Interpreting Outcomes 2-Statistical Significance and Clinical Meaningfulness: Linking Evidence to Practice.
Scores on outcome measures matter in the clinical world because they influence treatment decisions, and because payers are increasingly asking clinicians to justify their treatment decisions. For researchers, scores on outcome measures are the currency in which they trade; outcome scores provide the answers to research questions. Measuring outcomes is critical, but it's only half the job-data must be analyzed and interpreted appropriately. Determining whether a treatment is effective involves making judgments about (1) the size of the reported effect, (2) the precision of the effect, and (3) whether the effect is clinically meaningful. J Orthop Sports Phys Ther 2019;49(7):559-560. doi:10.2519/jospt.2019.0704.


Unconventional Route to Uniform Hollow Semiconducting Nanoparticles with Tailorable Dimensions, Compositions, Surface Chemistry, and Near-Infrared Absorption.
Despite impressive recent advances in the synthesis of lead chalcogenide solid nanoparticles, there are no examples of lead chalcogenide hollow nanoparticles (HNPs) with controlled diameter and shell thickness as current synthetic approaches for HNPs have inherent limitations associated with their complexity, inability to precisely control the dimensions, and limited possibilities with regard to applicable materials. Herein, we report on an unconventional strategy for crafting uniform lead chalcogenide (PbS and PbTe) HNPs with tailorable size, surface chemistry, and near-IR absorption. Amphiphilic star-like triblock copolymers [polystyrene-block-poly(acrylic acid)-block-polystyrene and polystyrene-block-poly(acrylic acid)-block-poly(3,4-ethylenedioxythiophene)] were rationally synthesized and exploited as nanoreactors for the formation of uniform PbS and PbTe HNPs. Compared to their solid counterparts, the near-IR absorption of the HNPs is blue-shifted owing to the hollow interior. This strategy can be readily extended to other types of intriguing low-band-gap HNPs for diverse applications.


Cytogenetic features of human neuroblastomas and cell lines.
We reviewed the banded karyotypes of 24 human neuroblastomas and cell lines to identify any consistent chromosomal abnormalities. Six of the 10 primary tumors and one of the 14 cell lines were studied at this institution. Of the 24 neuroblastomas karyotyped, 20 were near-diploid, one was near-triploid, and 3 were near-tetraploid. One primary tumor had a diploid karyotype without numerical or structural rearrangements. The 20 cases with a karyotype in the diploid range were statistically analyzed for gain or loss of while chromosomes and for structural abnormalities of each chromosome arm. The short arm of chromosome 1 was preferentially involved in structural rearrangements, occurring in 14 cases (p less than 0.01). In 11 of these cases, the abnormality of chromosome 1 included deletion of bands 1p32 leads to 1pter, rendering the cells monosomic for this genetic material. Of the remaining three cases, one involved a reciprocal translocation of chromosomes 1p and 12q, another had insertion of genetic material at band 1p13, and the third had an extra dark band at 1p36. No other numerical or structural abnormalities occurred with sufficient frequency to reach statistical significance (p greater than 0.20). Six of the primary tumors or cell lines in the diploid range had double minute chromatin bodies, four cell lines had homogeneously staining regions, and two cell lines had either double minute chromatin bodies or homogeneously staining regions in subpopulations of cells. Hence, partial monosomy for the short arm of chromosome 1 was the most consistent cytogenetic abnormality in the human neuroblastomas studied.


Inactivation of retinoblastoma gene product RB or an RB-related protein by SV40 T antigen in MDCK epithelial cells results in massive apoptosis.
SV40 T antigen (LT) transformation of renal MDCK epithelial cells resulted in massive apoptosis in the presence of serum. Cell death was dependent on the ability of LT to bind RB or a related protein, since MDCK cells expressing LT mutants unable to bind RB did not die. Apoptosis could be rescued by treatment of cells with EGF and TPA, a property linked to their ability to promote cell growth. Our results indicate an inverse correlation between proliferation and apoptosis. Thus LT transformation induced survival-factor dependence in epithelial cells, in contrast to its effect in fibroblasts. RB inactivation also resulted in a strong down-regulation of c-myc and c-fos, which were previously found to be highly and constitutively expressed in epithelial cells. RB gene transfer in MDCK(LT) cells restored cell viability and high c-myc expression. C-myc gene transfer in these cells also resulted in a significant survival effect. These results suggest that RB anti-cell death activity is at least partly mediated by up-regulation of c-myc. Overexpression of Bcl2 also protected cells against apoptosis. The role of RB and c-myc in cell survival is discussed and related to maintenance of the differentiation state rather than to their properties in cell cycle progression.


Ligand Field Theory and Angular Overlap Model Based Analysis of the Electronic Structure of Homovalent Iron-Sulfur Dimers.
The electronic structure of multinuclear transition metal complexes is a highly challenging problem for quantum chemical methods. The problems to be solved for a successful analysis include the following: (1) many unpaired electrons leading to "highly entangled" wave functions that cannot be calculated by standard electronic structure methods, (2) drastic differences between the one-particle and many-particle spectra and a high density of low-lying states, and (3) the interpretation of such highly complex wave functions in chemical terms. In this work, we continue our research on oligonuclear clusters by presenting an in-depth analysis of the electronic structure of a prototypical iron-sulfur (Fe2S2) dimer. Accurate wave functions are obtained from a variety of advanced wave function based methods. The wave function results are interpreted in terms of an effective Hamiltonian that in turn is parametrized in terms of the angular overlap model (AOM) that provides the chemical insights that we are striving for. A hierarchical analysis allows us to interpret the local electronic structure in terms of the thiolate, sulfide ligands, and metal-metal interaction strengths. The many-particle spectrum is analyzed in terms of configurations involving ligand and metal centers. Finally, we are able to derive simple yet effective interpretations of ligand interaction strengths, the metal-metal interaction strength, and the low-lying many-particle spectrum of the Fe2S2 dimer.


Computational modeling of high frequency oscillations recorded with clinical intracranial macroelectrodes.
High Frequency Oscillations (HFOs) are a potential biomarker of epileptogenic regions. They have been extensively investigated in terms of automatic detection, classification and feature extraction. However, the mechanisms governing the generation of HFOs as well as the observability conditions on clinical intracranial macroelectrodes remain elusive. In this paper, we propose a novel physiologically-relevant macroscopic model for accurate simulation of HFOs as invasively recorded in epileptic patients. This model accounts for both the temporal and spatial properties of the cortical patch at the origin of epileptiform activity. Indeed, neuronal populations are combined with a 3D geometrical representation to simulate an extended epileptic source. Then, by solving the forward problem, the contributions of neuronal population signals are projected onto intracerebral electrode contacts. The obtained signals are qualitatively and quantitatively compared to real HFOs, and a relationship is drawn between macroscopic model parameters such as synchronization and spatial extent on the one hand, and HFO features such as the wave and fast ripple (200-600 Hz) components, on the other hand.


Heat shock factor 1 promotes neurite outgrowth and suppresses inflammation in the severed spinal cord of geckos.
The low intrinsic growth capacity of neurons and an injury-induced inhibitory milieu are major contributors to the failure of sensory and motor functional recovery following spinal cord injury. Heat shock transcription factor 1 (HSF1), a master regulator of the heat shock response, plays neurogenetic and neuroprotective roles in the damaged or diseased central nervous system. However, the underlying mechanism has not been fully elucidated. In the present study, we used a gecko model of spontaneous nerve regeneration to investigate the potential roles of gecko HSF1 (gHSF1) in the regulation of neurite outgrowth and inflammatory inhibition of macrophages following spinal cord injury. gHSF1 expression in neurons and microglia at the lesion site increased dramatically immediately after tail amputation. gHSF1 overexpression in gecko primary neurons significantly promoted axonal growth by suppressing the expression of suppressor of cytokine signaling-3, and facilitated neuronal survival via activation of the mitogen-activated extracellular signal-regulated kinase/extracellular regulated protein kinases and phosphatidylinositol 3-kinase/protein kinase B pathways. Furthermore, gHSF1 efficiently inhibited the macrophage-mediated inflammatory response by inactivating IkappaB-alpha/NF-kappaB signaling. Our findings show that HSF1 plays dual roles in promoting axonal regrowth and inhibiting leukocyte inflammation, and provide new avenues of investigation for promoting spinal cord injury repair in mammals.


Prospective molecular markers for the identification of illegally traded angelsharks (Squatina) and dolphin (Sotalia guianensis).
Endangered angelsharks and a protected dolphin species are illegally traded in Brazil. In this study, we determined prospective molecular markers for detecting these species in the trade of angelshark carcasses and 'dolphin' eyeball amulets. We compiled publicly available as well as new and unpublished cytochrome b (cyt b) DNA sequences for species involved in these trades. These sequences were digested in silico using restriction enzymes. We then described prospective polymerase chain reaction (PCR)-restriction fragment length polymorphism markers for distinguishing between protected species and the species whose trade was legally allowed in these two trade groups. The prospective marker for identifying angelshark carcasses consists of cyt b PCR and digestion by BstXI, BsgI, BspMI, BsrDI, and HaeII restriction enzymes. The prospective marker for identifying eyeball amulets consists of cyt b PCR and digestion by ApoI, BtsI, HindII, BsaAI, BplI, and SspI restriction enzymes. This is the first study to deposit in GenBank cyt b sequences for the angelshark species Squatina argentina, Squatina guggenheim, and Squatina occulta. Moreover, the S. argentina haplotype is the first DNA sequence for this species deposited in GenBank.


The epidemiology of non-Hodgkin's lymphoma: why the increased incidence?
The incidence of non-Hodgkin's lymphoma continues to increase in the United States. Improvements in diagnostic techniques, changes in disease classifications, and the increase in AIDS-related lymphomas account for only a small percentage of the increase, leaving most of the increased incidence unexplained. Viruses clearly play a major role in the pathogenesis of some subtypes of non-Hodgkin's lymphoma, especially Epstein-Barr virus and HTLV-1, and improvements in molecular diagnostic techniques may identify additional viruses that have a role in the pathogenesis of lymphomas. Immunodeficiencies, whether acquired, congenital, or iatrogenic, clearly predispose to the development of non-Hodgkin's lymphoma. Numerous environmental exposures have also been linked to an increased risk of non-Hodgkin's lymphoma and may account for a portion of the continuing increased incidence of the disease.


