Interaction of RhoD and ZIP kinase modulates actin filament assembly and focal adhesion dynamics.
RhoD is a member of the classical Rho GTPases and it has an essential role in the regulation of actin dynamics. Furthermore, RhoD also localizes to early endosomes and recycling endosomes, indicating additional roles in the regulation of endosome trafficking. A yeast two-hybrid screen identified Zipper-Interacting Protein Kinase (ZIPK) as a RhoD target. We found that RhoD interacts with ZIP kinase in a GTP dependent manner and modulates actin and focal adhesion reorganization. Interestingly, while ectopic expression of ZIPK in fibroblasts induces actin reorganization and actomyosin contraction seen as stress fiber bundling and membrane blebbing, the concomitant expression of active RhoD suppressed this phenotype. Previously, RhoD has been associated with focal adhesion regulation, and in line with this notion, we observed that ZIPK resulted in reorganization of focal adhesion and increased adhesion size. Importantly, the RhoD activity suppressed ZIPK-dependent effects on FAK activity, indicating a functional interplay between RhoD and FAK in the focal adhesion dynamics.


Total Synthesis of (-)-5-Deoxyenterocin and Attempted Late-Stage Functionalization Reactions.
The first total synthesis of (-)-5-deoxyenterocin has been accomplished starting from pentane-1,3,5-triol (16 steps in the longest linear sequence, 0.2 % overall yield). (-)-Menthone served as the source of chirality to distinguish the enantiotopic hydroxymethyl groups of the substrate. Key steps of the synthesis include two aldol reactions to either end of the C5 -skeleton, a diastereoselective hydroxylation reaction and a biomimetic twofold intramolecular aldol reaction as the final step. Although this step suffered from geometrical constraints and was low yielding (10 %), enough synthetic material could be secured to substantiate the relative and absolute configuration of the natural product. Additional experiments were directed toward a C-H functionalization at carbon atom C5. Despite the fact that several protocols could be successfully applied to (3aR)-(+)-sclareolide as model substrate, (-)-5-deoxyenterocin withstood any selective functionalization.


A Comparative Study of the Performance for Predicting Biodegradability Classification: The Quantitative Structure-Activity Relationship Model vs the Graph Convolutional Network.
The prediction and evaluation of the biodegradability of molecules with computational methods are becoming increasingly important. Among the various methods, quantitative structure-activity relationship (QSAR) models have been demonstrated to predict the ready biodegradation of chemicals but have limited functionality owing to their complex implementation. In this study, we employ the graph convolutional network (GCN) method to overcome these issues. A biodegradability dataset from previous studies was trained to generate prediction models by (i) the QSAR models using the Mordred molecular descriptor calculator and MACCS molecular fingerprint and (ii) the GCN model using molecular graphs. The performance comparison of the methods confirms that the GCN model is more straightforward to implement and more stable; the specificity and sensitivity values are almost identical without specific descriptors or fingerprints. In addition, the performance of the models was further verified by randomly dividing the dataset into 100 different cases of training and test sets and by varying the test set ratio from 20 to 80%. The results of the current study clearly suggest the promise of the GCN model, which can be implemented straightforwardly and can replace conventional QSAR prediction models for various types and properties of molecules.


Congenital sensory neuropathy with anhydrosis-a case report and investigation of autonomic nervous system abnormalities.
A review of the clinical profile of congenital sensory neuropathy with anhydrosis is presented. It is stressed that major diagnostic criteria of this recessively inherited condition should be limited to insensitivity to pain with normal tactile perception, anhydrosis, recurrent unexplained fever, self-mutilation, mental retardation, hypotonia, histologically normal sweat glands and variable autonomic abnormality. A case conforming to this description is reported and compared with 13 published cases. Special investigations of the autonomic nervous system through measurement of urinary catecholamine metabolites and psychophysiologic variables were conducted on this patient. Based on the analysis of 5 X 24-hour urine, values of metabolites of dopamine and epinephrine were normal. Metabolites of norepinephrine, such as 3-methoxy-4-hydroxy phenylglycol and normetanephrine, however, were significantly low when compared with those of four controls, suggesting decreased peripheral and central norepinephrine activity. Polygraph recording and evaluation of some orienting response components revealed no obvious signs of autonomic perturbation and, specifically, no phasic electrodermal activity. These two findings (biochemical and electrodermal) strongly suggest an autonomic imbalance, specifically component, both central and peripheral. It is suggested that autonomic disorder is an integral part of the syndrome and may be demonstrated by special investigations.


Regulation of the pigment production by changing Cell morphology and gene expression of Monascus ruber in high-sugar synergistic high-salt stress fermentation.
Extreme environment of microbial fermentation is the focus of research, which provides new thinking for the production and application of Monascus pigments (MPs). In this work, the high-sugar synergistic high-salt stress fermentation (HSSF) of MPs was investigated. The Monascus fungus grew well under HSSF conditions with 35 g L-1 NaCl and 150 g L-1 glucose, and the extracellular yellow pigment and intracellular orange pigment yield in HSSF was 98% and 43% higher than that in conventional fermentation, respectively. Moreover, the mycelial morphology was maintained in a better status with more branches and complete surface structure, indicating good biocatalytic activity for pigment synthesis. Four extracellular yellow pigments (Y1, Y2, Y3, and Y4) were transformed into each other, and ratio of the relative content of intracellular orange pigments to yellow pigments (O/Y) significantly (P < 0.05) changed. Moreover, the ratio of unsaturated fatty acids to saturated fatty acids (unsaturated/saturated) was significantly (P < 0.05) increased, indicating that the metabolism and secretion of intracellular and extracellular pigment might be regulated in HSSF. The pigment biosynthesis genes mppB, mppC, mppD, MpPKS5, and MpFasB2 were up-regulated, whereas the genes mppR1, mppR2, and mppE were down-regulated, suggesting that the gene expression to regulate pigment biosynthesis might be a dynamic change process in HSSF. The HSSF system of MPs is successfully performed to improve the pigment yields. Mycelial morphology is varied to enhanced pigment secretion, and gene expression is dynamically regulated to promote pigment accumulation in HSSF.


Mentalizing and self-other distinction in visual perspective taking: the analysis of temporal neural processing using high-density EEG.
This high density EEG report dissects the neural processing in the visual perspective taking using four experimental comparisons (Arrow, Avatar and Self, Other). Early activation differences occurred between the Avatar and the Arrow condition in primary visual pathways concomitantly with alpha and beta phase locked responses predominant in the Avatar condition. In later time points, brain activation was stronger for the Avatar condition in paracentral lobule of frontal lobe. When taking the other's perspective, there was an increased recruitment of generators in the occipital and temporal lobes and later on in mentalizing and salience networks bilaterally before spreading to right frontal lobe subdivisions. Microstate analysis further supported late recruitment of the medial frontal gyrus and precentral lobule in this condition. Other perspective for the Avatar only showed a strong beta response located first in left occipito-temporal and right parietal areas, and later on in frontal lobes. Our EEG data support distinct brain processes for the Avatar condition with an increased recruitment of brain generators that progresses from primary visual areas to the anterior brain. Taking the other's perspective needs an early recruitment of neural processors in posterior areas involved in theory of mind with later involvement of additional frontal generators.


Development and Application of a Poly(ethylene glycol)-Supported Triarylphosphine Reagent: Expanding the Sphere of Liquid-Phase Organic Synthesis.
Continuing studies into the utility of poly(ethylene glycol) (PEG)-supported triarylphosphines as functional polymer reagents in liquid-phase organic synthesis (LPOS) are being pursued. This report describes the synthesis and NMR characterization of an aryl-alkyl ether-linked PEG-triarylphosphine derivative (2) and its subsequent application in LPOS. The utility of 2 as a mild stoichiometric reagent for ozonide reduction has been demonstrated, and a direct comparison between 2, a Merrifield resin-bound triarylphosphine derivative, and a solution-phase triphenylphosphine reagent revealed that the highest observed yields occur under liquid-phase conditions. Transformation of phosphine 2 into a phosphonium salt (3) then allowed the inherent aqueous solubility of PEG-functionalized moieties to be exploited by enabling a Wittig reaction, between a range of aldehydes and 3, to occur under mildly basic aqueous conditions. This led to the generation of substituted stilbenes in good to excellent yields. Finally, regeneration of 2 was achieved by reduction of the PEG-supported triphenylphosphine oxide byproduct 4 with alane (100% conversion, 75% yield). This combination of reaction, recovery, and regeneration expands the utility of PEG-supported triarylphosphine reagents across the spectra of both organic chemistry and solution-phase combinatorial strategies.


Inhibition of DNA synthesis in permeabilized mouse P815 mast cells by arabinofuranosyladenine 5'-triphosphate.
P815 mast cells (mouse leukemic cells) have been successfully permeabilized to 9-beta-arabinofuranosyladenine 5'-triphosphate (araATP) using lysolecithin. The permeabilized cells remained viable according to the following criteria: (a) exclusion of trypan blue after replacing the lysolecithin with culture medium; (b) cell growth rate identical to control cultures, and (c) intact DNA-synthesizing complex in permeable cells. It was shown that permeabilized cells incorporate [3H]thymidine and [3H]deoxyadenosine-triphosphate (dATP) into DNA when the suspension is supplied with the appropriate substrates and cofactors. Permeable cells break down araATP to 9-beta-D-arabinofuranosyladenine 5'-diphosphate only slightly after incubation for 60 min; no further dephosphorylation to 9-beta-D-arabinofuranosyladenine 5'-monophosphate or 9-beta-D-arabinofuranosyladenine occurs. In kinetic experiments it was shown that the DNA-replicating complex of permeabilized cells is competitively inhibited by araATP with respect to dATP; Ki(araATP) was determined to be 0.6 microM and the Km(dATP), 0.9 microM.


