Phenological, morpho-physiological and proteomic responses of Triticum boeoticum to drought stress.
Drought is the most important abiotic stress limiting wheat production worldwide. Triticum boeoticum, as wild wheat, is a rich gene pool for breeding for drought stress tolerance. In this study, to identify the most drought-tolerant and susceptible genotypes, ten T. boeoticum accessions were evaluated under non-stress and drought-stress conditions for two years. Among the studied traits, water-use efficiency (WUE) was suggested as the most important trait to identify drought-tolerant genotypes. According to the desirable and undesirable areas of the bi-plot, Tb5 and Tb6 genotypes were less and more affected by drought stress, respectively. Therefore, their flag-leaves proteins were used for two-dimensional gel electrophoresis. While, Tb5 contained a high amount of yield, yield components, and WUE, Tb6 had higher levels of water use, phenological related traits, and root related characters. Of the 235 spots found in the studied accessions, 14 spots (11 and 3 spots of Tb5 and Tb6, respectively) were selected for sequencing. Of these 14 spots, 9 and 5 spots were upregulated and downregulated, respectively. The identified proteins were grouped into six functional protein clusters, which were mainly involved in photosynthesis (36%), carbohydrate metabolism (29%), chaperone (7%), oxidation and reduction (7%), lipid metabolism and biological properties of the membrane (7%) and unknown function (14%). We report for the first time that MICP, in the group of lipid metabolism proteins, was significantly changed into wild wheat in response to drought stress. Maybe, the present-identified proteins could play an important role to understand the molecular pathways of wheat drought tolerance. We believe comparing and evaluating the similarity-identified proteins of T. boeoticum with the previously identified proteins of Aegilops tauschii, can provide a new direction to improve wheat tolerance to drought stress.


Congenital pyloric atresia and epidermolysis bullosa letalis in premature siblings.
Epidermolysis bullosa letalis has been associated with congenital pyloric atresia in an autosomal recessive syndrome. This report documents the second occurrence in premature siblings. Our review indicates that it is a lethal condition with death due to the septic complications of epidermolysis bullosa letalis. Surgical management of pyloric atresia should be withheld until the severity of the epidermolysis is known. Skin biopsy to document the type of epidermolysis bullosa is imperative as only the letalis form is documented to be lethal. The risk for subsequent siblings is 25% and parents should undergo genetic counseling. Prenatal diagnosis of epidermolysis bullosa letalis can be made by fetoscopic skin biopsy. We suggest nonoperative management of pyloric atresia unless the skin disease is responsive to treatment.


A novel assay for the determination of PreScission protease by capillary electrophoresis.
The detection of protease activity in the body plays a significant role in the early diagnosis of diseases. However, enzymes inevitably come into contact with various complex biological fluids in the body during the flow, which greatly increases the detection difficulty. Therefore, protease detection in vivo has great challenges. Herein, we report a new assay for detecting protease using capillary electrophoresis inside a capillary with semicircular bends. We first designed a peptide substrate, and then the peptide was self-assembled with quantum dots to form a QDs-peptide substrate. The capillary was bent to semicircular-shaped turns and served as a micro-reactor to allow protease and substrate react in it. Due to the different electrophoretic velocity, the protease and the substrate were mixed inside the bent capillary with sequential injections and the cleavage of the substrate can be detected using capillary electrophoresis combined with Förster resonance energy transfer technology. This novel assay will greatly expand the detection of enzyme activity in vivo.


Effects of the Brazilian phytopharmaceutical product Ierobina on lipid metabolism and intestinal tonus.
Ierobina is a Brazilian phytopharmaceutical product indicated for the treatment of dyspepsia. It contains the hydroethanolic extracts of Solanum paniculatum L. (Solanaceae), Remijia ferruginea D.C. (Rubiaceae), Jacaranda caroba D.C. (Bignoniaceae) and Erythraea centaurium (L.) Borkh. (Gentianaceae), species traditionally used to treat gastrointestinal disorders. The effect of Ierobina on the digestive system was investigated in rats fed with normal or high-fat (HF) diets, at doses of 2.16, 4.32 and 8.64 mg/kg. The product did not affect the plasmatic levels of glucose, total cholesterol and HDL-cholesterol in the evaluated doses, whereas the triacylglycerol (TAG) concentration showed a dose-dependent increase in HF-fed animals. TAG-rich lipoprotein uptake, estimated by measuring total lipoprotein lipase activity in epididymal adipose tissue, was accompanied by TAG increase in HF-fed rats, after Ierobina administration. The product also induced a concentration-dependent relaxant effect on spontaneous ileum contractions and on the rat ileum pre-contracted with carbachol. Together, these results support the indication of Ierobina as an anti-dyspeptic agent.


Study designs for timely estimation of influenza vaccine effectiveness using European sentinel practitioner networks.
European sentinel practitioner influenza surveillance networks represent a simple and feasible framework to conduct observational studies providing rapid and repeated influenza vaccine effectiveness estimates. The minimum requirements for those studies should be to correctly ascertain vaccination status, to include laboratory-confirmed influenza as outcome and to collect variables to control for confounding. Various study designs are possible including the screening method, computerised cohort and case control studies using various control groups. Selecting the study design is a compromise between methodological constraints, availability and ease of access to data sources and resources available. Results from practitioner-based studies complement other pieces of evidence (e.g. immunogenicity studies, vaccine efficacy, surveillance data) to assess the effect of influenza vaccination in the population.


The binding between p67 and eukaryotic initiation factor 2 plays important roles in the protection of eIF2alpha from phosphorylation by kinases.
Phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 is the major regulatory step in the initiation of protein synthesis in mammals. P67, a cellular glycoprotein, protects phosphorylation of eIF2alpha from kinases. Previously, we reported that the D6/2 mutant of p67 has higher levels of protection of eIF2alpha phosphorylation (POEP) activity. In this study, we report that the D6/2 mutant and its double mutants containing second-site alanine substitutions at the five conserved amino acid residues (D251, D262, H331, E364, and E459) show increased POEP activity in serum-starved rat tumor hepatoma cells. Serum-restoration to those cells did not abolish their increased POEP activity except the D6/2+H331A double mutant. The latter mutant shows slight inhibition of POEP activity during serum starvation and this inhibition increased significantly during serum restoration. KRC-7 cells constitutively expressing the D6/2 mutant showed slightly decreased levels of PKR phosphorylation and significantly low level of phosphorylation of ERKs 1 and 2. The D6/2 mutant also showed increased binding with eIF2alpha and eIF2gamma and almost similar binding with ERKs 1 and 2 as compared to wild type p67. Altogether, our data demonstrate that the increased binding of the D6/2 mutant with the subunits of eIF2 may be in part the cause for its high POEP activity.


Improvement of the antihypertensive capacity of candesartan and trityl candesartan by their SOD mimetic copper(II) complexes.
Two new complexes [Cu(Cand)(H2O)4] [1] and [Cu2(TCand)4(H2O)2]·4H2O [2] (Cand = candesartan; TCand = trityl candesartan) have been synthesized and thoroughly characterized. The FTIR, Raman, EPR and diffuse reflectance spectra of the solid compounds show a dimeric complex for [2] with carboxylate bridging of the type found in copper(II) acetate. Both elemental analysis and thermal measurements allow the determination of the total stoichiometries of both complexes. The stability measurements show that the compounds are stable in ethanolic solutions at least for 1h, while the preservation of the overall stochiometry for both species in solution has been determined by spectrophotometric titrations. By metal complexation the absence of antioxidant behavior of both sartans has been improved. Complexes [1] and [2] are strong superoxidedismutase mimetic compounds and complex [2] also behaves as a peroxyl radical scavenger. Furthermore, this higher antioxidant activity works in parallel with the improvement of the expansive activity over the angiotensin II-induced contracted human mesangial cells. These new complexes exhibit even higher efficiency as drugs in comparison with the free non-complexed medication with increased antioxidant ability expressing higher capacity to block the angiotensin II contractile effect. This study provides a new insight into the development of copper(II) complexes as potential drugs.


Low dose acetyl salicylic acid in severe preeclampsia.
Twenty pregnant patients in the third trimester with severe preeclampsia were allocated at random into two equal groups. The first group was treated for 10 days with a low dose (75 mg/day) of acetyl salicylic acid (ASA) then with conventional therapy for another 10 days. The second group received the same regimen but conventional therapy in the first 10 days and ASA in the second 10 days. Changes in systolic and diastolic blood pressure, albuminuria, lower limb edema and urinary output were closely monitored and recorded. This comparative crossover study indicated that both the low dose ASA and conventional therapy significantly reduced systolic and diastolic blood pressure which was more pronounced with ASA and in group I. Crossover from one treatment to the other maintained the response but was more beneficial when ASA was given first.


Diagnostic Accuracy of a Bedside Screening Tool for Dysphagia (BSTD) in Acute Stroke Patients.
an estimated 40-80% of acute ischemic stroke patients have dysphagia and about 14% develop stroke-associated pneumonia. However, it may be difficult to detect swallowing problems at admission. Moreover, there might not be an on-duty specialist skilled in the diagnosis of this condition. This study aimed at developing a user-friendly bedside examination to identify the risk of dysphagia in stroke patients at hospital admission. a diagnostic accuracy study was carried out to assess the concurrent validity of a simple Bedside Screening Tool for Dysphagia (BSTD) in acute stroke. All the consecutive stroke patients admitted between January and April 2018 were enrolled. Sensitivity, specificity, positive (PPV), negative predictive values (NPV) and the Cohen K concordance index scores, reported by nurses and speech-pathologists, were assessed. a total of 67/120 patients (55.8%) were male; overall average age was 67.4 (range 45-91) and 80.8% of the whole population had a history of ischemic stroke. The nursing staff identified 33.3% of dysphagia cases at admission and the speech pathologists 30%. The Cohen K was 0.92 (optimal concordance when K was > 0.8), sensitivity was 100%, specificity 95.2%, PPV 90% and NPV 100%. our BSTD had a 100% negative predictive value, indicating that this screening test is very useful in ruling out/confirming dysphagia in acute stroke patients.


