Interaction between endogenous and exogenous orienting in crossmodal attention.
Using a cue-target paradigm, we investigated the interaction between endogenous and exogenous orienting in cross-modal attention. A peripheral (exogenous) cue was presented after a central (endogenous) cue with a variable time interval. The endogenous and exogenous cues were presented in one sensory modality (auditory in Experiment 1 and visual in Experiment 2) whereas the target was presented in another modality. Both experiments showed a significant endogenous cuing effect (longer reaction times in the invalid condition than in the valid condition). However, exogenous cuing produced a facilitatory effect in both experiments in response to the target when endogenous cuing was valid, but it elicited a facilitatory effect in Experiment 1 and an inhibitory effect in Experiment 2 when endogenous cuing was invalid. These findings indicate that endogenous and exogenous cuing can co-operate in orienting attention to the crossmodal target. Moreover, the interaction between endogenous and exogenous orienting of attention is modulated by the modality between the cue and the target.


Streptavidin-conjugated C3 protein mediates the delivery of mono-biotinylated RNAse A into macrophages.
The C3 toxin produced by Clostridium botulinum (C3bot) catalyzes the mono-ADP-ribosylation of the small GTPases Rho A, B and C, resulting in their inactivation. Recently, a specific endocytotic uptake mechanism of C3bot was identified in macrophages and myeloid leukemia cells. Here, we present a novel delivery system based upon a mutant C3bot devoid of ADP-ribosylation activity (C3Mut) and wild-type streptavidin (Stv). The C3Mut moiety mediates endocytosis into macrophages, whereas Stv functions as an adaptor protein for attaching biotinylated molecules to facilitate their subsequent internalization. First, a bioconjugate consisting of recombinant C3Mut and Stv was generated via a thioether linkage that tightly interacted with biotinylated bovine serum albumin as demonstrated by dot blot analysis. We then showed the internalization of C3Mut-Stv into J774A.1 macrophages by confocal microscopy and observed translocation into the cytosol using cell fractionation. The C3Mut-Stv bioconjugate did not affect cell viability. Next, we prepared mono-biotinylated RNase A, which was attached to the C3Mut-Stv transporter, and demonstrated its C3Mut-Stv-mediated delivery into the cytosol of J774A.1 cells. Finally, C3Mut-Stv also promoted the efficient uptake of mono-biotinylated lysozyme into J774A.1 cells, highlighting its versatility. This study intriguingly demonstrates the use of the novel C3Mut-Stv delivery system for protein transduction and may provide a basis for future applications, in particular, of cytotoxic RNase A mutants.


Subgenual anterior cingulate activation to valenced emotional stimuli in major depression.
Major depression has been associated with anomalous activation in the subgenual anterior cingulate cortex, but its response to emotional stimuli is poorly understood. The primary goal of this study was to compare levels of activation in the subgenual anterior cingulate cortex of diagnosed depressed and nondepressed participants in response to happy and sad facial expressions of affect. Whereas cognitive theories of depression predict increased activation to negative stimuli, depressed participants were found to exhibit increased activation to both types of stimuli in the subgenual anterior cingulate cortex. Importantly, the loci were in different regions of the subgenual anterior cingulate cortex, suggesting that there is functional specialization in the processing of negatively and positively valenced stimuli.


Sitagliptin (MK0431) inhibition of dipeptidyl peptidase IV decreases nonobese diabetic mouse CD4+ T-cell migration through incretin-dependent and -independent pathways.
Treatment of NOD mice with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin preserved islet transplants through a pathway involving modulation of splenic CD4(+) T-cell migration. In the current study, effects of sitagliptin on migration of additional subsets of CD4(+) T-cells were examined and underlying molecular mechanisms were further defined. Effects of sitagliptin on migration of NOD mouse splenic, thymic, and lymph node CD4(+) T-cells were determined. Signaling modules involved in DPP-IV-, Sitagliptin- and incretin-mediated modulation of CD4(+) T-cell migration were studied using Western blot and Rac1 and nuclear factor-kappaB (NF-kappaB) activity assays. Migration of splenic and lymph node CD4(+) T-cells of diabetic NOD mice was reduced by sitagliptin treatment. In vitro treatment of splenic, but not thymic or lymph node CD4(+) T-cells, from nondiabetic NOD mice with soluble (s) DPP-IV increased migration. Sitagliptin abolished sDPP-IV effects on splenic CD4(+) T-cell migration, whereas incretins decreased migration of lymph node, but not splenic, CD4(+) T-cells. Splenic CD4(+) T-cells demonstrating increased in vitro migration in response to sDPP-IV and lymph node CD4(+) T-cells that were nonresponsive to incretins selectively infiltrated islets of NOD mice, after injection. Sitagliptin decreases migration of splenic CD4(+) T-cells through a pathway involving Rac1/vasodilator-stimulated phosphoprotein, whereas its inhibitory effects on the migration of lymph node CD4(+) T-cells involve incretin-activation of the NF-kappaB pathway. Benefits of sitagliptin treatment in diabetic NOD mice may be mediated through selective effects on subpopulations of T-cells that are related to autoimmunity.