The cost of cytoreductive surgery and perioperative intraperitoneal chemotherapy in the treatment of peritoneal malignancy in one Greek institute.
Cytoreductive surgery and perioperative intraperitoneal chemotherapy in the treatment of patients with peritoneal malignancy is expensive. The purpose of this study was to estimate the current cost of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy and identify the most significant related parameters in one center in Greece. A retrospective economic study was carried out on 105 patients that underwent 108 cytoreductive operations and hyperthermic intraoperative peritoneal chemotherapy (HIPEC) from 2006-2011 for peritoneal malignancy. The economic cost included the daily cost of hospital bed occupancy, the daily cost of occupancy in the intensive care unit (ICU), the expenditures (materials and drugs), and the preoperative, intraoperative, and postoperative examinations. The mean length of stay in the ICU and the mean hospitalization time was 5 and 23 days, respectively. The hospital mortality and morbidity was 5.6% (6 patients) and 48.17percnt; respectively. The mean cost of treatment was 15677.3±11910.6 euros (range=4258,47-95990,87) per patient. Morbidity (p=0.009), and prolonged stay in the ICU (p<0.001) were the parameters that influenced independently the cost of treatment. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy is an expensive treatment. The economic cost is largely influenced by morbidity and the length of stay in the ICU.


Targeting virulence regulation to disarm Acinetobacter baumannii pathogenesis.
The development of anti-virulence drug therapy against Acinetobacter baumannii infections would provide an alternative to traditional antibacterial therapy that are increasingly failing. Here, we demonstrate that the OmpR transcriptional regulator plays a pivotal role in the pathogenesis of diverse A. baumannii clinical strains in multiple murine and G. mellonella invertebrate infection models. We identified OmpR-regulated genes using RNA sequencing and further validated two genes whose expression can be used as robust biomarker to quantify OmpR inhibition in A. baumannii. Moreover, the determination of the structure of the OmpR DNA binding domain of A. baumannii and the development of in vitro protein-DNA binding assays enabled the identification of an OmpR small molecule inhibitor. We conclude that OmpR is a valid and unexplored target to fight A. baumannii infections and we believe that the described platform combining in silico methods, in vitro OmpR inhibitory assays and in vivo G. mellonella surrogate infection model will facilitate future drug discovery programs.


[Calcium, vitamin D and health].
The authors describe briefly recent views on physiological, pathological and practical aspects of calcium and vitamin D. The sources of calcium are the nutrients, mammal milk and milk products as well as pharmaceutical products. Their beneficial and potentially hazardous effects are discussed. The insufficiency of vitamin D [25(OH)D3] is a global health problem and the necessity of monitoring of this hepatic metabolite (as a marker) is emphasized due to its role in physio-logical and pathological processes.Key words: calcium - physiological and pathophysiological effects - vitamin D.


Expression of the multidrug transporter P-glycoprotein and in vitro chemosensitivity: correlation with in vivo response to chemotherapy in acute myeloid leukemia.
Thirty four patients with acute myeloid leukemia (AML) (30 de novo and 4 relapsed) were evaluated for P-glycoprotein (P-gp) expression, and in vitro chemosensitivity. The P-gp expression was evaluated by immunohistochemical method using JSB-1 monoclonal antibody and the results were visualized by peroxidase-antiperoxidase goat antimouse antibody and the in vitro chemosensitivity was measured by the semiautomated MTT colourimetric assay method. Depending upon the percent cells expressing P-gp and the intensity of P-gp staining, the samples were graded as absent, mild or strong for the relative P-gp expression, which was further correlated with the in vitro chemosensitivity and the clinical response of the tumors. Expression of P-gp was seen in 17 of the 30 de novo AML cases and all four relapse cases. Patients with no P-gp expression showed in vitro chemosensitivity while those with strong P-gp expression were resistant in vitro. Patients with mild P-gp expression showed varied chemosensitivity. P-gp expression correlated with clinical response to chemotherapy. Seven out of 11 patients with no P-gp achieved complete remission (C.R.). The other four died early in induction. Of five patients who expressed strong P-gp, four had resistant disease and the autopsy study of the remaining patient who died in induction revealed persistent disease. Of the 10 de novo AML patients who had mild P-gp expression, five achieved C.R. while one had resistant disease and four died in induction. All the four relapsed AML showed mild P-gp expression.(ABSTRACT TRUNCATED AT 250 WORDS)


Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma.
Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal 10B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[18F]fluorofenbufen ester boronopinacol (m-[18F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [18F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91±0.68μM) and COX-2 (IC50=0.33±0.24μM). [18F]FFBPin-derived 60-min dynamic PET scans predict the 10B-accumulation of 0.8-1.2ppm in liver and 1.2-1.8ppm in tumor and tumor to normal ratio=1.38±0.12. BNCT was performed 40-55min post intravenous administration of FBPin (20-30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[18F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83±3.00% (n=12) vs. 12.83±3.79% (n=10), P=0.05. The visualizing agent [18F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron-substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting of boron NSAIDs.


Inactivation of Pseudomonas aeruginosa by direct sunlight.
We determined the sensitivity of Pseudomonas aeruginosa to direct sunlight radiation, while maintaining the experimental temperature below levels harmful to the bacterium. The results presented here were similar to previous data on solar sensitivity obtained half a world away on another related bacterial species. The findings presented in this study suggest that related bacteria have a characteristic sensitivity to sunlight with their survival depending mainly on the fluence (photons) received in a dose-dependent manner that is otherwise relatively independent from latitude, atmospheric ozone and other local conditions. Conditions that inactivated P. aeruginosa did not result in measurable impairment of specific polymerase chain reaction (PCR) or enzyme-linked immunoassays (ELISA) tests suggesting that this germ could still be amenable to detection after inactivation by sunlight. The results presented in this study should assist in predicting the survival of P. aeruginosa outdoors and in monitoring the risk posed by this widespread organism in a variety of environmental settings.


Hematologic manifestations of Helicobacter pylori infection.
Helicobacter pylori (H. pylori) is the most common infection in humans, with a marked disparity between developed and developing countries. Although H. pylori infections are asymptomatic in most infected individuals, they are intimately related to malignant gastric conditions such as gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to benign diseases such as gastritis and duodenal and gastric peptic ulcers. Since it was learned that bacteria could colonize the gastric mucosa, there have been reports in the medical literature of over 50 extragastric manifestations involving a variety medical areas of specialization. These areas include cardiology, dermatology, endocrinology, gynecology and obstetrics, hematology, pneumology, odontology, ophthalmology, otorhinolaryngology and pediatrics, and they encompass conditions with a range of clear evidence between the H. pylori infection and development of the disease. This literature review covers extragastric manifestations of H. pylori infection in the hematology field. It focuses on conditions that are included in international consensus and management guides for H. pylori infection, specifically iron deficiency, vitamin B12 (cobalamin) deficiency, immune thrombocytopenia, and MALT lymphoma. In addition, there is discussion of other conditions that are not included in international consensus and management guides on H. pylori, including auto-immune neutropenia, antiphospholipid syndrome, plasma cell dyscrasias, and other hematologic diseases.


Cardiac arrest leadership: in need of resuscitation?
Leadership skills directly correlate with the quality of technical performance of cardiopulmonary resuscitation (CPR) and clinical outcomes. Despite an improved focus on non-technical skills in CPR training, the leadership of cardiac arrests is often variable. To assess the perceptions of leadership and team working among members of a cardiac arrest team and to evaluate future training needs. Cross-sectional survey of 102 members of a cardiac arrest team at an Acute Hospital Trust in the UK with 892 inpatient beds. Responses sought from doctors, nurses and healthcare assistants to 12 rated statements and 4 dichotomous questions. Of 102 responses, 81 (79%) were from doctors and 21 (21%) from nurses. Among specialist registrars 90% agreed or strongly agreed that there was clear leadership at all arrests compared with between 28% and 49% of nurses and junior doctors respectively. Routine omission of key leadership tasks was reported by as many as 80% of junior doctors and 50% of nurses. Almost half of respondents reported non-adherence with Advanced Life Support (ALS) guidelines. Among junior members of the team, 36% felt confident to lead an arrest and 75% would welcome further dedicated cardiac arrest leadership training. Leadership training is integrated into the ALS (Resus Council, UK) qualification. However, this paper found that in spite of this training; standards of leadership are variable. The findings suggest a pressing need for further dedicated cardiac arrest leadership training with a focus on improving key leadership tasks such as role assignment, team briefing and debriefing.


Aspects of the ecology of phlebotomine sand flies (Diptera: Psychodidae) in the Private Natural Heritage Reserve Sanctuary Caraça.
Leishmaniases are a set of parasitic diseases of zoonotic origin that are transmitted by sandfly vectors in wild, rural and urban environments. Their distribution is dependent not only the distribution of vectors, but also on the distribution of mammalian reservoirs. Only by understanding the transmission cycle of these diseases, such as knowing the participating vectors and reservoirs, can one can understand the epidemiology and ecological relationships of leishmaniases. Ecotourism has become an important area of economic growth in Brazil. One of the most visited tourist attractions in the state of Minas Gerais, the Reserva Particular do Patrimônio Natural Santuário do Caraça (RPPNSC) is located in the Quadrilátero Ferrífero. The aim of this study was to contribute to the control of leishmaniasis among tourists of the RPPNPC by surveying its sand fly fauna and testing for the presence of Leishmania DNA in females. Twenty-five CDC light traps were exposed on 7 trails of the RPPNPC where samples were collected bimonthly for a year, starting in June 2013. A total of 376 specimens of 18 species and 10 genera of sandflies were captured. The predominant species were Psychodopygus lloydi (72.34%) and Pintomyia monticola (5.59%). HaeIII restriction enzyme detected and characterized Leishmania braziliensis DNA in 2 of the samples for an infection rate of 0.7% (2/266). Recent studies found specimens of Ps. lloyd infected with Leishmania braziliensis elsewhere in Minas Gerais, which may be an indication that this species is involved in the transmission of Leishmania in this state.


Detection and quantification of enterovirus 71 genome from cerebrospinal fluid of an encephalitis patient by PCR applications.
Enterovirus 71 (EV71) is one of the causative agents of hand, foot, and mouth disease (HFMD) and is known to cause encephalitis, but several reports have identified EV71 in cerebrospinal fluid (CSF). We detected EV71 in CSF from a 20-month-old infant. The patient was diagnosed with brainstem encephalitis associated with HFMD. The clinical features of the patient were high fever (39.1C) and myoclonic jerks, and magnetic resonance imaging of the brain showed a bright signal area around the 4th ventricle. From a nasopharyngeal swab and rectal swab, EV71 was detected using reverse transcription (RT)-nested polymerase chain reaction (PCR). From CSF, the EV71 genome was identified using pan-enterovirus RT-nested PCR and sequencing. By real-time PCR, the nasopharyngeal swab, rectal swab, and CSF contained 1.8 x 10(4), 9.8 x 10(4), and 1.8 x 10 copies of the EV71 genome/microL, respectively. The enterovirus could only be isolated by cell culture from the rectal swab, and it was identified by a neutralization test using EV71-specific antiserum. RT-nested PCR and real-time PCR are considered to be sensitive tools for EV71 diagnosis in CSF.