Total discrimination of peritoneal malignant ascites from cirrhosis- and hepatocarcinoma-associated ascites by assays of ascitic cholesterol and lactate dehydrogenase.
No laboratory test completely distinguishes malignant ascites (MA) from ascites associated with cirrhosis and (or) hepatocellular carcinoma (A/C-HC). Ascitic cytology is highly specific but has a diagnostic sensitivity of only 40-60%. We determined 11 ascitic analytes and cytology in 58 patients with cirrhosis, 15 with hepatocellular carcinoma, and 21 with MA (10 ovarian cancers, 4 mesotheliomas, 6 gastrointestinal neoplasias, 1 leukemia). Ascitic total protein, cholesterol, pseudouridine, and lactate dehydrogenase (LD), and the ascitic:serum ratios of total protein and of LD showed the most significant differences between the two groups of patients. Stepwise multiple linear discriminant analysis (applying the Wilks' lambda criterion) of several variables, corroborated by the "jack-knife" reallocation procedure, showed that the ascitic cholesterol and ascitic LD association correctly identified 100% of MA and A/C-HC; cytology had a diagnostic specificity of 100%, but identified only 48% of MA. This association may represent a primary tool for the discrimination of ascites of unknown origin, particularly in the presence of negative cytology findings.


The role and influence of bacteria on the growth of Blastocystis sp. subtype 3.
Blastocystis sp. is an enteric protistan parasite that affects individuals worldwide with gastrointestinal symptoms such as abdominal discomfort, diarrhea, and flatulence. However, its pathogenicity is controversial due to its presence among asymptomatic individuals. Blastocystis sp. subtype 3 (ST3) is the most prevalent subtype among humans that have been associated with irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, and colorectal cancer. Axenization of the parasite has been shown to impede its growth thus revealing the importance of accompanying bacteria in ensuring Blastocystis sp. survival. This study aims to identify the influence of accompanying bacteria on the growth of Blastocystis sp. ST3. Blastocystis sp. cultures were treated with Meropenem, Vancomycin, and Amoxicillin-Clavulanic acid (Augmentin). Bacteria-containing supernatant of antibiotic-treated and control cultures were isolated and identified through 16 s rRNA sequencing. Morphological changes of antibiotic-treated Blastocystis sp. ST3 were also observed. The cultures treated with meropenem and augmentin exhibited opposing effects with reduced growth of isolates from symptomatic patients and a significant increase in asymptomatic isolates. Whereas, vancomycin-treated cultures had no difference in the growth of Blastocystis sp. ST3 isolates from symptomatic and asymptomatic patients. Isolates from symptomatic and asymtomatic patients had 6 and 2 distinct bacterial species identified with Proteus mirabilis as the common bacteria among both types of isolates. Morphologically, Blastocystis sp. ST3 cultures exposed to meropenem and augmentin demonstrated an increase in pre-cystic forms. These findings demonstrate the effects of accompanying bacteria on the growth of Blastocystis sp. ST3 that could translate into clinical manifestations observed among Blastocystis sp.-infected patients.


Identification and characterization of a serine protease inhibitor with two trypsin inhibitor-like domains from the human hookworm Ancylostoma duodenale.
Protease inhibitors play important roles in the parasitic nematodes' survival within their host, in the development and reproduction of the parasites. The present study described the isolation, identification, and characterization of a novel member of the Ascaris family of serine protease inhibitors, designated AduTIL-1, from the human hookworm Ancylostoma duodenale. AduTIL-1 is composed of a signal sequence and two trypsin inhibitor-like (TIL) domains, which showed the highest similarity with OdmCRP, a putative serine protease inhibitor with two TIL domains in Oesophagostomum dentatum. Each TIL domain of the AduTIL-1 was expressed in Escherichia coli, and their inhibitory activities against serine proteases from animals and human were characterized, respectively. Both of the two TIL domains inhibited human neutrophil elastase and pancreatic trypsin, but different in effectiveness. Although the first TIL domain of AduTIL-1 inhibited bovine pancreatic chymotrypsin (Ki=18.0 nM), both of the two domains showed no inhibitory activity against the human pancreatic chymotrypsin. Immunohistochemical studies demonstrated that AduTIL-1 was localized in esophagus, intestine, and cuticular surface of the adult worms. These results suggested that AduTIL-1 may be involved in the survival of A. duodenale in host by targeting related digestive enzymes and neutrophil elastase.


Muscle imaging in clinical practice: diagnostic value of muscle magnetic resonance imaging in inherited neuromuscular disorders.
This review reports on the use of muscle magnetic resonance imaging as a clinical and research tool in inherited neuromuscular disorders. Several papers published during the past few years have reported on the value of muscle magnetic resonance imaging in detecting patterns of muscle involvement in various muscular dystrophies and other inherited myopathies. The patterns of muscle involvement observed on muscle magnetic resonance imaging are often specific for distinct genetic entities. Our review of the literature suggests that muscle magnetic resonance imaging can provide information that is useful in clinical practice and may be used as an additional tool in a diagnostic flow chart to select appropriate genetic and biochemical investigations.


Testis-specific products of the Drosophila melanogaster sbr gene, encoding nuclear export factor 1, are necessary for male fertility.
The evolutionarily conserved nuclear export factor 1 (NXF1) provides mRNA export from the nucleus to the cytoplasm. We described several testis-specific transcripts of the Drosophila melanogaster nxf1 gene designated "sbr" in this species via different PCR approaches and CAGE-seq analysis. Characteristically, most of them have truncated 3′UTRs compared with those in other organs. In addition to regular transcripts, there are shorter transcripts that begin in intron 3 of the sbr gene. These short, 5′-truncated testis-specific transcripts vary in terms of transcription start site and their ability to exclude or retain the last 237 nucleotides of intron 3 in their 5′UTR. Using an anti-SBR antibody against the C-terminal portion of this protein, we detected the major SBR protein (74 kDa) in all analyzed organs of the fly as well as a new smaller protein (60 kDa) found only in the testes. This protein corresponds to the detected sbr transcripts that start in intron 3, based on its molecular mass. We investigated the sbr12 allele of the sbr gene, which is lethal in homozygous females and causes dominant sterility in heterozygous males. Sequencing of the sbr12 gene allele revealed a 30-bp deletion in exon 9 without a frame shift.Western blot analysiswith an SBR-specific antibody revealed two bands of the expected size in the testes of heterozygous males. Thus, a mutant protein along with the normal protein presents in the testes of lethal allele-bearing flies and the described shorter testis-specific variant of SBR may account for male sterility.


Nanozyme-Based Robotics Approach for Targeting Fungal Infection.
Fungal pathogens have been designated by the World Health Organization as microbial threats of the highest priority for global health. It remains a major challenge to improve antifungal efficacy at the site of infection while avoiding off-target effects, fungal spreading, and drug tolerance. Here, a nanozyme-based microrobotic platform is developed that directs localized catalysis to the infection site with microscale precision to achieve targeted and rapid fungal killing. Using electromagnetic field frequency modulation and fine-scale spatiotemporal control, structured iron oxide nanozyme assemblies are formed that display tunable dynamic shape transformation and catalysis activation. The catalytic activity varies depending on the motion, velocity, and shape providing controllable reactive oxygen species (ROS) generation. Unexpectedly, nanozyme assemblies bind avidly to fungal (Candida albicans) surfaces to enable concentrated accumulation and targeted ROS-mediated killing in situ. By exploiting these tunable properties and selective binding to fungi, localized antifungal activity is achieved using in vivo-like cell spheroid and animal tissue infection models. Structured nanozyme assemblies are directed to Candida-infected sites using programmable algorithms to perform precisely guided spatial targeting and on-site catalysis resulting in fungal eradication within 10 min. This nanozyme-based microrobotics approach provides a uniquely effective and targeted therapeutic modality for pathogen elimination at the infection site.


The molecular and fibrillar structure of collagen and its relationship to the mechanical properties of connective tissue.
The conformation of type I collagen molecules has been refined using a linked-atom least-squares procedure in conjunction with high-quality X-ray diffraction data. In many tendons these molecules pack in crystalline arrays and a careful measurement of the positions of the Bragg reflections allows the unit cell to be determined with high precision. From a further analysis of the X-ray data it can be shown that the highly ordered overlap region of the collagen fibrils consists of a crystalline array of molecular segments inclined by a small angle with respect to the fibril axis. In contrast, the gap region is less well ordered and contains molecular segments that are likely to be inclined by a similar angle but in a different vertical plane to that found in the overlap region. The collagen molecule thus has a D-periodic crimp in addition to the macroscopic crimp observed visually in the collagen fibres of many connective tissues. The growth and development of collagen fibrils have been studied by electron microscopy for a diverse range of connective tissues and the general pattern of fibril growth has been established as a function of age. In particular, relationships between fibril size distribution, the content and composition of the glycosaminoglycans in the matrix and the mechanical role played by the fibrils in the tissue have been formulated and these now seem capable of explaining many new facets of connective tissue structure and function.


[Clinical examination of the knee].
The clinical examination of the knee joint represents a great challenge as well as a great opportunity. In particular, ligamentous injuries are understood better despite their complexity and thus treated in a more differentiated way. A purely radiologically based diagnosis is only possible to a limited extent, especially for chronic injuries. Therefore, complex ligament injuries can be diagnosed with the aid of a differentiated clinical examination. This article gives an overview of the most important examination techniques of the knee joint, with which the decisive analysis of acute or chronic injuries and overuse syndromes of the knee can be carried out. Particularly in the field of ligament instability, this article provides a practical guide for the differentiated examination of complex rotational instability of the knee joint. In addition, the most important patellar and meniscal examination techniques are described.


Observer variability with conventional and digital subtraction carotid angiograms.
A study was carried out to evaluate the intra- and inter-observer variability in the determination of the severity of carotid artery stenosis on conventional and digital subtraction angiograms. The primary goal was to compare the two types of contrast studies as "gold standards" for the evaluation of non-invasive tests. Linear regression analysis of the continuous variable of percentage stenosis yielded correlation coefficients from 0.90 to 0.99. Findings were also evaluated in terms of the discrete variables formed by dividing the lesions into five categories of stenosis: kappa analysis ranged from 0.53 to 0.91. Although the digital subtraction arteriograms had greater variability than conventional ones, careful measurement of the digital images can provide a reliable estimate of the degree of stenosis.


Foods, fads, and fats in under fives.
Does manipulation of a child's diet in the first five years of life result in a reduced prevalence of coronary artery disease in later life? The findings of a recently published study (Bogalusa) are compared with British recommendations. Suitable modifications of the under fives' diet are suggested.


