Deep Learning for Estimating Lung Capacity on Chest Radiographs Predicts Survival in Idiopathic Pulmonary Fibrosis.
Background Total lung capacity (TLC) has been estimated with use of chest radiographs based on time-consuming methods, such as planimetric techniques and manual measurements. Purpose To develop a deep learning-based, multidimensional model capable of estimating TLC from chest radiographs and demographic variables and validate its technical performance and clinical utility with use of multicenter retrospective data sets. Materials and Methods A deep learning model was pretrained with use of 50 000 consecutive chest CT scans performed between January 2015 and June 2017. The model was fine-tuned on 3523 pairs of posteroanterior chest radiographs and plethysmographic TLC measurements from consecutive patients who underwent pulmonary function testing on the same day. The model was tested with multicenter retrospective data sets from two tertiary care centers and one community hospital, including (a) an external test set 1 (n = 207) and external test set 2 (n = 216) for technical performance and (b) patients with idiopathic pulmonary fibrosis (n = 217) for clinical utility. Technical performance was evaluated with use of various agreement measures, and clinical utility was assessed in terms of the prognostic value for overall survival with use of multivariable Cox regression. Results The mean absolute difference and within-subject SD between observed and estimated TLC were 0.69 L and 0.73 L, respectively, in the external test set 1 (161 men; median age, 70 years [IQR: 61-76 years]) and 0.52 L and 0.53 L in the external test set 2 (113 men; median age, 63 years [IQR: 51-70 years]). In patients with idiopathic pulmonary fibrosis (145 men; median age, 67 years [IQR: 61-73 years]), greater estimated TLC percentage was associated with lower mortality risk (adjusted hazard ratio, 0.97 per percent; 95% CI: 0.95, 0.98; P < .001). Conclusion A fully automatic, deep learning-based model estimated total lung capacity from chest radiographs, and the model predicted survival in idiopathic pulmonary fibrosis. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Sorkness in this issue.


Evaluation of hyperbilirubinemia in acute inflammation of appendix: a prospective study of 45 cases.
Hyperbilirubinemia is the result of imbalance between production and excretion of bilirubin by the liver. It may be because of hepatocellular, cholestatic or haemolytic diseases. Liver receives blood mainly through portal venous system, which receives blood from abdominal organs. Portal blood carries nutrients and other substances absorbed from gut including bacteria and its product (toxins). In small percentage, even in normal healthy people, bacteria are found in portal blood. It is commonly cleared by detoxification and immunological action of reticuloendothelial (RES) system of liver that act as first line defence in clearing toxic substances, bacteria and it's products. But when bacterial load overwhelms the Kuffer cell function, may cause dysfunction or damage to the hepatocytes (liver parenchyma). It reflects, rise in serum bilirubin (SB) alone or in combination with liver enzymes depending upon the type, severity and site of lesion. Recently, another substance known as Cytokines e.g. IL-6, Tumour necrosis factor (TNF), have also been labelled to be responsible for depressed excretory function of liver and may lead to increase in SB level without rise in liver enzymes. To evaluate hyperbilirubinemia associated in acute inflammation of appendix (acute appendicitis and its complication). This is a prospective study conducted at NGMC Teaching hospital Nepalgunj, Nepal during Oct.2004-Oct.2005. 45 Consecutive cases of acute appendicitis admitted in surgical unit III, were recruited for this study. Clinically suspected cases were subjected to investigations to confirm the diagnosis. Investigations included total leucocytes count, differential leucocytes count, urine analysis and ultrasound. These cases were also subjected to routine liver function tests. Subsequently these cases were operated and clinical diagnosis was confirmed per-operatively and post operatively by histopathological examination of the specimen. Their clinical and investigative data were compiled and analyzed and following observations were obtained. Routine liver function test results were compared with laboratory reference values given in Table- 1, 2 and 3. Case with acute appendicitis and its complication with test negative for HBSAg and no past history of jaundice. Case with acute appendicitis and its complication with test positive for HBSAg and /or past history of jaundice. Total number cases were 45. Of 45, 25 were males and 20 were females. Their age ranged from 11 years to 60 years. The average was 27.2 years. Duration of symptoms ranged from 5 hours to maximum 9 days. Among 45 cases diagnosed as acute appendicitis clinically (preoperatively), per operatively, 36 cases had inflamed appendix, 3 cases had gangrene, 5 cases had perforation with peritonitis (4 localized and 1 generalized peritonitis) and only a single case was noted to be of normal appendix (Table 4). Liver function tests (LFT) analysis revealed following results, Among 45 cases, SB was raised in 39 cases where as 6 cases had normal SB level. The raised SB ranged from 1.2 mg/dL to 8.4 mg/dL. The average level of SB was 2.38 mg/dL. All the cases had indirect fraction of SB above 15%. (Table 4). The rise in SB was without concomitant much rise in liver enzymes. Following conclusion can be drawn from the present study. Firstly, There was Hyperbilirubinemia in 86.6% of the patients of acute inflammation of appendix (i.e. acute appendicitis and its complications). Secondly, Raised SB ranged from 1.2mg/dL - 8.4 mg/dL. Thirdly, The rise in SB was mixed in type (both indirect and direct). Finally, The hyperbilirubinemia was intra hepatic cholestatic in type due either to abnormality in permeability of hepatocyte or ductular membrane enzyme inhibition as the liver enzymes were not much elevated.


Feeling the burn: the significant burden of febrile nonhemolytic transfusion reactions.
Febrile nonhemolytic transfusion reactions (FNHTRs) are characterized by a post-transfusion temperature rise (of ≥ 1°C, to ≥ 38°C) or chills/rigors unrelated to the underlying condition. FNHTRs are provoked by inflammatory cytokines in the product or by host antileukocyte antibodies against residual donor leukocytes. FNHTRs are among the most commonly reported transfusion disturbances and are generally deemed nonserious events. However, their impact on patients and hospitals may be underestimated. A search through two hemovigilance databases identified all known possible-to-definite FNHTRs over 3 years (2013-2015) at four academic hospitals using prestorage leukoreduced components. FNHTRs were assessed for frequency by product (red blood cells [RBCs], platelets [PLTs], intravenous immunoglobulin), diagnostics (bedside, chest imaging, serology, microbiology), and management (medications, disposition change). The definition of FNHTR was derived from Canada's Transfusion-Transmitted Injuries Surveillance System. For 437 FNHTRs, the overall per-product rate across all sites was 0.24%, or 0.17% with RBCs alone and 0.25% with PLTs alone. One-third of patients had significant fevers (≥ 39.0°C or a rise by ≥ 2.0°C). Approximately one-quarter underwent chest imaging within 48 hours, and 79% had blood cultures. A hospital admission directly attributable to the FNHTR, to exclude other causes of fever, occurred in 15% of FNHTR outpatients. An analysis of FNHTRs reveals a substantial burden of postreaction clinical activity in addition to the disturbance itself. Efforts to avoid this adverse event may save resources, reduce patient distress, and encourage compliance with more restrictive transfusion strategies.


Epithelial blood group antigens in human carcinomas of the distal colon: further studies on their pathologic significance.
Blood group antigen content of human carcinomas located in the distal large bowel (descending colon, sigmoid colon, and rectum) was determined by the specific red cell adherence reaction and was compared to several morphologic features of prognostic significance, e.g., differentiation, extent of tumor spread, peritumoral lymphoplasmocytic infiltration, and growth patterns. About 50% of the carcinomas expressed blood group antigens in either diffuse or patchy distribution. Classification of tumors according to the extent of local spread revealed that 60% of Dukes stage A tumors were blood group antigen-negative, whereas 58% of those in Dukes stage B were positive. Dukes stage C lesions had an intermediate position, and this limits the prognostic usefulness of blood group antigen determinations. No significant correlations were found between blood group antigenicity and the degree of histologic differentiation, the degree of peritumoral lymphoplasmocytic infiltration, and the mode of tumor growth.


Protection against chronic hepatitis C virus infection after rechallenge with homologous, but not heterologous, genotypes in a chimpanzee model.
An open question for hepatitis C virus (HCV) vaccine development is whether the various genotypes of this virus protect against the development of chronic infection after heterologous infection with different genotypes. We approached this question by challenging chimpanzees that had recovered from HCV genotype 1a or 1b infection with 6 heterologous genotypes as well as with a homologous genotype (for chimpanzees originally infected with genotype 1a). All 9 chimpanzees rechallenged with a homologous genotype developed self-limited infections. Of 11 chimpanzees challenged with 100 chimpanzee infectious doses of heterologous genotypes, 6 developed self-limited infections, with peak viral loads in acute-phase serum that were ~5-fold lower than those seen during primary infections. One chimpanzee (which had recovered from genotype 1b infection and was rechallenged with genotype 6a) did not develop viremia but did show an anamnestic cell-mediated immune response after rechallenge. Four of the 11 chimpanzees rechallenged with heterologous genotypes developed chronic infections with the genotypes used for rechallenge. These findings suggest that a universally protective HCV vaccine may need to incorporate epitopes from multiple genotypes.


Cryo-electron microscopy of low density lipoprotein and reconstituted discoidal high density lipoprotein: imaging of the apolipoprotein moiety.
Cryo-electron microscopy was used to analyze the structure of low density lipoprotein from normolipidemic subjects (N-LDL), phospholipid-depleted N-LDL (PD-LDL), small dense LDL from hypertriglyceridemic subjects (SD-LDL), and reconstituted discoidal high density lipoproteins (rHDL). In different projections of N-LDL, a high density component of the particle was visible as two parallel bands or as a single ring. Projections of PD-LDL were very similar to those of N-LDL, indicating that the contribution of phospholipid headgroups to the observed high density structure is minor. In preparations of SD-LDL, projections with two high density bands or a single high density ring were rare. Instead, triangular and diamond-shaped projections were recognized. In different projections of discoidal rHDL, a high density component was visible as a single band or as a single ring. The present results indicate that cryo-electron microscopy reveals the distribution of apolipoproteins within lipoprotein particles. Thus, apolipoprotein B-100 (apoB) in N-LDL appears to be organized as a double ring around the particle, while apoB in SD-LDL is indicated to have a different conformation. Cryo-electron micrographs of rHDL are consistent with the presence of apolipoprotein A-I on the periphery of the lipoprotein disc.