Domestic drinking water management: Quality assessment in Oforikrom municipality, Ghana.
Drinking water in Ghana is estimated at 79%, but this only represents the proportion of the population with access to improved drinking water sources without regard to the quality of water consumed. This study investigated the quality of household drinking water sources in the Oforikrom municipality where potable water requirements are on the rise due to an ever-increasing population. Both quantitative and qualitative methods were employed in this study. One Hundred households were randomly selected and interviewed on the available options for drinking water and household water treatment and safe storage. A total of 52 points of collection (POC) and 97 points of use (POU) water samples from households were collected for physicochemical and microbial water quality analysis. Amongst the available drinking water options, sachet water (46%) was mostly consumed by households. Water quality analysis revealed that the physicochemical parameters of all sampled drinking water sources were within the Ghana Standards Authority (GSA) recommended values expected for pH (ranging from 4.50 to 7.50). For the drinking water sources, bottled (100%, n = 2) and sachet water (91%, n = 41) showed relatively good microbial water quality. Generally, POC water samples showed an improved microbial water quality in comparison to POU water samples. About 38% (n = 8) of the households practicing water quality management, were still exposed to unsafe drinking water sources. Households should practice good water quality management at the domestic level to ensure access to safe drinking water. This may include the use of chlorine-based disinfectants to frequently disinfect boreholes, wells and storage facilities at homes.


Identifying the Dimensionality of Oral Language Skills of Children With Typical Development in Preschool Through Fifth Grade.
Language is a multidimensional construct from prior to the beginning of formal schooling to near the end of elementary school. The primary goals of this study were to identify the dimensionality of language and to determine whether this dimensionality was consistent in children with typical language development from preschool through 5th grade. In a large sample of 1,895 children, confirmatory factor analysis was conducted with 19-20 measures of language intended to represent 6 factors, including domains of vocabulary and syntax/grammar across modalities of expressive and receptive language, listening comprehension, and vocabulary depth. A 2-factor model with separate, highly correlated vocabulary and syntax factors provided the best fit to the data, and this model of language dimensionality was consistent from preschool through 5th grade. This study found that there are fewer dimensions than are often suggested or represented by the myriad subtests in commonly used standardized tests of language. The identified 2-dimensional (vocabulary and syntax) model of language has significant implications for the conceptualization and measurement of the language skills of children in the age range from preschool to 5th grade, including the study of typical and atypical language development, the study of the developmental and educational influences of language, and classification and intervention in clinical practice. https://doi.org/10.23641/asha.5154220.


Differential localization and expression of urokinase plasminogen activator (uPA), its receptor (uPAR), and its inhibitor (PAI-1) mRNA and protein in endometrial tissue during the menstrual cycle.
Normal endometrium is a highly dynamic tissue, which responds to ovarian steroids with cyclic proliferation, differentiation (secretion), and degradation (menstruation). The urokinase plasminogen activator (uPA)-dependent proteolytic cascade as well as ligand activation of the uPA receptor (uPAR) is critically involved in physiological as well as pathophysiological aspects of tissue expansion and remodelling. Cyclic variation and distribution of uPA, uPAR and plasminogen activator inhibitor 1 (PAI-1) mRNA were examined by in situ hybridization, real-time PCR and northern blot in normal endometrium. Their corresponding proteins were localized with immunohistochemistry. uPA mRNA is exclusively expressed by stromal cells, whereas uPA protein is present in both epithelial and stromal cells. Immunostaining for uPA protein is reduced or undetectable at midcycle, thus coinciding with peak concentration of uPA in the uterine fluid. uPAR mRNA is expressed by epithelial cells in the proliferative phase and by stromal cells in the secretory phase. However, epithelial cells stain for uPAR protein throughout the cycle, suggesting that uPAR may detach from stromal cells and then bind to epithelial cells in the secretory phase. PAI-1 mRNA is located in vessel walls. The late secretory phase has greatly increased expression of all three mRNA and their proteins, mainly in pre-decidual cells in the superficial stroma. Discordant localization of the mRNA and proteins suggest that uPA is produced by stromal cells, released and bound to epithelial cells in both the proliferative and secretory phases, whereas uPAR is released from the stroma and bound to epithelial cells in the secretory phase. Also, the present data together with earlier reports suggest that uPA is released from the epithelial cells to the uterine fluid.


Conformation-specific spectroscopy and populations of diastereomers of a model monolignol derivative: chiral effects in a triol chain.
Single-conformation spectroscopy of two diastereomers of 1-(4-hydroxy-3-methoxyphenyl)propane-1,2,3-triol (HMPPT) has been carried out under isolated, jet-cooled conditions. HMPPT is a close analog of coniferyl alcohol, one of the three monomers that make up lignin, the aromatic biopolymer that gives structural integrity to plants. In HMPPT, the double bond of coniferyl alcohol has been oxidized to produce an alkyl triol chain with chiral centers at C(α) and C(β), thereby incorporating key aspects of the β-O-4 linkage between monomer subunits that occurs commonly in lignin. Both (R,S)- and (R,R)-HMPPT diastereomers have been synthesized in pure form for study. Resonant two-photon ionization (R2PI), UV hole-burning (UVHB)/IR-UV hole-burning (IR-UV HB), and resonant ion-dip infrared (RIDIR) spectroscopy have been carried out, providing single-conformation UV spectra in the S(0)-S(1) region (35200-35800 cm(-1)) and IR spectra in the hydride stretch region. Five conformers of (R,S)- and four conformers of (R,R)-HMPPT are observed and characterized, leading to assignments for all nine conformers. Spectroscopic signatures for α-β-γ, γ-β-α, and α-γ-β-π chains and two cyclic forms [(αβγ) and (αγβ)] of the glycerol side chain are determined. Infrared ion-gain (IRIG) spectroscopy is used to determine fractional abundances for the (R,S) diastereomer and constrain the populations present in (R,R). The two diastereomers have very different conformational preferences. More than 95% of the population of (R,R) configures the glycerol side chain in a γ-β-α triol chain, while in (R,S)-HMPPT, 51% of the population is in α-β-γ chains that point in the opposite direction, with an additional 21% of the population in H-bonded cycles. The experimental results are compared with calculations to provide a consistent explanation of the diastereomer-specific effects observed.


All-Solid-State Lithium Ion Batteries Using Self-Organized TiO2 Nanotubes Grown from Ti-6Al-4V Alloy.
All-solid-state batteries were fabricated by assembling a layer of self-organized TiO2 nanotubes grown on as anode, a thin-film of polymer as an electrolyte and separator, and a layer of composite LiFePO4 as a cathode. The synthesis of self-organized TiO2 NTs from Ti-6Al-4V alloy was carried out via one-step electrochemical anodization in a fluoride ethylene glycol containing electrolytes. The electrodeposition of the polymer electrolyte onto anatase TiO2 NTs was performed by cyclic voltammetry. The anodized Ti-6Al-4V alloys were characterized by scanning electron microscopy and X-ray diffraction. The electrochemical properties of the anodized Ti-6Al-4V alloys were investigated by cyclic voltammetry and chronopotentiometry techniques. The full-cell shows a high first-cycle Coulombic efficiency of 96.8% with a capacity retention of 97.4% after 50 cycles and delivers a stable discharge capacity of 63 μAh cm-2 μm-1 (119 mAh g-1) at a kinetic rate of C/10.


[Chicken SREBP1 gene antiserums preparation and its tissue expression characterization].
The aim of this study was to prepare the antiserums against chicken sterol regulatory element binding protein1 (SREBP1), and to analyze the expression of SREBP1 in chicken tissues. The nuclear import sequence of SREBP1 was analyzed using the DNAStar programs to predict its major antigen epitopes, the fragment coding for SREBP1 major antigen epitopes (832-1 302 bp) was amplified by RT-PCR and inserted into pGEX-4T-1 to construct the expression vector pGEX-4T/SREBP1. The recombinant GST/SREBP1 was expressed in E.coli with IPTG induction and purified by Glutathione Sepharose 4B affinity chromatography. The purified recombinant GST/SREBP1 was used as immunogen in rabbits, and the titer and specificity of SREBP1 antiserums were detected by ELISA and Western blot. The tissue expression of chicken SREBP1 was analyzed with the antiserums. The titer of the antiserum determined by ELISA was 1:102 400, and the antiserums exhibited a high specificity through Western blot. Tissue expression analysis showed that the expression of chicken SREBP1 was much higher in abdominal adipose tissue and heart, but lower in liver, muscle stomach, duodenum, spleen, kidney, and no signal was detected in breast and leg muscle. The SREBP1 expression characteristics between fat and lean broiler lines was also detected, and the result showed that SREBP1 expressed significantly higher in the abdominal adipose tissue of fat line than that in lean line (P<0.05). The antiserum against chicken SREBP1 prepared in this study had high titer and specificity. SREBP1 was highly expressed in abdominal adipose tissue of broilers. Compared to lean broiler line, SREBP1 was expressed higher in the fat line.


Estrogen receptor β selective agonists reduce invasiveness of triple-negative breast cancer cells.
Metastasis to bone is a frequent problem of advanced breast cancer. Particularly breast cancers, which do not express estrogen receptor α (ERα) and progesterone receptor (PR) and which have no overexpression of human epidermal growth factor receptor 2 (HER2), so-called triple-negative breast cancers (TNBCs), are considered as very aggressive and have a poor prognosis. Recently we have shown that breast cancer cell invasion was dramatically increased when co-cultured with MG63 osteoblast-like cells. Using this model we have now analyzed whether estrogen receptor β (ERβ) plays a role in TNBC cell invasion in vitro. ERα and ERβ protein expression was analyzed using western blot analysis. Invasion was quantified by assessment of TNBC cell migration rate through an artificial basement membrane in a modified Boyden chamber during co-culture with MG63 osteoblast-like cells. The effects of ERβ agonist treatment on CXC motif chemokine receptor 4 (CXCR4) protein expression during co-culture with MG64 cells was quantified using western blot analysis. Proliferation was measured using alamarBlue assay. TNBC cell lines HCC1806 and HCC1937 showed no ERα but high ERβ protein expression. Cell invasion of HCC1806 and HCC1937 TNBC cells was significantly increased when co-cultured with MG63 osteoblast-like cells. Treatment with ERβ selective estrogen agonists liquiritigenin and ERB-041 reduced the ability to invade a reconstituted basement membrane and to migrate in response to the cellular stimulus. During co-culture CXCR4 protein expression of TNBC cell lines HCC1806 and HCC1937 was significantly increased. Treatment with liquiritigenin resulted in a significant decrease of CXCR4 protein expression. Both ERβ agonists showed no effect on TNBC cell proliferation. Our findings suggest that ERβ plays a major role in TNBC invasion. Bone-directed invasion can be inhibited by ERβ agonists.