Alveolar exhaled nitric oxide is elevated in hereditary hemorrhagic telangiectasia.
Patients with intrapulmonary shunt due to hepatopulmonary syndrome have diffuse pulmonary microvascular dilatation. Studies have shown that these patients have increased exhaled nitric oxide (NO) levels, suggesting that alveolar capillary NO production is increased. We speculated that alveolar capillary NO overproduction might have a similar mechanistic role in the development of shunting vessels, arteriovenous malformations, in hereditary hemorrhagic telangiectasia (HHT), in which 30-45% of patients have pulmonary arteriovenous malformations (PAVMs). Our objective was to determine if alveolar exhaled NO is elevated in patients with HHT compared to controls. We measured the alveolar fraction of exhaled NO (200 ml/s expiratory flow rate) in HHT subjects with and without a history of PAVMs and in healthy, nonsmoking controls with no known lung disease. We compared 58 HHT subjects to 49 healthy controls. Exhaled NO was significantly greater in HHT subjects (mean = 12.0 ppb, SD = 3.5) than in controls (mean = 10.5 ppb, SD = 3.2) (p = 0.02). We detected a significantly higher level of alveolar exhaled NO in subjects with HHT compared to healthy controls, suggesting that alveolar capillary NO production may be increased in HHT and may have a mechanistic role in PAVM formation.


[Basophil activation test as in vitro assay for cisplatin allergy].
During chemoembolization with gemcitabine, mitomycin and cisplatin of a cholangiocellular carcinoma and after receiving iodide contrast media, a 49-year-old patient developed a grade III anaphylactic reaction. We were asked to verify an adverse reaction to contrast media. Using the basophil activation test, we demonstrated a hypersensitivity reaction to cisplatin with distinct induction of CD63-expression on basophilic granulocytes.


Ameloblastic carcinoma containing melanocyte and melanin pigment in the mandible: a case report and review of the literature.
A case of ameloblastic carcinoma containing melanocyte and melanin in a 66-year-old male with swelling and an ulcerating firm mass in the left submandibular region is presented. The diagnosis was confirmed by biopsy. The current histopathological diagnosis and management are discussed.


Effect of urethan on the induction of ornithine decarboxylase in regenerating rat liver.
The effect of urethan on the induction of ornithine decarboxylase in the early stage of the regeneration of rat liver was studied. The induced activity of ornithine decarboxylase was suppressed by administration of urethan immediately after partial hepatectomy. Although ornithine decarboxylase was induced biphasically by partial hepatectomy, a single intraperitoneal injection of urethan resulted in the reduction of both phases. However, the ornithine decarboxylase activity induced by glucocorticoids and growth hormone was not suppressed by urethan. The increased level of 3',5'-cyclic adenosine monophosphate induced by partial hepatectomy was also reduced by urethan and this suppression was proportional to the suppression of ornithine decarboxylase activity. Reversal of the urethan-induced suppression of ornithine decarboxylase by administration of dibutyryl 3',5'-cyclic adenosine monophosphate was also observed.


Synthesis and characterization of zinc oxide nanoparticles from Morus nigra and its anticancer activity of AGS gastric cancer cells.
Gastric cancer was a foremost one among the majority of regular carcinoma cases globally. Even the achievements on enhanced treatment approaches and early findings cannot decrease the mortality and morbidity ranges of gastric cancer. This current work was planned to develop Morus nigra-loaded zinc oxide nanoparticles (MN-ZnONPs) and to evaluate the different characteristic methods likes UV-vis spectroscopy, TEM, SEM, FT-IR, EDX and XRD. Furthermore, the anticancer effect of MN-ZnONPs against AGS cells were analysed via cell viability, apoptotic morphological variations by AO/EtBr, alterations of mitochondrial membrane potential (MMP), cell cycle arrest, lipid peroxidation status (TBARS), antioxidants (SOD, GSH and CAT) and generation of ROS. Moreover, the status of apoptosis gene such as Bax, caspase-9, caspase-3 and Bcl-2 expressions was analysed by using RT-PCR techniques. We observed the synthesized MN-ZnONPs have a spherical shape, crystalline nature and present different functional groups. We also observed that gastric cancer cells demonstrated in cell death by MN-ZnONPs treatments. The MN-ZnONPs induced apoptosis by enhanced formation of ROS, decreased MMP, apoptotic morphological modifications were evaluated by AO/EtBr, increased lipid peroxidation, decreased antioxidants and induced cell cycle arrest were observed. Furthermore, to confirm the molecular mechanism demonstrated of MN-ZnONPs to induce apoptosis by altering the gene expressions of apoptosis markers were observed.


Serotonin in cisternal cerebrospinal fluid of rhesus monkeys: basal levels and effects of sertraline administration.
Studies of rodents suggest that extracellular fluid and cerebrospinal fluid (CSF) serotonin (5-HT) concentrations provide a better index of released 5-HT than the frequently obtained measure of CSF 5-hydroxyindoleacetic acid (5-HIAA). The measurement of cisternal CSF 5-HT levels in the monkey might offer a method of assessing the effects of agents and actions on central 5-HT functioning in primate brain. To address methodological issues related to the determination of monkey cisternal CSF 5-HT and to examine the effects of a selective serotonin reuptake inhibitor (SSRI) on the measure. Monkey CSF was obtained by cisternal puncture and 5-HT levels determined by high performance liquid chromatography, after screening for blood contamination. When blood contamination was minimized, a mean (+/-SD) basal concentration of cisternal CSF 5-HT 87+/-36 pg/ml (n=13) was observed. Good longitudinal stability (variances of 16 and 20%) of CSF 5-HT was demonstrated in two monkeys sampled over a 3-month period. A two-fold increase in CSF 5-HT was seen in seven animals treated with the SSRI sertraline (20 mg/kg PO, mean treatment period of 12 days): pre- and post-drug 5-HT concentrations were 85+/-39 and 162+/-53 pg/ml (P=0.0007); in contrast, levels of 5-HIAA decreased from 40.0+/-5.7 to 20.4+/-2.2 ng/ml (P=0.0001). The measurement of monkey cisternal CSF 5-HT appears to provide a useful index of central 5-HT release. Initial results tend to support a role for increased extracellular 5-HT in the mechanism of action of chronically administered SSRIs.


Middle cerebral artery occlusion in the rat: consistent protocol for a model of stroke.
Variability in the effects of the intraluminal suture method of middle cerebral artery occlusion (MCAO) in the rat has been a common and disadvantageous finding. Therefore, we systematically investigated the effects of suture type and rat strain on outcome. First, the clinical and neuropathological effects of permanent MCAO with either an uncoated or a silicone-coated nylon suture were studied over 7 days in Sprague-Dawley rats (n = 36 for each type of suture). Outcome was less severe with the uncoated compared with the silicone-coated suture (e.g. total cerebral infarct volume at 24 h before any fatalities was 119.9 +/- 79.8 mm3, cf. 183.0 +/- 36.5 mm3, n = 12 for each, P < 0.05; and overall mortality rate was 12.5% cf. 33%, respectively), but much more variable (coefficient of variation was 66.6% cf. 19.9%, respectively). Second, being more consistent in its effects, the silicone-coated suture was further studied in Wistar and Fischer-344 rats (n = 12 for each). Seventy-five per cent of the Wistar's died prematurely from gross hemispheric oedema. Motor deficit and extent of infarction in the Fischer-344 rats were both significantly greater compared with Sprague-Dawley rats (e.g. total cerebral infarct volume at 24 h in the former was 253.6 +/- 25.4 mm3, n = 11, P < 0.05), and more consistent (coefficient of variation was only 10.0%). It was concluded that the silicone-coated suture and the Fischer-344 rats strain produced the most consistent results and their novel combination provides a reliable acute stroke model.


Procurement of radioiodinated glucose derivative and its biological character.
Radiolabeled glucose derivatives are attracting great interest in the clinical field. Development of an analogous substrate labeled with a practical radionuclide, 123I, is most desirable, however, no radioiodine labeled glucose derivative has been reported as being chemically and biologically compatible. Thus, in the present study, a glucose derivative substituted at the C-2 position by a p-iodobenzyl group, a 2-O-(p-iodobenzyl)-D-glucose (IBG) was designed and its synthesis was carried out. A very easy and simple synthetic method was developed, and the obtained IBG showed appropriate purity and stability for its radioiodination. [125I]IBG was obtained by radioisotopic exchange reaction with high radiochemical purity and radiochemical yield, requiring no purification. The good in vivo and in vitro stability and the chemical and biological characteristic displayed by the new [125I]IBG stimulated the measurement of the brain uptake index (BUI). In the presence of glucose, brain uptake inhibition was detected, a good indication of a glucose carrier mediator for the transport of [125I]IBG through the blood-brain barrier, a similar feature to that of [14C]glucose or 3-O-[14C]methylglucose. The newly designed ligand IBG holds good promise for the study of regional cerebral glucose utilization, should the 123I become available.


The role of low avidity T cells in the protection against type 1 diabetes: a modeling investigation.
Cytotoxic T lymphocytes (CTLs) play a dominant role in the pathogenesis of autoimmune diabetes, commonly denoted Type 1 Diabetes (T1D). These CTLs (notably CD8(+) T cells) recognize and kill insulin-secreting pancreatic beta cells, reducing their number by approximately 90%. The resulting reduction of insulin secretion causes the defective regulation of glucose metabolism, leading to the characteristic symptoms of diabetes. Recognition of beta cells as targets by CTLs depends on the interactions between MHC-peptide complexes on the surface of beta cells and receptors (TCRs) on T cells. Those CTLs with high affinity TCRs (also called high avidity T cells) cause most of the harm, while those with low affinity TCRs (also called low avidity T cells) play a more mysterious role. Recent experimental evidence suggests that low avidity T cells accumulate as memory T cells during the disease and may be protective in NOD mice (a strain prone to developing T1D), delaying disease progression. It has been hypothesized that such low avidity T cells afford disease protection either by crowding the islets of Langerhans, where beta cells reside, or by killing antigen presenting cells (APCs). In this paper, we explore the hypothesized mechanisms for this protective effect in the context of a series of models for (1) the interactions of low and high avidity T cells, (2) the effect of APCs and (3) the feedback from beta cell killing to autoantigen-induced T cell proliferation. We analyze properties of these models, noting consistency of predictions with observed behaviour. We then use the models to examine the influence of various treatment strategies on the progression of the disease. The model reveals that progressive accumulation of memory low avidity autoreactive T cells during disease progression makes treatments aimed at expanding these protective T cell types more effective close to, or at the onset of clinical disease. It also provides evidence for the hypothesis that low avidity T cells kill APCs (rather than the alternate hypothesis that they crowd the islets).