Comparison of populations of human faecal bacteria before and after in vitro incubation with plant cell wall substrates.
Human faecal slurries were incubated anaerobically with larchwood xylan, oat spelt xylan, wheat bran, apple cell walls or sugar beet pulp as sole carbon sources. The populations which developed during incubation were different from the inoculum, the most marked changes being an increase in the number of Bacteroides species and a decrease in the number of Fusobacterium species for all carbon sources tested. With a water-soluble preparation of larchwood xylan the population was dominated by species able to ferment this substrate, in contrast to the population which developed with the insoluble substrates. The ability to use one plant cell wall substrate appeared to be related to the ability to use others. Strains capable of using plant cell wall substrates included Bacteroides spp., Clostridium clostridiiforme, Bifidobacterium longum, Fusobacterium spp. and Escherichia coli. When incubation with two contrasting substrates (bran and larchwood xylan) was replicated, the populations which developed were reproducibly different from the inoculum and from each other.


[Chemical Constituents of Citrus medica Fruit].
To study the chemical constituents of Citrus medica fruit. The fruit of Citrus medica was extracted with 95% EtOH, and the compounds were separated and purified by silica gel, RP-18 and Sephadex LH-20 column chromatography. The structures were identified by spectroscopic analysis. A total of 16 compounds were isolated and identified, including methyl ferulic acid (1), dihydro-N-caffeoyltyramine (2) acacetin (3), β-ecdysterone (4), (-)-balanophonin (5), p-methoxy cinnamic acid (6), umbelliferone (7), ferulic acid (8), pyrocatechualdehyde (9), diosmetin (10), 4-methoxy salicylic acid (1), β-amyrin acetate (12), epigallocatechin (13), betulinic acid (14), lupeol (15) and nicotinamide (16). All the compounds are isolated from the fruit of Citrus medica for the first time.


Upper Airway Reflexes are Preserved During Dexmedetomidine Sedation in Children With Down Syndrome and Obstructive Sleep Apnea.
The assessment of pharyngeal collapsibility is difficult to perform in children under normal sleep. An alternative is to perform the assessment under an anesthetic, such as dexmedetomidine (DEX), that induces non-rapid eye movement (NREM) sleep. The objectives of this study were to compare critical closing airway pressure (Pcrit) obtained during natural sleep to that obtained under DEX in patients with Down syndrome (DS) and persistent obstructive sleep apnea (OSA) and determine whether Pcrit measured under sedation predicts the severity of OSA. The passive and active Pcrit, which represent airway passive mechanical properties and active dynamic responses to airway obstruction, respectively, were measured. Upper airway reflex activity was estimated by calculating the difference between active and passive Pcrit. Subjects underwent overnight polysomnography during which Pcrit was measured during normal sleep. Pcrit was also measured during DEX sedation at a dose of 2 μg/kg/h. The study included 50 patients with median age of 11.4 years (interquartile range: 7.0-13.9) and median body mass index of 23.0 kg/m2 (interquartile range: 18.4-29.1), 66% male and 80% Caucasian. Passive Pcrit was significantly higher than active Pcrit when measured during normal sleep and DEX-induced sleep. There was a positive association between apnea-hypopnea index and passive Pcrit (Spearman r = 0.53, P = .0001) and active Pcrit (r = 0.55, P = .0002) under DEX-induced sleep. There were no significant differences between the Pcrit measurements during natural sleep and during DEX sedation. Patients with OSA can compensate for airway obstruction under DEX-induced sleep. The close association between Pcrit and apnea-hypopnea index suggests that airway responses with DEX sedation parallel those seen during natural sleep. ClinicalTrials.gov identifier: NCT01902407.


Hybrid zone analysis confirms cryptic species of banded newt and does not support competitive displacement since secondary contact.
When two putatively cryptic species meet in nature, hybrid zone analysis can be used to estimate the extent of gene flow between them. Two recently recognized cryptic species of banded newt (genus Ommatotriton) are suspected to meet in parapatry in Anatolia, but a formal hybrid zone analysis has never been conducted. We sample populations throughout the range, with a focus on the supposed contact zone, and genotype them for 31 nuclear DNA SNP markers and mtDNA. We determine the degree of genetic admixture, introgression, and niche overlap. We reveal an extremely narrow hybrid zone, suggesting strong selection against hybrids, in line with species status. The hybrid zone does not appear to be positioned at an ecological barrier, and there is significant niche overlap. Therefore, the hybrid zone is best classified as a tension zone, maintained by intrinsic selection against hybrids. While the two banded newt species can evidently backcross, we see negligible introgression and the pattern is symmetric, which we interpret as supporting the fact that the hybrid zone has been practically stationary since its origin (while extensive hybrid zone movement has been suggested in other newt genera in the region). Our study illustrates the use of hybrid zone analysis to test cryptic species status.


Structure of autocatalytically branched actin solutions.
The average branching number and cluster size in branched actin solutions with filament capping are evaluated using analytic theory and simulation methods. The average number of daughter branches per filament in steady state is much less than unity, regardless of the concentration of branching stimulant. Much more highly branched structures are obtained in the initial stages of polymerization.


The effects of family, school, and classroom ecologies on changes in children's social competence and emotional and behavioral problems in first grade.
This study tested the independent and interactive influences of classroom (concentrations of peer prosocial behaviors and victimization), family (household moves, mothers' education), and school (proportion of students receiving income assistance) ecologies on changes in children's social competence (e.g., interpersonal skills, leadership abilities), emotional problems (e.g., anxious, withdrawn behaviors), and behavioral problems (e.g., disruptiveness, aggressiveness) in first grade. Higher classroom concentrations of prosocial behaviors and victimization predicted increases in social competence, and greater school disadvantage predicted decreases. Multiple household moves and greater school disadvantage predicted increases in behavioral problems. Multiple household moves and low levels of mothers' education predicted increases in emotional problems for children in classrooms with few prosocial behaviors. Greater school disadvantage predicted increases in emotional problems for children in classrooms with low prosocial behaviors and high victimization. Policy implications of these findings are considered.


A generalized fuzzy clustering framework for incomplete data by integrating feature weighted and kernel learning.
Missing data presents a challenge to clustering algorithms, as traditional methods tend to pad incomplete data first before clustering. To combine the two processes of padding and clustering and improve the clustering accuracy, a generalized fuzzy clustering framework is proposed based on optimal completion strategy (OCS) and nearest prototype strategy (NPS) with four improved algorithms developed. Feature weights are introduced to reduce outliers' influence on the cluster centers, and kernel functions are used to solve the linear indistinguishability problem. The proposed algorithms are evaluated regarding correct clustering rate, iteration number, and external evaluation indexes with nine datasets from the UCI (University of California, Irvine) Machine Learning Repository. The results of the experiment indicate that the clustering accuracy of the feature weighted kernel fuzzy C-means algorithm with NPS (NPS-WKFCM) and feature weighted kernel fuzzy C-means algorithm with OCS (OCS-WKFCM) under varying missing rates is superior to that of seven conventional algorithms. Experiments demonstrate that the enhanced algorithm proposed for clustering incomplete data is superior.


Acrodysostosis.
Acrodysostosis refers to a group of rare skeletal dysplasias that share in common characteristic clinical and radiological features including brachydactyly, facial dysostosis, and nasal hypoplasia. In the past, the term acrodysostosis has been used to describe patients with heterogeneous phenotypes, including, in some cases, patients that today would be given alternative diagnoses. The recent finding that mutations impairing the cAMP binding to PRKAR1A are associated with "typical" acrodysostosis and hormonal resistance initiates the era where this group of disorders can be categorized on a genetic basis. In this review, we will first discuss the clinical, radiologic, and metabolic features of acrodysostosis, emphasizing evidence that several forms of the disease are likely to exist. Second, we will describe recent results explaining the pathogenesis of acrodysostosis with hormonal resistance (ADOHR). Finally, we will discuss the similarities and differences observed comparing patients with ADOHR and other diseases resulting from defects in the PTHR1 signaling pathway, in particular, pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism.


Sugar-driven prebiotic synthesis of 3,5(6)-dimethylpyrazin-2-one: a possible nucleobase of a primitive replication process.
Reaction of glyceraldehyde with alanine amide (or ammonia) under anaerobic aqueous conditions yielded 3,5(6)-dimethylpyrazin-2-one that is considered a possible complementary residue of a primitive replicating molecule that preceded RNA. Synthesis of the dimethylpyrazin-2-one isomers under mild aqueous conditions (65 degrees C, pH 5.5) from 100 mM glyceraldehyde and alanine amide (or ammonia) was complete in about 5 days. This synthesis using 25 mM glyceraldehyde and alanine amide gave a total pyrazinone yield of 9.3% consisting of 42% of the 3,5-dimethylprazin-2-one isomer and 58% of the 3,6-dimethylpyrazin-2-one isomer. The related synthesis of the dimethylpyrazin-2-one isomers from glyceraldehyde and ammonia was about 200-fold less efficient than the alanine amide reaction. This synthetic process is considered a reasonable model of origin-of-life chemistry because it uses plausible prebiotic substrates, and resembles modern biosynthesis by employing the energized carbon groups of sugars to drive the synthesis of small organic molecules. Possible sugar-driven pathways for the prebiotic synthesis of polymerizable 2-pyrazinone monomers are discussed.


Protection of human plasma kallikrein from inactivation by C1 inhibitor and other protease inhibitors. The role of high molecular weight kininogen.
High Mr kininogen increases the activation rate of prekallikrein by activated factor XII on a surface. The resulting serine protease, plasma kallikrein, Mr 88 000, is inhibited in plasma by C1 inhibitor, Mr 105 000. Since prekallikrein circulates in plasma with high Mr kininogen as a complex and a kallikrein-high Mr kininogen complex can be formed in purified systems, we studied whether the inhibition of kallikrein by C1 inhibitor was influenced by high Mr kininogen. With C1 inhibitor in excess, the inactivation of kallikrein followed pseudo-first-order kinetics. The second-order rate constant for the reaction was 1.7 X 10(4) M-1 s-1, and a kallikrein-C1 inhibitor complex, Mr 190 000 was identified on polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Kallikrein and C1 inhibitor formed an irreversible complex without measurable prior equilibrium. The rate of this reaction was decreased by 50% in the presence of high Mr kininogen (1 unit/mL or 0.73 muM). Kinetic analysis indicated that this protection was the result of the formation of a reversible complex between kallikrein and high Mr kininogen, which had a dissociation constant of 0.75 muM. However, low Mr kininogen did not protect kallikrein from inactivation by C1 inhibitor. High Mr kininogen also protected kallikrein from inactivation by diisopropyl fluorophosphate. These findings suggest that the kallikrein-high Mr kininogen complex was formed by noncovalent interactions between the light chains of both kallikrein and high Mr kininogen.