[Age structure of the modules of clonal Heteropappus altaicus population on weedy meadow steppe in Songnen Plain of China].
Heteropappus altaicus is a root sucker type perennial herbaceous clonal plant of compositae. The age structure of its modules on the weedy meadow in Songnen Plain of China was studied by a method, in which, age class was compartmentalized according to the propagared generations in bud section of taproot. The results showed that both ramets and buds of the clonal population consisted of 4 age classes. The modules of ramets showed stable age structure, with the age spectrum being 22.6%, 44.8%, 28.8% and 3.8% from 1st to 4th age classes at flowerbud stage, respectively. At milk stage, the modules of reproductive ramets showed a stable age structure, with the proportion of 2nd age class being the largest (45.6%) and of 4th age class being the least (0.8%), while those of vegetative ramets showed an expansive age structure, with the largest proportion (47.5%) of 1st age class and the least (1.1%) of 4th age class. The taproot of the ramets could survive for five years at most. The productivity of 2nd age class ramets was most vigorous at different growth stages. The ramets of 1st age class had the biggest productive potential, while the ramet productivity of 4th age class was generally weakened at milk stage. The potential population in the bud banks presented an expansive age structure.


One-Year Efficacy and Safety of Evolocumab in Japanese Patients - A Pooled Analysis From the Open-Label Extension OSLER Studies.
Evolocumab, a fully human monoclonal antibody against PCSK9, significantly reduced low-density lipoprotein-cholesterol (LDL-C) levels in Japanese patients by up to 76% when administered with a statin. We evaluated the efficacy and safety of 1 year of evolocumab in a pooled analysis of patients from the 12-week YUKAWA studies who continued into the open-label extension (OLE) OSLER studies.Methods and Results:YUKAWA-1 and YUKAWA-2 were conducted in hypercholesterolemic, high-cardiovascular-risk Japanese patients who were receiving statin therapy. Patients completing these studies were eligible for an OLE study. At OLE entry, patients were re-randomized 2:1 to evolocumab+standard of care (SOC) or SOC alone (OSLER-1: evolocumab 420 mg monthly; OSLER-2: evolocumab 140 mg biweekly or 420 mg monthly). A 1-year analysis was performed on patients enrolled from the YUKAWA studies into OSLER. At parent-study baseline (YUKAWA-1 or YUKAWA-2 patients continuing into OSLER), mean (SD) age was 61 (10) years; 39% were female; mean (SD) baseline LDL-C (on statin) was 119.7 (33.0) mg/dL. Overall rates of adverse events were comparable between evolocumab+SOC and SOC alone. In YUKAWA patients receiving evolocumab+SOC, mean (SE) reductions in LDL-C from parent-study baseline to OLE 1 year were 69.1% (1.2%; OSLER-1) and 65.1% (2.2%; OSLER-2). In a pooled 1-year analysis of Japanese patients in the ongoing OSLER studies, treatment with evolocumab+SOC was well tolerated and resulted in sustained LDL-C reductions at 1 year.


Differences in the locomotion biomechanics and dynamic postural control between individuals with chronic ankle instability and copers: a systematic review.
An empirical consensus of differences between chronic ankle instability (CAI) individuals and copers (individuals who sprained ankle once and without recurrent symptoms or injury) has not been reported. This study aimed to review the locomotion biomechanics and dynamic postural control between these two populations. Database of ScienceDirect, PubMed and Web of Science was used to search ('chronic ankle instability' OR 'ankle instability') AND ('ankle sprain' OR 'coper*') until 30 November 2020. Articles that made a comparison about changes in biomechanical parameters between Copers and CAI individuals during locomotor or functional tasks were included in this review. Twenty-three articles met the inclusion criteria. CAI individuals exhibited an increased hip flexion to maintain stability, suggesting the adopted hip strategy compared to copers during landing. Dorsiflexion angle and ankle frontal displacement increased considerably compared to copers, which might increase risks of lateral ankle sprain injury. CAI individuals reduced the ankle displacements in the sagittal plane and indicated worse performance of Star Excursion Balance Test in the posterior-lateral direction compared to copers. Identified motion deficits or altered motion strategies provide opportunities for targeted intervention and scheme after index sprain or in CAI individuals.


Amplification on Undirected Population Structures: Comets Beat Stars.
The fixation probability is the probability that a new mutant introduced in a homogeneous population eventually takes over the entire population. The fixation probability is a fundamental quantity of natural selection, and known to depend on the population structure. Amplifiers of natural selection are population structures which increase the fixation probability of advantageous mutants, as compared to the baseline case of well-mixed populations. In this work we focus on symmetric population structures represented as undirected graphs. In the regime of undirected graphs, the strongest amplifier known has been the Star graph, and the existence of undirected graphs with stronger amplification properties has remained open for over a decade. In this work we present the Comet and Comet-swarm families of undirected graphs. We show that for a range of fitness values of the mutants, the Comet and Comet-swarm graphs have fixation probability strictly larger than the fixation probability of the Star graph, for fixed population size and at the limit of large populations, respectively.


Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression.
Non small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States and worldwide. Unfortunately, standard therapies remain inadequate. An increased understanding of the molecular biology of lung cancer biology is required to develop more effective new therapies. In this report, we show that the Wnt pathway is activated through Dishevelled (Dvl) overexpression in NSCLC. Analysis of freshly resected tumors and lung cancer cell lines demonstrate that Dvl-3, a critical mediator of Wnt signaling, is overexpressed. Specifically, Dvl-3 was overexpressed significantly in 75% of fresh NSCLC microdissected samples compared to control paired matched normal lung samples. To evaluate the biological significance of Wnt signaling and, in particular, Dvl function in lung cancer, we transfected siRNA (designed to inhibit selectively human Dvl-1, -2, and -3), to the NSCLC cell line H1703, which is known to have beta-catenin-mediated Tcf-dependent transcriptional activity. Here, we demonstrate that Dvl-specific siRNA treatment in H1703 decreases significantly Dvl and beta-catenin expression, resulting in reduction of Tcf-dependent transcriptional activity, and, importantly, growth inhibition. Taken together, these data support the novel hypothesis that Dvl overexpression is critical to Wnt signaling activation and cell growth in NSCLC.


Induction of Systemic Resistance against Aphids by Endophytic Bacillus velezensis YC7010 via Expressing PHYTOALEXIN DEFICIENT4 in Arabidopsis.
Aphids are the most destructive insect pests. They suck the sap and transmit plant viruses, causing widespread yield loss of many crops. A multifunctional endophytic bacterial strain Bacillus velezensis YC7010 has been found to induce systemic resistance against bacterial and fungal pathogens of rice. However, its activity against insects attack and underlying cellular and molecular defense mechanisms are not elucidated yet. Here, we show that root drenching of Arabidopsis seedlings with B. velezensis YC7010 can induce systemic resistance against green peach aphid (GPA), Myzus persicae. Treatment of bacterial suspension of B. velezensis YC7010 at 2 × 107 CFU/ml to Arabidopsis rhizosphere induced higher accumulation of hydrogen peroxide, cell death, and callose deposition in leaves compared to untreated plants at 6 days after infestation of GPA. Salicylic acid, jasmonic acid, ethylene, and abscisic acid were not required to confer defense against GPA in Arabidopsis plants treated by B. velezensis YC7010. Bacterial treatment with B. velezensis YC7010 significantly reduced settling, feeding and reproduction of GPA on Arabidopsis leaves via strongly expressing senescence-promoting gene PHYTOALEXIN DEFICIENT4 (PAD4) while suppressing BOTRYTIS-INDUCED KINASE1 (BIK1). These results indicate that B. velezensis YC7010-induced systemic resistance to the GPA is a hypersensitive response mainly dependent on higher expression of PAD4 with suppression of BIK1, resulting in more accumulation of hydrogen peroxide, cell death, and callose deposition in Arabidopsis.


Qualitative examination of flow experience among top Japanese athletes.
The purpose of the present study was two-fold, (1) to examine the psychological elements of flow state experienced by top athletes during competition and (2) to explore the psychological states leading to flow experience. Semistructured interviews were conducted with 29 Japanese athletes regarding experiences in which they felt they were able to display 100% of their abilities and which they fully enjoyed. Interview contents were classified by the main investigator and independently by an external examiner. Analysis indicated that 92.6% of elements agreed with Csikszentmihalyi's model of flow. Three categories in Jackson's nomenclature (1996), unambiguous feedback, concentration on the task at hand, and autotelic experience, reported at a higher rate in the present study, may be the basic characteristics of flow state. The psychological states leading up to flow state were placed into six categories: relaxed, self-confident, highly motivated, completely focused, lack of negative thoughts and feelings, and extremely positive. Relaxed, self-confident, and highly motivated were reported by most of the athletes, suggesting they are primary elements for an optimal experience.


Aging Triggers Mitochondrial Dysfunction in Mice.
Direct analysis of isolated mitochondria from old mice enables a better understanding of heart senescence dysfunction. Despite a well-defined senescent phenotype in cardiomyocytes, the mitochondrial state in aged cardiomyocytes is still unclear. Here, we report data about mitochondrial function in old mice. Isolated cardiomyocytes' mitochondria were obtained by differential centrifugation from old and young mice hearts to perform functional analyses of mitochondrial O2 consumption, transmembrane potential, ROS formation, ATP production, and swelling. Our results show that mitochondria from old mouse hearts have reduced oxygen consumption during the phosphorylative states of complexes I and II. Additionally, these mitochondria produced more ROS and less ATP than those of young hearts. Mitochondria from old hearts also showed a depolarized membrane potential than mitochondria from young hearts and, as expected, a greater electron leak. Our results indicate that mitochondria from senescent cardiomyocytes are less efficient in O2 consumption, generating more ROS and producing less ATP. Furthermore, the phosphorylative state of complexes I and II presents a functional defect, contributing to greater leakage of protons and ROS production that can be harmful to the cell.