A double-blind randomized trial on subendometrial injection of vasopressin to control bleeding in postpartum hysterectomy due to abnormally invasive placenta.
To investigate the effect of subendometrial vasopressin injection in patients with abnormally invasive placenta (AIP), who underwent cesarean section and hysterectomy. This randomized double-blinded clinical trial was conducted on pregnant women diagnosed with AIP grade 4 and 5 by ultrasonography during cesarean section. Women were randomly divided into two equal groups including group 1 (vasopressin) and group 2 (control) who underwent 20 units of vasopressin and 20 cc normal saline injection, respectively. Vasopressin and placebo were injected subendometrially 1 cm medial to the uterine vessels into the lower uterine segment. The exclusion criteria include presence of myocardial infarction, cardiomyopathy, congestive heart failure, uncontrolled hypertension, chronic obstructive pulmonary disease, pelvic malignancy. The outcome of the study was total quantitative blood loss during the cesarean section. We estimated blood loss by measuring the blood volume in one of the suction bottles with addition for weight changes of mops, pads, and soaked linen savers. Sixty patients were recruited into the study, 30 as the vasopressin group and 30 as the controls; with no excluded case. The amount of bleeding in the vasopressin group was significantly lower compared with that in the control group (P < 0.001). In the vasopressin group, 83.4% of patients had bleeding of less than 1.5 L, while only 3.3% of the control women had bleeding of less than 1.5 L (relative risk = 5). In addition, the number of injected packed cells was lower in the vasopressin group (P < 0.001). It was shown that vasopressin injection can help prevent excess hemorrhage and the subsequent risks of anemia or blood transfusions during abdominal hysterectomy in women with AIP.


Antiplasmodial activity of two marine polyherbal preparations from Chaetomorpha antennina and Aegiceras corniculatum against Plasmodium falciparum.
The ocean covers more than 70% of earth surface and hosts most 300,000 described species of plants and animals to use, which have been virtually unexploited for the development of medicines. Marine plants are the good source of biologically active entities which exhibit therapeutic properties, when applied single or in combination of different plant extracts (polyherbal). Polyherbal preparations are always a complex mixture of different forms and thus different compounds, which might act as agonistic, synergistic, complementary, antagonistic or toxic way. The present study was initially carried out to test the antiplasmodial activity of 13 mangrove plants and eight seaweeds species distributed along the coast of south India. Of these, mangrove species Aegiceras corniculatum and the seaweed species Chaetomorpha antennina have shown maximum antiplasmodial activity. Hence, the present study was mooted out to increase the percentage of antiplasmodial activity when applied as polyherbal preparations. The effect of marine polyherbal preparations from the methanolic extracts of two marine plants A. corniculatum and C. antennina for their antiplasmodial activity was tested. It shows that the polyherbal extract showed 63.50 ± 0.408% suppression of parasitaemia against Plasmodium falciparum at 1.5 mg ml⁻¹ concentration. In vivo test was carried out with rat animal model to find out the effectiveness of the polyherbal extracts in the live system, which reveals that polyherbal extracts have exhibited remarkable antiplasmodial activity (50.57 ± 0.465%) against Plasmodium berghei at 120 mg kg⁻¹ bw. This study shows that combinations of mangrove plants and seaweeds extracts had a source of lead compounds for the development of new drugs for the treatment of malaria.


Correlation between anti-Xa and occurrence of thrombosis and haemorrhage in post-surgical patients treated with either Logiparin (LMWH) or unfractionated heparin. Post-surgery Logiparin Study Group.
A total of 1290 patients (Pts) undergoing general surgery were enrolled in a randomized, multicentre double-blind study in order to investigate the efficacy and safety of two different doses of a low molecular weight heparin (LMWH) (Logiparin) for the prevention of deep vein thrombosis. Patients were randomized to either 5,000 IU unfractionated heparin twice daily, 2,500 anti-Xa or 3,500 anti-Xa units of Logiparin once daily. Each treatment was given subcutaneously two hours before surgery and continued for seven to ten days. All coagulation tests were performed blindly in a core laboratory. Blood samples were collected before surgery and then 3 hours after injection on Day 3 and 5 after surgery. Anti-Xa amidolytic activities were significantly higher in the two LMW Heparin groups than in the unfractionated heparin group (mean peak levels +/- s.e.m. on Day 3: 0.097 +/- 0.004; 0.152 +/- 0.004 and 0.034 +/- 0.003 IU respectively). As expected a significant correlation was observed between anti-Xa activity and the dose of LMW Heparin injected. The correlation coefficient was higher when the doses were expressed in anti-Xa units/kg body weight. However, the body weight accounts for only 16% of the interindividual variability of anti-Xa activity. Therefore, there is no clear evidence to suggest that weight-adjusted doses should be recommended when this LMW Heparin is used as prophylactic treatment in general surgery. A weak negative correlation was found between anti-Xa activity and thrombosis as demonstrated by a positive radiolabelled fibrinogen uptake test and confirmed by positive phlebography. No significant correlation was demonstrated between anti-Xa activity and the occurrence of postoperative bleeding.


Pathogenicity of seed transmittedFusarium spp. to triticale seedlings.
In the conducted studies 13 species ofFusarium were isolated into pure culture from triticale seed. Their pathogenicity was assessed under laboratory and greenhouse conditions. Most of the species studied were highly pathogenic to the first leaf see-dlings of triticale 'Grado' and 'Lasko' under both sets of conditions. It was shown, that seed-transmitted Fusarium spp. considerably reduced the ability of seeds to germinate and incited seedling blight. On average, triticale 'Lasko' was more resistant toFusarium spp. than 'Grado', but in some instances a reverse reaction was observed.


The role of the media on maternal confidence in provider HPV recommendation.
Despite a growing understanding of the importance of provider HPV recommendation on parental acceptance, U.S. HPV vaccination rates remain suboptimal. Given the prevalence and use of the media for health decisions, this study examined the relationship between the media and provider HPV recommendation on maternal HPV vaccine hesitancy. Thirty individual interviews with HPV vaccine-accepting mothers in the Midwest U.S. were conducted to examine their feelings of hesitancy around the decision to accept HPV vaccination at the time of provider recommendation and their suggestions for improving the recommendation experience by addressing media concerns. Media exposure was an antecedent to hesitancy for three main vaccination concerns: safety, protection/efficacy and sexual stigma. Although mothers accepted vaccination, they continued to feel confused and hesitant about HPV vaccination. They had several recommendations for how providers could combat hesitancy to improve confidence in HPV vaccine acceptance. Providers' approach to HPV vaccination recommendation must consider concerns reported in the media with delivery techniques modified to adjust to maternal fears absorbed from adverse media information.


Purification and characterization of a 43-kDa protease of Bacteroides gingivalis.
From the culture supernatant of Bacteroides gingivalis ATCC 33277, a thiol protease was purified to homogeneity by fractional ammonium sulfate precipitation, ion-exchange chromatography, gel filtration, and isoelectric focusing. Its molecular weight was 43 kDa and showed similar enzymatic properties to a 300-kDa protease that was previously characterized.


Purlisin, a toxin-like defensin derived from clinical pathogenic fungus Purpureocillium lilacinum with both antimicrobial and potassium channel inhibitory activities.
Clinical fungal infections always cause a negative impact on human health. Moreover, during the interaction of pathogenic fungi with the environment and host, many biologically active substances are produced. Here, we report a new toxin-like defensin of purlisin derived from a clinical pathogenic isolate of Purpureocillium lilacinum. The analysis of its genomic and mRNA sequences revealed an open reading frame of 444 bp without introns. The deduced precursor peptide was composed of 147 amino acids, and the mature peptide were identified at protein level by LC-ESI-Q-TOF-MS/MS. After posttranslational processing, the precursor peptide of purlisin was split into two independent peptides. The two mature defensins, purlisin-NT and purlisin-CT, are consisting of 36 and 38 amino acid residues, which can form three and four intramolecular disulfide bonds, respectively. The results of circular dichroism and homology modeling revealed that they adopted a representative cysteine-stabilized α-helical and β-sheet motif. The purlisin-NT showed a dose-dependent selective inhibition of immune-related hKv1.3 target channel with IC50 value of 0.2 ± 0.04 μM but no obvious antibacterial activity, while the purlisin-CT displayed antimicrobial activities against gram-positive bacteria as well as clinical isolates of MRSA and low affinities for potassium channels. Our findings suggest that purlisin-NT with immunosuppressive effects and purlisin-CT possessing antibacterial activities are adapted to the survival and pathogenicity of clinical P lilacinumis. Moreover, they can also be used as templates for the design of novel antibacterial peptide and immunosuppressive agents.


The effect of dairy consumption on blood pressure in mid-childhood: CAPS cohort study.
It has been postulated that a higher dairy consumption may affect blood pressure regulation. The aim of this study was to examine the association between dairy consumption and blood pressure in mid-childhood. Subjects (n = 335) were participants of a birth cohort at high risk of asthma with information on diet at 18 months and blood pressure at 8 years. Multivariate analyses were used to assess the association of dairy consumption (serves) and micronutrient intakes (mg). In a subgroup of children (n = 201), dietary intake was also measured at approximately 9 years. Children in the highest quintile of dairy consumption at 18 months had lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 8 years (2.5 mm Hg, P=0.046 and 1.9 mm Hg, P = 0.047, respectively) than those in the lowest quintiles. SBP was lowest among children in the highest quintiles of calcium, magnesium and potassium intakes. Significant negative linear trends were observed between SBP and intakes of dairy serves, calcium, magnesium and potassium. Furthermore, SBP and DBP were lowest in the group of children that consumed at least two dairy serves at both 18 months and the follow-up dietary data collection at 9 years, compared with all other children (SBP 98.7 vs 101.0 mm Hg, P = 0.07; and DBP 56.5 vs 59.3 mm Hg, P = 0.006, respectively). These results are consistent with a protective effect of dairy consumption in childhood on blood pressure at age 8 years.