A nanoscale metal alkoxide/oxide adhesion layer enables spatially controlled metallization of polymer surfaces.
Seeding polymer substrates for the attachment and growth of metallic contacts is an important problem in modern microcircuit fabrication. A new method to effect such polymer metallization is described in which the polymer is first treated with vapor of zirconium or titanium tetra-tert-butoxide and then thermalyzed to give several monolayers of zirconium or titanium oxides that are attached to the polymer surfaces. The thickness of this layer can be controlled by the vapor exposure time. The thin oxide layers withstand removal by strenuous flexing of the polymers, and they absorb copper sulfate from an aqueous solution. Upon simple treatment with dialkylaminoborane or sodium borohydride, the polymer is metallized with copper. The tetra-tert-butoxides can be deposited through a mask, and patterned metallization of the polymers is easily accomplished.


Evidence that Orai1 does not contribute to store-operated TRPC1 channels in vascular smooth muscle cells.
Ca2+-permeable store-operated channels (SOCs) mediate Ca2+ entry pathways which are involved in many cellular functions such as contraction, growth, and proliferation. Prototypical SOCs are formed of Orai1 proteins and are activated by the endo/sarcoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1). There is considerable debate about whether canonical transient receptor potential 1 (TRPC1) proteins also form store-operated channels (SOCs), and if they do, is Orai1 involved. We recently showed that stimulation of TRPC1-based SOCs involves store depletion inducing STIM1-evoked Gαq/PLCβ1 activity in contractile vascular smooth muscle cells (VSMCs). Therefore the present work investigates the role of Orai1 in activation of TRPC1-based SOCs in freshly isolated mesenteric artery VSMCs from wild-type (WT) and Orai1-/- mice. Store-operated whole-cell and single channel currents recorded from WT and Orai1-/- VSMCs had similar properties, with relatively linear current-voltage relationships, reversal potentials of about +20mV, unitary conductances of about 2pS, and inhibition by anti-TRPC1 and anti-STIM1 antibodies. In Orai1-/- VSMCs, store depletion induced PLCβ1 activity measured with the fluorescent phosphatidylinositol 4,5-bisphosphate/inositol 1,4,5-trisphosphate biosensor GFP-PLCδ1-PH, which was prevented by knockdown of STIM1. In addition, in Orai1-/- VSMCs, store depletion induced translocation of STIM1 from within the cell to the plasma membrane where it formed STIM1-TRPC1 interactions at discrete puncta-like sites. These findings indicate that activation of TRPC1-based SOCs through a STIM1-activated PLCβ1 pathway are likely to occur independently of Orai1 proteins, providing evidence that TRPC1 channels form genuine SOCs in VSMCs with a contractile phenotype.


Malignant fibrous histiocytoma of the breast. A case report.
Primary malignant fibrous histiocytoma of the breast was diagnosed in a 45-year-old Indian woman. She presented with a large ulcerated lesion and had lung metastases. Treatment was by radiotherapy, toilet mastectomy and chemotherapy. The patient died of rapid extension of lung metastases 15 months after first being seen. Although this tumour has previously been considered to have a relatively good prognosis, this report emphasises its fully malignant metastatic potential.


X-ray crystallographic and kinetic correlation of a clinically observed human fumarase mutation.
Fumarase catalyzes the reversible conversion of fumarate to S- malate during the operation of the ubiquitous Kreb's cycle. Previous studies have shown that the active site includes side chains from three of the four subunits within the tetrameric enzyme. We used a clinically observed human mutation to narrow our search for potential catalytic groups within the fumarase active site. Offspring homozygous for the missense mutation, a G-955-C transversion in the fumarase gene, results in the substitution of a glutamine at amino acid 319 for the normal glutamic acid. To more fully understand the implications of this mutation, a single-step site-directed mutagenesis method was used to generate the homologous substitution at position 315 within fumarase C from Escherichia coli. Subsequent kinetic and X-ray crystal structure analyses show changes in the turnover number and the cocrystal structure with bound citrate.


Current and future methodology for monitoring sleep.
Sleep is much more than simply decreased consciousness, and the distinctions among the stages of nonREM and REM sleep are of significance for the polysomnographer because of their implications for physiologic events. The rules for staging sleep are essentially unchanged since their original description in 1968. This article describes this system for sleep staging, some of its weaknesses, and potential new approaches.


The roles of KCa, KATP, and KV channels in regulating cutaneous vasodilation and sweating during exercise in the heat.
We recently showed the varying roles of Ca2+-activated (KCa), ATP-sensitive (KATP), and voltage-gated (KV) K+ channels in regulating cholinergic cutaneous vasodilation and sweating in normothermic conditions. However, it is unclear whether the respective contributions of these K+ channels remain intact during dynamic exercise in the heat. Eleven young (23 ± 4 yr) men completed a 30-min exercise bout at a fixed rate of metabolic heat production (400 W) followed by a 40-min recovery period in the heat (35°C, 20% relative humidity). Cutaneous vascular conductance (CVC) and local sweat rate were assessed at four forearm skin sites perfused via intradermal microdialysis with: 1) lactated Ringer solution (control); 2) 50 mM tetraethylammonium (nonspecific KCa channel blocker); 3) 5 mM glybenclamide (selective KATP channel blocker); or 4) 10 mM 4-aminopyridine (nonspecific KV channel blocker). Responses were compared at baseline and at 10-min intervals during and following exercise. KCa channel inhibition resulted in greater CVC versus control at end exercise (P = 0.04) and 10 and 20 min into recovery (both P < 0.01). KATP channel blockade attenuated CVC compared with control during baseline (P = 0.04), exercise (all P ≤ 0.04), and 10 min into recovery (P = 0.02). No differences in CVC were observed with KV channel inhibition during baseline (P = 0.15), exercise (all P ≥ 0.06), or recovery (all P ≥ 0.14). With the exception of KV channel inhibition augmenting sweating during baseline (P = 0.04), responses were similar to control with all K+ channel blockers during each time period (all P ≥ 0.07). We demonstrated that KCa and KATP channels contribute to the regulation of cutaneous vasodilation during rest and/or exercise and recovery in the heat.


Immunogenicity and safety of a new hexavalent rotavirus vaccine in Chinese infants: A randomized, double-blind, placebo-controlled phase 2 clinical trial.
Rotavirus remains a major cause of diarrhea among 5-y-old children, and vaccination is currently the most effective and economical measure. We conducted a randomized, double-blind, placebo-controlled phase II clinical trial designed to determine the dosage, immunogenicity, and safety profile of a novel hexavalent rotavirus vaccine. In total, 480 eligible healthy infants, who were 6-12 weeks of age at the time of randomization were randomly allocated (1:1:1) to receive 105.5 focus-forming unit (FFU) or 106.5FFU of vaccine or placebo on a 0, 28 and 56-d schedule. Blood samples were collected 28 d after the third dose to assess rotavirus immunoglobulin A (IgA) antibody levels. Adverse events (AEs) up to 28 d after each dose and serious adverse events (SAEs) up to 6 months after the third dose were recorded as safety measurements. The anti-rotavirus IgA seroconversion rate of the vaccine groups reached more than 70.00%, ranging from 74.63% to 76.87%. The postdose 3 (PD3) geometric mean concentrations (GMCs) of anti-rotavirus IgA among vaccine recipients ranged from 76.97 U/ml to 84.46 U/ml. At least one solicited AE was recorded in 114 infants (71.25%) in the high-dose vaccine group, 106 infants (66.25%) in the low-dose vaccine group and 104 infants (65.00%) in the placebo group. The most frequently solicited AE was fever. The novel oral hexavalent rotavirus vaccine was safe and immunogenic in infants support the conclusion to advance the candidate vaccine for phase 3 efficacy trials.


What Are the Ingredients for an Inequity Paradigm? Manipulating the Experimenter's Involvement in an Inequity Task with Dogs.
Cooperation is only beneficial if the outcome is equally shared between individuals involved in the cooperative interaction. A mechanism to limit the development of unequal cooperation is inequity aversion, the negative reaction to unequal treatment. While inequity aversion has been studied extensively across many animal species, it remains unclear whether inequity aversion elicited in experimental settings is directed to the cooperative partner animal or rather to the experimenter distributing the rewards unequally. In the current study we aimed to further investigate whether the presence of an experimenter distributing rewards is essential in order to elicit inequity aversion in dogs. We tested 22 dog dyads in an inequity task, requiring dyads to alternately press a buzzer in order to receive rewards of equal or unequal value. We manipulated the extent of the experimenter's involvement in the task: in the experimenter-present version an experimenter gave a command to the dogs to press the buzzer and delivered the rewards by pushing the bowls into the dogs' enclosure. In contrast, in the experimenter-absent version, no experimenter was visible and the buzzer and bowls were moved from behind a curtain. We found that dogs did not respond to the unequal treatment regardless of the experimenter's involvement in the task. Nonetheless, we found that dogs based their behavior on frustration and social facilitation in the experimenter-absent version of the task, suggesting that a social interaction with an experimenter may be one aspect necessary to elicit inequity aversion. One potential explanation for the absence of inequity aversion in the experimenter-present version of the task might be the reward delivery method. Using separate sets of reward bowls for each dog instead of a shared bowl could have removed a potentially important competitive aspect (i.e., shared resource) from the inequity paradigm. In addition, delivering the rewards via bowls, rather than directly handing the rewards to the dogs, might have caused dogs to perceive the task as less cooperative. These results suggest that both the presence of an experimenter causing inequity and the inclusion of a competitive or cooperative element in the task may be basic requirements for eliciting inequity aversion.


Neurohemal contact in the internal zone of the rabbit median eminence.
The concept of neurosecretion as the mechanism by which neural control of adenohypophyseal function is accomplished was based on the observation that long capillary loops penetrate deeply into the supraopticohypophyseal tract as it passes through the median eminence internal zone. However, neural contact upon these capillary loops has not been demonstrated in the mammalian median eminence. The present transmission electron microscopic investigation of the rabbit median eminence demonstrates neurohemal contact in the median eminence internal zone. Axons containing small lucent vesicles 53.3 +/- 3.28 nm in diameter (mean +/- SEM) or small lucent and large granular vesicles with a mean diameter of 122.4 (+/- 3.28 nm) in their terminals make neurohemal contact with capillary loops in the internal zone and form a cuff about them. These terminals resemble terminals found in the external zone. Intravenous injection of the false neurotransmitter 5-hydroxydopamine (5-OH-DA) renders small lucent vesicles granular in both the external and internal zone. The effect of 5-OH-DA injection is abolished by concurrent reserpine administration. Whereas large granular vesicles in many terminals become lucent after reserpine administration, in others they remained electron dense. Viewed in the light of previous studies our findings suggest that the internal plexus arises from the external plexus and invaginates the neuropil carrying connective tissue and parvicellular axon terminals of aminergic and peptidergic systems from the external zone into the internal zone, that some elements making neurohemal contact with long capillary loops are terminals of the noradrenergic reticular infundibular tract arising outside the hypothalamus in the brainstem, and that long capillary loops form a system of repeating microvascular modules which markedly increase the surface available for neurohemal contact.