Enzyme enhancers for the treatment of Fabry and Pompe disease.
Lysosomal storage disorders (LSD) are a group of heterogeneous diseases caused by compromised enzyme function leading to multiple organ failure. Therapeutic approaches involve enzyme replacement (ERT), which is effective for a substantial fraction of patients. However, there are still concerns about a number of issues including tissue penetrance, generation of host antibodies against the therapeutic enzyme, and financial aspects, which render this therapy suboptimal for many cases. Treatment with pharmacological chaperones (PC) was recognized as a possible alternative to ERT, because a great number of mutations do not completely abolish enzyme function, but rather trigger degradation in the endoplasmic reticulum. The theory behind PC is that they can stabilize enzymes with remaining function, avoid degradation and thereby ameliorate disease symptoms. We tested several compounds in order to identify novel small molecules that prevent premature degradation of the mutant lysosomal enzymes α-galactosidase A (for Fabry disease (FD)) and acid α-glucosidase (GAA) (for Pompe disease (PD)). We discovered that the expectorant Ambroxol when used in conjunction with known PC resulted in a significant enhancement of mutant α-galactosidase A and GAA activities. Rosiglitazone was effective on α-galactosidase A either as a monotherapy or when administered in combination with the PC 1-deoxygalactonojirimycin. We therefore propose both drugs as potential enhancers of pharmacological chaperones in FD and PD to improve current treatment strategies.


Catabolism of 4-hydroxybenzoate in Candida parapsilosis proceeds through initial oxidative decarboxylation by a FAD-dependent 4-hydroxybenzoate 1-hydroxylase.
The first two steps in the catabolism of 4-hydroxybenzoate by the ascomycetous yeast Candida parapsilosis CBS604 were investigated. In contrast to the well-known bacterial pathways and to what was previously assumed, metabolism of 4-hydroxybenzoate in C. parapsilosis proceeds through initial oxidative decarboxylation to give 1,4-dihydroxybenzene. This reaction is catalyzed by a NAD(P)H and FAD-dependent 4-hydroxybenzoate 1-hydroxylase. Further metabolism of 1,4-dihydroxybenzene to the ring-fission substrate 1,2,4-trihydroxybenzene is catalyzed by a NADPH-specific FAD-dependent aromatic hydroxylase acting on phenolic compounds. 19F-NMR experiments with cell extracts and 2-fluoro-4-hydroxybenzoate as the model compound confirm this metabolic pathway and exclude the alternative pathway proceeding through initial 3-hydroxylation followed by oxidative decarboxylation in the second step.


SIX4 promotes metastasis via activation of the PI3K-AKT pathway in colorectal cancer.
Several studies report aberrant expression of sine oculis homeobox (SIX) homolog family members during cancer development and progression. SIX4 participates in organ development, such as myogenesis and neurogenesis. However, the expression and clinical implication of SIX4 in colorectal cancer (CRC) remains unclear. The SIX4 expression levels in colorectal patients were assessed in nine different human cancer arrays and compared using patient survival data. SIX4 expression was silenced in two cell culture lines for invasion and wound healing assessment. Finally, bioinformatics assessments ascertained the pathways impacted by SIX4. SIX4 was upregulated in The Cancer Genome Atlas CRC cohort and other gene expression omnibus (GEO) cohorts. In addition, SIX4 expression significantly correlated with lymph node metastasis and advanced Tumor Node Metastasis (TNM) stages. Moreover, SIX4 overexpression was related to unfavorable prognosis in CRC patients. Silencing SIX4 inhibited CRC cell metastasis by surpressing AKT phosphorylation. SIX4 is upregulated in CRC and can be used as a prognosis biomarker.


Code-51: keeping suicidal veterans safe in the emergency department.
Safety of suicidal veterans is a national issue. Veterans have a higher rate of depressive disorder than the general population, which puts them at higher risk for suicide. The staff in the emergency department (ED) of one Department of Veterans Affairs hospital developed and implemented an innovative process that increases the safety of suicidal veterans in the hospital setting. This process is called Code-51 and is similar to a military unit watch. This is one of the first unit watches implemented throughout an entire Veteran Affairs hospital, not only in the ED. The Code-51 process is a model for other EDs in both public and private sectors to help keep suicidal patients safe.


Cholestatic liver dysfunction after long-term phenytoin therapy.
Cholestatic jaundice developed in a 64-year-old woman who had received phenytoin sodium for more than 40 years. Discontinuation of phenytoin therapy resulted in resolution of the hepatic abnormalities, which recurred on rechallenge, strongly suggesting a causal relation to the drug. Phenytoin therapy was discontinued again, with complete resolution of the hepatic abnormalities. The liver biopsy specimen obtained during therapy showed cholestasis compatible with obstruction of the biliary tree, although an obstructive process was never demonstrated. The biochemical abnormalities and histologic features observed most likely represent an unusual response to phenytoin therapy.


Multicolour single-molecule tracking of mRNA interactions with RNP granules.
Ribonucleoprotein (RNP) granules are non-membrane-bound organelles that have critical roles in the stress response1,2, maternal messenger RNA storage3, synaptic plasticity4, tumour progression5,6 and neurodegeneration7-9. However, the dynamics of their mRNA components within and near the granule surface remain poorly characterized, particularly in the context and timing of mRNAs exiting translation. Herein, we used multicolour single-molecule tracking to quantify the precise timing and kinetics of single mRNAs as they exit translation and enter RNP granules during stress. We observed single mRNAs interacting with stress granules and P-bodies, with mRNAs moving bidirectionally between them. Although translating mRNAs only interact with RNP granules dynamically, non-translating mRNAs can form stable, and sometimes rigid, associations with RNP granules with stability increasing with both mRNA length and granule size. Live and fixed cell imaging demonstrated that mRNAs can extend beyond the protein surface of a stress granule, which may facilitate interactions between RNP granules. Thus, the recruitment of mRNPs to RNP granules involves dynamic, stable and extended interactions affected by translation status, mRNA length and granule size that collectively regulate RNP granule dynamics.


Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus.
To assess the efficacy, safety and dose-response relationship of once-daily teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. In this randomized, double-blind, placebo-controlled, parallel-group study, patients (n = 324) were randomized to receive teneligliptin 10, 20 or 40 mg, or placebo, once daily before breakfast for 12 weeks. The primary endpoint was the change in haemoglobin (Hb)A1c from baseline to week 12. All teneligliptin-treated groups showed significantly greater reductions in HbA1c and fasting plasma glucose (FPG) than did the placebo group. The differences between the teneligliptin 10, 20 or 40 mg groups and the placebo group for the change in HbA1c were -0.9 [least-squares (LS) mean; 95% confidence interval: -1.0, -0.7], -0.9 (-1.1, -0.7) and -1.0 (-1.2, -0.9)%, respectively (all, p < 0.001). The respective LS means for FPG were -17.8 (-23.4, -12.1), -16.9 (-22.6, -11.2) and -20.0 (-25.7, -14.3) mg/dl (all, p < 0.001). There were no significant differences in HbA1c among the three doses of teneligliptin. The incidence of adverse events and adverse drug reactions was similar in each group. The incidence of hypoglycaemia was not significantly different among the four groups. Treatment with teneligliptin for 12 weeks provided significant and clinically meaningful reductions in HbA1c and FPG across the dose range studied and was generally well tolerated in Japanese patients with T2DM.


Characterization of an estrogen-binding protein in the yeast Saccharomyces cerevisiae.
This paper further characterizes the estrogen-binding protein we have described in the cytosol of the yeast Saccharomyces cerevisiae. [3H]Estradiol was used as the radioprobe, and specific binding of cytosol fractions was measured by chromatography on Sephadex minicolumns. Other 3H-steroids did not exhibit specific binding. [3H]Estradiol binding was destroyed by treatment with trypsin, but not RNase, DNase, or phospholipase; N-ethylmaleimide substantially decreased the binding. The yeast did not metabolize estradiol added to the medium, and extraction and chromatography of the bound moiety showed it to be unmetabolized estradiol. Scatchard analysis of cytosol from both a and alpha mating types as well as the a/alpha diploid cell revealed similar binding properties: an apparent dissociation constant or Kd(25 degrees) for [3H]estradiol of 1.6-1.8 nM and a maximal binding capacity or Nmax of approximately 2000-2800 fmol/mg of cytosol protein. Gel exclusion chromatography on Sephacryl S-200 and high performance liquid chromatography suggested a Stokes radius of approximately 30 A. Sucrose gradient centrifugation showed a sedimentation coefficient of approximately 5 S, and the complex did not exhibit ionic dependent aggregation. The estrogen binder in S. cerevisiae differed in its steroidal specificities from classical mammalian estrogen receptors in rat uterus. 17 beta-Estradiol was the best competitor, 17 alpha-estradiol had about 5% the activity, and diethylstilbestrol exhibited negligible binding affinity as did tamoxifen, nafoxidine, and the zearalenones. In summary, a high affinity, stereospecific, steroid-selective binding protein has been demonstrated in the cytosol of the simple yeast S. cerevisiae. We speculate that this molecule may represent a primitive hormone receptor system, possibly for an estrogen-like message molecule.


Revisited old and new CT findings in unruptured larger arteriovenous malformations of the brain.
Several papers have already described the computed tomographic (CT) findings in arteriovenous malformations (AVMs) of the brain. In a population of larger and unruptured AVMs, however, improved resolution CT has made it possible to demonstrate findings not previously appreciated: (a) major and minor mass effects in the absence of rupture of an AVM (33 of 60 cases); (b) cisternal enlargement secondary to vessel ectasia and tortuosity; (c) extensive edema of white matter; (d) the detailed features of finer and coarser calcifications of the malformation; (e) gray matter changes, disturbances in the gray-white matter interface, and intrinsic hypodense regions within the AVM; and (f) visualization of small vessels on intravenous enhancement.