Intermittent exposures to mixed atmospheres of nitrogen dioxide and sulfuric acid: effect on particle clearance from the respiratory region of rabbit lungs.
Nitrogen dioxide (NO2) and sulfuric acid (H2SO4) are important constituents of the gas-particle complex in ambient air. The purpose of this study was to examine the effects of combined exposures upon the clearance of insoluble tracer particles from the respiratory region of the lungs. Rabbits were the animal model, and were exposed for 2 h/day for 14 days to either 0.3 ppm NO2, 1 ppm NO2, or 500 microgram/m3 H2SO4 alone, or to mixtures of the low and high NO2 concentrations with acid. Inhaled singly, both concentrations of NO2 accelerated clearance while H2SO4 retarded it, compared to control. Exposure to the combination of 0.3 ppm NO2 plus H2SO4 resulted in a response which was not different from that due to the acid alone. However, exposure to 1 ppm NO2 plus H2SO4 resulted in a clearance pattern which differed from that of both NO2 and H2SO4, but was more similar to that of the latter.


Increased catabolism of muscle proteins as a manifestation of radiation myopathy.
Exposure of the hindquarter of the rat to 1000 rad of gamma-radiation caused a significant increase in the release of glutamine and alanine into the perfusion fluid at 4 h post-irradiation. The extent of the release of glutamine exceeded that of alanine. Furthermore, the exposure to gamma-radiation brought about a significant lowering of the intra-/extracellular concentration gradient with respect to glutamine and alanine.


Evaluation of surgical malpractice in Turkey.
The aim of this retrospective study was to differentiate complications from malpractices in surgical cases and to help specialists who work as court experts in malpractice litigations. We reviewed 366 malpractice cases notified to The Higher Health Council by Criminal Courts between 1995 and 2000. Of these, 93 had General surgical malpractice cases. The data showed that a large proportion of malpractice litigations against surgeons resulted from deviations of the surgeons from their own field of study. The surgeons did not obtain informed consent from patients in the majority of the cases. The rate of autopsy in deaths from malpractices was 79.6%. Fifty percent of malpractice litigations were groundless. It can be suggested that incessant exposure to criticisms and complaints may make innocent surgeons less willing to take risks for patients.


Toilet seat contact dermatitis.
Allergic contact dermatitis to wooden toilet seats was a previously well-recognized pattern of regional dermatitis. We report a recent occurrence in a child that highlights a possible resurgence in this presentation, associated with the increasing popularity of wooden toilet seats.


The image of motor units architecture in the mechanomyographic signal during the single motor unit contraction: in vivo and simulation study.
The mechanomyographic (MMG) signal analysis has been performed during single motor unit (MU) contractions of the rat medial gastrocnemius muscle. The MMG has been recorded as a muscle surface displacement by using a laser distance sensor. The profiles of the MMG signal let to categorize these signals for particular MUs into three classes. Class MMG-P (positive) comprises MUs with the MMG signal similar to the force signal profile, where the distance between the muscle surface and the laser sensor increases with the force increase. The class MMG-N (negative) has also the MMG profile similar to the force profile, however the MMG is inverted in comparison to the force signal and the distance measured by using laser sensor decreases with the force increase. The third class MMG-M (mixed) characterize the MMG which initially increases with the force increases and when the force exceeds some level it starts to decrease towards the negative values. The semi-pennate muscle model has been proposed, enabling estimation of the MMG generated by a single MU depending on its localization. The analysis have shown that in the semi-pennate muscle the localization of the MU and the relative position of the laser distance sensor determine the MMG profile and amplitude. Thus, proposed classification of the MMG recordings is not related to the physiological types of MUs, but only to the MU localization and mentioned sensor position. When the distance sensor is located over the middle of the muscle belly, a part of the muscle fibers have endings near the location of the sensor beam. For the MU MMG of class MMG-N the deflection of the muscle surface proximal to the sensor mainly influences the MMG recording, whereas for the MU MMG class MMG-P, it is mainly the distal muscle surface deformation. For the MU MMG of MMG-M type the effects of deformation within the proximal and distal muscle surfaces overlap. The model has been verified with experimental recordings, and its responses are consistent and adequate in comparison to the experimental data.


Kinked DNA. Energetics and conditions favoring its formation.
Theoretical calculations demonstrate that the formation of kinks in DNA in the manner proposed by Crick and Klug produces a conformation which corresponds to a local energy minimum when the phosphate backbone is charged. This conformation becomes the global minimum under certain conditions which neutralize the anionic backbone oxygens. A sequence preference for kink formation is predicted. The possible role of kinking in experimentally observed phenomena and experimental means of demonstrating the existence of kinks are discussed.


A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism.
Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.


Disturbance in the growth of the tibia and femur in dogs.
The clinical and radiographic features associated with premature cessation of the growth of the tibia (four) and femur (eight) in 12 dogs are described. Surgical correction of the resultant deformity was possible in only a few cases. Trauma was thought to be the cause of the local growth plate disorder.


Serum CD64 as a Marker for Chronic Periprosthetic Joint Infection.
Serum cluster of differentiation 64 (CD64) has emerged as a diagnostic test for musculoskeletal infections. The purpose of this study was to evaluate the utility of serum CD64 in diagnosing periprosthetic joint infections (PJIs) compared to conventional markers like white blood count (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and interleukin-6 (IL-6). A prospective case-control study on patients undergoing revision hip or knee arthroplasty surgery >6 weeks after their index surgery was performed at a single institution. Whole blood samples were drawn within 24 hours prior to revision surgery for white blood count, ESR, CRP, IL-6, and CD64. Intraoperative cultures were obtained during the revision, and PJI was defined using the major criteria from the 2018 Musculoskeletal Infection Society criteria. Two-sample Wilcoxon rank-sum test and Fisher's exact test were used to determine if there were significant differences in serum laboratory values between patients with and without infection. The sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy of each test were calculated. With an average age of 67 years, 39 patients with 15 revision THAs and 24 TKAs, were included. 19 patients (48.7%) were determined to have PJI. Patients with PJI had significantly higher CD64 (P = .036), CRP (P = .016), and ESR (P = .045). CD64 had the highest specificity (100%) and PPV (100%), moderate accuracy (69.2%), but low sensitivity (37.0%) and negative predictive value (62.5%). Given the high specificity, PPV, and accuracy, CD64 may be an excellent confirmatory test to help diagnose PJI.


Sedation and analgesia to facilitate mechanical ventilation.
Regardless of age, health care professionals have a professional and ethical obligation to provide safe and effective analgesia to patients undergoing painful procedures. Historically, newborns, particularly premature and sick infants, have been undertreated for pain. Intubation of the trachea and mechanical ventilation are ubiquitous painful procedures in the neonatal intensive care unit that are poorly assessed and treated. The authors review the use of sedation and analgesia to facilitate endotracheal tube placement and mechanical ventilation. Controversies regarding possible adverse neurodevelopmental outcomes after sedative and anesthetic exposure and in the failure to treat pain is also discussed.


Comparing new treatments for idiopathic pulmonary fibrosis--a network meta-analysis.
The treatment landscape for idiopathic pulmonary fibrosis, a devastating lung disease, is changing. To investigate the effectiveness of treatments for idiopathic pulmonary fibrosis we undertook a systematic review, network meta-analysis and indirect comparison. We searched MEDLINE, EMBASE and The Cochrane library for relevant studies. Randomised controlled trials of pirfenidone, nintedanib or N-acetylcysteine were eligible. Predefined processes for selecting references, extracting data and assessing study quality were applied. Our network meta-analysis of published data used a fixed effect model. For forced vital capacity measures a standardised mean difference approach was used and converted to odds ratios for interpretation. Of 1076 references, 67 were retrieved and 11 studies included. Studies were of reasonable size, populations were similar, and the overall quality was good. Only two treatments, pirfenidone (odds ratio 0.62, 95% credible interval 0.52, 0.74) and nintedanib (0.41, 95% credible interval 0.34, 0.51) produced a statistically significant slowing in the rate of forced vital capacity decline compared with placebo. In an indirect comparison, results indicate that nintedanib is statistically significantly better than pirfenidone in slowing forced vital capacity decline (odds ratio 0.67, 95% credible interval 0.51, 0.88). Results were stable in scenario analysis and random effects models. Indirect comparisons of mortality were not statistically significant between nintedanib and pirfenidone. Two treatments show beneficial effects and when compared indirectly nintedanib appears to have superior benefit on forced vital capacity. Limitations to indirect comparisons should be considered when interpreting these results, however, our findings can be useful to inform treatment decisions.


Sensitive method for carbohydrate composition analysis of glycoproteins by high-performance liquid chromatography.
A new high-performance liquid chromatographic system has been developed for separating completely the neutral alditols and aminoalditols derived from sugars in complex carbohydrates. In combination with reduction by NaB3H4, this system affords a very sensitive and rapid method of monosaccharide composition analysis of glycoproteins and glycolipids.


Ophiopogon root (Radix Ophiopogonis) prevents ultra-structural damage by SO2 in an epithelial injury model for studies of mucociliary transport.
We studied the action of the herb, Ophiopogon root (OR) in a epithelial injury model, hypothesizing that it may have beneficial effects on mucociliary transport following injury to the palate induced by sodium metabisulphite (MB) which releases SO(2) on contact with water. OR (extract from 1g of root/ml)-incubated palates and non-incubated palates were compared to assess the effect of MB on mucociliary clearance on the bull frog palate. MB 10(-1) M, acutely increased mucociliary clearance time (MCT) by 254.5 +/- 57.3% in untreated and 243.3 +/- 98.5% in OR-incubated palates, (over all significance assessed by one-way ANOVA, F = 12.82, p < 0.001, df = 8,54 for MB and F = 10.56, p < 0.001, df = 8,54 for OR). MCT returned to normal during recovery in OR-treated palates following MB. In untreated palates, MCT did not return to control values during a similar recovery period. ANOVA comparing MCTs in the recovery period in untreated vs OR-treated palates was significantly different (F = 2.92, p < 0.03, df = 5,36). SEM images of epithelial tissue, analyzed by morphometry, showed a 25 +/- 12% loss of ciliated cells in untreated palates and little or no damage to cilia in OR-treated palates. Intact groups of ciliated cells were found in SEM micrographs of mucus from MB-treated palates. We conclude that the loss of cilia or ciliated cells prevented full recovery of MCT after MB in untreated palates. In OR-incubated palates, mucociliary transport was completely restored within 20 min after topical application of MB, possibly through a protective action on the extra-cellular matrix.