Analysing Local Sparseness in the Macaque Brain Network.
Understanding the network structure of long distance pathways in the brain is a necessary step towards developing an insight into the brain's function, organization and evolution. Dense global subnetworks of these pathways have often been studied, primarily due to their functional implications. Instead we study sparse local subnetworks of the pathways to establish the role of a brain area in enabling shortest path communication between its non-adjacent topological neighbours. We propose a novel metric to measure the topological communication load on a vertex due to its immediate neighbourhood, and show that in terms of distribution of this local communication load, a network of Macaque long distance pathways is substantially different from other real world networks and random graph models. Macaque network contains the entire range of local subnetworks, from star-like networks to clique-like networks, while other networks tend to contain a relatively small range of subnetworks. Further, sparse local subnetworks in the Macaque network are not only found across topographical super-areas, e.g., lobes, but also within a super-area, arguing that there is conservation of even relatively short-distance pathways. To establish the communication role of a vertex we borrow the concept of brokerage from social science, and present the different types of brokerage roles that brain areas play, highlighting that not only the thalamus, but also cingulate gyrus and insula often act as "relays" for areas in the neocortex. These and other analysis of communication load and roles of the sparse subnetworks of the Macaque brain provide new insights into the organisation of its pathways.


Update on recent molecular and genetic advances in frontotemporal lobar degeneration.
Great strides have been made in the last 2 years in the field of frontotemporal lobar degeneration (FTLD), particularly with respect to the genetics and molecular biology of FTLD with ubiquitinated inclusions. It is now clear that most cases of familial FTLD with ubiquitinated inclusions have mutations in the progranulin gene, located on chromosome 17. It is also clear that most ubiquitinated inclusions in FTLD with ubiquitinated inclusions are composed primarily of TAR DNA-binding protein-43. Thus, FTLDs can be separated into 2 major groups (i.e. tauopathies and ubiquitinopathies), and most of the ubiquitinopathies can now be defined as TAR DNA-binding protein-43 proteinopathies. Many of the familial FTLDs are linked to chromosome 17, including both the familial tauopathies and the familial TAR DNA-binding protein-43 proteinopathies with progranulin mutations. This review highlights the neuropathologic features and the most important discoveries of the last 2 years and places these findings into the historical context of FTLD.


Smoking in immigrants: do socioeconomic gradients follow the pattern expected from the tobacco epidemic?
Although socioeconomic patterns of smoking across the different stages of the tobacco epidemic have been well researched, less is known about these patterns among immigrant populations. This paper aims to assess the smoking prevalence and its socioeconomic gradients among three immigrant populations. Three cross-sectional studies, using structured face-to-face interviews, were conducted in three representative (for socioeconomic status) samples of 385 Turkish, 316 Moroccan, and 1072 Surinamese first-generation immigrants aged 35-60 years in Amsterdam, The Netherlands. Information gathered included information about smoking behaviour, educational level and background characteristics. The associations between educational level and smoking rates were assessed using logistic regression analyses stratified by age and sex, for each ethnic group separately. The prevalence of smoking differed per group, being highest among Turkish and Surinamese men (63% and 55%, respectively), followed by Moroccan men and Turkish and Surinamese women (30%, 32% and 27%, respectively). Higher smoking rates were found among women with higher educational levels, except for Surinamese women aged 35-44 years. However, among Turkish and Moroccan men aged 35-44 years and Surinamese men, smoking rates were higher in lower socioeconomic groups. The prevalence figures and educational associations suggest that the socioeconomic gradient changes in earlier stages of the epidemic in immigrant populations than in the Western host populations, particularly in men. This provides indications to suggest that smoking prevention measures in male immigrant groups need to be tailored to lower socioeconomic groups in particular throughout the tobacco epidemic, and to higher socioeconomic groups among women.


Material Evaluation and Dynamic Powder Deposition Modeling of PEEK/CF Composite for Laser Powder Bed Fusion Process.
Polymeric composites such as Poly-ether-ether-ketone (PEEK)/carbon fiber (CF) have been widely utilized due to outstanding performances such as high specific strength and specific modulus. The PEEK/CF components via powder bed fusion additive manufacturing usually show brittle fracture behaviors induced by their poor interfacial affinity and inner voids. These defects are strongly associated with powder packing quality upon deposition. The particle dynamic model has been widely employed to study the interactions of particle motions. Powder property, bulk material property, and interfacial features of composite powders are key factors in the particle dynamic model. In this work, an efficient and systematic material evaluation is developed for composite powders to investigate their deposition mechanism. The discrete element method is utilized to simulate the dynamic behaviors of PEEK/CF composite powders. The powder properties, bulk material properties, and interfacial features of powders are calibrated and justified by experimental measurement, numerical simulation, and design of experiments. The particle dynamic model can explain the powder flow behaviors and interactions. The experimental and simulation AOR results show a maximal deviation of 4.89%. It reveals that the addition of short CF particles can assist the flow of PEEK powders and improve the packing quality of the composite powders. The results show an experimental improvement of 31.3% and 55.2% for PEEK/CF_30wt% and PEEK/CF_50wt%, with a simulated improvement of 27.4% and 50.2% for corresponding composite powders.


Are glycopeptides still appropriate and convenient for empiric use?
The glycopeptides vancomycin and teicoplanin are widely used, and indeed recommended for, the treatment of severe or resistant Gram-positive infections. Therapeutic drug monitoring is widely used for vancomycin but less commonly for teicoplanin, and remains controversial. We report the cost savings of a formulary decision to replace teicoplanin with daptomycin for the empiric treatment of complicated skin and soft tissue infections (CSSTIs), staphylococcal bacteraemia and hospital-acquired Gram-positive sepsis. In the Intensive Therapy Unit (ITU) we optimised treatment of serious Gram-positive infections by substituting teicoplanin with vancomycin administered by continuous infusion. Costs were calculated using British National Formulary (BNF) prices and costs for therapeutic drug monitoring. Daptomycin (350 mg/d) use was associated with a cost saving per 7 days of treatment of 86 pounds and vancomycin with 51 pounds (4 g/d) to 276 pounds (2 g/d) compared to the 600 mg teicoplanin dose. Our own formulary re-positioning of glyco/lipopeptides, i.e. the preferential use of vancomycin in the ITU and substitution of teicoplanin with daptomycin, is cost-effective and provides better therapeutic alternatives. Continuous vancomycin infusion in the ITU setting guarantees optimal dosing for severely ill patients. Daptomycin use on surgical and medical wards, apart from being marginally cheaper than teicoplanin, guarantees optimal dosing without the need for drug monitoring.


Infant sensitivity to negative maternal emotional shifts: Effects of infant sex, maternal postnatal depression, and interactive style.
This study examined the effects of infant sex, maternal postnatal depression, and maternal interactive style on infant sensitivity to maternal negative emotional shifts. Face-to-face interactions of 68 mother-infant dyads were analyzed at 8 and 18 weeks. Twenty-five (28%) mothers had postnatal depression. Interactions were analyzed in terms of overall maternal interactive style: "sensitive," "anxious," "intrusive," and "sad." Episodes of negative shifts in maternal emotional expression were recorded, along with expressions of infant sensitivity to these changes. Daughters of depressed mothers showed higher rates of sensitivity to maternal negative emotion whereas their sons showed lower rates, in comparison to both girl and boy infants of well mothers. While maternal interactive style had no effect on 8-week infant sensitivity to maternal negative emotional shifts, high rates of 18-week infant sensitivity were predicted by both an 8-week and a concurrent, "sad" maternal interactive style. The findings are discussed in relation to theories of emotional and interpersonal development.


Toward an Early Diagnosis for Alzheimer's Disease Based on the Perinuclear Localization of the ATM Protein.
Alzheimer's disease (AD) is the most common neurodegenerative dementia, for which the molecular origins, genetic predisposition and therapeutic approach are still debated. In the 1980s, cells from AD patients were reported to be sensitive to ionizing radiation. In order to examine the molecular basis of this radiosensitivity, the ATM-dependent DNA double-strand breaks (DSB) signaling and repair were investigated by applying an approach based on the radiation-induced ataxia telangiectasia-mutated (ATM) protein nucleoshuttling (RIANS) model. Early after irradiation, all ten AD fibroblast cell lines tested showed impaired DSB recognition and delayed RIANS. AD fibroblasts specifically showed spontaneous perinuclear localization of phosphorylated ATM (pATM) forms. To our knowledge, such observation has never been reported before, and by considering the role of the ATM kinase in the stress response, it may introduce a novel interpretation of accelerated aging. Our data and a mathematical approach through a brand-new model suggest that, in response to a progressive and cumulative stress, cytoplasmic ATM monomers phosphorylate the APOE protein (pAPOE) close to the nuclear membrane and aggregate around the nucleus, preventing their entry in the nucleus and thus the recognition and repair of spontaneous DSB, which contributes to the aging process. Our findings suggest that pATM and/or pAPOE may serve as biomarkers for an early reliable diagnosis of AD on any fibroblast sample.


Probing Charge Transport through Peptide Bonds.
We measure the conductance of unmodified peptides at the single-molecule level using the scanning tunneling microscope-based break-junction method, utilizing the N-terminal amine group and the C-terminal carboxyl group as gold metal-binding linkers. Our conductance measurements of oligoglycine and oligoalanine backbones do not rely on peptide side-chain linkers. We compare our results with alkanes terminated asymmetrically with an amine group on one end and a carboxyl group on the other to show that peptide bonds decrease the conductance of an otherwise saturated carbon chain. Using a newly developed first-principles approach, we attribute the decrease in conductance to charge localization at the peptide bond, which reduces the energy of the frontier orbitals relative to the Fermi energy and the electronic coupling to the leads, lowering the tunneling probability. Crucially, this manifests as an increase in conductance decay of peptide backbones with increasing length when compared with alkanes.