[The protease inhibitor system of macaques. The identification of alleles using isoelectric focusing and family analysis].
Five alpha-1-antitrypsin (alpha-1-AT) phenotypes have been revealed by isoelectrofocusing (IEF) in sera of 215 crab-eating macaques. Alpha-1-AT was monomorphic in sera of 250 Rhesus monkeys. A new allele of macaque Pi-system, designated as B' was postulated in addition to existing two (B and C) on the basis of IEF data. The above conclusion was supported by family analysis, based on 35 monkey birth cases. Alpha-1-AT phenotype frequencies were in agreement with Hardy-Weinberg equation both in wild and capture born crab-eating macaques. Alpha-1-AT was found to be microheterogeneous: several zones of the protein were revealed by IEF and Western blotting with anti human alpha-1-AT serum. The pregnancy caused a sharp increase of one band. This may lead to false identification of alpha-1-AT phenotypes, particularly when acid starch gel electrophoresis is used for alpha-1-AT identification. Such misinterpretation during alpha-1-AT phenotyping may explain the disagreement with Hardy-Weinberg equation described earlier for crab-eating macaques.


Plasmodium vivax: restricted tropism and rapid remodeling of CD71-positive reticulocytes.
Plasmodium vivax merozoites only invade reticulocytes, a minor though heterogeneous population of red blood cell precursors that can be graded by levels of transferrin receptor (CD71) expression. The development of a protocol that allows sorting reticulocytes into defined developmental stages and a robust ex vivo P vivax invasion assay has made it possible for the first time to investigate the fine-scale invasion preference of P vivax merozoites. Surprisingly, it was the immature reticulocytes (CD71(+)) that are generally restricted to the bone marrow that were preferentially invaded, whereas older reticulocytes (CD71(-)), principally found in the peripheral blood, were rarely invaded. Invasion assays based on the CD71(+) reticulocyte fraction revealed substantial postinvasion modification. Thus, 3 to 6 hours after invasion, the initially biomechanically rigid CD71(+) reticulocytes convert into a highly deformable CD71(-) infected red blood cell devoid of host reticular matter, a process that normally spans 24 hours for uninfected reticulocytes. Concurrent with these changes, clathrin pits disappear by 3 hours postinvasion, replaced by distinctive caveolae nanostructures. These 2 hitherto unsuspected features of P vivax invasion, a narrow preference for immature reticulocytes and a rapid remodeling of the host cell, provide important insights pertinent to the pathobiology of the P vivax infection.


Ground state, growth, and electronic properties of small lanthanum clusters.
The DMol cluster method based on density-functional theory has been employed to study the structural stability and electronic structure of La(n) (n=2-14) clusters. The ground states have been found out for lanthanum clusters. The Jahn-Teller effect plays an important role in this process because there are many isomers near the ground state. The magnetism is not sensitive to interatomic spacing when the change of interatomic spacing is in a small range. Lanthanum clusters grow in an icosahedral pattern. The results of the mean binding energy, of the second derivative of binding energy, and of the formation energy show strong odd-even alternation and that 7- and 13-atom clusters are magic. Further, the HOMO-LUMO gap, the mean nearest bond lengths, and the mean magnetic moments suggest that the convergence to bulk is slow and it shows an oscillatory behavior for small lanthanum clusters.