Results of modified Bristow procedure.
A modified Bristow procedure was performed on 23 patients over a two-year period. The modification consisted of splitting the subscapularis muscle in line with its fibers and attaching the coracoid process to the neck of the scapula with a malleolar screw. The results were evaluated by questionnaire, physical examination, and radiographs. The average age of the patients was 24 years. There were 20 men and three women. The patients presented 16 left shoulders and seven right shoulders; nine were dominant. The number of previous dislocations was 12. The average follow-up period was 25 months and the average hospital stay was two days. There were no blood transfusions. Each patient returned to his or her preoperative activity level; no patient had pain in the shoulder at rest. With overhead activity, five patients had some pain and 18 had none. Of the nine patients whose surgery was on the dominant side, only two had difficulty in throwing. There were no postoperative recurrent dislocations. There was an average loss of external rotation of 13 degrees and an average loss of internal rotation of 12 degrees. Bony fusion of the coracoid to the neck of the scapula occurred in only one out of 13 shoulders. Complications were minor and resolved completely. The advantages of the procedure are good surgical exposure, minimal tissue trauma, insignificant blood loss, and fewer days in the hospital per patient. The procedure was relatively safe and generally effective.


Medical conditions and medication use in adults with Down syndrome: a descriptive analysis.
We examined the presence of medical conditions and medication use within a sample of adults with Down syndrome. Retrospective chart review using a sample of 141 adults with Down syndrome and age range of 30 to 65 years. We identify 23 categories of commonly occurring medical conditions and 24 categories of medications used by adults with Down syndrome. Approximately 75 of older adults with Down syndrome in our sample experience memory loss and dementia. Hypothyroidism, seizures, and skin problems also occur commonly. The prevalence of cancer (i.e., solid tumours) and hypertension is extremely low. Older adults with Down syndrome use anticonvulsant more often than younger adults with Down syndrome. The use of multivitamins and medications such as pain relievers, prophylactic antibiotics, and topical ointments is common.


Topical benzydamine hydrochloride for prevention of postoperative sore throat in adults undergoing tracheal intubation for elective surgery: a systematic review and meta-analysis.
Postoperative sore throat has a negative impact on patient satisfaction and recovery. Benzydamine hydrochloride is a non-steroidal anti-inflammatory drug available for topical use. We performed a systematic review and meta-analysis to assess the efficacy and safety of topical application of benzydamine to prevent postoperative sore throat in adults undergoing elective surgery under general anaesthesia. We searched PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials to identify relevant randomised controlled trials and pooled the data using a random effects model. The primary outcomes were the incidence and severity of sore throat 24 h after surgery/extubation, and adverse events. The quality of evidence was assessed using the grading of recommendations, assessment, development and evaluation (GRADE) criteria. Thirteen randomised controlled trials involving 1842 patients were included. Compared with control patients who did not receive analgesia, benzydamine was associated with a decreased incidence of postoperative sore throat, with a risk ratio (95%CI) of 0.31 (0.20-0.47), but not with significantly reduced severity, the standardised mean difference (95%CI) being -0.27 (-0.63 to 0.08). There were no significant adverse events related to benzydamine. Benzydamine was also associated with a reduced incidence of postoperative sore throat when compared with lidocaine, with a risk ratio (95%CI) of 0.18 (0.07-0.43). We judged the evidence for the outcome 'incidence of postoperative sore throat' as high quality.


Effects of dietary zinc levels on the activities of enzymes, weights of organs, and the concentrations of zinc and copper in growing rats.
Zinc (Zn) is an essential nutrient that is required in humans and animals for many physiological functions, including immune and antioxidant function, growth, and reproduction. The present study was performed to investigate the effects of three Zn levels, including Zn adequate (35.94 mg/kg, as a control), Zn deficiency (3.15 mg/kg), and Zn overload (347.50 mg/kg) in growing male rats for 6 wk. This allowed for evaluation of the effects that these Zn levels might have on body weight, organ weight, enzymes activities, and tissues concentrations of Zn and Cu. The results showed that Zn deficiency has negative effects on growth, organ weight, and biological parameters such as alkaline phosphatase (ALP) and Cu-Zn superoxide dismutase (Cu-Zn SOD) activities, whereas Zn overload played an effective role in promoting growth, improving the developments of organs and enhancing immune system. Hepatic metallothionein (MT) concentration showed an identical increase tendency in rats fed both Zn-deficient and Zn-overload diets. The actual mechanism of reduction of Cu concentration of jejunum in rats fed a Zn-overload diet might involve the modulation or inhibition of a Cu transporter protein by Zn and not by the induction of MT.


As vivid as a weed… Medicinal and cosmetic plant uses amongst the urban youth in French Guiana.
French Guiana is a French overseas territory with a rich history of migration that has led to a highly intercultural society. Today, its population is one of the youngest in the French territory and is rapidly increasing. Despite a context of cultural revival seeking "tradition", a distanced baseline of local practices is still lacking. This work addresses some aspects of the cultural hybridizations in progress in urban areas. Semi directed interviews were conducted with willing participants aged between 18 and 40. Interviews took place in French Guiana's two main urban centres: Cayenne and Saint Laurent du Maroni. People were interviewed about the last medicinal plant they used in the preceding year. Due to the high use of plant baths in French Guiana, a focus was made on baths. Eighty-three people answered: 43 women and 40 men (mean age of 28.7 years old). In total, 226 remedies were counted in our study, 155 single plant remedies and 71 compound remedies leading to 316 use reports of plants from 16 cultural groups. A surprising number of 108 botanical species were recorded. Eighty-one recipes for baths were also collected. Despite this high citation rate, a rather low proportion of people declare a systematic and regular recourse upon local pharmacopoeia (46%; 38/83). Although many interviewees used plants, far from the majority used them on a regular basis. In practice, 50% of the species (54/108 spp.; 99/316 URs) are non-native but domesticated exotic species, imported from Asia, Europe, Africa or remote parts of America, either during colonization, the slave trade era, or more recently with the latest migrations. Although phytotherapy use is often thought to be related to countryside dwellers and older people, medicinal plants seem to play an important role in the lives of urban French Guianese youth. Research shows a large diversity of medicinal species used linked with the great cultural diversity of the Guianese cities. One characteristic of this population is the hybridization process leading to a perpetual renewal of practices, both in terms of species and practice.


ALTERNATIVE DEVICES IN AIRWAY VISUALIZATION.
The Macintosh laryngoscope has been the most widely used device for intubation since its invention by Foregger in the 1940s. Recently, video and optic laryngoscopy assisted tracheal intubation has been used widely in patients with difficult airways. Their routine use, however, is not widely practiced. This review will summarize some of the newly available devices to assist tracheal intubation, with their advantages and disadvantages when compared with conventional laryngoscopes. It also presents the reasons to support their use in both elective and emergency airway management.


Posttraumatic enophthalmos and diplopia.
Malposition of the globe and failure to fuse visual images are late-developing complications of orbital injury. This article reviews the causes of specific sequelae, such as enophthalmos, hypophthalmos, and diplopia, and describes a procedure of strategic implantation of autogenous bone grafts to correct the condition(s). Using quantifiable methods of assessing globe position and motility, the authors demonstrate improvement in 18 of 19 patients. Vision is reported unchanged or improved in 13 sighted patients. Several cases are presented with analyses of preoperative and postoperative photographs. Indications, contraindications, advantages, and disadvantages of the surgical procedure are described and compared to others.


The comparison of decrease in mice mass preserved with formalin 4% and neutralize with sodium bicarbonate.
Anatomy studies require cadavers to study the human body. Generally in Indonesia, the dead human body will be buried. This causes problems because the decomposition process of a cadaver that is preserved with formalin will be delayed and it causes environmental pollution. The toxicity of formalin can be reduced by neutralizing the formalin. This study aimed to compare the decrease of mice mass that were preserved with formalin then neutralized with sodium bicarbonate and those that were not neutralized. This study used 18 mice (Mus musculus) which were divided into 3 groups. They were the control group (not given preservative), group preserved with 4% formalin, and group preserved with 4% formalin then neutralized with sodium bicarbonate. All groups of mice were buried for 6 weeks. The changes in mass were assessed with an analysis of the percentage loss in mass. Based on the results of this study, the formalin group had a greater percentage of total mass reduction than the neutralize group. The formalin group had a higher decomposition rate than the neutralizing sodium bicarbonate group. The effectiveness of reducing the concentration of formalin is similar with neutralize group. Therefore, it can be concluded that 4% formalin is recommended for use to accelerate the occurrence of decay and decrease in mass.


Extracellular matrix promotes rat Sertoli cell histotypic expression in vitro.
We describe procedures for the preparation of a cell-free seminiferous tubule biomatrix, and provide evidence demonstrating that this material constitutes a useful substratum for maintaining the normal architecture of Sertoli cells in primary culture. Seminiferous tubule biomatrix, which has the morphological appearance of a fibrillar network rich in filaments and amorphous substance, is shown to consist of about 50% protein, most of which is collagen and glycoproteins. Fibronectin and laminin are also present in the seminiferous tubule biomatrix, as judged by immunofluorescence microscopy. Sertoli cell aggregates plated on this substratum retain a cuboidal to columnar shape, spread very slowly to form a monolayer, and survive for at least 3 weeks when cultured in a hormone-free, serum-free, chemically defined medium. In contrast, Sertoli cells plated onto uncoated polystyrene readily spread to form a monolayer of flat squamous cells which do not survive as well. Other morphological and ultrastructural characteristics are described which indicate that cells cultured on the seminiferous tubule biomatrix more closely resemble those of Sertoli cells in vivo than do cells plated on uncoated plastic. These differences in cell structure, including the maintenance of normal polarity as indicated by the presence of basolateral tight junctional complexes, remain evident for periods of 10 to 14 days after plating Sertoli cells onto biomatrix substratum. Rates of DNA synthesis by immature Sertoli cells plated onto biomatrix are less than rates by cells plated onto uncoated plastic. The data are discussed in relation to the role of substratum in the preservation of normal functions and histotype of Sertoli cells.