PKC-Mediated Modulation of Astrocyte SNAT3 Glutamine Transporter Function at Synapses in Situ.
Astrocytes are glial cells that have an intimate physical and functional association with synapses in the brain. One of their main roles is to recycle the neurotransmitters glutamate and gamma-aminobutyric acid (GABA), as a component of the glutamate/GABA-glutamine cycle. They perform this function by sequestering neurotransmitters and releasing glutamine via the neutral amino acid transporter SNAT3. In this way, astrocytes regulate the availability of neurotransmitters and subsequently influence synaptic function. Since many plasma membrane transporters are regulated by protein kinase C (PKC), the aim of this study was to understand how PKC influences SNAT3 glutamine transport in astrocytes located immediately adjacent to synapses. We studied SNAT3 transport by whole-cell patch-clamping and fluorescence pH imaging of single astrocytes in acutely isolated brainstem slices, adjacent to the calyx of the Held synapse. Activation of SNAT3-mediated glutamine transport in these astrocytes was reduced to 77 ± 6% when PKC was activated with phorbol 12-myristate 13-acetate (PMA). This effect was very rapid (within ~20 min) and eliminated by application of bisindolylmaleimide I (Bis I) or 7-hydroxystaurosporine (UCN-01), suggesting that activation of conventional isoforms of PKC reduces SNAT3 function. In addition, cell surface biotinylation experiments in these brain slices show that the amount of SNAT3 in the plasma membrane is reduced by a comparable amount (to 68 ± 5%) upon activation of PKC. This indicates a role for PKC in dynamically controlling the trafficking of SNAT3 transporters in astrocytes in situ. These data demonstrate that PKC rapidly regulates the astrocytic glutamine release mechanism, which would influence the glutamine availability for adjacent synapses and control levels of neurotransmission.


A latent normal distribution model for analysing ordinal responses with applications in meta-analysis.
We consider the comparison of two treatments (or a treatment and a control/placebo) with responses that are classified into ordinal categories. By operating on the assumption that the responses are manifestations of some underlying continuous variables and that the definitions of the categories for the treatment group and the placebo group are the same in the same clinical test centre, we develop a model to examine the possible treatment effects. These treatment effects can be identified as location effect or dispersion effect. The method can be generalized to analyse clinical test results coming from different centres, where each centre may have its own standard in classifying responses. The method is technically undemanding and can be implemented in a very simple and straightforward way by using easily accessible software that can be downloaded at no cost. Real data sets are analysed for illustration.


[Correctional health care].
Court decisions taking away someone's freedom by requiring them to serve a jail sentence should not deny them access to the same health care available to free citizens in full compliance with patient confidentiality. Health institutions, responsible for administering somatic care, offer a comprehensive response to the medical needs of those under justice control, both in jails and conventional care units. For a physician, working in the correctional setting implies accepting its constraints, and violence, and protecting and enforcing fundamental rights, as well as rights to dignity, confidential care and freedom to accept or refuse a treatment.


Scanning electron microscopic screening of 20 medicinally important Asteroideae taxa.
In the present study anatomical characterization of 20 medicinally important Asteroideae species were done under light and scanning electron microscopy. Variety of qualitative and quantitative anatomical characters like epidermal cells, stomata, guard cells, subsidiary cells, trichomes and oil droplets were observed. Generally pentagonal, polygonal, irregular or hexagonal, smooth, undulating thick walled epidermal cells were observed in studied species. In abaxial surface Thymophylla tenuiloba L. possessed the largest length of epidermal cell that is, 221.6 (156.6-286.6) μm whereas Bellis perenis L. showed the smallest length that is, 46.4 (32.6-60.2) μm. Average width of epidermal cells ranged from 57 (22-92) μm to 169 (127.9-210.1) μm. Cosmos sulphureus Cav. had smallest width while Thymophylla tenuiloba L. had the largest width. In adaxial surface Artemisia absinthium L. possessed the largest length of epidermal cell that is, 269 (165.1-372.9) μm whereas Bellis perenis L. showed the smallest length that is, 61.4 (42.6-80.2) μm. Average width of epidermal cells ranged from 50.8 (32.6-69) μm to 260 (116-202) μm. Thymophylla tenuiloba L. had smallest width while Dahlia pinnata Cav. had the largest width. Among stomatal characters anisocytic, anomocytic, and diacytic stomata were observed in selected species of Asteroideae. Nonglandular uniserate, multicellular, unbranched pointed tips with bulbous base trichomes were reported in some Asteroideae members while some possessed glandular, capitates mushroom like multicellular trichomes covered with tubercle papicles. Rounded, oval, triangular shaped oil droplets were observed in some species. It is concluded that qualitative and qualitative anatomical variations in trichomes, stomata and epidermal cells are of good taxonomic value for the Asteroideae species.


Binding competition of toxic shock syndrome toxin 1 and other staphylococcal exoproteins for receptors on human peripheral blood mononuclear cells.
Binding of toxic shock toxin 1 (TSST-1) and staphylococcal enterotoxin A (SEA) to human peripheral blood mononuclear cells (PBMC) was investigated by using 125I-labeled ligands. Scatchard analyses revealed similar numbers of receptors (approximately 5,000 to 8,000) and similar dissociation constants (Kd, approximately 20 to 25 nM) per PBMC. SEA but not enterotoxin B, C1, C2, C3, D, or E significantly inhibited binding of 125I-TSST-1 to PBMC. Cross-competition of TSST-1 and SEA in binding assays suggests that they may bind to overlapping or separate epitopes on the same receptor.


Three-dimensional high-density culture of HepG2 cells in a 5-ml radial-flow bioreactor for construction of artificial liver.
A three-dimensional high-density cell culture is essential for the construction of an artificial tissue. Many researchers have reported that three-dimensional cell culture enhances cell function. The use of a radial-flow bioreactor (RFB) has enabled the cultivation of cells at high density for constructing a three-dimensional tissue. In this study, we have developed a novel, small RFB, which has a bed volume of 5 ml and is equipped with a porous support as an immobilized scaffold; its performance was tested using the hepatoblastoma cell line, HepG2. Among the other supports tested here, hydroxyl apatite was selected from the viewpoint of its ability to support good cell growth at high density with uniform distribution in a bioreactor. The HepG2 cells grew well in the scaffold under a sufficient supply of nutrients by radial flow and were used to construct a three-dimensional tissue in the scaffold. The concentration of the cells cultivated in this 5-ml RFB reached 10(8) cells/ml and the glucose consumption rate was almost similar to that obtained when using a 30-ml RFB, which has already been reported previously. This high glucose consumption continued over 7 d after the growth phase. Furthermore, albumin production was maintained in the stable phase. Gene expression profiles of cells obtained from long-term cultures in the 5-ml RFB were analyzed. It was found that the expressions of genes encoding the cell cycle-related proteins, cyclins, and cell cycle division 2 (cdc2) were suppressed in the stable phase. In addition, the number of cells incorporating 5'-bromo-2'-deoxyuridine (BrdU) in the stable phase markedly decreased compared with that in the growth phase. These results indicated that the majority of cells in the stable phase remain in the G0/G1 phase. Furthermore, this implies that the three-dimensional tissue constructed in the 5-ml RFB showed the high function similar to a normal liver in the human body. Therefore, the 5-ml RFB was considered as a useful tool and a substitute method for animal experiments.


Introducing solid foods to infants in the Asia Pacific region.
For infants' optimal growth and development, the introduction of nutritionally suitable solid foods at the appropriate time is essential. However, less attention has been paid to this stage of infant life when compared with studies on breastfeeding initiation and duration. The practice of introducing solid foods, including the types of foods given to infants, in the Asia Pacific region was reviewed. In total nine studies using the same questionnaire on infant feeding practices were analysed to gain a better understanding of trends in the introduction of solid foods in this region. All studies showed less than optimal duration of exclusive breastfeeding indicating an earlier time of introduction of solid foods than recommended by the WHO. Most mothers commonly used rice or rice products as the first feed. In many studies, the timing of introducing solid foods was associated with breastfeeding duration. Compared with the Recommended Nutrient Intakes for infants aged above six months, rice/rice products are of lower energy density and have insufficient micronutrients unless they have been fortified. Although the timing of introducing solid foods to infants is important in terms of preventing later health problems, the quality of the foods should also be considered. Recommendations to improve the introduction of solid foods include measures to discourage prelacteal feeding, facilitating breastfeeding education and providing better information on healthier food choices for infants.


Genetic interactions derived from high-throughput phenotyping of 6589 yeast cell cycle mutants.
Over the last 30 years, computational biologists have developed increasingly realistic mathematical models of the regulatory networks controlling the division of eukaryotic cells. These models capture data resulting from two complementary experimental approaches: low-throughput experiments aimed at extensively characterizing the functions of small numbers of genes, and large-scale genetic interaction screens that provide a systems-level perspective on the cell division process. The former is insufficient to capture the interconnectivity of the genetic control network, while the latter is fraught with irreproducibility issues. Here, we describe a hybrid approach in which the 630 genetic interactions between 36 cell-cycle genes are quantitatively estimated by high-throughput phenotyping with an unprecedented number of biological replicates. Using this approach, we identify a subset of high-confidence genetic interactions, which we use to refine a previously published mathematical model of the cell cycle. We also present a quantitative dataset of the growth rate of these mutants under six different media conditions in order to inform future cell cycle models.


Hamstring musculotendon mechanics of prospectively injured elite rugby athletes.
The musculotendon mechanics of the hamstrings during high-speed running are thought to relate to injury but have rarely been examined in the context of prospectively occurring injury. This prospective study describes the hamstring musculotendon mechanics of two elite rugby players who sustained hamstring injuries during on-field running. Athletes undertook biomechanical analyses of high-speed running during a Super Rugby pre-season, prior to sustaining hamstring injuries during the subsequent competition season. The biceps femoris long head muscle experienced the greatest strain of all hamstring muscles during the late swing phase. When expressed relative to force capacity, biceps femoris long head also experienced the greatest musculotendon forces of all hamstring muscles. Musculotendon strain and force may both be key mechanisms for hamstring injury during the late swing phase of running.


Synthesis, structural, and magnetic studies on a redox family of tetrametallic vanadium clusters: {VIV4}, {VIII2VIV2}, and {VIII4} butterfly complexes.
The synthesis, crystal structures, and magnetic properties are reported for a redox family of butterfly-type tetrametallic vanadium alkoxide clusters, namely [V2(VO)2(acac)4(RC{CH2O}3)2] (R=Me 1, Et 2, CH2OH 3), [V2(VO)2(acac)2(O2CPh)2(MeC{CH2O}3)2] (5), [(VO)4(MeOH)2(O2CPh)2({HOCH2}C{CH2O}3)2] (6), [V4Cl2(dbm)4(RC{CH2OH}3)2] (R=Me 7, Et 8, CH2OH 9), and [V4Cl2(dbm)4(MeO)6] (10). The cluster cores are {VIV4} (6), {VIII2VIV2} (1-5), and {VIII4} (7-10), with examples of both isomeric forms of the of the mixed-valence cores (either VIII or VIV ions forming the butterfly body). Magnetic studies reveal the clusters to be dominated by antiferromagnetic exchange interactions in each case. The magnetic exchange parameters are determined for representative examples of each core type. {VIV4} and {VIII4} have diamagnetic ground states. The two isomeric {VIII2VIV2} types are found to give rise to either an S=0 ground state with a number of low-lying excited states due to competing antiferromagnetic exchange interactions (VIII2 butterfly body) or to a well-isolated S=1 ground state (VIV2 butterfly body).