Association between Cognitive Distortion, Type D Personality, Family Environment, and Depression in Chinese Adolescents.
Purpose. Depression prevalence and risk increase among adolescents are related to biological, psychosocial, and cultural factors. Little is known about the association between cognitive distortion, type D personality, family environment, and depression. The aim of this paper was to examine the relationships of cognitive distortion, type D personality, family environment, and depression in a sample of Chinese adolescents. Methods. A sample of Chinese adolescents with depression and the controls were investigated cross-sectionally with life orientation test-revised (LOT-R), type D personality Scale-14 (DS14), family environment scale (FES), and Zung self-depression scale (SDS); respectively, all scales were administered in Chinese. Results. Chinese-depressed adolescents showed more cognitive distortion, type D personality, and adverse family environment than control groups. Furthermore, lower level of Optimism, negative affectivity, and poor family cohesion may increase the risk of depression in Chinese adolescents. Conclusions. Our study indicates that lower level of Optimism, Negative Affectivity, and poor Family Cohesion factors were implicated to contribute to depression in Chinese adolescents. Lower level of optimism and negative affectivity may be crucial associated factors of depression among these samples. our findings pointed to the importance of broad screening and intervention of vulnerable population.


Auditory Threshold Variability in the SAMP8 Mouse Model of Age-Related Hearing Loss: Functional Loss and Phenotypic Change Precede Outer Hair Cell Loss.
Age-related hearing loss (ARHL) is the most common sensory deficit in aging society, which is accompanied by increased speech discrimination difficulties in noisy environments, social isolation, and cognitive decline. The audiometric degree of ARHL is largely correlated with sensory hair cell loss in addition to age-related factors not captured by histopathological analysis of the human cochlea. Previous studies have identified the senescence-accelerated mouse prone strain 8 (SAMP8) as a model for studying ARHL and age-related modifications of the cochlear redox environment. However, the SAMP8 population exhibits a large variability in auditory function decline over age, whose underlying cause remains unknown. In this study, we analyzed auditory function of SAMP8 mice by measuring auditory brainstem response (ABR) thresholds at the age of 6 weeks (juvenile), 12 weeks (young adult), and 24 weeks (adult). Consistent with previous studies, SAMP8 mice exhibit an early progressive, age-related decline of hearing acuity. However, a spatiotemporal cytohistological analysis showed that the significant increase in threshold variability was not concurrently reflected in outer hair cell (OHC) loss observed in the lower and upper quartiles of the ABR threshold distributions over age. This functional loss was found to precede OHC loss suggesting that age-related phenotypic changes may be contributing factors not represented in cytohistological analysis. The expression of potassium channels KCNQ4 (KV7.4), which mediates the current IK,n crucial for the maintenance of OHC membrane potential, and KCNQ1 (KV7.1), which is an essential component in potassium circulation and secretion into the endolymph generating the endocochlear potential, showed differences between these quartiles and age groups. This suggests that phenotypic changes in OHCs or the stria vascularis due to variable oxidative deficiencies in individual mice may be predictors of the observed threshold variability in SAMP8 mice and their progressive ARHL. In future studies, further phenotypic predictors affected by accumulated metabolic challenges over age need to be investigated as potentially underlying causes of ARHL preceding irreversible OHC loss in the SAMP8 mouse model.


2,2,6,6-Tetramethylpiperydinyl-1-oxyl (TEMPO) Functionalized Benzoxazines Prepared with a One-Pot Synthesis for Reactive/Crosslinkable Initiators of Nitroxide Mediated Polymerization.
In this work, the incorporation of a 2,2,6,6-tetramethylpiperydinyl-1-oxyl (TEMPO) group to a benzoxazine ring is performed using a one-pot synthesis for the preparation of TEMPO-functionalized benzoxazine compounds and polymers as reactive and crosslinkable initiators for nitroxide-mediated polymerization (NMP). The TEMPO-functionalization reaction of benzoxazine, traced with 1 H NMR, is conducted with sequential radical transfer and coupling reactions. Moreover, polystyrene-grafted polybenzoxazine copolymers are prepared with the TEMPO-benzoxazine initiator and NMP of styrene. The polymerization system exhibits the characteristics of controlled radical polymerization, including controlled molecular weights of products and ability for sequential polymerization. Moreover, based on the chemical reactivity and crosslinking ability of benzoxazine groups, the synthesis route developed in this work will widen the scope of the design and synthesis of functional and high-performance polymers.