Targeted Annotation of S-Sulfonylated Peptides by Selective Infrared Multiphoton Dissociation Mass Spectrometry.
Protein S-sulfinylation (R-SO2-) and S-sulfonylation (R-SO3-) are irreversible oxidative post-translational modifications of cysteine residues. Greater than 5% of cysteines are reported to occupy these higher oxidation states, which effectively inactivate the corresponding thiols and alter the electronic and physical properties of modified proteins. Such higher oxidation states are reached after excessive exposure to cellular oxidants, and accumulate across different disease states. Despite widespread and functionally relevant cysteine oxidation across the proteome, there are currently no robust methods to profile higher order cysteine oxidation. Traditional data-dependent liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods generally miss low-occupancy modifications in complex analyses. Here, we present a data-independent acquisition (DIA) LC/MS-based approach, leveraging the high IR absorbance of sulfoxides at 10.6 μm, for selective dissociation and discovery of S-sulfonated peptides. Across peptide standards and protein digests, we demonstrate selective infrared multiphoton dissociation (IRMPD) of S-sulfonated peptides in the background of unmodified peptides. This selective DIA IRMPD LC/MS-based approach allows identification and annotation of S-sulfonated peptides across complex mixtures while providing sufficient sequence information to localize the modification site.


International emergency medicine: a review of the literature.
The field of international emergency medicine has grown rapidly over the past several decades, with an increase in the number of interested individuals and in the range of topics included under its rubric. One of the greatest obstacles, however, faced by international emergency medicine researchers and practitioners alike remains the lack of a high-quality, consolidated, and easily accessible evidence base of literature. In response to this perceived need, members of the Emergency Medicine Residents' Association International Emergency Medicine Committee, in conjunction with members of the Society for Academic Emergency Medicine International Interest Group, embarked on the task of creating a recurring review of international emergency medicine literature. Articles for this first annual review, covering research published in 2005, were selected according to explicit, predetermined criteria that included both methodological quality and perceived impact of the research. It is our hope that this annual review will act as a forum for disseminating best practices, while also stimulating further research in the field of international emergency medicine.


Newcastle 1000 (NEW1000) Study: an Australian population-based prospective pregnancy cohort study design and protocol.
Multiple cohort studies have been established to investigate the impact of early life factors on development and health outcomes. In Australia the majority of these studies were established more than 20 years ago and, although longitudinal in nature, are inherently susceptible to socioeconomic, environmental and cultural influences which change over time. Additionally, rapid leaps in technology have increased our understanding of the complex role of gene-environment interactions in life course health, highlighting the need for new cohort studies with repeated biological sampling and in-depth phenotype data across the first 1000 days of life from conception. The Newcastle 1000 (NEW1000) Study, based in the regional city of Newcastle, New South Wales, was developed after an extensive consultation process involving 3 years of discussion with key stakeholders and healthcare consumer organisations and seven healthcare consumer workshops. This prospective population-based pregnancy cohort study will recruit 500 families per year for 5 years, providing detailed, longitudinal, multisystem phenotyping, repeated ultrasound measures and serial sample collection to investigate healthcare consumer identified health outcomes of priority. Stage 1 will involve recruitment of pregnant participants and their partners at 14 weeks gestation, with dense phenotype data and biological samples collected at 14, 20, 28 and 36 weeks gestation and serial ultrasound measures at 20, 28, 36 and 40 weeks, with postpartum follow-up at 6 weeks and 6 months. Biological samples will be used for biomarker discovery and sequencing of the genome, transcriptome, epigenome, microbiome and metabolome. Ethics approval was obtained from Hunter New England Local Health District Ethics Committee (2020/ETH02881). Outcomes will be published in peer-reviewed journals, disseminated to participants through the NEW1000 website, presented at scientific conferences, and written reports to local, state and national government bodies and key stakeholders in the healthcare system to inform policy and evidence-based practice.


Histological and Histomorphometrical Determination of the Biogradation of β-Tricalcium Phosphate Granules in Maxillary Sinus Floor Augmentation: A Prospective Observational Study.
We have recently used highly pure β-TCP (beta-tricalcium phosphate) as the bone grafting material to avoid highly invasive autogenous bone grafting. We evaluated the osseoconduction potential of highly pure β-TCP in sinus augmentation surgery treatment. The study group comprised 13 patients who underwent maxillary sinus floor augmentation with β-TCP alone. Seven patients underwent sinus augmentation and implant placement simultaneously. Six patients were treated with a staged approach. Six months after surgery, specimens were obtained from 7 patients (for lateral biopsy) and 6 patients (for vertical biopsy). Histological and histomorphometrical analysis showed a mean bone proportion of 30.8% (vertical) and 12.0% (lateral) for new bone formation and good integration of the β-TCP. New bone formation was lower in the lateral biopsy specimens than in the vertical. Highly pure β-TCP is a safe bone-grafting material with superior osteoconductive properties. Histologic and radiographic examinations indicate that β-TCP is slowly resorbed, which results in unresorbed graft material remaining even 6 months after the procedure, and that new bone replacement occurs slowly for approximately 1 year.


A tag-free collisionally induced fragmentation approach to detect drug-adducted proteins by mass spectrometry.
The covalent modification of proteins by toxicants, new chemical entities or drug molecules, either by metabolic activation or the presence of inherently reactive functional groups, is commonly implicated in organ toxicity and idiosyncratic reactions. In efforts to better prosecute protein modifications, we investigated a tag-free technique capable of detecting protein-small molecule adducts based solely on the collision-induced dissociation (CID) of the protein-small molecule complex. Detection of proteins using unique CID small molecule (SM) product ions would mitigate common issues associated with tagging technologies (e.g., altered reactivity/affinity of the protein-SM complex). A Waters SYNAPT G2 mass spectrometer (MS) was operated in MS(e) mode with appropriate collision energy conditions during the MS(2) acquisition for fragmentation of protein-small molecule adducts to generate characteristic small molecule product ions. Ibrutinib, an acrylamide-containing small molecule drug, was shown to form adducts with rat serum albumin in ex vivo experiments and these adducts were detected by relying solely on the CID product ions generated from ibrutinib. Additionally, ibrutinib produced three CID product ions, one of which was a selective protein-ibrutinib fragment ion not produced by the compound alone. Herein we describe a tag-free mass spectral detection technique for protein-small molecule conjugates that relies on the unique product ion fragmentation profile of the small molecule. This technique allows the detection of macromolecular ions containing the adducted small molecule from complex protein matrices through mass range selection for the unique product ions in the CID spectra.


Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models.
Even decades after the discovery of Cadmium (Cd) toxicity, research on this heavy metal is still a hot topic in scientific literature: as we wrote this review, more than 1440 scientific articles had been published and listed by the PubMed.gov website during 2017. Cadmium is one of the most common and harmful heavy metals present in our environment. Since pregnancy is a very particular physiological condition that could impact and modify essential pathways involved in the handling of Cd, the prenatal life is a critical stage for exposure to this non-essential element. To give the reader an overview of the possible mechanisms involved in the multiple organ toxic effects in fetuses after the exposure to Cd during pregnancy, we decided to compile some of the most relevant experimental studies performed in experimental models and to summarize the advances in this field such as the Cd distribution and the factors that could alter it (diet, binding-proteins and membrane transporters), the Cd-induced toxicity in dams (preeclampsia, fertility, kidney injury, alteration in essential element homeostasis and bone mineralization), in placenta and in fetus (teratogenicity, central nervous system, liver and kidney).


Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer.
The critical pathogenic role of tumor necrosis factor (TNF)alpha in inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease is well established. The role played by TNFalpha in both the treatment and pathogenesis of cancer remains less understood. Recent advances help to create a framework for understanding seemingly paradoxical effects of TNFalpha as both an anti-tumour agent and a mediator of tumour growth. High pharmacological doses of TNFalpha combined with chemotherapy can regress otherwise intractable tumours, and efforts continue to optimize delivery to avoid severe toxicities. Mounting evidence demonstrates that pathophysiological concentrations of endogenous TNFalpha act to promote tumour genesis and growth. The cellular and molecular pathways mediating these phenomena are starting to be clarified. Current data support the continued development of both TNFalpha and anti-TNFalpha therapy for clinical treatment of cancers in distinct settings.


Definitive three-dimensional high-dose-rate brachytherapy for inoperable endometrial cancer.
To report our experience on high-dose-rate brachytherapy (HDR-BT) in patients with stage I-III endometrial cancer unfit to surgery. Seventeen patients underwent HDR-BT as definitive treatment. Median age was 79 years (range, 60-95), median Karnofsky performance status 90% (range, 60-100). Histology was endometrial adenocarcinoma in 14 (82%), and non-endometrial in 3 (18%) patients. In 15 (88%) patients, clinical stage was I and in remaining 2 (12%) was III. All patients were evaluated with computed tomography (CT) and endometrial biopsy. Using the Fletcher applicator, a CT-based planning HDR-BT was delivered. Local control (LC) was obtained when there was an interruption of vaginal bleeding in absence of CT-imaging progression. Fourteen patients underwent HDR-BT alone and three external beam radiotherapy (EBRT) combined with HDR-BT. All patients had a clinical LC, after a median follow-up of 53 months (range, 6-131), 3 and 6 years LC rates were 86% and 69%, respectively. Cancer specific survival (CSS) at 1, 2, and 6 years was 93%, 85%, and 85%, respectively. Age, stage, dose, and type of radiotherapy did not result significant prognostic factors for LC and CSS. Only histology significantly influenced LC: for high-risk histology (i.e., non-endometrial carcinoma or grade [G] 3 endometrial adenocarcinoma) LC was 73% at 1 year and 36% at 6 years; for low-risk histology (i.e., G1-2 endometrial adenocarcinoma) was 100% at 1 and 6 years (p = 0.05). Two (12%) patients had G2 acute toxicity and two others (12%) G1 late toxicity. Although some limitations of our analysis (relatively few number of patients recruited, retrospective evaluation, and consequent suboptimal patient selection), it confirms effectiveness and safety of definitive HDR-BT for medically inoperable stage I-III endometrial cancer. The best LC was obtained in stage I low-risk histology.