Comparison of plant-type phosphoenolpyruvate carboxylases from rice: identification of two plant-specific regulatory regions of the allosteric enzyme.
Phosphoenolpyruvate carboxylase (PEPC) is a key enzyme of primary metabolism in bacteria, algae and vascular plants, and it undergoes allosteric regulation by various metabolic effectors. Rice (Oryza sativa) has five plant-type PEPCs, four cytosolic and one chloroplastic. We investigated their kinetic properties using recombinant proteins and found that, like most plant-type PEPCs, rice cytosolic isozymes were activated by glucose 6-phosphate and by alkaline pH. In contrast, no such activation was observed for the chloroplastic isozyme, Osppc4. In addition, Osppc4 showed low affinity for the substrate phosphoenolpyruvate (PEP) and very low sensitivities to allosteric inhibitors aspartate and glutamate. By comparing the isozyme amino acid sequences and three-dimensional structures simulated on the basis of the reported crystal structures, we identified two regions where Osppc4 has unique features that can be expected to affect its kinetic properties. One is the N-terminal extension; replacement of the extension of Osppc2a (cytosolic) with that from Osppc4 reduced the aspartate and glutamate sensitivities to about one-tenth of the wild-type values but left the PEP affinity unaffected. The other is the N-terminal loop, in which a conserved lysine at the N-terminal end is replaced with a glutamate-alanine pair in Osppc4. Replacement of the lysine of Osppc2a with glutamate-alanine lowered the PEP affinity to a quarter of the wild-type level (down to the Osppc4 level), without affecting inhibitor sensitivity. Both the N-terminal extension and the N-terminal loop are specific to plant-type PEPCs, suggesting that plant-type isozymes acquired these regions so that their activity could be regulated properly at the sites where they function.


Recent Progress in the Design of Monodisperse, Sequence-Defined Macromolecules.
This review describes different synthetic strategies towards sequence-defined, monodisperse macromolecules, which are built up by iterative approaches and lead to linear non-natural polymer structures. The review is divided in three parts: solution phase-, solid phase-, and fluorous- and polymer-tethered approaches. Moreover, synthesis procedures leading to conjugated and non-conjugated macromolecules are considered and discussed in the respective sections. A major focus in the evaluation is the applicability of the different approaches in polymer chemistry. In this context, simple procedures for monomer and oligomer synthesis, overall yields, scalability, purity of the oligomers, and the achievable level of control (side-chains, backbone, stereochemistry) are important benchmarks.


Saudi womens acceptance and attitudes towards companion support during labor: should we implement an antenatal awareness program?
Despite the known benefits of support during chilbirth, most hospitals in Saudi Arabia do not allow a companion during labor. This can be due to cultural beliefs among pregnant Saudi women. The aims of this study are to describe Saudi women's preferences towards supportive companions during labor and to explore their attitudes and knowledge about the importance of support during childbirth. Prospective cohort study conducted in three governmental tertiary hospitals within Riyadh. Women who consented were interviewed during their postpartum hospital stay using a validated standardized Arabic questionnaire. Participants were asked about their preferences and attitudes towards companions during childbirth, as well as about their knowledge on the importance of such support. Of 402 women who participated in the study, 182 women (45.3%) preferred the presence of a companion during childbirth and only 57 of all interviewed women (14.2%) had ever had a supportive companion during any of their previous childbirths. The mother (58%) or husband (51%) was the most preferred person as a childbirth companion. Age, level of educational, or antenatal, intrapartum or postpartum status had no impact on their decision. However, women who had some sort of antenatal educational classes and/or read educational material about childbirth were more likely to prefer support during labor. More than one-third of participants (35.9%) thought that having a companion as support during labor would not help, but the most common reason for not preferring to have a companion was their fear of being exposed most of the time to their companion (64.1%). A significant percentage of surveyed Saudi women preferred not to have a supportive companion during childbirth. The reason might be a lack of understanding of the positive role of a companion during childbirth or because of cultural beliefs. Education of women during their antenatal care about the importance and the implementation of such a practice are warranted.


The Association among Difficulties in Emotion Regulation, Hostility, and Empathy in a Sample of Young Italian Adults.
The aim of the present study was to assess the role of empathy in mediating the association between difficulties in emotion regulation and hostility. Three hundred and sixty young Italian adults (220 women and 140 men) were enrolled in the study. Psychopathological assessments included the Difficulties in Emotion Regulation Scale (DERS), the Interpersonal Reactivity Index and the Buss-Durkee Hostility Inventory (BDHI). Perspective taking (PT) and Personal distress (PD) are significantly associated with both DERS total score and BDHI total score. A mediational model analyzing the direct and indirect effects of DERS on BDHI through the mediating role of PT and PD showed that the relation between DERS and BDHI was partially mediated by PT total score (b = 0.16; se = 0.01; p = 0.02). Taken together our findings support the possibility that PT skills could play a crucial role in inhibiting hostility behaviors.


Multifunctional Nanoflowers for Simultaneous Multimodal Imaging and High-Sensitivity Chemo-Photothermal Treatment.
Liver cancer is currently among the most challenging cancers to diagnose and treat. It is of prime importance to minimize the side effects on healthy tissues and reduce drug resistance for precise diagnoses and effective treatment of liver cancer. Herein, we report a facile but high-yield approach to fabricate a multifunctional nanomaterial through the loading of chitosan and metformin on Mn-doped Fe3O4@MoS2 nanoflowers. Mn-doped Fe3O4 cores are used as simultaneous T1/T2 magnetic resonance imaging (MRI) agents for sensitive and accurate cancer diagnosis, while MoS2 nanosheets are used as effective near-infrared photothermal conversion agents for potential photothermal therapy. The surface-functionalized chitosan was able not only to improve the dispersibility of Mn-doped Fe3O4@MoS2 nanoflowers in biofluids and increase their biocompatibility, but also to significantly enhance the photothermal effect. Furthermore, metformin loading led to high suppression and eradication of hepatoma cells when photothermally sensitized, but exhibited negligible effects on normal liver cells. Due to its excellent combination of T1/T2 MRI properties with sensitive chemotherapeutic and photothermal effects, our study highlights the promise of developing multifunctional nanomaterials for accurate multimodal imaging-guided, and highly sensitive therapy of liver cancer.


Long-term safety of GM-CSF (molgramostim) administration after allogeneic bone marrow transplantation for hematologic malignancies: five-year follow-up of a double-blind randomized placebo-controlled study.
In a double-blind, randomized study performed between 1988 and 1990, 40 patients undergoing allogeneic BMT from HLA-identical siblings for hematologic malignancies received 8 mg/kg/d rHuGM-CSF (molgramostim, n = 20) for 14 days. The median neutrophil count on day 14 was significantly higher in the GM-CSF group (1.90 vs 0.46 yen 10(9)/L, P < .0001). The incidence of acute GVHD and transplant-related mortality were comparable. Only two deaths occurred after 6 months; one due to pulmonary fibrosis in the GM-CSF group on day 1591, and one due to relapse on day 1590 in the placebo group. The Karnofsky score of the 10 survivors, 3 in the placebo group and 7 in the GM-CSF group, is 90-100% (median 100%), and none has chronic GVHD requiring therapy. There was no evidence of increased relapse in the GM-CSF group with only two relapses occurring; both in the placebo group. With a follow-up of 4.5-6.8 years (median 5.5 years), these patients are amongst the longest surviving patients to have received a recombinant growth factor post-allograft. We conclude that the administration of GM-CSF after allogeneic BMT does not appear to be associated with an increased incidence of chronic GVHD or relapse, or of other adverse effects such as the development of myelodysplasia.


[Snakebites in the State of Goiás, Brazil].
Ophidic accidents are a serious health problem for tropical countries, because are responsible for the high incidence of morbidity and mortality. This article describes aspects of snakebite epidemiology in the State of Goiás, Brazil. Notifications about the accidents caused by poisonous snakes have been analysed for Government of the State of Goiás (Brazil), Health Department, from 1998 to 2000. In this period, 3261 accidents caused by poisonous snakes have been notified, which represented the average annual incidence rate of 20 to 23/100,000 persons. The vast majority of cases occurred from October to April. The classification of the snake genus had been possible in 2350 cases and the distribution was: Bothrops (78.6%), Crotalus (20.8%) and Micrurus (6%). The age distribution shows that the accidents had been suffered by 20 to 39 year old people with great predominance in males (78%). The anatomical areas more frequently bitten were feet (43.6%), legs (23.2%) and hands (20.1%). At the health center 80% of the patients had been treated within sixth hour after the accident. The distribution according to the severity of poisoning was: light (31.6%), moderate (47.5%) and severe (9.6%). The most common complications were necrosis bite site (31.8%) in bothropic envenoming and acute renal failure (1.2%) in crotalic envenoming. The case fatality rate was 0.46%, been the most rate observed in crotalic envenoming (1%). Accidents owing to poisonous snakes are frequent in the State of Goiás, the young male population is more often attacked and they are an important cause of death.


Safety and benefits of antenatal oral iron supplementation in low-income countries: a review.
The World Health Organization recommends universal iron supplementation of 30-60 mg/day in pregnancy but coverage is low in most countries. Its efficacy is uncertain, however, and there has been a vigorous debate in the last decade about its safety, particularly in areas with a high burden of malaria and other infectious diseases. We reviewed the evidence on the safety and efficacy of antenatal iron supplementation in low-income countries. We found no evidence that daily supplementation at a dose of 60 mg leads to increased maternal Plasmodium infection risk. On the other hand, recent meta-analyses found that antenatal iron supplementation provides benefits for maternal health (severe anaemia at postpartum, blood transfusion). For neonates, there was a reduced prematurity risk, and only a small or no effect on birth weight. A recent trial showed, however, that benefits of antenatal iron supplementation on maternal and neonatal health vary by maternal iron status, with substantial benefits in iron-deficient women. The benefits of universal iron supplementation are likely to vary with the prevalence of iron deficiency. As a consequence, the balance between benefits and risks is probably more favourable in low-income countries than in high-income countries despite the higher exposure to infectious pathogens.


A review of literature along with a cadaveric study of the prevalence of the Giacomini vein (the thigh extension of the small saphenous vein) in the Indian population.
Short saphenous has most variable anatomy in the inferior extremity which become more relevant especially in varicose vein surgery. Present study on cadavers was undertaken to report the prevalence of the thigh extension of the short saphenous vein (Giacomini vein) in the Indian population and to discuss it with the prior studies reported in the literature on other populations. Dissection was performed on both the sides of 50 embalmed cadavers to study the prevalence of the Giacomini vein. Mode of termination of the proximal extension of the short saphenous vein in the thigh was studied for different criteria. Ninety-two percent of the lower extremities showed prevalence of the Giacomini vein. In 71% specimens the short saphenous vein terminated into the popliteal vein. Most common mode of extension in the thigh was anastomosis with the great saphenous vein. Prevalence of Giacomini vein in Indian population was highest (92%) compared to previous studies by various authors in other populations. Aforementioned anatomical facts including the mode of termination of the thigh extension of the short saphenous vein can be important for surgeons planning intervention in this area. The complex anatomy of this vein and different reports in the literature regarding its clinical significance suggest further studies in this direction.