Vertebral end-plate lesions (Schmorl's nodes) in the dorsolumbar spine.
The distribution of end-plate lesions (Schmorl's nodes) and their relationship to bone density and disc degeneration have been studied in 50 post-mortem spines below D9 in subjects aged 13-96 years. Lesions were present in 76% of cases with a predominance in males. They were found more frequently in the lower than in the upper vertebral end-plate. They were also more common and more severe in the dorsolumbar (D10-L1) region than in the lower lumbar (L2-L5 region). In adults they were unrelated to age and bone density. Lesions were significantly related to disc degeneration in the D10-L1 region but not in the L2-L5 region. It is suggested that end-plate lesions arising in adolescence (or before) may predispose the dorsolumbar spine to disc degeneration in later life.


Salicylic acid metabolism and signalling coordinate senescence initiation in aspen in nature.
Deciduous trees exhibit a spectacular phenomenon of autumn senescence driven by the seasonality of their growth environment, yet there is no consensus which external or internal cues trigger it. Senescence starts at different times in European aspen (Populus tremula L.) genotypes grown in same location. By integrating omics studies, we demonstrate that aspen genotypes utilize similar transcriptional cascades and metabolic cues to initiate senescence, but at different times during autumn. The timing of autumn senescence initiation appeared to be controlled by two consecutive "switches"; 1) first the environmental variation induced the rewiring of the transcriptional network, stress signalling pathways and metabolic perturbations and 2) the start of senescence process was defined by the ability of the genotype to activate and sustain stress tolerance mechanisms mediated by salicylic acid. We propose that salicylic acid represses the onset of leaf senescence in stressful natural conditions, rather than promoting it as often observed in annual plants.


[Diagnostic problems in childhood epilepsy].
The correct diagnosis of the epileptic patient must establish the type of seizures according to the 1981 ILAE ICES, and the epileptic syndrome according to the 1989 ILAE ICE. Some children, at the onset of epilepsy, are difficult to classify. These are the reasons which can cause the diagnostic problems: 1. Misdiagnosis as epilepsy the non-epileptic seizures. 2. Misclassifying the type of seizures for incomplete or inadequate information. 3. Misclassifying the type of epileptic syndromes due to overlapping of different syndromes or because the patient presents more than one syndrome at the same time or during the course of the illness. It follows from this that it is not easy to classify all cases of epilepsy. The 'forced' as inadequate classification can give rise to a therapeutic or prognostic misdiagnosis.


Occurrence of bilateral sacroiliitis and ossification of anterior spinal ligaments in the same patient.
Abstract Enthesopathy and ligament calcification may occur in both the degenerative and inflammatory types of diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis. Despite their fairly frequent occurence in rheumatic disease care settings, few reports of their presence in the same patient have appeared in the literature. In this report, we present the case of a male patient with chronic low back pain, who had both ossification of anterior spinal ligaments and bilateral sacroiliac joint ankylosis, and discuss the known pathogenesis of diffuse idiopathic skeletal hyperostosis.


Mnemons: encoding memory by protein super-assembly.
Memory is mainly understood as the recollection of past events. The human brain and its simplest unit, the synapse, belong to the places in which such memories are physically stored. From an experimental point of view, memory can be tested in humans by recall. However, in other organisms, memory is reflected in its use by individuals to learn about and adapt their behavior to their environment. Under this criterion, even unicellular organisms are able to learn from their environments and show the ability to adapt their responses to repeating stimuli. This indicates that they are able to keep track of their histories and use these traces to elaborate adapted responses, making these traces akin to memory encodings. Understanding these phenomena may even help us to dissect part of the rather complex molecular orchestration happening in our synapses. When exposed unsuccessfully to mating pheromone, i.e. when mating does not happen, budding yeast cells become refractory to the mating signal. This refractory state is restricted to the mother cell and not inherited by the daughter cells, even though it is stable for most if not the entire life span of the mother cell. Interestingly, both stability and asymmetric segregation of the acquired state are explained by the molecular mechanism underlying its establishment, which shows important analogies and distinctions to prions. Here we discuss these similarities and differences.


Hydra, a model system for environmental studies.
Hydra have been extensively used for studying the teratogenic and toxic potential of numerous toxins throughout the years and are more recently growing in popularity to assess the impacts of environmental pollutants. Hydra are an appropriate bioindicator species for use in environmental assessment owing to their easily measurable physical (morphology), biochemical (xenobiotic biotransformation; oxidative stress), behavioural (feeding) and reproductive (sexual and asexual) endpoints. Hydra also possess an unparalleled ability to regenerate, allowing the assessment of teratogenic compounds and the impact of contaminants on stem cells. Importantly, Hydra are ubiquitous throughout freshwater environments and relatively easy to culture making them appropriate for use in small scale bioassay systems. Hydra have been used to assess the environmental impacts of numerous environmental pollutants including metals, organic toxicants (including pharmaceuticals and endocrine disrupting compounds), nanomaterials and industrial and municipal effluents. They have been found to be among the most sensitive animals tested for metals and certain effluents, comparing favourably with more standardised toxicity tests. Despite their lack of use in formalised monitoring programmes, Hydra have been extensively used and are regarded as a model organism in aquatic toxicology.


Counseling families with hereditary gastrointestinal polyposis syndromes.
Counseling for families with one of the hereditary polyposis and/or colon cancer syndromes can be offered by a number of different professional persons depending upon the emotional needs of the counselee. It is sometimes difficult to persuade at-risk persons in polyposis families to institute a medical surveillance plan with their physicians because of their reactions to knowledge (or lack of it) of the family diagnosis. Counseling may reveal both emotional and financial problems as deterrents to needed medical planning. Support organizations and explanatory literature are helpful in allaying fears and promoting compliance.


[Isolation of influenza viruses in different species of bird in Canada in 1978].
As part of the international program on the ecology of influenza virus in animals sponsored by W.H.O., 357 influenza A viruses isolated from 2 293 cloacal samples collected from ducks and other bird species in Eastern Canada during the 1978 season were characterized antigenically. Seven hemagglutinin (Hsw 1, H2, H3, Hav2, Hav4, Hav6, Hav7) and six neuraminidase subtypes (N1, N2, Neq2, Nav1, Nav5, Nav6) in 18 different combinations were found. A comparison with viruses isolated during previous seasons indicates that subtypes do change from year-to-year and from place-to-place. Isolation of few viruses from passerine birds requires additional studies to determine if these species are truly infected with influenza virus in nature. This large reservoir of influenza A viruses circulating at the same time in ducks may well be involved in the appearance of new viruses in other species, including humans.


Molecular cloning and expression analysis of a novel member of the Disintegrin and Metalloprotease-Domain (ADAM) family.
We cloned and characterized the cDNA and the expression pattern of a novel member of the murine 'Disintegrin and Metalloprotease-Domain Family' (ADAM). The predicted protein sequence reveals highest homology to the testase-subgroup, composed of ADAM 24, ADAM 25 and ADAM 26 and is therefore called testase 4. Reverse transcription-polymerase chain reaction showed a strong expression of testase 4 in the adult testis, but not in any other organ or embryonic stage tested. Careful characterization by in situ hybridization confirmed specific expression of testase 4 in maturing sperm cells of 6-week-old mice, whereas no specific hybridization pattern was detectable in testes of 2.5-week-old mice. These data indicate a correlation between testase 4 expression and spermatogenesis and/or fertilization.


Comparing a longitudinal integrated clerkship with traditional hospital-based rotations in a rural setting.
Longitudinal integrated clerkships (LIC) are widely used as an educational method, particularly in rural areas. They are good for facilitating hands-on learning and deep relationships between student, patients, and supervisors. This study sought to examine and compare learning experience of third-year rural medical students studying specialties (women's health, aged care, child and adolescent heath, mental health, general practice) by either a traditional hospital-based rotation or a LIC in a rural general practice setting. Data was collected from two groups of rural students (LIC; traditional hospital-based) over two academic years, utilizing focus groups to investigate general experiences of living and learning rurally, within the different educational models. Results reaffirmed that there was no perceived academic disadvantage to studying medicine rurally. Studying medicine in a rural area provides increased access to patients, more hands-on experience, and close relationships with patients and colleagues. LIC students reported increased confidence in clinical skills, felt better prepared for internship, however experienced more social isolation than students in hospital-based rotations. Students undergoing a rural LIC feel more confident in their clinical skills and preparedness for practice than other rural students. This study supports the use of LICs as a powerful educational tool.


Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair.
After 9/11, threat of nuclear attack on American urban centers prompted government agencies to develop medical radiation countermeasures to mitigate hematopoietic acute radiation syndrome (H-ARS) and higher-dose gastrointestinal acute radiation syndrome (GI-ARS) lethality. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS in preclinical models, no mitigator potentially deliverable under mass casualty conditions preserves GI tract. Here, we report generation of an anti-ceramide 6B5 single-chain variable fragment (scFv) and show that s.c. 6B5 scFv delivery at 24 hours after a 90% lethal GI-ARS dose of 15 Gy mitigated mouse lethality, despite administration after DNA repair was complete. We defined an alternate target to DNA repair, an evolving pattern of ceramide-mediated endothelial apoptosis after radiation, which when disrupted by 6B5 scFv, initiates a durable program of tissue repair, permitting crypt, organ, and mouse survival. We posit that successful preclinical development will render anti-ceramide 6B5 scFv a candidate for inclusion in the Strategic National Stockpile for distribution after a radiation catastrophe.


Utility stress as a social determinant of health: exploring the links in a remote Aboriginal community.
The implications of the high cost of water on the poverty and subsequent health of Aboriginal residents in a remote community in Australia. During 2003, a focus group session was held with adults at Umoona Aboriginal community in South Australia. Participants were asked to comment on key issues of concern in the provision of the domestic water supply. The Umoona community members in Coober Pedy identified the high cost of water and electricity as key hardship factors. Plans under the National Water Initiative to move to full cost recovery for water and the privatisation of public utilities may result in increased hardship for low-income groups such as Aboriginal people. Utility stress (difficulties paying water, electricity, gas or telephone accounts by the due date) increases poverty and relative deprivation, both key factors in the social determinants of health. Increased community service obligations (CSO) and rebates need to be made available to all low-income groups in order to reduce the negative impact of poverty.