A comparison of predictors for mortality and bacteraemia in patients suspected of infection.
Stratification by clinical scores of patients suspected of infection can be used to support decisions on treatment and diagnostic workup. Seven clinical scores, SepsisFinder (SF), National Early Warning Score (NEWS), Sequential Orgen Failure Assessment (SOFA), Mortality in Emergency Department Sepsis (MEDS), quick SOFA (qSOFA), Shapiro Decision Rule (SDR) and Systemic Inflammatory Response Syndrome (SIRS), were evaluated for their ability to predict 30-day mortality and bacteraemia and for their ability to identify a low risk group, where blood culture may not be cost-effective and a high risk group where direct-from-blood PCR (dfbPCR) may be cost effective. Retrospective data from two Danish and an Israeli hospital with a total of 1816 patients were used to calculate the seven scores. SF had higher Area Under the Receiver Operating curve than the clinical scores for prediction of mortality and bacteraemia, significantly so for MEDS, qSOFA and SIRS. For mortality predictions SF also had significantly higher area under the curve than SDR. In a low risk group identified by SF, consisting of 33% of the patients only 1.7% had bacteraemia and mortality was 4.2%, giving a cost of € 1976 for one positive result by blood culture. This was higher than the cost of € 502 of one positive dfbPCR from a high risk group consisting of 10% of the patients, where 25.3% had bacteraemia and mortality was 24.2%. This may motivate a health economic study of whether resources spent on low risk blood cultures might be better spent on high risk dfbPCR.


Pressure-Volume Loops for Reviewing Right Ventricular Physiology and Failure in the Context of Left Ventricular Assist Device Implantation.
Right ventricular (RV) function is complex as a number of determinants beyond preload, inotropy and afterload play a fundamental role. In particular, arterial elastance (Ea), ventriculo-arterial coupling (VAC), and (systolic) ventricular interdependence play a vital role for the right ventricle. Understanding and actively visualizing these interactions in the failing RV as well as in the altered hemodynamic and morphological situation of left ventricular assist device (LVAD) implantation may aid clinicians in their understanding of RV dysfunction and failure. While, admittedly, hard data is scarce and invasive pressure-volume loop measurements will not become routine in cardiac surgery, we hope that clinicians will benefit from the comprehensive, simulation-based review of RV pathology. In particular, the aim of this article is to first, address and clarify the pathophysiologic hemodynamic factors that lead to RV dysfunction and then, second, expand upon this basis examining the changes occurring by LVAD implantation. This is illustrated using Harvi software which shows elastance, ventricular arterial coupling, and ventricular interdependence by simultaneously showing pressure volume loops of the right and left ventricle.


Pharmacokinetics of a single oral dose of clobazam in patients with liver disease.
The pharmacokinetic effect of a single oral in dose of 20 mg clobazam was studied in 15 patients with liver disease and in 6 healthy volunteers. Plasma concentrations of clobazam and its main metabolite, norclobazam, were measured by gas liquid chromatography. Clobazam was rapidly absorbed. Peak plasma concentrations were 350 +/- 63 ng/ml at 1.7 +/- 0.8 hr in healthy volunteers, 239 +/- 70 ng/ml at 3 +/- 1.9 hr in patients with viral hepatitis and 240 +/- 113 ng/ml at 2.5 +/- 1.5 hr in patients with cirrhosis. Total distribution volume was 173 +/- 88 l and 168 +/- 71 l in patients with viral hepatitis and cirrhosis respectively, and 81 +/- 20 l in volunteers. Corresponding half-life values were 47 +/- 18 hr and 51 +/- 21 hr in patients and 22 +/- 6.3 hr in volunteers. The difference between patients was not significant, whereas the difference between patients and volunteers was significant.


Alkaloids from beach spider lily (Hymenocallis littoralis) induce apoptosis of HepG-2 cells by the fas-signaling pathway.
Alkaloids are the most extensively featured compounds of natural anti-tumor herbs, which have attracted much attention in pharmaceutical research. In our previous studies, a mixture of major three alkaloid components (5, 6-dihydrobicolorine, 7-deoxy-trans-dihydronarciclasine, littoraline) from Hymenocallis littoralis were extracted, analyzed and designated as AHL. In this paper, AHL extracts were added to human liver hepatocellular cells HepG-2, human gastric cancer cell SGC-7901, human breast adenocarcinoma cell MCF-7 and human umbilical vein endothelial cell EVC-304, to screen one or more AHL-sensitive tumor cell. Among these cells, HepG-2 was the most sensitive to AHL treatment, a very low dose (0.8μg/ml) significantly inhibiting proliferation . The non- tumor cell EVC-304, however, was not apparently affected. Effect of AHL on HepG-2 cells was then explored. We found that the AHL could cause HepG-2 cycle arrest at G2/M checkpoint, induce apoptosis, and interrupt polymerization of microtubules. In addition, expression of two cell cycle-regulated proteins, CyclinB1 and CDK1, was up-regulated upon AHL treatment. Up-regulation of the Fas, Fas ligand, Caspase-8 and Caspase-3 was observed as well, which might imply roles for the Fas/FsaL signaling pathway in the AHL-induced apoptosis of HepG-2 cells.


Effect of oxytocin administration on nerve recovery in the rat sciatic nerve damage model.
Growth factors such as nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) have been shown to play a role in the healing process of nerve injury. Recent researches have also shown that oxytocin administration activates these growth factors of importance for the healing of nerve tissue. The objective of the present study was to evaluate the effects of oxytocin on peripheral nerve regeneration in rats. Twenty-four male Sprague-Dawley rats were underwent transection damage model on the right sciatic nerve and defective damage model on the left sciatic nerve. The animals were assigned to one of two groups: control group or treatment group (received 80 mg/kg oxytocin intraperitoneally for 12 weeks). The sciatic nerve was examined, both functionally (on the basis of climbing platform test) and histologically (on the basis of axon count), 3, 6, 9, and 12 weeks after the injury. Also, stereomicroscopic and electrophysiological evaluations were carried out. Significantly greater improvements in electrophysiological recordings and improved functional outcome measures were presented in the treatment group at 12-week follow-up. Stereomicroscopic examinations disclosed prominent increases in vascularization on proximal cut edges in the oxytocin group in comparison with the control group. Higher axon counts were also found in this group. Intraperitoneal oxytocin administration resulted in accelerated functional, histological, and electrophysiological recovery after different sciatic injury models in rats.


Opioid Use and Morbidities during Left Ventricular Assist Device Support.
The use of opioids during left ventricular assist device (LVAD) support is increasing, but the implication remains unknown. We investigated the association between the use of opioid and morbidities during LVAD supports. We retrospectively reviewed the clinical data of patients who received LVAD between 2014 and 2017, which were stratified by the use of opioid at post-LVAD 3 months. Among 136 patients, 77 (57%) were in the opioid group. Hemoglobin and albumin were lower, and C-reactive protein was higher at baseline and 3 months later in the opioid group (P < 0.05 for all). The opioid group displayed worse hemodynamics, with higher pulmonary capillary wedge pressure and central venous pressure (P < 0.05 for both). Furthermore, the opioid group had higher incidences of gastrointestinal bleeding (31% versus 17%, P = 0.043) and sepsis (30% versus 13%, P = 0.036) during the 1 year observational period, whereas survivals were not stratified by the use of opioid (83% versus 90%, P = 0.27). Opioid use was associated with morbidities accompanied by poor hemodynamics during LVAD supports. The detailed causality of opioid use on morbidities remains a future concern.


Development of Biodegradable Rigid Foams from Pineapple Field Waste.
Pineapple materials sourced from agricultural waste have been employed to process novel bio-degradable rigid composite foams. The matrix for the foam consisted of starch extracted from pineapple stem, known for its high amylose content, while the filler comprised non-fibrous cellulosic materials sourced from pineapple leaf. In contrast to traditional methods that involve preparing a batter, this study adopted a unique approach where the starch gel containing glycerol were first formed using a household microwave oven, followed by blending the filler into the gel using a two-roll mill. The resulting mixture was then foamed at 160 °C using a compression molding machine. The foams displayed densities ranging from 0.43-0.51 g/cm3 and exhibited a highly amorphous structure. Notably, the foams demonstrated an equilibrium moisture content of approximately 8-10% and the ability to absorb 150-200% of their own weight without disintegration. Flexural strengths ranged from 1.5-4.5 MPa, varying with the filler and glycerol contents. Biodegradability tests using a soil burial method revealed complete disintegration of the foam into particles measuring 1 mm or smaller within 15 days. Moreover, to showcase practical applications, an environmentally friendly single-use foam tray was fabricated. This novel method, involving gel formation followed by filler blending, sets it apart from previous works. The findings highlight the potential of pineapple waste materials for producing sustainable bio-degradable foams with desirable properties and contribute to the field of sustainable materials.


Fluorescence correlation spectroscopy and photon counting histogram on membrane proteins: functional dynamics of the glycosylphosphatidylinositol-anchored urokinase plasminogen activator receptor.
The oligomerization of glycosylphosphatidylinositol-anchored proteins is thought to regulate their association with membrane microdomains, subcellular sorting, and activity. However, these mechanisms need to be comprehensively explored in living, unperturbed cells, without artificial clustering agents, and using fluorescent protein-tagged chimeras that are fully biologically active. We expressed in human embryo kidnay 293 (HEK293) cells a biologically active chimera of the urokinase plasminogen activator receptor (uPAR), the uPAR-mEGFP-GPI. We also produced HEK293/D2D3-mEGFP-GPI cells expressing the truncated form of the receptor, lacking biological activity. We studied the dynamics and oligomerization of the two proteins, combining fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) analyses, and using subclones with homogenously low expression levels. Overall, the mobile fractions of the two proteins, constituted by monomers and dimers, had comparable diffusion coefficients. However, the diffusion coefficient decreased in monomer-enriched fractions only for the active receptor, suggesting that uPAR monomers might be preferentially engaged in multiprotein transmembrane signaling complexes. Our approach helps in limiting the alteration of the data due to out-of-focus effects and in minimizing the overestimation of the molecular brightness. In addition to a careful design of the cellular model, it gives reliable estimates of diffusion coefficients and oligomerization of GPI-anchored proteins, in steady-state conditions, at low expression levels, and in live, unperturbed cells.