Yeast mutants affecting possible quality control of plasma membrane proteins.
Mutations gef1, stp22, STP26, and STP27 in Saccharomyces cerevisiae were identified as suppressors of the temperature-sensitive alpha-factor receptor (mutation ste2-3) and arginine permease (mutation can1(ts)). These suppressors inhibited the elimination of misfolded receptors (synthesized at 34 degrees C) as well as damaged surface receptors (shifted from 22 to 34 degrees C). The stp22 mutation (allelic to vps23 [M. Babst and S. Emr, personal communication] and the STP26 mutation also caused missorting of carboxypeptidase Y, and ste2-3 was suppressed by mutations vps1, vps8, vps10, and vps28 but not by mutation vps3. In the stp22 mutant, both the mutant and the wild-type receptors (tagged with green fluorescent protein [GFP]) accumulated within an endosome-like compartment and were excluded from the vacuole. GFP-tagged Stp22p also accumulated in this compartment. Upon reaching the vacuole, cytoplasmic domains of both mutant and wild-type receptors appeared within the vacuolar lumen. Stp22p and Gef1p are similar to tumor susceptibility protein TSG101 and voltage-gated chloride channel, respectively. These results identify potential elements of plasma membrane quality control and indicate that cytoplasmic domains of membrane proteins are translocated into the vacuolar lumen.


Green approach for synthesis of gold nanoparticles from Nigella arvensis leaf extract and evaluation of their antibacterial, antioxidant, cytotoxicity and catalytic activities.
In the present work, we studied the reduction of gold ions into gold nanoparticles using Nigella arvensis leaf extract in the one-step green synthesis method. The formation of N. arvensis gold nanoparticles (NA-GNPs) was confirmed by UV-Vis spectroscopy, XRD, FT-IR and TEM analyses. The XRD pattern confirmed the crystal structure of NA-GNPs, and TEM image showed the small size (3-37 nm) and almost spherical shape of NA-GNPs. NA-GNPs have not shown enhanced antioxidant properties compared to the plant extract while they were active against the clinical isolated bacterial strains. These nanoparticles showed the cytotoxicity effects against H1299 and MCF-7 cancer cell lines with an IC50 value of 10 and 25 μg/ml, respectively. The extract of N. arvensis contained 212 μg/ml flavonoids and 145 μg/ml phenolic compounds. The contents of total phenolics and flavonoids of biosynthesized NA-GNPs were 68 and 189 μg/ml, respectively. Plant extract and NA-GNPs exhibited a maximum DPPH scavenging activity of 32% and 12%, respectively. The catalytic activity of NA-GNPs against methylene blue was 44%. In conclusion, these results suggest that NA-GNPs can act as a promising candidate for different medical applications produced by cost-effective, eco-friendly and straightforward green method.


The role of age of acquisition in picture and word naming in dyslexic adults.
To date, there has been numerous reports that early acquired pictures and words are named faster than late acquired pictures and words in normal reading but it is not established whether age of acquisition (AoA) has the same impact on adult dyslexic naming, especially in a transparent orthography such as Turkish. Independent ratings were obtained for AoA, frequency, name agreement, and object familiarity in Turkish for all items in the Snodgrass and Vanderwart line drawing set. Dyslexic (N= 15) and non-dyslexic (N= 15) university undergraduates were asked to name 30 early acquired and 30 late acquired pictures and picture names standardized and selected from these norms. As predicted, there were main effects for (a) AoA with reaction times (RTs) for Early items named faster than Late items, (b) reader status with non-dyslexic students faster than dyslexic students, and (c) stimuli types with pictures named slower than words. A two-way interaction between reader status and stimuli type was also significant. Implications of the results for theoretical frameworks of AoA within the cognitive architecture and normal and impaired models of reading are discussed.


Peptidergic pathways in the avian brain.
The results obtained by topographical studies on the immunoreactive peptide systems in the embryonic and adult avian brain (domestic fowl, domestic mallard, pigeon, Japanese quail, and zebra finch) can be realized only by means of phylogenetical comparisons. The comparative studies mainly demonstrate a fascinating constancy of the immunological properties and the spatial distribution of the neuropeptides. Independent of the development of the neopallium, and the increasing cerebral complexity, the spatial distribution of the neuropeptides, the location of their main perikaryal accumulations which are interconnected by immunoreactive fiber projections (and thereby forming widespread but continuous peptide systems) remain nearly unchanged during vertebrate evolution. The recognition of the neuropeptides as integral parts of the central nervous system is demonstrated by the fact that neuropeptidergic structures connect sensory inputs with central nervous areas as well as with the peripheral endocrinium.


A simple surgical technique for splitting a single donor cornea for performing deep anterior lamellar keratoplasty and Descemet membrane endothelial keratoplasty without using a microkeratome.
To describe a simple manual surgical technique for splitting a single-donor eye for performing both deep anterior lamellar keratoplasty (DALK) and Descemet membrane endothelial keratoplasty (DMEK) without using a microkeratome. Twenty-three eyes with anterior stromal pathology and 23 eyes with irreversible endothelial dysfunction were evaluated for keratoplasty at a tertiary eye care referral center. Twenty-three healthy donor corneas were split into two parts. The Descemet's membrane was stripped and used for DMEK. The stripped stroma was used for DALK. Best-corrected visual acuity (BCVA) of both DALK and DMEK, endothelial cell density, and endothelial cell loss in DMEK were noted at 1-year follow-up, along with any intraoperative or postoperative complications and failures. In the DALK group, mean BCVA improved from 1.264 ± 0.25 log Mar preoperatively to 0.355 ± 0.27 log Mar at 12 months follow-up. There were no complications and failures. In the DMEK group, mean BCVA improved from 1.537 ± 0.61 log Mar preoperatively to 0.592 ± 0.67 log Mar and the mean donor ECD was 3071.66 (range, 2783-3487) cells/mm2 preoperatively, which was reduced to 1989.33 (range, 1546-2543) cells/mm2 at 12 months follow-up indicating a mean endothelial cell loss of 35%. The failure rate was 21.7%. This study demonstrates that with a single donor corneal tissue, both DALK and DMEK can be performed successfully without any complications. Our technique will help corneal surgeons in all developing countries to cost effectively perform more lamellar surgeries and help in reducing the magnitude of corneal blindness without the need for expensive microkeratomes.


[Factors controlling tumor promotion induced by TPA].
Phospholipase A2 inhibitors and lipoxygenase inhibitors markedly suppressed mouse skin ODC (ornithine decarboxylase) induction and promotion of papilloma by TPA. The inhibitory potency was related to the inhibition of epidermal 12-lipoxygenase. Lipoxygenase inhibitors, such as AA 861 and tetrahydrochalcone were lacking in the inhibitory action on protein kinase C. Moreover, palmitoylcarnitin, a protein kinase C inhibitor, inhibited TPA-induced differention of HL 60 cells and TPA-induced epidermal ODC induction and tumor promotion in mouse skin. Intraperitoneal injection of TPA also induced ODC in liver, kidney and spleen, but not in the skin of mice. In isolated mouse epidermal cells, TPA and diacylglycerol induced ODC. The induction of ODC was inhibited by phospholipase A2 inhibitors, lipoxygenase inhibitors, anticalmodulines, Ca++ entry blockers and Ca++ antagonists. These results indicate that intracellular Ca++ is involved in TPA induction of ODC.


Sphingosine-1-phosphate is a possible fibrogenic factor in gluteal muscle fibrosis.
Gluteal muscle contracture (GMC) is a chronic fibrotic disease of gluteal muscles due to multiple etiologies. The main pathologic process is characterized by proliferation of fibroblasts and excessive accumulation of collagen in the extracellular matrix of the muscle. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and has been reported to be associated with various fibrotic diseases. However, the role of S1P in GMC remains unknown. Here in this article, High-performance liquid chromatography and immunohistochemistry were applied to evaluate S1P localization and expression in clinical samples from patients with GMC, Quantitative real time PCR, Western blot, and enzyme-linked immunosorbent assay were used to explore the link between transforming growth factor-beta1 (TGF-beta1), plasminogen activator inhibitor-1 (PAI-1) and S1P. The results showed that S1P was enhanced in contraction band (CB) tissues. Studies using the cell proliferation and transformation assay indicated that exogenous S1P stimulated CB fibroblast proliferation in a time-dependent manner and in higher concentration also in a dose-dependent manner. Furthermore, we demonstrated that S1P not only promoted collagen type I production, but also up-regulated mRNA and protein expression of transforming growth factor-beta1 and plasminogen activator inhibitor-1. These findings suggest that S1P may regulate increased synthesis of collagen and other fibrogenic factors, and significantly contributes to the process of gluteal muscle scarring in patients with GMC.


Direct calcium binding results in activation of brain serine racemase.
Serine racemase (SR) is a brain enzyme present in glial cells, where it isomerizes L-serine into D-serine that, in turn, diffuses and coactivates the N-methyl-D-aspartate receptor through the binding to the so-called "glycine site." We have developed a method for the slow expression of SR in a eukaryotic vector that permits the correct insertion of the prosthetic group into the active site, rendering functional SR with a K(m) toward L-serine of 4.8 mm. Divalent cations such as calcium or manganese were necessary for complete enzyme activity, whereas the presence of chelators such as EDTA completely inhibited the enzyme. Moreover, direct binding of calcium to SR was evidenced using (45)Ca(2+). Gel filtration of the recombinant SR revealed the protein to be in a dimer-tetramer equilibrium. The addition of EDTA to a calcium-saturated serine racemase evokes a profound conformational change, as monitored by both fluorescence and circular dichroism techniques. Fluorescence titration allowed us to calculate a binding constant for calcium of 6.2 microm. Reagents that react with sulfhydryl groups, such as cystamine, were potent inhibitors of SR, in a clear reflection that one or more cysteine residues are important for enzyme activity. Additionally, 16 serine analogues were tested as a putative SR substrate or inhibitors. Significant inhibition was only observed for L-Ser-O-sulfate, L-cycloserine, and L-cysteine. Finally, activation of brain SR as a result of the changes in calcium concentration was studied in primary astrocytes. Treatment of astrocytes with the calcium ionophore, as well as with compounds that augment the intracellular calcium levels such as glutamate or kainate led to an increase in the amount of d-serine present in the extracellular medium. These results suggest that there might be a glutamatergic-mediated regulation of SR activity by intracellular calcium concentration.