Proacrosin gene expression in rat spermatogenic cells.
Mammalian proacrosin gene expression was considered to be exclusively postmeiotic until recent studies detected the presence of proacrosin mRNA in mouse pachytene spermatocytes. To determine if rat proacrosin gene expression was initiated during meiosis, a 314-bp proacrosin cDNA fragment was amplified from rat round spermatid RNA, using proacrosin-specific primers, for use as a probe. Sequence analysis of the round spermatid 314-bp cDNA fragment confirmed > 99% identity with the rat proacrosin cDNA sequence. This 314-bp fragment was subsequently used for Northern blot analysis of RNA isolated from testicular germ cells. A 1.6-kb transcript was detected in pachytene spermatocytes, round spermatids, and a mixed population of condensing spermatids/residual bodies, with the highest level of expression in round spermatids. Northern blot analysis of testicular RNA during development revealed the earliest timepoint of expression to be at 24 days of age, further demonstrating the association of proacrosin mRNA with spermatocytes. These data demonstrate diploid expression of the rat proacrosin gene, in agreement with mouse proacrosin gene expression but in contrast to the apparent haploid expression of proacrosin described for the bull and the boar. These studies provide evidence that, in the rat, the process of acrosome biogenesis begins during meiosis.


Biotransformation of melatonin in human breast cancer cell lines: role of sulfotransferase 1A1.
The biologically active melatonin metabolite, 6-hydroxymelatonin (6-OHMel), is conjugated to form 6-hydroxymelatonin sulfate (6-OHMelS). To elucidate the role of the sulfotransferase (SULT) enzyme 1A1, considerably expressed in normal and malignant human breast cells, we measured the formation of 6-OHMelS by ELISA in hormone-dependent MCF-7 and hormone-independent MDA-MB231 (MDA) breast cancer cell lines after stable transfection with SULT1A1. In parent MDA cells, low SULT1A1 mRNA expression was associated with moderate 6-OHMelS formation as determined after application (24 hr) of 0.1 microM 6-OHMel. As expected, overexpression of SULT1A1 in MDA cells resulted in a 2.9- and 110-fold increase in 6-OHMelS in the cytosol and cellular supernatant respectively. Furthermore, 6.3- and 115-fold increases were observed after 0.5 microM, and 12.6- and 101-fold increases after 1 microM 6-OHMel respectively. In MCF-7 cells, because of high basal SULT1A1 expression, only two- to threefold increases in 6-OHMelS were observed after transfection with the enzyme. In total, 866 and 539 pmol/mg protein 6-OHMelS were formed from 1 microM 6-OHMel in SULT1A1 overexpressing MDA and MCF-7 cells, respectively, whereas application of 1 microM melatonin produced only <1% of 6-OHMelS. Possible interactions with the SULT1A1 substrate tamoxifen (tam), an anti-estrogen applied in the therapy of breast cancer, were also studied. A concentration of 1 microM tam increased 6-OHMelS formation by approximately threefold in the presence of 1 microM melatonin or 1 microM 6-OHMel respectively. However, no alterations were detected after application of 1 microM 4-hydroxy-tamoxifen. In summary, we demonstrate the importance of SULT1A1 for the biotransformation of 6-OHMel in human breast cancer cells. Our data further suggest that tam can modulate melatonin biotransformation.


A bis(disulfide)-linked offset cryptophane.
A new bis(disulfide)-linked offset dimer is formed from a dithiolated analogue of cyclotriguaiacylene. Unlike a similar tris(disulfide)-linked example, this is not a true cryptophane as the offset nature of the dimerisation and intramolecular host-guest interactions preclude its use as a host.


Chronotype-dependent circadian rhythmicity of driving safety.
Among the factors associated with driving safety, sleep-related variables constitute a leading cause of road accidents. Circadian fluctuations of driver's somnolence has been previously linked to road safety. However, the role of chronotype in this relationship has been poorly investigated. Thus, the aim of the present work was to address whether driving performance is influenced by circadian patterns, in turn modulated by the driver's chronotype and the time of day (i.e. synchrony effect). We assessed 47 healthy young adults with specific chronotypes in several simulated driving sessions, both in the morning and in the evening. We collected driving performance data, along with self-reported levels of activation prior to each driving session and other sleep-related variables. Participants drove less safely when testing times took place outside their optimal time of day, as determined by their chronotype and confirmed by self-reported levels of activation. These differences were more pronounced in the morning, when morning types shown a better driving performance. Our results suggest that chronotype plays an important role as a modulator of the relationship between the time of day and driving safety. Therefore, it is necessary to acknowledge this variable in theoretical models of driving behavior, and for the improvement of occupational accidents prevention programs.