Bridging the Gap between Basic Research and Clinical Practice: The Growing Role of Translational Neurorehabilitation.
Translational neuroscience is intended as a holistic approach in the field of brain disorders, starting from the basic research of cerebral morphology and with the function of implementing it into clinical practice. This concept can be applied to the rehabilitation field to promote promising results that positively influence the patient's quality of life. The last decades have seen great scientific and technological improvements in the field of neurorehabilitation. In this paper, we discuss the main issues related to translational neurorehabilitation, from basic research to current clinical practice, and we also suggest possible future scenarios.


(E)-2,2'-[3-(2-Nitro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-cyclo-hex-2-en-1-one).
In the title compound, C(21)H(21)NO(6), each of the cyclo-hexenone rings adopts a half-chair conformation. Each of the pairs of hy-droxy and carbonyl O atoms are oriented to allow for the formation of intra-molecular O-H⋯O hydrogen bonds, which are typical of xanthene derivatives.


[The sodium-iodide symporter. Pathophysiologic, diagnostic and therapeutic significance].
The sodium iodide symporter NIS) is an intrinsic plasma membrane protein that mediates the active transport of iodide in the thyroid gland and a number of extrathyrioidal tissues, in particular lactating mammary gland. Because of its crucial role in the ability of thyroid follicular cells to trap iodide of NIS opened an exciting and extensivenew field of thyroid-related research. Cloning and molecular characterization of NIS allowed investigation of its expression and regulation in thyroidal and nonthyroidal tissues, and its potential pathophysiological and therepeutic implications is benign and malignant thyroid diseases. In addition, NIS-mediated iodide accumulation allows diagnostic thyroid scintigraphy as well as effective therapeutic application of radio-iodide in benign and malignant thyroid disease. characterization and application of NIS as a novel therapeutic gene for cytoreductive gene therapy of extrathyroidal tumors, and the presence of high endogenous NIS expression in the majority of breast cancers further suggest a promising role of NIS in diagnosis and therapy of cancer outside the thyroid gland.


Electrographic patterns in patients with posterior reversible encephalopathy syndrome and seizures.
Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic encephalopathic state associated with reversible cerebral vasogenic edema. Seizures are a common clinical presentation in PRES, however its electroencephalographic and radiologic pattern correlation is limited in this subset of patients. The aim of this study is to analyze the origin of electrographic dysfunction according to the radiologic pattern in patients with PRES and seizures. We retrospectively identified 46 cancer patients who developed PRES and seizures at The University of Texas MD Anderson Cancer Center between January 2006 and June 2012. Clinical, radiographic and electroencephalographic data were abstracted from their records and reviewed for our analysis. The average age at presentation was 49.9±19.7years. Thirty-four (73.9%) patients were women. Twenty-two (47.8%) patients had a primary hematological malignancy whereas the rest had a solid tumor. Thirty-three (71.7%) patients had received some form of chemotherapy. The mean systolic blood pressure (SBP) variation was 23.7±16.4mmHg at onset of symptoms. On brain MRI, 32 (69.6%) patients had typical pattern while 14 (30.4%) had an atypical pattern. Thirty-seven (80.4%) patients had scalp electroencephalogram (EEG) evaluation. Thirty-three (89.2%) had abnormal EEG findings: diffuse theta/delta slowing (N=12, 36.4%), followed by diffuse slowing with focal dysfunction (N=8, 24.2%), focal dysfunction with epileptiform discharges (N=4, 12.1%), non-convulsive status epilepticus (N=4, 12.1%), focal seizure activity and burst suppression (N=2, 6.1% each). Lateralized Periodic Discharges (LPDs) were recorded in 1 case. Four patients had focal dysfunction localized to areas without conventional MRI signal changes. Four patients had recurrent seizures, of which 3 had an atypical PRES pattern. PRES appears to be a diffuse neurotoxic encephalopathic state. Origin of seizures seen on scalp EEG may not correlate with the location of vasogenic edema/MRI signal changes raising the possibility of greater degree of dysfunction which may exist beyond those areas.


Giardia lamblia infection induces different secretory and systemic antibody responses in mice.
The adult mouse model of Giardia lamblia infection serves as an excellent animal model to understand the immunological mechanisms involved in the control and clearance of Giardia infection. Little is known about the G. lamblia-specific antigens that stimulate the humoral immune response in this model of giardiasis. We analysed the secretory and systemic antibody responses to G. lamblia during primary and secondary infection in C3H/HeJ adult mice. Faecal IgA and Serum IgG anti-G. lamblia antibodies were observed at week 2 post-infection. Serum IgG responses remained constant over the next several weeks, whereas faecal IgA titres continued to rise from weeks 2-6 post-infection. Western blot analysis revealed that intestinal IgA and serum IgG antibody responses were directed toward several distinct proteins of G. lamblia. Certain proteins appeared to be recognized by both faecal IgA and serum IgG, whereas other antigens were specific for either the secretory or systemic antibody responses. G. lamblia primary and secondary infections were associated with differences in the antibody recognition pattern. The biochemical and immunological characterization of these antigens will help us to better understand the immunobiology of the G. lamblia-host interaction.


Anti-inflammatory/antiarthritic ketonic bisphosphonic acid esters.
Bisphosphonate ester 2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds 6e, 6i, 6j, and 6m, which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.


Giant light-harvesting nanoantenna for single-molecule detection in ambient light.
Here, we explore the enhancement of single molecule emission by polymeric nano-antenna that can harvest energy from thousands of donor dyes to a single acceptor. In this nano-antenna, the cationic dyes are brought together in very close proximity using bulky counterions, thus enabling ultrafast diffusion of excitation energy (≤30 fs) with minimal losses. Our 60-nm nanoparticles containing >10,000 rhodamine-based donor dyes can efficiently transfer energy to 1-2 acceptors resulting in an antenna effect of ~1,000. Therefore, single Cy5-based acceptors become 25-fold brighter than quantum dots QD655. This unprecedented amplification of the acceptor dye emission enables observation of single molecules at illumination powers (1-10 mW cm-2) that are >10,000-fold lower than typically required in single-molecule measurements. Finally, using a basic setup, which includes a 20X air objective and a sCMOS camera, we could detect single Cy5 molecules by simply shining divergent light on the sample at powers equivalent to sunlight.


Cardiorenal anemia syndrome in chronic kidney disease.
Anemia is a frequently encountered problem of chronic kidney disease (CKD) and deteriorates as renal function declines. Anemia increases the risk of death in CKD patients with diabetes and hypertension, which are the 2 leading causes of CKD. Recent studies suggest that correction of anemia improves patient quality of life and may delay the progression to end-stage renal disease. Anemia is often only treated in the late stages of CKD or after the initiation of renal replacement therapy. Thus, anemia of CKD is often unnoticed and lacks appropriate treatment. To practically manage high-risk patients with CKD and its associated cardiovascular diseases, it is mandatory to diagnose and appropriately treat anemia of CKD earlier. The optimal level of hemoglobin for greatest clinical benefit is unclear, but at present, it is recommended to remain > or = 11 g/dL. This paper provides recommendations for the diagnosis and management of anemia associated with CKD based on international practice guidelines.


Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology.
Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients' primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.


Synergistic effect of diethylstilbestrol on the mutagenicity of 2-acetylaminofluorene and N-hydroxy-acetylaminofluorene in the Salmonella assay system.
Salmonella typhimurium, TA-1538, was used to investigate the mutagenic potential of N-2-acetylaminofluorene (2-AAF), N-hydroxy-N-2-acetylaminofluorene (N-OH-2-AAF) and diethylstilbestrol (DES) individual and in combination. In the presence of an induced or uninduced rat liver metabolizing system (S-9), the histidine requiring strain of bacteria was reverted to prototrophy by the aromatic amines but not by the synthetic estrogen. However, when DES was combined with 2-AAF or N-OH-I-AAF in the presence of the induced S-9 fraction, the number of revertant colonies was increased 2- to 4-fold above the levels obtained with the aromatic amines alone. The synergistic effect of DES, a non-mutagen, on the mutagenicity of these aromatic amines was observed only when a 3-methylcholanthrene induced rat liver S-9 fraction was used as the source of mammalian enzymes. When uninduced mouse or rat liver S-9 fractions were used in this test system, an inhibitory effect rather than an enhancing effect was observed.


[Formulation optimization and drug release in vitro of membrane controlled tablets of puerarin inclusion compound].
To prepare membrane controlled tablets of puerarin sinclusion compound and to investigate the drug release in vitro. The single factors affecting drug release in vitro were investigated. Then, uniform design was used to optimize the formulation of controlled osmotic-pump tablets. Drug release profiles in vitro were affected obviously by membrane thickness, penetrating agents and porogen. Membrane controlled tablets of puerarin inclusion compound were prepared according to the optimal formulation with zero-order kinetics.


Task-specific effects of biological sex and sex hormones on object recognition memories in a 6-hydroxydopamine-lesion model of Parkinson's disease in adult male and female rats.
Many patients with Parkinson's disease (PD) experience cognitive or memory impairments with few therapeutic options available to mitigate them. This has fueled interest in determining how factors including sex and sex hormones modulate higher order function in this disease. The objective of this study was to use the Novel Object Recognition (NOR) and Object-in-Place (OiP) paradigms to compare the effects of a bilateral neostriatal 6-hydroxydopamine (6-OHDA) lesion model of PD in gonadally intact male and female rats, in orchidectomized male rats and in orchidectomized males supplemented with 17β-estradiol or testosterone propionate on measures of recognition memory similar to those at risk in PD. These studies showed that 6-ODHA lesions impaired discrimination in both tasks in males but not females. Further, 6-OHDA lesions disrupted NOR performance similarly in all males regardless of whether they were gonadally intact, orchidectomized or hormone-supplemented. In contrast, OiP performance was disrupted in males that were orchidectomized or 6-OHDA-lesioned but was spared in orchidectomized and orchidectomized, 6-OHDA lesioned males supplemented with 17β-estradiol. The distinct effects that sex and/or sex hormones have on 6-OHDA lesion-induced NOR vs. OiP deficits identified here also differ from corresponding impacts recently described for 6-OHDA lesion-induced deficits in spatial working memory and episodic memory. Together, the collective data provide strong evidence for effects of sex and sex hormones on cognition and memory in PD as being behavioral task and behavioral domain specific. This specificity could explain why a cohesive clinical picture of endocrine impacts on higher order function in PD has remained elusive.