Sepsis Alert - a triage model that reduces time to antibiotics and length of hospital stay.
To study if a modified triage system at an Emergency Department (ED) combined with educational efforts resulted in reduced time to antibiotics and decreased length of hospital stay (LOS) for patients with severe infection. A retrospective, observational study comparing patients before and after the start of a new triage model at the ED of a University Hospital. After the implementation of the model, patients with fever and abnormal vital signs were triaged into a designated sepsis line (Sepsis Alert) for rapid evaluation by the attending physician supported by a infectious diseases (IDs) specialist. Also, all ED staff participated in a designated sepsis education before Sepsis Alert was introduced. Medical records were evaluated for patients during a 3-month period after the triage system was started in 2012, and also during the corresponding months in 2010 and 2014. A total of 1837 patients presented with abnormal vital signs. Of these, 221 patients presented with fever and thus at risk of having severe sepsis. Among patients triaged according to the new model, median time to antibiotics was 58.5 at startup and 24.5 minutes at follow-up two years later. This was significantly less than for patients treated before the new model, 190 minutes. Also, median LOS was significantly decreased after introduction of the new triage model, from nine to seven days. A triage model at the ED with special attention to severe sepsis patients, led to sustained improvements of time to antibiotic treatment and LOS.


Relaxin Inhibits High Glucose-Induced Matrix Accumulation in Human Mesangial Cells by Interfering with TGF-β1 Production and Mesangial Cells Phenotypic Transition.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). DN is characterized by glomerular extracellular matrix accumulation, mesangial expansion, basement membrane thickening, and renal interstitial fibrosis. To date, mounting evidence has shown that H2 relaxin possesses powerful antifibrosis properties; however, the mechanisms of H2 relaxin on diabetic nephropathy remain unknown. Here, we aimed to explore whether H2 relaxin can reduce production of extracellular matrix (ECM) secreted by human mesangial cells (HMC). HMC were exposed to 5.5 mM glucose (NG) or 30 mM glucose (HG) with or without H2 relaxin. Fibronectin (FN) and collagen type IV levels in the culture supernatants were examined by solid-phase enzyme-linked immunoadsorbent assay (ELISA). Western blot was used to detect the expression of α-smooth muscle actin (α-SMA) protein. Quantitative polymerase chain reaction (qPCR) method was employed to analyze transforming growth factor (TGF)-β1 mRNA expression. Compared with the normal glucose group, the levels of fibronectin and collagen type were markedly increased after being cultured in high glucose medium. Compared with the high glucose group, remarkable decreases of fibronectin, collagen type IV, α-smooth muscle actin, and TGF-β1 mRNA expression were observed in the H2 relaxin-treated group. The mechanism by which H2 relaxin reduced high glucose-induced overproduction of ECM may be associated with inhibition of TGF-β1 mRNA expression and mesangial cells' phenotypic transition. H2 relaxin is a potentially effective modality for the treatment of DN.


Conventional vascular risk factors: their role in the association between migraine and cardiovascular diseases.
Migraine, in particular migraine with aura, has been found to be associated with cardiovascular disease. However, the role of conventional vascular risk factors in the association is still debated. The aim of the present review is to address the association between migraine and conventional cardiovascular risk factors as well as to address their possible role in the association between migraine and cardiovascular disease. Data for this review were obtained through searches in multiple sources up to May 2014 using the terms "migraine" OR "headache" in combination with all the vascular risk factors of interest. Data about the possible association between migraine and high blood pressure values are heterogeneous, hindering any final conclusion. Data addressing the possible association between migraine and diabetes mellitus indicate the lack of any association or in some cases a negative association between the two conditions. The body of evidence on the role of dyslipidemia in migraineurs is relatively homogeneous and, with few exceptions, reports an association between migraine and an unfavorable lipid profile; however, the difference in lipid levels between migraineurs and non-migraineurs is small and its clinical implication unclear. Regarding obesity, a trend has been observed of increased risk of migraine with increasing obesity, especially in young patients, albeit in the midst of conflicting data. Evidence about the association between cigarette smoking and migraine mostly indicates that migraineurs are more commonly smokers than non-migraineurs. On the other hand, the majority of the available studies report less alcohol use in migraineurs than in non-migraineurs. Finally, many of the available studies suggest a more frequent family history of cardiovascular disease in migraineurs as compared to non-migraineurs. Since most of the studies that supported the association between migraine and cardiovascular disease adjusted the analyses for the presence of several vascular risk factors, they cannot entirely explain this association. Based on the available reported data, it seems unlikely that the higher risk of cardiovascular disease in migraineurs is mediated by any single vascular risk factor. For this reason the role of specific interactions among risk factors with the contribution of genetic, environmental, personality and psychological factors should be appropriately investigated.


Chemical and biological characterization of the lipopolysaccharide of Bacteroides fragilis subspecies fragilis.
Bacterial lipopolysaccharides extracted from Bacteroides fragilis subspecies fragilis lacked 2-keto-3-deoxyoctonate and heptose, sugars which make up part of the inner core of most bacterial endotoxins. Over 98% of the lipid portion of this material could be removed easily with chloroform-methanol and alcohol, a finding which indicates a loose association between the polysaccharide and lipid moieties. The lipopolysaccharides caused gelation of limulus lysate at a concentration significantly higher than that for the endotoxin of Salmonella typhi. None of the extracts was lethal in 10-day-old chick embryos at doses of greater than 200 mug per egg, whereas the endotoxin of Neisseria meningitidis was lethal at a dose of 1.2 mug per egg. The local Shwartzman reaction could not be induced by levels of B. fragilis endotoxin of up to 1,000 mug per rabbit, whereas a (control) endotoxin of S. typhi induced this phenomenon at a level of 3 mug per rabbit. Intact oxygen-killed B. fragilis failed to provoke the local Shwartzman reaction at doses of 2,500 mug. These results indicate that B. fragilis has a lipopolysaccharide different from that of most gram-negative bacteria. Although it retains some of the chemical and biologic properties of classical endotoxin, it seems to lack others. This observation may have significant clinical implications.


Characterisation of the lysosomal heterogeneity in Chinese-hamster fibroblasts.
1. Homogenates of Chinese hamster fibroblasts have been fractionated by analytical centrifugation techniques. Lysosomes have been characterised and identified by the distinctive behaviour of specific marker constituents. 2. The acid hydrolases of hamster fibroblasts were located in two distinct organelles, characterised by differences in their equilibrium densities and rates of sedimentation. The lighter population of lysosomes with a modal density of 1.10 g cm-3, contained glycosidases, nucleases and acid phosphatase. The denser population, with a modal density of 1.15 g cm-3, contained proteases and arylsulphatase B. 3. Acid hydrolases in both populations showed similar degrees of latency and structure-linked sedimentability. 4. The heterophagic activity of hamster fibroblasts was investigated by growing the cells in the presence of [14C]sucrose, [14C]inulin and Triton WR 1339. These compounds are taken up by the cells and appear to be located in the denser population of lysosomes. 5. The low density of the lighter population of lysosomes appears to result from a high content of cholesterol esters and triacylglycerols. It is suggested that the lysosomes may be the site of storage of a considerable proportion of these lipids in cultured hamster cells.


Affinity purified oval antigen for diagnosis of Opisthorchiasis viverrini.
Monoclonal antibodies (MAb) were raised against an oval antigen of the liver fluke Opisthorchis viverrini which is the causative agent of a parasitosis, i.e. opisthorchiasis in Thailand. The antibodies were used in an affinity column to purify the O. viverrini oval antigen from a crude extract of adult parasites by chromatography. The oval antigen was then used in a membrane (dot) ELISA for detecting antibodies in serum samples of parasitologically confirmed Opisthorchis viverrini infected individuals (adult parasites were found in stools after praziquantel treatment and salt purgation), as well as of individuals infected with other parasites and parasite-free controls. The MAb-based dot-ELISA using the affinity purified O. viverrini oval antigen revealed 100% sensitivity, specificity and accuracy for detecting O. viverrini infection. The test is simple, rapid and highly reproducible. Several samples can be tested at the same time without the requirement for special equipment or much increase in testing time; thus it is suitable for mass screening for O. viverrini exposure, especially in new endemic areas. Furthermore using serum specimens could increase patient and community compliance compared to the conventional parasitological survey which uses stool samples for the detection of O. viverrini ova, without treatment and subsequent salt purgation, this conventional method shows a low sensitivity and is also unpleasant to both the sample donors and the laboratory technicians which has historically shown a further negative impact on the final outcome.


Multicentre, randomised, placebo-controlled trial of extract of Japanese herbal medicine Daikenchuto to prevent bowel dysfunction after adult liver transplantation (DKB 14 Study).
This multicentre randomised controlled clinical trial will aim to determine the ability of an extract (TJ-100) of Daikenchuto (traditional Japanese herbal medicine; Kampo) to prevent bowel dysfunction in at least 110 patients after liver transplantation (LT). The following co-primary end points will be evaluated on postoperative day 7: total oral and enteral caloric intake, abdominal distension and abdominal pain. The secondary end points will comprise sequential changes of total oral and enteral caloric intake after LT, sequential changes in numeric rating scales for abdominal distension and pain, elapsed time to the first postoperative passage of stool, quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese version), postoperative liver function, liver regeneration rate, incidence of bacteraemia and bacterial strain, trough level of immunosuppressants, occurrence of acute cellular rejection, discharge or not within 2 months after LT, sequential changes of portal venous flow to the graft and ascites discharge. The two arms of the study will comprise 55 patients per arm. The study has been conducted according to the CONSORT statement. All participants signed a written consent form, and the study has been approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals. The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014.