The expression of the epithelial blood-group substances: normal and malignant tissues.
The blood-group isoantigens are macromolecules localized to the plasma membranes of certain epithelial tissues. These substances are not detectable on the epithelium once it has undergone malignant transformation. Results of this investigation have demonstrated that the loss of detectability of the blood-group isoantigens does not appear to be related to a "masking" effect by an increase in surface sialic acid. Using fluorescein-labeled lectins specific for sugar subunits which are components of the blood-group oligosaccharide chain, it was found that the malignant cells and cells of the parabasal layer of normal oral epithelium had high levels of N-acetyl-D-glucosamine (GlcNAC), the subterminal sugar residue of the blood-group chain. The basal cells of normal epithelium and a minority of the malignant cells demonstrated levels of D-galactose-N-acetyl-D-galactosamine, which are the most proximal blood-group sugar subunits, as well as subunits of other membrane antigens. Our results indicate that malignant cells seem to be capable of synthesizing the blood-group oligosaccharide chains to the same level as the normal cells of the parabasal layer of stratified squamous epithelium. This level is just subjacent to the terminal D-galactose residue of the blood-group precursor chain. Increased or decreased differentiation characteristics of squamous cell carcinomas did not alter the level of blood-group synthesis. However, there may be a correlation between the level of synthesis of these antigens and the ability of the cells to demonstrate motility and to proliferate.


Phagocytosis and intracellular killing of serum-opsonized Staphylococcus aureus by mouse fibroblasts expressing human Fcgamma receptor type IIa (CD32).
Phagocytes bear more than one class of receptors for the Fc domain of IgG (FcgammaR). In addition the same ligand can interact with different classes of FcgammaR. This complexity makes it difficult to study the contribution of the various classes of FcgammaR to antimicrobial functions. To circumvent this difficulty, in the present study mouse 3T6 fibroblasts transfected with cDNA encoding for human FcgammaR type IIa (FcgammaRIIa-expressing cells) were used to determine the role of this receptor in phagocytosis and intracellular killing of serum-opsonized Staphylococcus aureus. Experiments using microbiological and fluorescent techniques to discriminate between cell-adherent and intracellular bacteria revealed that serum-opsonized bacteria are phagocytized by FcgammaRIIa-expressing cells, but not by parental fibroblasts. Non-opsonized bacteria were poorly internalized by FcgammaRIIa-expressing as well as parental fibroblasts. Furthermore, incubation of FcgammaRIIa-expressing cells with opsonized bacteria at 4oC and incubation of FcgammaRIIa-expressing cells with cytochalasin E prior to addition of opsonized bacteria inhibited the phagocytosis of these bacteria almost completely. Phagocytosis of opsonized bacteria by FcgammaRIIa-expressing cells was partly inhibited by selective inhibition of protein tyrosine kinases (PTK). FcgammaRIIa cross-linking initiated transient tyrosine phosphorylation of various proteins in FcgammaRIIa-expressing cells. These data indicate that activation of PTK is involved in the FcgammaRIIa-mediated phagocytosis of opsonized S. aureus by transfected fibroblasts. Human serum from normal individuals and agammaglobulinemic patients triggered the intracellular killing of S. aureus by FcgammaRIIa-expressing fibroblasts. Surprisingly, heat-inactivated human serum, IgG and incubation with anti-FcgammaRII antibodies followed by a bridging secondary antibody did not stimulate the killing process. The possibility that these ligands did not interact with FcgammaRIIa on the cells can be excluded since they induced tyrosine phosphorylation of cellular proteins. The serum factor that stimulates the intracellular killing of bacteria by FcgammaRIIa-expressing cells is not yet identified. Oxygen-independent mechanisms are thought to be responsible for the killing of intracellular bacteria by these cells since the NADPH oxidase inhibitor diphenylene iodonium did not affect the serum-stimulated intracellular killing of S. aureus and no reactive oxygen and nitrogen intermediates were produced by FcgammaRIIa-expressing cells after appropiate stimulation. Taken together, these data show that phagocytosis but not intracellular killing of S. aureus is mediated via FcgammaRIIa on cells expressing this receptor.


α-Quaternary Proline Derivatives by Intramolecular Diastereoselective Arylation of N-Carboxamido Proline Ester Enolates.
Pyrrolidine-2-carboxylate esters substituted in the 3-, 4- or 5-positions were converted to their N'-aryl urea derivatives. Deprotonation at the 2-position to form a potassium enolate led to migration of the N'-aryl substituent to the 2 position of the pyrrolidine ring, followed by cyclization of the resulting urea to give bicyclic α-aryl hydantoin derivatives of substituted prolines. Depending on the substitution pattern of the starting material, high diastereoselectivity was observed in the aryl migration, allowing formation of the products in enantiomerically enriched form, despite the intermediacy of a planar enolate. The hydrolysis of the bicyclic hydantoins under basic conditions gave a range of enantiopure and enantioenriched quaternary α-aryl proline derivatives.