Heparin and phentolamine combined, rather than heparin alone, improves hepatic microvascular procurement in a non-heart-beating donor rat-model.
Improvement of organ procurement from non-heart-beating donors (NHBDs) could increase the donor organ pool for liver transplantation. Whether anti-coagulative and anti-vasospastic substances can improve hepatic microvascular preservation from NHBDs is unknown. In donor rats which were pretreated with either heparin (n = 6) or heparin combined with phentolamine (n = 7) 10 min prior to cardiac arrest, the extent and homogeneity of hepatic microvascular reperfusion was assessed at the end of a 60-min period of cardiac arrest using in situ fluorescence microscopy. Non-pretreated animals with cardiac arrest for 60 min served as controls (n = 6). In the non-treated NHBDs, arterial gravity perfusion of 100 cm H2O with HTK-solution led to a hepatic acinar reperfusion of only approximately 22 % with a remarkably diminished sinusoidal density. Application of heparin prior to cardiac arrest resulted in a two-fold, but insignificant increase of acinar perfusion and sinusoidal density with a still considerable heterogeneity of both parameters. Livers of NHBDs that additionally received phentolamine exhibited significantly increased values of both acinar perfusion and sinusoidal density. Phentolamine was found to reduce heterogeneity of organ microperfusion. Thus, our results indicate that the combined application of heparin and phentolamine is a useful additive for optimizing the quality of organs harvested from NHBDs.


High level of inbreeding in final phase of 1000 Genomes Project.
The 1000 Genomes Project provides a unique source of whole genome sequencing data for studies of human population genetics and human diseases. The last release of this project includes more than 2,500 sequenced individuals from 26 populations. Although relationships among individuals have been investigated in some of the populations, inbreeding has never been studied. In this article, we estimated the genomic inbreeding coefficient of each individual and found an unexpected high level of inbreeding in 1000 Genomes data: nearly a quarter of the individuals were inbred and around 4% of them had inbreeding coefficients similar or greater than the ones expected for first-cousin offspring. Inbred individuals were found in each of the 26 populations, with some populations showing proportions of inbred individuals above 50%. We also detected 227 previously unreported pairs of close relatives (up to and including first-cousins). Thus, we propose subsets of unrelated and outbred individuals, for use by the scientific community. In addition, because admixed populations are present in the 1000 Genomes Project, we performed simulations to study the robustness of inbreeding coefficient estimates in the presence of admixture. We found that our multi-point approach (FSuite) was quite robust to admixture, unlike single-point methods (PLINK).


bletl - A Python package for integrating BioLector microcultivation devices in the Design-Build-Test-Learn cycle.
Microbioreactor (MBR) devices have emerged as powerful cultivation tools for tasks of microbial phenotyping and bioprocess characterization and provide a wealth of online process data in a highly parallelized manner. Such datasets are difficult to interpret in short time by manual workflows. In this study, we present the Python package bletl and show how it enables robust data analyses and the application of machine learning techniques without tedious data parsing and preprocessing. bletl reads raw result files from BioLector I, II and Pro devices to make all the contained information available to Python-based data analysis workflows. Together with standard tooling from the Python scientific computing ecosystem, interactive visualizations and spline-based derivative calculations can be performed. Additionally, we present a new method for unbiased quantification of time-variable specific growth rate μ ⃗ t based on unsupervised switchpoint detection with Student-t distributed random walks. With an adequate calibration model, this method enables practitioners to quantify time-variable growth rate with Bayesian uncertainty quantification and automatically detect switch-points that indicate relevant metabolic changes. Finally, we show how time series feature extraction enables the application of machine learning methods to MBR data, resulting in unsupervised phenotype characterization. As an example, Neighbor Embedding (t-SNE) is performed to visualize datasets comprising a variety of growth/DO/pH phenotypes.


Higher coagulation activity in hip fracture patients: A case-control study using rotational thromboelastometry.
Trauma-induced coagulopathy has been extensively investigated in the multitrauma setting, but only sparsely following moderate orthopedic trauma. The purpose of this study was to evaluate changes in the hemostatic profile of patients with hip fractures, using rotational thromboelastometry (ROTEM). 198 patients with hip fractures who underwent surgery were included in the study. A matched group of 52 healthy individuals was also enrolled. Demographics, conventional laboratory assays, and ROTEM parameters were recorded and compared between patients and healthy adults. The preoperative and postoperative ROTEM values of fractured patients were also compared. The conventional coagulation assays were similar for the 2 groups. However, several ROTEM parameters including EXTEM MCF (P < .001), EXTEM alpha angle (P < .001), INTEM MCF (P < .001), INTEM A10 (P < .001), and INTEM alpha angle (P < .001) significantly differed between the 2 groups indicating a higher coagulation potential following hip fractures. Also, fractured patients had significantly lower INTEM and EXTEM CT values (P = .008 and P = .012, respectively) and significantly lower INTEM and EXTEM CFT values (P < .001). Adjusted analysis for confounders further confirmed the direct relationship between hip fracture and higher coagulation activity. Last, INTEM CT and CFT significantly decreased (P = .008 and P < .001, respectively), while INTEM MCF, A10, and alpha angle significantly increased (P < .001) postoperatively, indicating that surgery further increases the coagulation potential. A higher coagulation activity following hip fractures and surgical treatment can be detected by ROTEM shortly after the injury, even when this is undetectable by conventional coagulation assays.


Hemodynamic changes in a patient with esophageal varices after endoscopic injection sclerotherapy evaluated by endoscopic color Doppler ultrasonography.
A 46-year-old man with alcoholic cirrhosis was admitted to our hospital for treatment of high-risk esophageal varices in February 2000. Images of the esophageal varices, paraesophageal veins and palisade veins were obtained by endoscopic color Doppler ultrasonography (ECDUS) before endoscopic injection sclerotherapy (EIS). Prophylactic EIS was performed six times per week for esophageal varices, and EIS was continued until the esophageal varices were completely eradicated. In July 2002, endoscopy revealed esophageal varices graded as Cb, F1, Lm, and RC(-), and color flow images of the palisade veins (hepatofugal flow), esophageal varices, and a developed paraesophageal vein were obtained with ECDUS. In April 2003, endoscopy showed esophageal varices graded as Cb, F1, Lm, and RC(-), and color flow images of the palisade veins and esophageal varices were obtained using ECDUS. The blood in the palisade veins flowed in an alternate direction on color flow images, and pulsatile waves were delineated at the gastroesophageal junction. In January 2004, endoscopy revealed esophageal varices graded as F0 and RC(-), and pulsatile waves were delineated in the lower esophagus with ECDUS. However, the esophageal varices and palisade veins had disappeared from color flow images. In conclusion, ECDUS was useful for evaluating hemodynamic changes after EIS.


A sensitive silver stain for proteins in agarose gels.
A silver stain for proteins in agarose gels which is at least 10 times as sensitive as Coomassie blue is described. The method is simple to use and is particularly useful for the study of protein bands in the gamma region on electrophoresis of fluids such as cerebrospinal fluid in which the protein concentration is low. It readily detects bands of IgG containing 20 to 40 ng/band (approx 3 to 6 ng of IgG/mm2 of gel).


[A case of chronic pleuritis by Paragonimus Westermani infection resistant to standard chemotherapy and cured by three additional cycles of chemotherapy].
A 16-year-old boy had eaten Chinese freshwater crabs soaked in liquor in October 2000, and the left pleural effusion was pointed out on chest X-ray films at a regular medical checkup at school in June 2002. Since his father and friends had suffered from Paragonimiasis Westermani and had been treated in January 2001, the patient agreed to immunoserological examination, and Paragonimiasis Westermani was diagnosed. After drainage of pleural effusion, the patient was treated with praziquantel for three days at a daily dosage of 75 mg/kg, but without effect. The patient received drainage of pleural effusion again, and was treated with praziquantel for 3 days at a daily dosage of 75 mg/kg in a series of three treatments at three week interval. After that, improvement of the disease was achieved.


Potential functions and applications of diverse microbial exopolysaccharides in marine environments.
Exopolysaccharides (EPSs) from microorganisms are essential harmless natural biopolymers used in applications including medications, nutraceuticals and functional foods, cosmetics, and insecticides. Several microbes can synthesize and excrete EPSs with chemical properties and structures that make them suitable for several important applications. Microbes secrete EPSs outside their cell walls, as slime or as a "jelly" into the extracellular medium. These EPS-producing microbes are ubiquitous and can be isolated from aquatic and terrestrial environments, such as freshwater, marine water, wastewater, and soils. They have also been isolated from extreme niches like hot springs, cold waters, halophilic environments, and salt marshes. Recently, microbial EPSs have attracted interest for their applications such as environmental bio-flocculants because they are degradable and nontoxic. However, further efforts are required for the cost-effective and industrial-scale commercial production of microbial EPSs. This review focuses on the exopolysaccharides obtained from several extremophilic microorganisms, their synthesis, and manufacturing optimization for better cost and productivity. We also explored their role and applications in interactions between several organisms.


Molecular dissection of a rice microtubule-associated RING finger protein and its potential role in salt tolerance in Arabidopsis.
Although a number of RING E3 ligases in plants have been demonstrated to play key roles in a wide range of abiotic stresses, relatively few studies have detailed how RING E3 ligases exert their cellular actions. We describe Oryza sativa RING finger protein with microtubule-targeting domain 1 (OsRMT1), a functional RING E3 ligase that is likely involved in a salt tolerance mechanism. Functional characterization revealed that OsRMT1 undergoes homodimer formation and subsequently autoubiquitination-mediated protein degradation under normal conditions. By contrast, OsRMT1 is predominantly found in the nucleus and microtubules and its degradation is inhibited under salt stress. Domain dissection of OsRMT1 indicates that the N-terminal domain is required for microtubule targeting. Bimolecular fluorescence complementation analysis and degradation assay revealed that OsRMT1-interacted proteins localized in various organelles were degraded via the ubiquitin (Ub)/26S proteasome-dependent pathway. Interestingly, when OsRMT1 and its target proteins were co-expressed in N. benthamiana leaves, the protein-protein interactions appeared to take place mainly in the microtubules. Overexpression of OsRMT1 in Arabidopsis resulted in increased tolerance to salt stress. Our findings suggest that the abundance of microtubule-associated OsRMT1 is strictly regulated, and OsRMT1 may play a relevant role in salt stress response by modulating levels of its target proteins.