MicroRNA‑455 is downregulated in gastric cancer and inhibits cell proliferation, migration and invasion via targeting insulin‑like growth factor 1 receptor.
Gastric cancer is the fourth most common and the second leading cause of cancer mortality worldwide. The dysregulation of microRNAs has been demonstrated to be significant in gastric cancer carcinogenesis and progression due to changes in expression of their target genes. In the current study, microRNA‑455 (miR‑455) was identified to be significantly downregulated in gastric cancer tissue samples and cell lines. A low expression level of miR‑455 was correlated with the clinical stage, lymph node metastasis and tumor invasion in gastric cancer. Restoration of miR‑455 expression inhibited cell proliferation, migration and invasion of gastric cancer cells in vitro. Bioinformatic analysis and luciferase reporter assay revealed that miR‑455 directly targeted the 3'‑untranslated region of insulin‑like growth factor 1 receptor (IGF‑1R). In addition, the IGF‑1R mRNA expression level was increased in gastric cancer tissue samples and was inversely correlated with miR‑455 expression levels. Restoration of miR‑455 downregulated IGF‑1R mRNA and protein expression levels in gastric cancer cells. Furthermore, silencing of IGF‑1R significantly inhibited gastric cancer cell proliferation, migration and invasion, which was similar to the functions induced by miR‑455 overexpression. Thus, these results indicate that miR‑455 is involved in gastric cancer progression by directly targeting IGF‑1R and may serve as a novel therapeutic target for the treatment of gastric cancer.


Appendectomy in the gynecological setting: intraoperative findings and corresponding histopathology.
To evaluate the intraoperative findings and corresponding histopathology associated with appendectomies performed during benign gynecological surgery. Retrospective case series. Twenty-two appendectomies were performed from 2002 through 2008 at Hutzel Women's Hospital due to intraoperative findings of inflammation or erythema (n = 8), periappendiceal adhesions (n = 5), injury to the appendix or mesoappendix (n = 2), fecalith (n = 2), dilation of the appendix (n = 1), adnexal mass involving the appendix (n = 1), and suspected lipoma (n = 1). Final pathology was consistent with significant findings such as acute inflammation, periappendicitis, and adhesions or endometriosis involving the appendix in 68.2% of cases. In the benign gynecological setting, appendectomies were primarily performed due to inflammation or erythema. In the majority of cases, significant appendiceal pathology was confirmed.


Contact allergy to a cocobolo bracelet.
Tropical woods are highly valued because of their strength, hardness, and resistance to moisture. These characteristics make them easy to work with and extremely durable, and that is why they have been used in the manufacture of wooden jewelry, musical instruments, furniture, and handles of many different objects. We present a case of a 44-year-old man who developed pruritus, erythema, and blistering around his right wrist, corresponding exactly to the area where he had worn a wooden bracelet. Thin-layer chromatography performed with the extract of the shavings revealed (R)-4-methoxydalbergione and obtusaquinone (the main components of cocobolo wood) and (S)-4'-hydroxy-4-methoxydalbergione (in lower amounts). Patch-testing with sawdust from the bracelet resulted in a very strong reaction. Patch tests with the pure constituents yielded +++ reactions to the main sensitizers of cocobolo, including obtusaquinone, but also to sensitizers present in other rosewoods. This last fact can be explained by cross-reactivity between different dalbergiones. Contact dermatitis from tropical woods is more frequent than thought, owing to their high sensitizing properties. An exhaustive search can identify the allergen responsible in many cases.


Feasibility studies towards future self-sufficient supply of the (99)Mo-(99m)Tc isotopes with Japanese accelerators.
In order to establish a self-sufficient supply of (99m)Tc, we studied feasibilities to produce its parent nucleus, (99)Mo, using Japanese accelerators. The daughter nucleus, (99m)Tc, is indispensable for medical diagnosis. (99)Mo has so far been imported from abroad, which is separated from fission products generated in nuclear reactors using enriched (235)U fuel. We investigated (99m)Tc production possibilities based on the following three scenarios: (1) (99)Mo production by the (n, 2n) reaction by spallation neutrons at the J-PARC injector, LINAC; (2) (99)Mo production by the (p, pn) reaction at Ep = 50-80 MeV proton at the RCNP cyclotron; (3) (99m)Tc direct production with a 20 MeV proton beam from the PET cyclotron. Among these three scenarios, scenario (1) is for a scheme on a global scale, scenario (2) works in a local area, and both cases take a long time for negotiations. Scenario (3) is attractive because we can use nearly 50 PET cyclotrons in Japan for (99m)Tc production. We here consider both the advantages and disadvantages among the three scenarios by taking account of the Japanese accelerator situation.


OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression.
OLA1, an Obg-family GTPase, has been implicated in eukaryotic initiation factor 2 (eIF2)-mediated translational control, but its physiological functions remain obscure. Here we report that mouse embryos lacking OLA1 have stunted growth, delayed development leading to immature organs-especially lungs-at birth, and frequent perinatal lethality. Proliferation of primary Ola1(-/-) mouse embryonic fibroblasts (MEFs) is impaired due to defective cell cycle progression, associated with reduced cyclins D1 and E1, attenuated Rb phosphorylation, and increased p21(Cip1/Waf1) Accumulation of p21 in Ola1(-/-) MEFs is due to enhanced mRNA translation and can be prevented by either reconstitution of OLA1 expression or treatment with an eIF2α dephosphorylation inhibitor, suggesting that OLA1 regulates p21 through a translational mechanism involving eIF2. With immunohistochemistry, overexpression of p21 protein was detected in Ola1-null embryos with reduced cell proliferation. Moreover, we have generated p21(-/-) Ola1(-/-) mice and found that knockout of p21 can partially rescue the growth retardation defect of Ola1(-/-) embryos but fails to rescue them from developmental delay and the lethality. These data demonstrate, for the first time, that OLA1 is required for normal progression of mammalian development. OLA1 plays an important role in promoting cell proliferation at least in part through suppression of p21 and organogenesis via factors yet to be discovered.


The renascence of neurotic depression: its varied dynamics and implications for outcome research.
Kraepelin's observation of an emotion-connected subgroup of depressions led to the division of the common clinical depressions into endogenous and neurotic. But although the connotation of the former was clear, the latter had no positive diagnostic features, with the result that it fell very largely out of use. This paper presents evidence that there are depressions that are a consequence of neurotic anxiety. They can be positively diagnosed, and are resolved by overcoming the underlying neurotic anxieties. The neurotic basis of many cases of depression explains the success of different psychotherapeutic strategies in alleviating nonpsychotic depression, since 50% of neurotic cases respond to the nonspecific impact of the therapeutic interview. Unfortunately, the various outcome studies are muddied by failure to realize that a variety of psychopathologies are represented in nonpsychotic depression.


Efficacy and Patient Satisfaction Associated With Intramuscular Triamcinolone Therapy for Acute Flares of Hidradenitis Suppurativa.
A lack of consensus exists regarding acute flare management in hidradenitis suppurativa (HS). Intramuscular triamcinolone (IMTAC) therapy is useful in numerous inflammatory conditions; however, it has not been investigated for acute HS flares. To evaluate the efficacy and patient experience associated with IMTAC therapy for acute, severe HS flares. Retrospective analysis and surveys of 45 HS patients were conducted at Albert Einstein College of Medicine/ Montefiore HS Center, Bronx, NY, USA. Follow-up visits 6.77 (4.45) weeks after IMTAC therapy revealed significant reductions in mean HS-Physician Global Assessment (PGA) (P < .001), C-Reactive Protein (CRP) (P = .03), increased hemoglobin (P = .004), and improved pain scores (P < .001). Adjusting for age, sex and concomitant medications, multivariate analysis yielded significantly reduced pain (P = .02) and increased hemoglobin (P = .03). Patient surveys indicate that IMTAC was well-tolerated, as reflected in positive mean responses for satisfaction (29 [64%]) and willingness to receive IMTAC injections again (42 [93%]). These novel findings demonstrate that IMTAC is a safe, effective, and well accepted adjunct for acute HS management.


Self-Reported Eating Speed and Incidence of Gestational Diabetes Mellitus: the Japan Environment and Children's Study.
There is little evidence linking eating speed to gestational diabetes mellitus (GDM) incidence. We therefore aimed to evaluate the prospective association of eating speed with GDM incidence. Overall, 97,454 pregnant women were recruited between January 2011 and March 2014. Singleton pregnant women who did not have GDM, heart disease, stroke, cancer, type 1 diabetes, and/or type 2 diabetes at the time of study enrollment were eligible. Each woman was asked about her eating speed at that time via a questionnaire. Odds ratios of GDM in relation to eating speed were obtained using logistic regression. Among the 84,811 women eligible for analysis, 1902 cases of GDM were identified in medical records. Compared with women who reported slow eating speed, the age-adjusted odds ratios (95% confidence interval) of GDM for women who reported medium, relatively fast, or very fast eating speed were 1.03 (0.90, 1.18), 1.07 (0.94, 1.23), and 1.28 (1.05, 1.58), respectively. Adjustment for demographic, lifestyle-related, and dietary factors including dietary fat, dietary fiber, and energy intakes yielded similar results. The association was attenuated and no longer significant after further adjustment for pre-pregnancy body mass index. The mediation analysis showed that being overweight accounted for 64% of the excess risk of GDM associated with eating speed. In conclusion, women who reported very fast eating speed, compared with those reporting slow eating speed, were associated with an increased incidence of GDM, which may be largely mediated by increased body fat.


Medical management of patients with brain tumors.
The most common medical problems in brain tumor patients involve the management of seizures, peritumoral edema, medication side effects, and venous thromboembolism. Despite the importance of these issues, there are very few studies specifically addressing them. Nonetheless, there has been some progress in recent years. There is increasing evidence that brain tumor patients who have not had a seizure do not benefit from prophylactic antiepileptic medications. Patients taking corticosteroids are at greater risk of Pneumocystis carinii pneumonia and may benefit from prophylactic therapy. There is also growing evidence suggesting that anticoagulation may be more effective than inferior vena cava filtration devices for treating venous thromboembolism in brain tumor patients and that the risk of hemorrhage with anticoagulation is relatively small.