[Anhidrosis and hyperthermia associated with treatment with topiramate].
It has been observed that if topiramate (TPM) is given together with other antiepileptic drugs when the temperature of the environment is high, a disorder involving sweating and thermo regulation may be seen as a side effect. We describe ten patients, of an average age of 7 years and 8 months, with refractory epileptic seizures. All were treated with topiramate, associated with the antiepileptic drugs they had been taking previously. During the summer months, when the environmental temperature was over 37 C, they had slight hyperthermia, hypohydrosis or more usually anhydrosis, red faces and tiredness which was markedly worse on effort. In one case there was also retention of urine and four others had known side effects. In seven patients the symptoms disappeared when the dose of TPM was reduced or the environment became cooler. In the other three cases TPM was withdrawn, due to the severe adverse effects seen in two cases and for being ineffective as treatment in the other cases. It is considered that in predisposed children, TPM causes autonomic dysfunction, probably of central origin, which is seen as a disorder of sweating and thermoregulation. Although the mechanism of this disorder is not known, since it occurs when the temperature is over 37 C, it would seem that it is due to a reduction in carbonic anhydrase isoenzymes II and IV. We suggest that it would be useful to establish a method to predict the patients at risk in summer, in hot regions, at the first sign of fatigability.


A community-wide approach to reducing risky drinking cultures in young people in rural Australia.
This study evaluated the impact of a multi-faceted, harm minimisation program addressing youth alcohol change and risky drinking behaviours in rural Australia. The role and influence of a multi-tiered community approach to changing alcohol cultures is examined. An alcohol culture change project for young people (12-18 years) was implemented in rural Victoria. It was informed by the Alcohol Cultures Framework, comprising community-wide events and youth-focused activities, co-designed with young people. The approach aimed at maximising engagement and reducing alcohol-related harm by targeting the shared activities and drinking practices of young people, parents and the community. Participants (n = 446) provided feedback specific to three key program activities for promoting alcohol change. Mixed methods: Feedback sheets were collected, and interviews and focus groups were conducted with program participants. Participants indicated that the program had informed their understanding of the way people in their region drink, and the social norms and practices around alcohol that encourage risky drinking. It influenced their short- and medium-term reactions, learnings and activities relating to alcohol consumption. The impact of the program was greatest in adults than young people although reflective learning and some behaviour change were evident across all age groups and community clusters. Community-wide health promotion events offer participants a deeper understanding of the ways in which dominant alcohol cultures inform the practices and activities of young people within a broader community context. Ensuring health promotion programs within a whole-of-community approach are established longer term, is recommended.


Analysis of lectin-bound glycoproteins in snake venom from the Elapidae and Viperidae families.
This paper describes an efficient method of studying the glycoproteins found in snake venom. The glycosylation profiles of the Elapidae and Viperidae snake families were analyzed using FITC-labeled lectin glycoconjugates. The Con A-agarose affinity enrichment technique was used to fractionate glycoproteins from the N. naja kaouthia venom. The results revealed a large number of Con A binding glycoproteins, most of which have moderate to high molecular weights. To identify the proteins, the isolated glycoprotein fractions were subjected to two-dimensional electrophoresis and MALDI-TOF MS. Protein sequences were compared with published protein databases to determine for their biological functions.


[Ovarian endometriosis: characteristics of the blood circulatory bed].
Glandular cystic ovarian endometriosis (OE) is characterized by a more intensive blood supply than cystic OE. This type of OE is characterized by a high proliferative glandular epithelial activity detected by an immunohistochemical study using antibodies to PCNA and CA-125. Moreover, a positive correlation is found between the serum concentration of CA-125 and the expression of this antigen in the epitheliocytes of an endometrioid cyst in both glandular-cystic and cystic OE. Thus, the findings permit the determination of the morphofunctional activity of a type of OE and its aptness to the progression of the disease and to the development of recurrences.


Efficiency of methylated DNA immunoprecipitation bisulphite sequencing for whole-genome DNA methylation analysis.
We compared four common methods for measuring DNA methylation levels and recommended the most efficient method in terms of cost and coverage. The DNA methylation status of liver and stomach tissues was profiled using four different methods, whole-genome bisulphite sequencing (WG-BS), targeted bisulphite sequencing (Targeted-BS), methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA immunoprecipitation bisulphite sequencing (MeDIP-BS). We calculated DNA methylation levels using each method and compared the results. MeDIP-BS yielded the most similar DNA methylation profile to WG-BS, with 20 times less data, suggesting remarkable cost savings and coverage efficiency compared with the other methods. MeDIP-BS is a practical cost-effective method for analyzing whole-genome DNA methylation that is highly accurate at base-pair resolution.