A randomized Phase II trial of systemic chemotherapy with and without trastuzumab followed by surgery in HER2-positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301 (Trigger Study).
Pre-operative chemotherapy with S-1 plus cisplatin is considered to be acceptable as one of the standard treatment options for gastric cancer patients with extensive lymph node metastases in Japan. Addition of trastuzumab to chemotherapy is shown to be effective for HER2-positive advanced gastric cancer patients, and we have commenced a randomized Phase II trial in March 2015 to evaluate S-1 plus cisplatin plus trastuzumab compared with S-1 plus cisplatin alone in the neoadjuvant setting for HER2-positive gastric cancer patients with ELM, which are followed by adjuvant chemotherapy with S-1 for 1 year. A total of 130 patients will be accrued from 41 Japanese institutions over 3 years. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, response rate of pre-operative chemotherapy, proportion of patients with R0 resection, proportion of patients who complete the pre-operative chemotherapy and surgery, proportion of patients who complete the protocol treatment including post-operative chemotherapy, pathological response rate and adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN 000016920.


The corticocortical projections of the physiologically defined eye field in the rat medial frontal cortex.
This study investigated in the rat the corticocortical projections of the frontal eye field (FEF), which is located within the medial frontal cortex. The experiments were carried out on Wistar rats. Seven animals received a single iontophoretic injection of Phaseolus vulgaris leucoagglutinin in an FEF site within the medial frontal cortex where intracortical microstimulation elicited eye movements. In these cases, anterogradely labeled fibers and terminal-like elements were found in both hemispheres. The densest labeling was seen in the injected hemisphere, where labeled fibers prevailed in the visual cortex and their laminar distribution differed between the primary and secondary visual cortices. Dense labeled fibers were also seen in the frontal and retrosplenial cortex, whereas a columnar arrangement of terminal-like elements was detected in a restricted part of area 1 of the somatosensory cortex. Contralaterally to the injection site, labeled fibers were distributed mainly in the homotopic region. In two animals, the tracer was injected in a site at the FEF border whose stimulation evoked eye and whisker movements. In these animals, a different distribution of labeling was observed with respect to the other rats in which the tracer was deposited within the FEF, and anterograde labeling was observed in areas 1 and 2 of the parietal cortex of both hemispheres; in addition, no labeling was observed in these cases in the primary visual cortex. These findings suggest that cortical sites confined within the rat FEF are implicated in the control of orienting and exploring behaviors in addition to the control of eye movement.


Determining heavy metal pollution in sediments from the largest impounded lake in the eastern route of China's South-to-North Water Diversion Project: Ecological risks, sources, and implications for lake management.
The eastern route of the South-to-North Water Diversion Project (ER-SNWDP) is a major human health project designed to alleviate the water scarcity in the Beijing-Tianjin-Hebei region in China. Impounded lake water security is directly related to the water diversion project effectiveness. At present, there is not a thorough understanding of the sediment heavy metals in Lake Hongze, the largest impounded lake of the ER-SNWDP. Consequently, this study reports a distribution analysis of Cu, Zn, Pb, Cr, Cd, As, Hg, and Ni in 101 sediment samples from Lake Hongze; we, utilized the enrichment factor, geoaccumulation index, and potential ecological risk index for the are to determine the ecological risk of heavy metals. The heavy metal source was examined with correlation analysis and principal component analysis-multiple linear regressions. The results showed that the average heavy metal content (Cu, Zn, Pb, Cr, Cd, As, Hg, Ni) were 0.03-1.57 times greater than the Jiangsu Province background values. Cd, As, and Hg were the main contributors to the Lake Hongze ecological risk. Spatially, the open water area was the most polluted among the four lake parts, and most of the flushing area had a low ecological risk. Chengzi bay and the western lake area have similar risk profiles, but are lower than the open water area risk. Source analysis showed that nonpoint-source agricultural pollution and industrial production were important pollution sources, while a considerable portion of the heavy metal content came from atmospheric deposition and natural sources. This study identified the main contamination areas and revealed the possible sources of each heavy metal; as such, this study can serve as a reference for the remediation and management of Lake Hongze to ensure the water safety of the ER-SNWDP.


Molecular probe dynamics and free volume in organic glass-formers and their relationships to structural relaxation: 1-propanol.
A joint study of the rotational dynamics and free volume in amorphous 1-propanol (1-PrOH) as a prototypical monohydroxy alcohol by electron spin resonance (ESR) or positron annihilation lifetime spectroscopy (PALS), respectively, is reported. The dynamic parameters of the molecular spin probe 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and the annihilation ones of the atomic ortho-positronium (o-Ps) probe as a function of temperature are compared. A number of coincidences between various effects in the ESR and PALS responses at the corresponding characteristic ESR and PALS temperatures were found suggesting a common origin of the underlying dynamic processes that were identified using viscosity (VISC) in terms of the two-order parameter (TOP) model and broadband dielectric spectroscopy (BDS) data.


Endometrial cancer: population attributable risks from reproductive, familial and socioeconomic factors.
In this study, based on the Swedish Family-Cancer Database, risk factors and their population attributable fractions (PAFs) for endometrial cancer were studied. Over 700,000 women at ages 51-68 years, accumulating 23 million person-years at risk, were entered into Poisson analysis. Overall, reproductive factors (parity and age at last birth) showed a relative risk (RR) of 1.91 and a PAF of 45.51% when the reference group was women with a parity of 3+ and the last childbirth at ages over 34 years. The RR for family history was 2.33 but the PAF was only 2.09%. The RR for socioeconomic factors was a modest 1.12 but the PAF was 6.34%. The combined PAF of these three types of risk factors was 51.84%. Although the present analysis lacked data on some important risk factors for endometrial cancer, the results suggest that a large proportion of the etiology of endometrial cancer can be defined by known epidemiological risk factors.


The clinical value of ultrasonic cardiac output monitor in very-low birth-weight and extremely-low-birth-weight infants undergoing PDA ligation.
Cardiorespiratory instability occurs very often in very-low-birth-weight (VLBW) and extremely-low-birth-weight (ELBW) infants undergoing patent ductus arteriosus (PDA) ligation during the early postoperative period. This study aimed to investigate ultrasonic cardiac output monitor (USCOM) as a bedside tool by evaluating the hemodynamic changes in preterm infants following PDA ligation and assessing factors that may influence these changes. This was a single-center prospective observational study at a third-level neonatal intensive care unit. A total of 33 infants, including 21 VLBW and 12 ELBW infants, were involved. Hemodynamic measurements were performed in these infants using a USCOM preoperatively as well as 0-1 h, 8-10 h, and 24 h postoperatively. The PDA ligation was associated with reductions of the left ventricular cardiac output (LVCO) (P < 0.001), cardiac index (P < 0.001), flow time corrected (FTC) (P < 0.001), Smith-Madigan inotropy index (SMII) (P < 0.001), oxygen delivery (DO2) (P < 0.001), and oxygen delivery index (DO2I) (P < 0.001) and an increase of the systemic vascular resistance index (SVRI) (P < 0.001) at 0-1 h, 8-10 h, and 24 h post-ligation compared with the respective preoperative values. Compared with the respective values at 0-1 h post-ligation, there was no significant difference in the CI, SMII, or FTC at 8-10 h and 24 h post-ligation. However, the SVRI decreased at 8-10 h and 24 h post-ligation. Moreover, the DO2I increased at 8-10 h and 24 h post-ligation, and the LVCO and DO2 increased at 24 h post-ligation. Our study confirmed that the hemodynamic changes measured by the USCOM were similar to those measured by echocardiography in previous reports. Thus, USCOM is a useful and convenient bedside tool for assessing hemodynamic changes to guide the use of fluids, inotropic agents, and vasopressors and help modify the post-ligation course, and they may be a surrogate for repeated echocardiography during the early post-ligation period in preterm infants or a preliminary screening method.


Recalled Number of Falls in the Past Year-Combined With Perceived Mobility-Predicts the Incidence of Future Falls in Unilateral Lower Limb Prosthesis Users.
Falls are a frequent and costly concern for lower limb prosthesis (LLP) users. At present, there are no models that clinicians can use to predict the incidence of future falls in LLP users. Assessing who is at risk for falls, therefore, remains a challenge. The purpose of this study was to test whether easily accessible clinical attributes and measurements predict the incidence of future falls in LLP users. In this prospective observational study, a secondary analysis of data from 60 LLP users was conducted. LLP users reported the number of falls that they recalled over the past year before prospectively reporting falls over a 6-month observation period via monthly telephone calls. Additional candidate predictor variables were recorded at baseline. Negative binomial regression was used to develop a model intended to predict the incidence of future falls. The final model, which included the number of recalled falls (incidence rate ratio = 1.13; 95% CI = 1.01 to 1.28) and Prosthetic Limb Users Survey of Mobility T-scores (incidence rate ratio = 0.949; 95% CI = 0.90 to 1.01), was significantly better than a null model at predicting the number of falls over the next 6 months (χ22 = 9.76) and fit the observed prospective fall count data (χ256 = 54.78). The number of recalled falls and Prosthetic Limb Users Survey of Mobility T-scores predicted the incidence of falls over the next 6 months in established, unilateral LLP users. The success and simplicity of the final model suggests that it may serve as a screening tool for clinicians to use for assessing risk of falls. Additional research to validate the proposed model in an independent sample of LLP users is needed. Owing to its simplicity, the final model may serve as a suitable screening measure for clinicians to ascertain an initial evaluation of fall risk in established unilateral LLP users. Analyzing falls data as counts rather than as a categorical variable may be an important methodological consideration for falls prevention research.