The gene encoding the major proline transporter of Aspergillus nidulans is upregulated during conidiospore germination and in response to proline induction and amino acid starvation.
In Aspergillus nidulans a highly specific L-proline transporter is encoded by the prnB gene which is tightly linked to all other genes involved in proline catabolism. In mycelia, the expression of the prn structural genes is finely co-regulated in response to proline induction and nitrogen/carbon catabolite repression. In this study we establish that prnB expression is also activated during germination of conidiospores. This activation persists until the development of 6 h-old mycelia and it is independent of proline induction mediated by the pathway-specific prnA gene product. We then show that, in mycelia, prnB transcription is activated in response to proline or histidine starvation. This process has two components: a prnA-dependent and a prnA-independent component. A cis-acting element that conforms to the consensus target of the GCN4/CPC1 transcriptional activators mediating amino acid biosynthesis activation in other fungi is involved in the activation of prnB transcription in response to amino acid starvation. We also show that the stimulation of prnB expression in germinating conidiospores is not due exclusively to transient internal amino acid starvation occurring during the transition from conidiospore to mycelium. This is the first report that an amino acid transporter gene is upregulated during development and in response to amino acid starvation and specific amino acid induction.


The Current Role of Whole Brain Radiation Therapy in Non-Small Cell Lung Cancer Patients.
The incidence of brain metastases has increased in patients with NSCLC as a result of better systemic disease control and advances in imaging modalities. Whole brain radiotherapy (WBRT) has been the mainstay treatment of multiple symptomatic brain metastases for years. A number of recent publications have questioned its place in the absence of a survival and quality of life benefit and the possible risk for long-term neurotoxicity. Omission or deferral of WBRT and strategies consisting of stereotactic radiosurgery or delivery of systemic therapies alone are being proposed more and more. However, critical analysis of the literature shows that WBRT still has relevant indications in well-selected patients. Within this review, we discuss the place of WBRT in the modern management of patients with NSCLC.


Chemical modification of Streptococcus flagellar motors.
Video techniques were used to record changes in motility of cells of Streptococcus sp. strain V4051 exposed to a variety of protein modification reagents. Starved cells were tethered to glass by a single flagellum, energized metabolically with glucose, or treated with valinomycin and energized artificially via shifts to media containing low concentrations of potassium ion. Experiments were devised that distinguished reagents that lowered the proton motive force from those that blocked the generation of torque (damaged the flagellar motors). Imidazole reagents blocked the generation of torque. Amino, sulfhydryl, dithiol, and disulfide reagents did not. Some of the imidazole, amino, and sulfhydryl reagents had long-term effects on the direction of flagellar rotation.


Late Effects of 16O-Particle Radiation on Female Social and Cognitive Behavior and Hippocampal Physiology.
The radiation environment in space remains a major concern for manned space exploration, as there is currently no shielding material capable of fully protecting flight crews. Additionally, there is growing concern for the social and cognitive welfare of astronauts, due to prolonged radiation exposure and confinement they will experience on a mission to Mars. In this artice, we report on the late effects of 16O-particle radiation on social and cognitive behavior and neuronal morphology in the hippocampus of adult female mice. Six-month-old mice received 16O-particle whole-body irradiation at doses of either 0.25 or 0.1 Gy (600 MeV/n; 18-33 cGy/min) at the NASA's Space Radiation Laboratory in Upton, NY. At nine months postirradiation, the animals underwent behavioral testing in the three-chamber sociability, novel object recognition and Y-maze paradigms. Exposure to 0.1 or 0.25 Gy 16O significantly impaired object memory, a 0.25 Gy dose impaired social novelty learning, but neither dosage impaired short-term spatial memory. We observed significant decreases in mushroom spine density and dendrite morphology in the dentate gyrus, cornu ammonis 3, 2 and 1 of the hippocampus, which are critical areas for object novelty and sociability processing. Our data suggest exposure to 16O modulates hippocampal pyramidal and granular neurons and induces behavioral deficits at a time point of nine months after exposure in females.


Functional and psychological characteristics of belgian men with premature ejaculation and their partners.
Physiological, behavioral, cognitive, and emotional factors are generally acknowledged to play a role in premature ejaculation (PE). However, the nature and the extent of their etiological impact remain largely imprecise. The present study examined functional and psychometric dynamics at work in a PE population. A total of 461 men with PE and 80 partners completed an online questionnaire. The main outcome measures were self-reported ejaculatory latency time, the feeling of control upon ejaculation, sexual satisfaction, distress related to PE, trait anxiety (STAI-B), sexual cognitions (Sexual Irrationality Questionnaire [SIQ]), social anxiety (Liebowitz's Social Anxiety Scale [LSAS] and Social Interaction Self-Statement Test [SISST]), and personality traits (Temperament and Character Inventory-Revised [TCI-R]). In our sample, the median latency time to ejaculation was between 1 and 2 min. Sexual satisfaction and distress correlated more strongly with the feeling of control than with the self-reported latency time. Men experienced more distress and dissatisfaction related to PE than did their partners, while overestimating their partners' distress and dissatisfaction. PE participants' scores differed significantly, albeit slightly, from STAI-B, SIQ, LSAS, and SISST norms. The differences were negligible on TCI-R. Some differences became stronger when subtypes were considered. Participants combining generalized and lifelong PE with self-reported latency times of <30 s reported lower sexual satisfaction and control, higher distress, higher social anxiety, and harm avoidance (TCI-R/HA) scores. By contrast, the situational subtype of PE was found to be characterized by a higher level of satisfaction, a greater feeling of control, less distress, and higher trait anxiety scores. However, the trends remained statistically discrete.


Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases.
Reactive oxygen species (ROS) are reactive intermediates of molecular oxygen that act as important second messengers within the cells; however, an imbalance between generation of reactive ROS and antioxidant defense systems represents the primary cause of endothelial dysfunction, leading to vascular damage in both metabolic and atherosclerotic diseases. Endothelial activation is the first alteration observed, and is characterized by an abnormal pro-inflammatory and pro-thrombotic phenotype of the endothelial cells lining the lumen of blood vessels. This ultimately leads to reduced nitric oxide (NO) bioavailability, impairment of the vascular tone and other endothelial phenotypic changes collectively termed endothelial dysfunction(s). This review will focus on the main mechanisms involved in the onset of endothelial dysfunction, with particular focus on inflammation and aberrant ROS production and on their relationship with classical and non-classical cardiovascular risk factors, such as hypertension, metabolic disorders, and aging. Furthermore, new mediators of vascular damage, such as microRNAs, will be discussed. Understanding mechanisms underlying the development of endothelial dysfunction is an important base of knowledge to prevent vascular damage in metabolic and cardiovascular diseases.


'Lifelong investment in health': the discursive construction of 'problems' in Hong Kong health policy.
This paper reflects on the contemporary health policy debate in Hong Kong, and the shape assigned to particular 'problems'. Health reform discourses are identified to reveal the tensions that exist between the dominant biomedical discourse that focuses on individual responsibility, lifestyle change and health education while articulating a community development approach to health care reform. A critical review of the Consultation Document on Health Care Reform in Hong Kong, entitled Lifelong Investment in Health, will reveal a rhetorical commitment to health care reform alongside proposals that suggest little understanding of the changes required to implement such reform. In fact, the document proposes a model of health care that not only remains within the biomedical paradigm, but which if enacted may extend the influence of medicine into the psychosocial sphere. Edelman has defined policy as 'a set of shifting, diverse, and contradictory responses to a spectrum of political interests'. The starting point from this perspective is the identification of the discursive construction of policy problems and the associated 'spectrum of political interests'. It is an attempt to reveal the operation of power in places in which administrative, political and professional discourses tend to obscure it.


[In vitro measurement of the inhibitory effect of macrolides, lincosamides and synergestines on the growth of Toxoplasma gondii].
The in vitro inhibitory effect of macrolides, synergestines and lincosamides on Toxoplasma gondii was evaluated using an enzyme immunoassay performed directly on the infected cultures. Antimicrobial agents were tested at various concentrations, and regression models were used to quantify the relationship between optical density values (correlated to Toxoplasma count in the cultures) and drug concentrations in the cultures. A significant inhibitory effect was observed with the macrolides (erythromycin, roxithromycin, midecamycin, spiramycin, josamycin and oleandomycin) for concentration of 0.1 to 4 micrograms/ml. This effect progressively increased with increasing concentration of drug in the cultures and reached its maximum value for concentrations of 40 to 250 micrograms/ml. Similarly, clindamycin was found to have a significant inhibitory effect for concentration ranging from 0.5 ng/ml to 100 micrograms/ml. Only a partial inhibitory effect was noted with virginiamycin, pristinamycin and lincomycin. The concentrations giving a 50% inhibition of Toxoplasma growth in the culture were determined from regression models and ranged between 0.15 and 12 micrograms/ml according to the drug. This results confirm that macrolides, lincosamides are effective against Toxoplasma gondii in vitro, and can be proposed for treatment of toxoplasmosis because of their large diffusion, their good tolerance and their concentration in tissues such as lung and placenta.


Surfactant Modified Graphite Paste Electrode as an Electrochemical Sensor for the Enhanced Voltammetric Detection of Estriol with Dopamine and Uric acid.
Purpose: Estriol (ERL) is a type of hormone among the groups of estrogen hormone that was detected through the voltammetric technique by constructing an electrochemical sensor based on the octoxynol-9 modified graphite paste electrode (OXL-9MGPE). Methods: Using the strategy of cyclic voltammetry (CV) and differential pulse voltammetry (DPV) with a bare graphite paste electrode (BGPE) immobilized with OXL-9, ERL electro-oxidation has been assessed in 0.2 M phosphate buffer solution (PBS) of pH 6.0. The fabricated electrode has substantial electrochemical sensing efficiency, and the ERL oxidation at the OXL-9MGPE was the irreversible process. The surface morphological characteristics of BGPE and OXL-9MGPE were differentiated with the help of field emission scanning electron microscopy (FE-SEM). Results: The impact of various factors such as scan rate, pH, reproducibility, repeatability, and stability on the electro-oxidation of ERL was evaluated. Techniques of CV and DPV were utilized to determine ERL, dopamine (DAN), and uric acid (URA) simultaneously with the projected sensor. The peak current was varied with ERL concentration in the range from 4×10-5 to 1.2×10-4 M at OXL-9MGPE. From this, the detection limit 1.4×10 -6 M and limit of quantification (LOQ) 4.7×10-6 M have been attained. Conclusion: As a result, OXL-9MGPE was successfully achieved as an electrochemical detector for the electro analysis of ERL via the CV technique.