Synthesis and characterization of graphene: influence of synthesis variables.
The optimization of graphene growth on copper foils using an atmospheric pressure chemical vapor deposition setup is reported. CH4 and H2 were used as precursor gases and Raman spectroscopy as the main graphene characterization technique. Different growth parameters, including temperature and reaction time, the molar ratio of CH4/H2 in the feed and total flow of gases during the reaction step, were studied in detail. It was shown that graphene growth was not homogeneous in the entire sample, multilayer graphene was present in most of the sample, however as the synthesis parameters were optimized, graphene gained better quality, obtaining bilayer graphene over most of the sheet in the final optimized sample. Homemade software was used to analyze the quality of the synthesised graphene, obtaining a more quality graphene according to the synthesis parameters optimized. An optimal bilayer graphene sample was prepared at the lowest growth time (10 min) and the highest synthesis temperature (1050 °C), using a CH4/H2 flow ratio and a total flow rate ratio of precursors of 7% and 60 Nml (CH4 + H4) per min respectively.


A pathologist׳s perspective on the perinatal autopsy.
The perinatal autopsy is an important tool in the investigation of fetal and neonatal death, and a complete understanding of its risks and benefits is necessary for providers of perinatal care. This review, from the perspective of a perinatal pathologist, reports the details of the autopsy procedure, its goals, its value to individual patients and the health care system in general, and its alternatives. Even with new emerging technologies, the conventional perinatal autopsy remains the gold standard for determining the cause of death and the final summary of all pathologic findings. Therefore, the information provided in this review can help providers properly convey information about perinatal autopsy to bereaved families.


Analysing the impact of myopia on the Stiles-Crawford effect of the first kind using a digital micromirror device.
Photoreceptor light acceptance is closely tied to the Stiles-Crawford effect of the first kind (SCE-I). Whether the SCE-I plays a role in myopic development remains unclear although a reduction in directionality has been predicted for high myopia. The purpose of this study is to analyse the relationship between foveal SCE-I directionality, axial eye length, and defocus for emmetropic subjects wearing ophthalmic trial lenses during psychophysical measurements and for myopic subjects with their natural correction. A novel uniaxial flicker system has been implemented making use of a Digital Micromirror Device (DMD) to flicker between a 2.3 visual degrees circular reference and a set of circular test patterns in a monocular Maxwellian view at 0.5 Hz. The brightness of the test is adjusted by the duty cycle of the projected light to an upper limit of 22 727 Hz. The wavelength and bandwidth are set by a tuneable liquid-crystal filter centred at 550 nm. A total of four measurement series for 11 pupil entrance points have been realized for the right eye of 6 emmetropic and 10 myopic subjects whose pupils were dilated with tropicamide. Five of the emmetropic subjects wore ophthalmic trial lenses in the range of -3 to +9 dioptres to mimic hyperopic to highly myopic vision and resulting visibility plots have been fitted to a Gaussian SCE-I function. In turn, the myopic subjects wore their natural correction during the analysis of the SCE-I. All subjects had their axial eye length determined with an ultrasound device. A SCE-I directionality parameter in the range of 0.03 to 0.06/mm2 was found for the emmetropic subjects with corrected vision in fair agreement to values in the literature. The results also revealed a marked reduction in directionality in the range from 16% to 30% with every 3 dioptre increase of simulated myopia, as well as a 10% increased directionality in simulated hyperopic eyes. For both emmetropic and myopic subjects, a decrease in directionality with increase in axial length was found in agreement with theoretical expectations. The study confirms a clear link between SCE-I directionality, uncorrected defocus, and axial eye length. This may play a role for emmetropization and thus myopic progression as cone photoreceptors capture light from a wider pupil area in elongated eyes due to a geometrical scaling.