Mesenchymal stem cells: A new therapeutic tool for chronic kidney disease.
Chronic kidney disease (CKD) has a major impact on public health, which could progress to end-stage kidney disease (ESRD) and consume many medical resources. Currently, the treatment for CKD has many flaws, so more effective treatment tools are urgently required for CKD. Mesenchymal stem cells (MSCs) are primitive cells with self-renewal and proliferation capacity and differentiation potential. Extensive preclinical and clinical data has shown that cell-based therapies using MSCs can modulate immunity, inhibit inflammatory factors, and improve renal function in CKD, suggesting that MSCs have the potential to be a new, effective therapeutic tool for CKD. In this review, we will describe different kinds of MSCs and MSCs products for the treatment of CKD in experimental models and clinical trials, potential signaling pathways, therapeutic efficacy, and critical issues that need to be addressed before therapeutic application in humans.


The balanced and introspective brain.
Transfers of large-scale neural activity into, within and between corticothalamic neural populations and brain hemispheres are analysed using time-integrated transfer functions and state parameters obtained from neural field theory for a variety of arousal states. It is shown that the great majority of activity results from feedbacks within the corticothalamic system, including significant transfer between hemispheres, but only a small minority arises via net input from the external world, with the brain thus in a near-critical, highly introspective state. Notably, the total excitatory and inhibitory influences on cortical neurons are balanced to within a few per cent across arousal states. Strong negative intrahemispheric feedforward exists to the cortex, and even larger interhemispheric positive feedforward, but these are modified by feedback loops to yield near-critical positive overall gain. The results underline the utility of transfer functions for the analysis of brain activity.


Duloxetine for major depressive episodes in the course of psychotic disorders: an observational clinical trial.
Patients with psychotic disorders often suffer from intercurrent major depressive episodes (MDE). Case reports suggested successful antidepressive treatment with duloxetine, a selective dual reuptake inhibitor of serotonin and norepinephrine. We initiated this open prospective clinical trial to evaluate efficacy, safety and tolerability of this approach. Patients with a psychotic lifetime diagnosis suffering from mildly severe MDE were treated with duloxetine over a period of 6 weeks. We evaluated effects on mood, monitored the psychotic psychopathology and assessed side effects, basal clinical and pharmacological parameters. Twenty patients were included and experienced a significant improvement of their MDE during the observation period (Calgary Depression Scale for Schizophrenia and Hamilton Depression Scale). Psychotic positive symptoms remained stably absent, while negative syndrome and global psychopathology considerably improved (Positive and Negative Syndrome Scale). In general, the treatment was well tolerated, serum prolactin levels stayed unchanged, but pharmacokinetic interactions with a number of antipsychotic agents were observed. This open prospective evaluation showed antidepressive efficacy of duloxetine in patients with co-morbid psychotic disorders. With regard to the psychotic disorder, the treatment appears to be safe and well tolerable. Further investigations should involve a randomized control group.


Mothers' and fathers' racial socialization in African American families: implications for youth.
Mothers' and fathers' cultural socialization and bias preparation with older (M=13.9 years) and younger (M=10.31 years) siblings were studied in 162 two-parent, African American families. Analyses examined whether parental warmth and offspring age and gender were linked to parental practices and whether parents' warmth, spouses' racial socialization, or youth age or gender moderated links between racial socialization and youth outcomes. Parental warmth was linked to parents' socialization. Mothers engaged in more socialization with older offspring, and fathers more with sons. Mothers' cultural socialization was positively related to youth ethnic identity and fathers' was negatively related to youth depression symptoms. Youth exhibited a lower locus of control when mothers were high but fathers were low in racial socialization.


Participation of hippocampal formation in negative feedback inhibition of penile erection in the rat.
Detailed information on how the central nervous system regulates penile erection, particularly the inhibitory aspect, is sparse. We observed in Sprague-Dawley rats anesthetized and maintained with chloral hydrate that administration of papaverine (400 microg) directly into the corpora cavernosum of the penis produced an increase in intracavernous pressure (ICP). This elicited experimental index for penile erection was accompanied by a transient increase in the root mean square values, concurrent with a shift in the contribution of Theta (increase) and delta (decrease) power to the hippocampal electroencephalographic (hEEG) activity. Reversal blockade of these hEEG responses with xylocaine, given either intrathecally at the L6-S1 spinal levels or unilaterally to the hippocampal formation, significantly heightened and prolonged the ICP response. Pretreatment with xylocaine by itself, however, did not alter appreciably the baseline ICP or hEEG activity. These results suggest the presence of a novel negative feedback inhibitory mechanism in the hippocampal formation, which is triggered by ascending sensory inputs initiated by tumescence of the penis during normal erectile processes.


Theory-Guided Discovery of Novel Materials.
The traditional approach for materials discovery has been the domain of experimentalists, where elemental composition and synthesis conditions are often based on a trial-and-error method. Such processes are time-consuming and expensive. To minimize cost and to develop new materials at a faster pace, an alternate approach is to use theory to predict new materials with tailored properties and have experiments validate such predictions. The phenomenal increase in computing power, development of new first-principles methodologies, and a myriad of advanced computer codes in recent years have enabled researchers to predict novel materials that can be verified by later experiments. In this Perspective, we present advances in density functional theory-based methods and computational procedures that have made possible the discoveries of materials with varying size, composition, and dimensionalities. The challenges and opportunities in theory-guided discovery of materials, going forward, are also discussed.


[Effects of metals (silver, nickel, cobalt and chromium) on the reactive oxygen species generating capacity of human neutrophils and on the serum opsonic activity].
Many metal materials are used in clinical medicine and the number used is increasing. However, there are a few papers concerning the biological effects, especially effects of clinically used metals on cellular immunity. In this paper, silver (Ag), nickel (Ni), cobalt (Co), and chromium (Cr), clinically commonly used metals, the effects of which on neutrophilic activity have already reported using the luminol-dependent chemiluminescence (LDCL) method, were examined to determine their influence on the reactive oxygen species (ROS) generating capacity of human neutrophils and on a serum opsonic activity. Silver suppressed the ROS generating capacity of neutrophils in a dose-dependent manner but did not affect the serum opsonic activity. Nickel also suppressed the ROS generating capacity of neutrophils but, at some concentrations, caused the serum opsonic activity to increase. In contrast, Cobalt increased both the ROS generating capacity of neutrophils and the serum opsonic activity. Like silver, chromium did not affect the serum opsonic activity and suppressed the ROS generating capacity of neutrophils. However, the suppression of ROS generating by chromium occurred differently from that of silver. In the cases of nickel and cobalt, effects of these metals on hemolyzing activity of serum complements (CH-50) were measured and consumption of complements was observed at the same metal concentration at which serum opsonic activity was elevated. In this paper, we report that some metals influence not only the ROS generating capacity of neutrophils but also the serum opsonic activity, results thought to be important for more details studies of the effects of metals on cellular immunity.


Comparison of gastrointestinal blood loss induced by cloximate in two formulations and by naproxen.
In a double-blind baseline controlled crossover trial gastrointestinal blood loss induced by cloximate in two different formulations (enteric-coated and non-enteric coated) was compared with naproxen. Gastrointestinal blood loss increased more in the naproxen group (0.41 ml/24 h) than in the group treated with non-enteric coated cloximate. The group treated with coated cloximate had a higher mean increase in gastrointestinal blood loss (0.36 ml/24 h) compared with placebo than those treated with non-coated cloximate.


[Screening mammography may be a rapid and effective investigation of mamma cancer in asymptomatic women].
The purpose of this article was to describe the incidence of mamma cancer and ductal carcinoma in situ (DCIS) two years after a screening mammography in women offered a screening mammography instead of a clinical mammography. The mammography was abnormal for 6.3% of the women, 0.1% had DCIS and 1.0% was diagnosed with mamma cancer. 1.0% of women with a normal mammography were diagnosed with cancer within two years of the mammography. More widespread use of screening mammography may contribute to a rapid and effective investigation of mamma cancer in asymptomatic women.


[Laparoscopic treatment of retroperitoneal fibrosis.]
Retroperitoneal fibrosis is a disease that may condition a severe involvement of various organs, mainly upper urinary tract, even causing renal insufficiency. It was first described by Albarran in 1905 and it is also known as Ormonds disease. The correct diagnosis includes, in many cases, the performance of one or more tests: CT scan, MRI, renal scan, etc. It is often necessary the insertion of double J catheters on percutaneous nephrostomy tubes with the aim to preserve renal function. Initial treatment is medical, based on corticoids, and , less frequent, immunosuppressive or chemotherapy drugs. Surgery is the treatment of choice when ureteral entrapment by the fibrous plaque is not solved with medical treatment. Such operation may be performed with a conventional open approach (laparotomy) or by pure, hand assisted laparoscopic surgery, or robotic surgery. In all cases, the technique involves freeing the ureters from the fibrous plaque that entraps them, leaving them intraperitoneal, and it is recommendable to wrap them with an omental flap. The implantation of minimally invasive techniques has made that, in groups with experience in laparoscopy, open surgery is being abandoned and the laparoscopic approach indication is increasing. Our group has performed 10 laparoscopic ureterolysis from 2005. In two patients, it was bilateral. Despite surgical repair, two renal units were lost, keeping the rest with different levels of renal function depending on the preoperative level of disease. We did not have major complications and the mean hospital stay was 5.5 days. Although, there is not important published scientific evidence about this technique and it is unlikely we will have it in an immediate future, due to the rarity of this disease, and the different degree of involvement that conditions. It is not unreasonable to propose that, based on the literature reviewed and our own experience, laparoscopic approaches, despite being complex, may solve the ureteral entrapment with similar results to open surgery but less morbidity and shorter hospital stay.


Pattern of Use of Antibiotics Following Snake Bite in a Tertiary Care Hospital.
There are several conflicting recommendations on the use of antibiotics in snakebite victims. This study aimed to identify the pattern of antibiotics used following snake envenomation in a tertiary care hospital of Kerala. Retrospective review of case records from January to August 2011 was done and all the cases filed as snakebite were reviewed and details entered in a structured performa. Data was analysed using SPSS 16 and results were expressed mainly using descriptive statistics. Three hundred and thirteen cases were evaluated with mean age 37.58± 14.54 year and 51.1% were males. Out of total, 94.6% received antibiotics of which 88.85% were oral, 8.1% parenteral and 3.04% both. There were total 454 prescriptions of antibiotics. In all seven different types of antibiotics were prescribed alone or in combination of which Ampicillin (205) was the commonest followed by Cloxacillin (194). The mean antibiotic usage was 1.46±0.716 per patient and the mean duration of antibiotic use was 3.16±1.446 days. In patients with no envenomation the mainly prescribed antibiotic was Cloxacillin (126). Intravenous antibiotics like Piperacillin plus Tazobactam were given only in patients with either local or systemic envenomation. The main pattern of use of antibiotics following snakebite envenomation is Ampicillin alone or in combination empirically, Cloxacillin prophylatically and Piperacillin with Tazobactam for severe established infections. The choice of antibiotics is based on the clinician's discretion. Since the study setting is in a developing country the prophylactic use of antibiotics may be justified weighing the concerns of secondary infections.


