors reported that higher coordination correlated positively with intermuscular synchrony, but correlated negatively with corticomuscular synchrony. They proposed that these two diverse motor systems operate differently depending on task demands. Similar experimental paradigms could identify motor mechanisms in patients with neurological disorders to design novel rehabilitation strategies.


Brominated and chlorinated flame retardants in tree bark from around the globe.
Brominated and chlorinated flame retardants were measured in about 40 samples of tree bark from 12 locations around the globe. The analytes were polybrominated diphenyl ethers (PBDE), Dechlorane Plus (DP), decabromodiphenylethane (DBDPE), hexabromocyclododecane (HBCD), hexabromobenzene (HBB), pentabromoethylbenzene (PBEB), pentabromobenzene (PBBz), and tetrabromo-p-xylene (pTBX). The highest concentrations of these compounds were detected at an urban site in Downsview, Ontario, Canada. Total PBDE and DP concentrations ranged from 2.1 to 190 ng/g lipid weight and from 0.89 to 48 ng/g lipid weight, respectively. Relatively high levels of DP (46 ± 4 ng/g lipid weight) were found at a remote site at Bukit Kototabang in Indonesia. The concentrations of total PBDE, DP, PBEB, and HBCD in the tree bark samples were significantly associated with human population in the nearby areas (r(2) = 0.21-0.56; P < 0.05). In addition, the concentrations of total PBDE and DP were significantly associated (r(2) = 0.40-0.64; P < 0.05). with the corresponding atmospheric concentrations of these compounds over a concentration range of 2-3 orders of magnitude.


Effects of low serum triglyceride on stroke mortality: a prospective follow-up study.
Low serum triglyceride (TG) has been suggested as a predictor of mortality after cardiovascular disease. However, the relationship between the level of TGs and the outcome after stroke remains to be elucidated. We hypothesized that the influence of TG levels on post-stroke mortality varies according to stroke mechanism: cardioembolic (CE) vs. non-CE causes. We prospectively enrolled a consecutive series of patients with first-ever acute ischemic stroke for 5 years (n=1067), and followed them until the end of 2007 to obtain information on mortality and cause of death. We divided the level of TG into the quartiles, and classified the patients into CE (n=226) and non-CE stroke groups (n=841). The influence of TG level on mortality (all-cause death and vascular death) was examined by univariate and multivariate analyses using Cox regression. All-cause death and vascular death rates showed inverse relationships to the quartiles of TG levels in all patients (p<0.001, both) and also in non-CE stroke group (p<0.001, both), but not in CE stroke group (p=0.17 and p=0.37, respectively). In the Cox-regression analysis, compared with the highest quartile, the adjusted hazard ratio (HR) of the lowest quartile for all-cause death was 2.58 [95% confidence interval (CI), 1.38-4.82] and that for vascular death was 3.50 (95% CI, 1.39-8.82) in non-CE stroke group. These same associations, however, were not significant in CE stroke group. Our results indicate that low serum TG is an independent predictor of mortality after ischemic stroke brought on by non-CE causes.


Melittin Induced G1 Cell Cycle Arrest and Apoptosis in Chago-K1 Human Bronchogenic Carcinoma Cells and Inhibited the Differentiation of THP-1 Cells into Tumour- Associated Macrophages
Background: Bronchogenic carcinoma (lung cancer) is one of the leading causes of death. Although many compounds isolated from natural products have been used to treat it, drug resistance is a serious problem, and alternative anti-cancer drugs are required. Here, melittin from Apis mellifera venom was used, and its effects on bronchogenic carcinoma cell proliferation and tumour-associated macrophage differentiation were evaluated. Methods: The half maximal inhibitory concentration (IC50) of melittin was measured by MTT. Cell death was observed by annexin V and propidium iodide (PI) co-staining followed by flow cytometry. Cell cycle arrest was revealed by PI staining and flow cytometry. To investigate the tumour microenvironment, differentiation of circulating monocytes (THP-1) into tumour-associated macrophages (TAMs) was assayed by sandwich-ELISA and interleukin (IL)-10 levels were determined. Cell proliferation and migration was observed by flat plate colony formation. Secretion of vascular endothelial growth factor (VEGF) was detected by ELISA. The change in expression levels of CatS, Bcl-2, and MADD was measured by quantitative RT-PCR. Results: Melittin was significantly more cytotoxic (p < 0.01) to human bronchogenic carcinoma cells (ChaGo-K1) than to the control human lung fibroblasts (Wi-38) cells. At 2.5 μM, melittin caused ChaGo-K1 cells to undergo apoptosis and cell cycle arrest at the G1 phase. The IL-10 levels showed that melittin significantly inhibited the differentiation of THP-1 cells into TAMs (p < 0.05) and reduced the number of colonies formed in the treated ChaGo-K1 cells compared to the untreated cells. However, melittin did not affect angiogenesis in ChaGo-K1 cells. Unlike MADD, Bcl-2 was up-regulated significantly (p < 0.05) in melittin-treated ChaGo-K1 cells. Conclusion: Melittin can be used as an alternative agent for lung cancer treatment because of its cytotoxicity against ChaGo-K1 cells and the inhibition of differentiation of THP-1 cells into TAMs.