Sealing Behaviour of Container Closure Systems under Frozen Storage Conditions: Nonlinear Finite Element Simulation of Serum Rubber Stoppers.
There has been a growing interest in recent years in the assessment of suitable vial/stopper combinations for storage and shipment of frozen drug products. Considering that the glass transition temperature (Tg) of butyl rubber stoppers used in container closure systems (CCSs) is between -55 °C to -65 °C, a storage or shipment temperature of a frozen product below the Tg of the rubber stopper may require special attention because below the Tg the rubber becomes more plastic like and loses its elastic (sealing) characteristics. Thus, they risk not maintaining container closure integrity (CCI). Given that the rubber regains its elastic properties and reseals after rewarming to ambient temperature, leaks during frozen temperature storage and transportation are transient and the CCI methods used at room temperature conditions are unable to confirm CCI in the frozen state. Hence, several experimental methods have been developed in recent years in order to evaluate CCI at low temperatures. Finite element (FE) simulations were applied in order to investigate the sealing behaviour of rubber stoppers for the drug product CCS under frozen storage conditions. FE analysis can help in reducing the experimental design space and thus the number of measurements needed, as they can be used as an add-on to experimental testing. Several scenarios have been simulated including the effect of thermal history, rubber type, storage time, worst-case CCS geometric tolerances, and capping pressure. The results of these calculations have been validated with experimental data derived from laboratory experiments (CCI at low temperatures), and a concept for tightness has been developed. It has been concluded that FE simulations have the potential to become a powerful predictive tool toward a better understanding of the influence of cold storage on the rubber sealing properties (and hence on CCI) when dealing with frozen drug products.LAY ABSTRACT: The growing interest in the assessment of suitable vial/stopper combinations for storage and shipment of frozen drug products has led to the development of a number of experimental methods to evaluate container closure integrity at low temperatures. The application of finite element simulations could aid in the investigation of the sealing behaviour of rubber stoppers for drug product container closure systems under frozen storage conditions by simplifying the experimental design space and the number of experimental measurements needed. In this work several scenarios have been simulated including the effect of thermal history, rubber type, storage time, worst-case container closure system geometric tolerances, and capping pressure. The results have been further validated with experimental data derived from laboratory experiments and a concept for tightness was developed. In conclusion, finite element simulations have shown the potential to become a powerful predictive tool toward a better understanding of the influence of cold storage on the rubber sealing properties (and hence on container closure integrity) when dealing with frozen drug products.


Efficiency of antiscatter grids for flat-detector CT.
Flat-panel detector CT (FD-CT) scanners offer large volume coverage, but as a consequence are more susceptible to scatter artifacts than standard clinical CT scanners with smaller cone angles. FD-CT scanners can employ antiscatter grids as a scatter rejection technique. We evaluated three standard fluoroscopic antiscatter grids for two different field sizes with respect to scatter suppression efficiency and image quality improvement. The evaluations included simulations and measurements. Regarding the simulation a hybrid model combining deterministic and Monte Carlo (MC) calculations was used combined with an analytical calculation of grid transmission. The scatter-to-primary ratio (SPR) was measured using an adapted collimator technique in order to validate our simulations. The SPR obtained by simulations and measurements with and without antiscatter grids were in agreement typically within 10%. The employment of a grid does not generally provide a significant improvement of the signal-to-noise ratio (SNR). Antiscatter grids led to a significant reduction of cupping artifacts in all cases. There is a trade-off between the SNR and the reduction of the scatter intensity described by the signal-to-noise improvement factor (SNR(if)). For low- or medium-scatter conditions the increase in noise caused by the reduced primary transmission through the grid has to be compensated by a higher exposure. For high scatter conditions SNR(if) is significantly greater than 1; i.e. a decrease of dose of up to 50% can be reached.


Analysis of the specificity of anti-PM-Scl autoantibodies.
To compare the specificity of anti-PM-Scl autoantibodies in serum samples from 43 patients with myositis, scleroderma, or both. Anti-PM-Scl immunoprecipitates from HeLa cell extract were used as antigen for immunoblot analyses to determine the antigenic components. A series of complementary DNA fragments was expressed in Escherichia coli for immunoblot examination of the reaction with the 100-kd protein. The immunoblot against immunoprecipitates was sensitive and specific for detecting reactions with components of the PM-Scl antigen: 42 of 43 sera (97.7%) reacted with the 100-kd, 27 of 43 (62.8%) with the 70-kd, and 5 of 43 (11.6%) with the 37-kd protein (not previously recognized as antigenic). Forty-one sera reacted with N-terminal protein S1 (amino acids 11-437), 39 with central protein S2 (amino acids 439-749), and 24 with C-terminal protein S3 (amino acids 750-882). Of 42 sera tested, 28 (66.7%) reacted most strongly with S1, and 6 (14.3%) reacted most strongly with S2. Absorption studies implied additional, conformational epitopes not present on the bacterially expressed antigen. There was an overall similarity in reactivity to the PM-Scl antigen, but there were differences in the reactivity to the 70-kd and 37-kd proteins, as well as in the relative strength of the reactivity to the S2 protein.


Understanding consumers' health information preferences: development and validation of a brief screening instrument.
The impact of health communication is generally enhanced when it is targeted or tailored to the needs of a specific population or individual. In a segmentation analysis of the U.S adult population - using data from 2,636 respondents to a mail panel survey - we identified four segments of the adult population that vary significantly with regard to health information preferences based on their degree of engagement in health enhancement, and their degree of independence in health decision making. We also created a brief (10 item), easy-to-administer screening instrument that indicates into which segment people fall. The purpose of this article is to describe the segments, and the screening instrument, and to present initial tests of its validity. We believe this instrument offers a practical tool for differentiating motivationally coherent subgroups of the adult population with regard to their health information preferences, and therefore may have practical value in improving health communication and health services provision efforts. Additional research is needed to further validate the tool and test its utility in guiding the creation of targeted health messages and programs.


Investigating local and systemic intestinal signalling in health and disease with Drosophila.
Whole-body health relies on complex inter-organ signalling networks that enable organisms to adapt to environmental perturbations and to changes in tissue homeostasis. The intestine plays a major role as a signalling centre by producing local and systemic signals that are relayed to the body and that maintain intestinal and organismal homeostasis. Consequently, disruption of intestinal homeostasis and signalling are associated with systemic diseases and multi-organ dysfunction. In recent years, the fruit fly Drosophila melanogaster has emerged as a prime model organism to study tissue-intrinsic and systemic signalling networks of the adult intestine due to its genetic tractability and functional conservation with mammals. In this Review, we highlight Drosophila research that has contributed to our understanding of how the adult intestine interacts with its microenvironment and with distant organs. We discuss the implications of these findings for understanding intestinal and whole-body pathophysiology, and how future Drosophila studies might advance our knowledge of the complex interplay between the intestine and the rest of the body in health and disease.


[What is behind masked hypertension?].
In approximately 10% of adults, ambulatory blood pressures recorded during everyday activities or selfmeasured blood pressures are abnormally elevated whereas office blood pressures are in a normal range. This type of blood pressure behavior, known as masked hypertension, is associated with an increased cardiovascular risk. It may be pertinent to search for the presence of masked hypertension in individuals having sometimes elevated, sometimes normal office blood pressures, as well as in very high risk patients and in patients requiring an optimal blood pressure control, such as for instance in those with diabetes or nephropathy.


[A new needle for colon-proctological surgery: personal experience].
Rectocele and haemorrhoidal prolapse are two pathologies that in all cases entail partial excision of anorectal tissue possibly with less invasive surgical procedures. For these pathologies, the authors have recently improved their treatment procedures, introducing the sequential transfixed stitch technique (STST) for rectocele and the transfixed stitch technique (TST) for haemorrhoidal prolapse, and thereby obtaining a significant technical and clinical improvement in terms of both outcomes (complete correction of rectal prolapse and haemorrhoidal prolapse) and discomfort and quality of life in the postoperative period. Moreover, in the present study the authors propose a subsequent innovation of the technique developed recently for the treatment of rectocele and haemorrhoidal disease using a new curved siliconate needle, thinner than the traditional lanceolate needles, with a longer, more rigid needle-thread junction in order to achieve less invasiveness and mucosal trauma, enabling the surgeon to perform sutures in a simple, easy manner. Ten consecutive patients with a clinical and instrumental diagnosis of rectocele--6 type II and 4 type III--were treated with TSTS and 20 patients with third (12 patients) and fourth degree (8 patients) haemorrhoidal disease were treated with TST. The surgical procedures were the same for all patients, although patients were divided into two groups. To the first group (A) were allocated patients treated with traditional stitches with a cylindrical, half circle needle, (Hr 25.9 mm). To the second group (B) were allocated, for the same objective, patients treated with the new siliconate needle, with an ultrafine tip, manufactured by Assut Europe S.p.A. The mean duration of the TST surgical procedures was 16 minutes using the new siliconate needle, whereas the mean duration using the traditional lanceolate needle was 17 minutes (p = ns). The surgical team judged the TST performed with the siliconate needle to be easier in 90% of cases in comparison to 70% of cases treated with the traditional lanceolate needle (p < 0,05). In patients treated with TSTS using the traditional lanceolate needle the mean duration of the surgical procedures was 20 minutes as against 18 minutes in the cases treated with the siliconate needle (p = ns). The surgical team judged the TSTS performed with the siliconate needle to be easier in all cases, while in two cases treated with the traditional lanceolate needle there were technical difficulties related to the use of the needle. The use of the ultrafine siliconate siliconate needle is more effective for the treatment of rectocele with TSTS and for haemorrhoidectomy with TST, particularly with a view to improving the surgical procedures and limiting the extent of mucosal damage related to suture oedema.