Evaluation of anti-fatigue property of the extruded product of cereal grains mixed with Cordyceps militaris on mice.
Fatigue is a biological phenomenon that involves a feeling of extreme physical or mental tiredness that could potentially cause some severe chronic diseases. Recently, diet therapy has provided a new alternative to alleviate physical fatigue. In our previous study, addition of Cordyceps militaris (C. militaris) into an extruded product was shown to provide high nutrition and unique flavors; however, little is known whether this product has some scientific evidence regarding anti-fatigue property. The purpose of this study was to evaluate the anti-fatigue effects of extruded products of cereal grains (EC) and EC mixed with C. militaris (ECC). The mice were divided into seven groups: one group received distilled water (Control group, n = 20), and the other groups received different dosages of EC (5, 10 and 20 g/kg body weight, n = 20 per group) or of ECC (5, 10 and 20 g/kg body weight, n = 20 per group) solution in water. All of the mice were administered with distilled water, EC or ECC continuously for 30 days by gavage and the anti-fatigue activity was evaluated using a weight-loaded swimming test, along with assessments of fatigue-related indicators. The mode of fighting fatigue was investigated by determining changes in exercise endurance and biochemical markers, including exhaustive swimming time, lactate dehydrogenase (LDH), blood lactic acid (BLA), creatine kinase (CK), blood urea nitrogen (BUN), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), and hepatic and muscle glycogen levels. EC and ECC prolonged the swimming endurance time of mice compared to the control. The content of BLA at high dose of ECC group (20 g/kg) was significantly lower than that in the negative control group. CK, BUN and MDA levels were significantly reduced by treatment with EC and ECC compared to the negative control, while the low and middle dose of EC had no significant effect on MDA levels. Additionally, only the middle and high dose of EC (10, 20 g/kg) could significantly decrease the BUN level. EC and ECC treatments increased glycogen, LDH, SOD, CAT and GSH-Px levels. Low and middle dose of EC had no significant effects on muscle glycogen. Moreover, low dose of EC could increase the level of SOD but it was not statistically significant. Compared to the EC treatment groups, ECC demonstrated the efficacy of anti-fatigue potential, particularly at a high dose of ECC, the best performance in relieving fatigue. These results suggest that EC and ECC could prevent exercise-induced fatigue in mice and ECC provided a better effect. In addition, C. militaris in ECC might play a crucial role in the anti-fatigue activity of ECC.


Participation of the nociceptin/orphanin FQ receptor in ethanol-mediated locomotor activation and ethanol intake in preweanling rats.
Activation of nociceptin/orphanin FQ (NOP) receptors seems to attenuate ethanol-induced reinforcement in adult rodents. Since early ethanol exposure results in later increased responsiveness to ethanol, it is important to analyze NOP receptor modulation of ethanol-related behaviors during early ontogeny. By measuring NOP involvement in ethanol intake and ethanol-induced locomotor activation, we analyzed the specific participation of NOP receptors on these ethanol-related behaviors in two-week-old rats. In each experiment animals were pre-treated with the endogenous ligand for this receptor (nociceptin/orphanin FQ at 0.0, 0.5, 1.0 or 2.0 μg) or a selective NOP antagonist (J-113397 at 0.0, 0.5, 2.0 or 5.0 mg/kg). Results indicated that activation of the nociceptin receptor system had no effect on ethanol or water intake, while blockade of the NOP receptor has an unspecific effect on consummatory behavior: J-113397 increased ethanol (at a dose of 0.5 mg/kg) and water intake (at 0.5 and 5.0 mg/kg). Ethanol-mediated locomotor stimulation was attenuated by activation of the NOP system (nociceptin at 1.0 and 2.0 μg). Nociceptin had no effect on basal locomotor activity. Blockade of NOP receptors did not modify ethanol-induced locomotor activation. Contrary to what has been reported for adult rodents, nociceptin failed to suppress intake of ethanol in infants. Attenuation of ethanol-induced stimulation by activation of NOP receptor system suggests an early role of this receptor in this ethanol-related behavior.


[Review of relationship between alcohol drinking and esophageal varices].
The adequate treatment for patients with thrombocytopenia, encephalopathy, ascites and esophagogastric varices due to portal hypertension are very important. This review explains the relations between heavy drinkers and symptoms of portal hypertension, especially with regard to the form of esophageal varices. Between heavy drinker and non-heavy drinker, there was no significant differences for form, color and red color sign of varices. In heavy drinker, the ratio of strong red color sign might be higher than non-heavy drinker. Value of portal pressure in heavy drinker might be higher. These results can bring sudden variceal bleeding in heavy drinkers.


Aetiology of ischaemic heart disease.
There is evidence from population studies of strong positive associations between smoking, arterial pressure and serum cholesterol concentration and risk of ischaemic heart disease, and these appear to be independent of one another, but the evidence from unifactorial trials of risk factor reduction is less impressive. For smoking, there is no good experimental evidence that cessation reduces the risk of IHD, but there are good observational data to show that those who choose to cease have a lower mortality from IHD, and all causes of death, compared with those who continue to smoke. For arterial pressure, none of the randomized controlled trials has shown any benefit from a reduction in arterial pressure in relation to IHD, although the same studies have shown that risk of stroke is reduced substantially. The best trial evidence for risk factor reduction is seen for serum cholesterol, and in all three major placebo control trials, reduction was associated with a corresponding decrease in the incidence of IHD; for each 1% decrease in serum cholesterol concentration there was a 3% reduction in risk of IHD. However, total mortality was unchanged, and in the case of the WHO Co-Operative Study there was a statistically significant excess of deaths in the treatment group. The use of drugs in the primary prevention of IHD is a matter of judgement based on the risk of disease, the efficacy of the treatment and side effects.


Reasoning training in the ACTIVE study: how much is needed and who benefits?
To characterize change through 5-year follow-up, associated with training, booster, adherence, and other characteristics. Sample included all individuals randomly assigned to reasoning training (N = 699). Piecewise latent growth modeling was used to examine trajectory of performance on outcome measures. Training resulted in improved reasoning performance through Year 5. A significant third annual booster effect was one-half the size of the training effect. Training adherence resulted in greater training effects. Higher education, Mini-Mental State Exam (MMSE), better health, and younger age related to higher baseline performance. Higher MMSE was related to larger training effects, larger linear slopes, and smaller booster effects. Significant functional outcomes included a training effect for complex reaction time (CRT), and first annual booster effects for the CRT and observed tasks of daily living. Initial training gain was comparable with magnitude of age-related cognitive decline over 5 years with no training. Neither age nor gender predicted training or booster effects, indicating the generality of training effects across age (65-90 years).


Purification, crystallization and preliminary crystallographic analysis of archaeal 6-pyruvoyl tetrahydrobiopterin synthase homologue PH0634 from Pyrococcus horikoshii OT3.
6-Pyruvoyl tetrahydrobiopterin synthase (PTPS) catalyses the conversion of dihydroneopterin triphosphate to 6-pyruvoyl tetrahydropterin, the second of the three enzymatic steps in the synthesis of tetrahydrobiopterin from GTP. PH0634, a 13.51 kDa archaeal PTPS homologue from Pyrococcus horikoshii OT3, was overexpressed as native and selenomethionine-substituted protein and the purified protein was crystallized by the oil-microbatch method at 295 K. X-ray diffraction data were collected to 2.1 A resolution from the native crystal using synchrotron radiation at 100 K. The crystal belongs to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 35.83, b = 95.71, c = 105.65 A. Threefold noncrystallographic symmetry was identified from self-rotation calculations. Assuming the presence of a trimer in the asymmetric unit, the solvent content is 45% (V(M) = 2.24 A3 Da(-1)). The selenomethionine-substituted crystal is isomorphous to the native crystal and diffracts X-rays to 2.9 A.


Attachment of Arcobacter butzleri, a new waterborne pathogen, to water distribution pipe surfaces.
The capability of Arcobacter butzleri to attach to various water distribution pipe surfaces, such as stainless steel, copper, and plastic, was evaluated using scanning electron microscopy. Our results indicated that Arcobacter cells could easily attach to all surface types and the number of attached cells depended on the length of exposure and temperatures (4 and 20 degrees C). Extracellular fibrils were also observed on the stainless steel surface, especially after 72 h of contact times at both refrigeration and ambient temperatures. In addition, the surface energy value of each material was estimated by contact angle measurements using water, alpha-bromonaphthalene, and dimethylsulfoxide. The surface energy of A. butzleri was 58.6 mJ x m(-2) and the surface energy values of the three surfaces studied showed that plastic had a low energy surface (26.1 mJ x m(-2)) as did copper (45.8 mJ x m(-2)) and stainless steel (65.7 mJ x m(-2)).


Environmental DNA Collected from Snow Tracks is Useful for Identification of Mammalian Species.
Noninvasive genetic analysis is being used increasingly in field surveys. However, detecting large and middle-sized mammals, such as Carnivora species, using noninvasive samples, such as scat or hair, is time- and labor-intensive due to their low densities and elusive behaviors. As snow tracks are the most frequently encountered natural signs of terrestrial mammals in winter, we employed several methods to recover environmental DNA (eDNA) from snow tracks. We performed both DNA metabarcoding and Sanger sequence analyses, in combination with universal primers on the mitochondrial 12S rRNA gene for mammals and taxon-specific primers on the mitochondrial NADH dehydrogenase subunit 2 gene for Martes species (martens and sables in Mustelidae). Snow samples of four Martes melampus tracks, one Cervus nippon track, one Vulpes vulpes track, and the track of an unidentified Carnivora species were collected from a snowfall area in Kyoto, Japan, in February 2018. Regarding DNA metabarcoding analyses, the sequences of three Carnivora species (M. melampus, V. vulpes, and Canis lupus familiaris) and a deer (C. nippon) were obtained from their respective snow tracks. Using Sanger sequencing, eDNA on snow tracks was recovered at the species level except for M. melampus using universal primers, while eDNA of M. melampus was sequenced using Martes-specific primers. Snow track surveys in combination with eDNA techniques could dramatically improve the efficiency of monitoring and conservation of mammals.