Structural and functional implications of metal ion selection in aminopeptidase P, a metalloprotease with a dinuclear metal center.
The effect of metal substitution on the activity and structure of the aminopeptidase P (APPro) from Escherichia coli has been investigated. Measurements of activity in the presence of Mn2+, Mg2+, Zn2+, Na+, and Ca2+ show that significant activity is seen only in the Mn-bound form of the enzyme. The addition of Zn2+ to [MnMn(APPro)] is strongly inhibitory. Crystal structures of [MnMn(APPro)], [MgMg(APPro)], [ZnZn(APPro)], [ZnMg(APPro)], [Ca_(APPro)], [Na_(APPro)], and [apo(APPro)] were determined. The structures of [Ca_(APPro)] and [Na_(APPro)] have a single metal atom at their active site. Surprisingly, when a tripeptide substrate (ValProLeu) was soaked into [Na_(APPro)] crystals in the presence of 200 mM Mg2+, the structure had substrate, but no metal, bound at the active site. The structure of apo APPro complexed with ValProLeu shows that the N-terminal amino group of a substrate can be bound at the active site by carboxylate side chains that normally bind the second metal atom, providing a model for substrate binding in a single-metal active enzyme. Structures of [MnMn(APPro)] and [ZnZn(APPro)] complexes of ProLeu, a product inhibitor, in the presence of excess Zn reveal a third metal-binding site, formed by two conserved His residues and the dipeptide inhibitor. A Zn atom bound at such a site would stabilize product binding and enhance inhibition.


Pulmonary venous flow in normal dogs recorded by transthoracic echocardiography: techniques, anatomic validations and flow characteristics.
To observe pulmonary venous flow in dogs, the echocardiographic imaging planes and the techniques for examination, and the validations of anatomic location were investigated. Then, the velocity pattern of pulmonary venous flow was recorded in normal conscious dogs. Six imaging planes were available for observing the right or left caudal lobe pulmonary venous flow with two-dimensional or pulsed Doppler echocardiography. Of these, the left lateral apical 4-chamber view can be applied as standard view, because the pulmonary venous flow and transmitral flow could be recorded in this view simultaneously with small sampling angle. The velocity pattern of pulmonary venous flow demonstrated two forward waves in 19 of 20 dogs examined, with one peak occurring during ventricular systole and another during ventricular diastole. A reversed flow during atrial contraction was also seen in 11 dogs. In the two forward waves, the mean peak velocity and velocity-time integral of ventricular diastolic forward flow were significantly higher than those of systolic forward flow (46.49 +/- 6.79 vs. 31.13 +/- 4.92 cm/s, p < 0.0001 and 8.18 +/- 1.84 vs. 5.14 +/- 0.82 cm, p < 0.0001, respectively). The deceleration time of diastolic forward flow shortened with the increase of heart rate (r = -0.87, p < 0.0001). Pulmonary venous flow in dogs can be observed under transthoracic two-dimensional or pulsed Doppler echocardiography.


Factor Structure Evaluation of the French Version of the Digital Natives Assessment Scale.
"Digital natives" concept defines young adults particularly familiar with emerging technologies such as computers, smartphones, or Internet. This notion is still controversial and so far, the primary identifying criterion was to consider their date of birth. However, literature highlighted the need to describe specific characteristics. The purpose of this research was to evaluate the factor structure of a French version of the Digital Natives Assessment Scale (DNAS). The sample of this study includes 590 participants from a 6-week massive open online course and from Web sites, electronic forums, and social networks. The DNAS was translated in French and then back-translated to English. A principal component analysis with orthogonal rotation followed by a confirmatory factorial analysis showed that a 15-item four-correlated component model provided the best fit for the data of our sample. Factor structure of this French-translated version of the DNAS was rather similar than those found in earlier studies. This study provides evidence of the DNAS robustness through cross-cultural and cross-generational validation. The French version of the DNAS appears to be appropriate as a quick and effective questionnaire to assess digital natives. More studies are needed to better define further features of this particular group.


Pro-apoptotic properties of (1,3)(1,4)-β-D-glucan from Avena sativa on human melanoma HTB-140 cells in vitro.
In this study, the growth-inhibitory effect of polysaccharide (1,3)(1,4)-β-D-glucan from oat, Avena sativa L. grains was explored on the human skin melanoma HTB-140 cells in vitro. The oat β-D-glucan (OBG) exerted cytotoxic action on HTB-140 cells. After 24h of incubation, LD50 (concentration at which 50% of the cells were found dead) was obtained of 194.6 ± 9.8 μg/mL. The oat β-D-glucan caused a concentration-dependent increase of caspase-3/-7 activation and appearance of phosphatidylserine on the external surface of cellular membranes where it was bound to annexin V-FITC, demonstrating the induction of apoptosis. Intracellular ATP level decreased along with the mitochondrial potential, which suggested a mitochondrial pathway of apoptosis. A cell cycle analysis showed increase in the number of apoptotic cells, increase in the number of cells in G1 phase and decrease in the number of cells in G2/M. Although the detailed mechanism for the anti-tumor activity of the oat β-D-glucan still needs further investigation, this study provides preliminary insights into this direction along with perspectives of developing it as an anti-tumor agent.


Long-term efficacy and safety of secukinumab in Japanese patients with moderate to severe plaque psoriasis: 3-year results of a double-blind extension study.
Secukinumab, a fully human monoclonal antibody neutralizing interleukin-17A, has been shown to have significant efficacy in the treatment of moderate to severe psoriasis. Long-term (3-year) efficacy and safety of secukinumab in Japanese patients with moderate to severe psoriasis were evaluated in an extension study of a large phase 3 global study (SCULPTURE). In the core study, 52 Japanese patients with 75% improvement of Psoriasis Area and Severity Index (PASI-75) response at week 12 were re-randomized to a fixed interval (FI; every 4 weeks) schedule and retreatment as needed (RAN), in which patients received placebo until start of relapse, at which time secukinumab was reinitiated. Fifty Japanese patients completed the 52-week core study, and 47 patients entered the extension study with the same double-blind regimens up to week 152. All patients in the secukinumab 300 mg FI and seven patients in 150 mg FI groups completed 3 years of treatment. PASI-90 and -100 at the end of year 3 were achieved in 69.2% and 53.8%, respectively, in 300 mg FI and 42.9% and 42.9%, respectively, in 150 mg FI, indicating high sustained response in 300 mg FI. Mean absolute PASI was continually low in 300 mg FI and numerically higher in 150 mg FI. Dermatology Life Quality Index of 0/1 was maintained by approximately two-thirds of 300 mg FI patients, and all EuroQoL 5-Dimension Health Questionnaire domain measures were also improved. FI dosing was consistently more efficacious than RAN. The safety profile of secukinumab remained favorable, with no new safety concerns identified.


Structural basis of transcription initiation: an RNA polymerase holoenzyme-DNA complex.
The crystal structure of Thermus aquaticus RNA polymerase holoenzyme (alpha2betabeta'omegasigmaA) complexed with a fork-junction promoter DNA fragment has been determined by fitting high-resolution x-ray structures of individual components into a 6.5-angstrom resolution map. The DNA lies across one face of the holoenzyme, completely outside the RNA polymerase active site channel. All sequence-specific contacts with core promoter elements are mediated by the sigma subunit. A universally conserved tryptophan is ideally positioned to stack on the exposed face of the base pair at the upstream edge of the transcription bubble. Universally conserved basic residues of the sigma subunit provide critical contacts with the DNA phosphate backbone and play a role in directing the melted DNA template strand into the RNA polymerase active site. The structure explains how holoenzyme recognizes promoters containing variably spaced -10 and -35 elements and provides the basis for models of the closed and open promoter complexes.


Developments of real-time emittance monitors.
Under the upgrade program of an azimuthally varying field (AVF) cyclotron in progress at the Research Center for Nuclear Physics (RCNP), an emittance monitor is being developed to improve the beam injection efficiency from ion sources to the AVF cyclotron. In order to evaluate the quality of the beams extracted from ion sources quickly, we developed the Pepper-Pot type Emittance Monitor at the RCNP. After improving an analysis method for emittance estimation using LabVIEW, we achieved a measurement frequency of 4 Hz.


OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion.
Optic Atrophy 1 (OPA1) has well-established roles in both mitochondrial fusion and apoptotic crista remodeling and is required for the maintenance and distribution of mitochondrial DNA (mtDNA), which are essential for energy metabolism. However, the relationship between OPA1 and mitochondrial metabolism and the underlying mechanisms remain unclear. Here, we show that OPA1-Exon4b modulates mitochondrial respiration and rescues inner mitochondrial membrane potential (Δψm), independent of mitochondrial fusion. OPA1-Exon4b is required for the maintenance of normal TFAM distribution and enhances mtDNA transcription by binding the D-loop of mtDNA. Finally, we show that mRNA levels of OPA1 isoforms containing Exon4b are specifically downregulated in hepatocellular carcinoma (HCC), leading to a reduction in Δψm. Thus, our study demonstrates a novel mitochondrial functional self-recovery pathway involving enhanced mtDNA transcription-mediated recovery of mitochondrial respiratory chain proteins. This mitochondrial fusion-independent pathway may contribute to mitochondrial multi-functional switches in tumorigenesis.


Transcriptional profiling of five isolated size-matched stages of human preantral follicles.
Little is known of the early stages of human follicular development and the complex processes that regulate follicular growth. To identify genes of potential importance, we analysed follicle-related transcripts in five populations of isolated size-matched human preantral follicles by microarray analysis. Oocyte-specific genes were found to be the most abundant and differentially expressed transcripts and included germ cell transcription factors LHX8 and SOHLH2 which were significantly down-regulated during preantral follicle development. Differentially expressed genes also included transcription factors of NOTCH signalling, IGF2, orphan nuclear receptor LRH-1, and homeobox gene HOXA7, indicating potentially important regulatory roles for these genes during early human folliculogenesis. We also found that FSHR mRNA and protein were present in the earliest stages of preantral follicles, whereas LHR was absent. In conclusion, our data identify specific oocyte and somatic genes in small human follicles that impact early follicle growth, and provide foundation for further analysis of the signalling pathways involved in early human folliculogenesis.


Recovery of respiration after neuromuscular blockade with alcuronium.
Alcuronium 0.2 mg kg-1 was given to six patients to investigate the simultaneous recovery of breathing and peripheral neuromuscular function. Anaesthesia was maintained with 66% nitrous oxide in oxygen supplemented with 0.5% halothane, and the patients were ventilated to normocarbia. Patients were disconnected from the ventilator after the reappearance of the tetanic response. This response returned at a mean time of 19.2 min after the injection of alcuronium and oxygenation was maintained thereafter by means of apnoeic diffusion. Spontaneous breathing returned at a mean time of 23.6 min after the injection of alcuronium. Sixty minutes after the administration of alcuronium, respiratory exchange was judged adequate, and at that time neuromuscular function was still markedly depressed with a tetanic height less than 25% of control. It was concluded that, because of the slow recovery of neuromuscular function, alcuronium should be reserved for the longer surgical procedure.