A "no-restraint" psychiatric department: operative protocols and outcome data from the "Opened-doors experience" in Trento.
The "Open Doors" and no restraint project in the psychiatric department of Trento originated from de-institutionalization and empowerment practices, amply extended in the Mental Health Service of Trento over the past years. This paper aims to present the authorized operative protocols of no restraint methods and data from the first four years experience of no restraint management in the psychiatric Department of Trento. Avoiding physical restraint and confinement force every member of the ward staff to look for innovative solutions and means a deeper and strenuous engagement of the staff in the therapeutic relationship. We are aware that this is basically a small thing, and that certainly it will create many contradictions. We chose to stay on the other hand in these contradictions, and to witness that it is possible, and indeed useful. The great lesson we learnt over past years in Community Psychiatry was that only the hard experience of these contradictions can allow people to regain health, not just as assimilation to stereotyped models, but as adhibition of resources and self-determination, normally stolen by psychiatric illness.


Epibolin: a protein of human plasma that supports epithelial cell movement.
Earlier studies suggested that there is a specific activity in mammalian serum and plasma that supports epidermal (epithelial) cell movement. This activity was shown to be nondialyzable and heat labile. In the studies reported here, using standard biochemical procedures--i.e., ammonium sulfate fractionation, ion-exchange and gel filtration chromatography, isoelectric precipitation, and preparative polyacrylamide gel electrophoresis--we have purified a factor from human plasma that supports epidermal cell movement. The factor travels as an apparent single band on disc gel electrophoresis and corresponds to a glycosylated single-chain protein of approximately 65,000 +/- 3,000 daltons. The purified fraction is necessary and sufficient for dissociated epidermal cells, (ii) outgrowth of epithelial sheets from skin explants, and (iii) epiboly, epithelial sheet movement over a floating skin explant. The purified fraction is active at a concentration of 1-2 micrograms/ml of growth medium. It is destroyed by trypsin and its activity is augmented more than 10-fold by a second, as yet unpurified, fraction of plasma. These studies support the notion that a single protein of plasma supports epidermal cell movement and that this protein may play an important role in wound closure. Because it supports epiboly, the most biologically relevant of the assays, it has been named epibolin.


Long Noncoding RNA NEAT1 Aggravates Aβ-Induced Neuronal Damage by Targeting miR-107 in Alzheimer's Disease.
Alzheimer's disease (AD) is the most common neurodegenerative disease, with a rising prevalence worldwide. Long noncoding RNAs (lncRNAs) have been found to play important roles in the development and treatment of AD. However, the exact role of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in neuronal damage in AD is largely unknown. The AD model was established in SH-SY5Y and SK-N-SH cells via treatment with amyloid β1-42 (Aβ). The expression of NEAT1 and microRNA-107 (miR-107) was measured by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were detected by MTT assay, immunocytochemistry, and flow cytometry. The expression of phosphorylated tau protein (p-Tau) was measured by Western blot. The interaction between NEAT1 and miR-107 was explored by bioinformatics analysis, luciferase activity, and RNA immunoprecipitation assays. NEAT1 expression was enhanced in Aβ-treated SH-SY5Y and SK-N-SH cells, and its knockdown attenuated Aβ-induced inhibition of viability and promotion of apoptosis and p-Tau levels. NEAT1 was indicated as a decoy of miR-107. miR-107 abundance was reduced in Aβ-treated cells, and its overexpression reversed Aβ-induced injury. Moreover, interference of miR-107 abated silencing of NEAT1-mediated inhibition of neuronal damage in Aβ-treated SH-SY5Y and SK-N-SH cells. LncRNA NEAT1 aggravated Aβ-induced neuronal damage by sponging miR-107, indicating a novel avenue for treatment of AD.


The influence of two different sets of information and suggestions on the subjective effects of relaxation.
The study compared the subjective effects of different relaxation techniques and their susceptibility to influence by information and suggestions provided by the trainers. Two groups of twelve subjects each were trained in autogenic training and in progressive relaxation successively. On three occasions during their training, each group was given one of two contrasting sets of information and suggestions concerning the subjective effects to be expected. At the end of training, differences in the subjective effects accompanying the two relaxation techniques were found but no significant effect of the contrasting sets of information and suggestions emerged. These results suggest that the subjective effects of relaxation were resistant to simple suggestions and, being more robust and real than often thought, could constitute a basis for differential indications of various relaxation methods.


Beneficial use of immunoglobulins in the treatment of Sydenham chorea.
This double case report indicates that treatment with intravenous immunoglobulins (IVIG) is effective in patients with Sydenham chorea (SC). SC is a rare but impressive clinical manifestation following streptococcal infection. This movement disorder characterised by chorea, emotional lability and muscle weakness, is one of the major criteria of acute rheumatic fever. Treatment of SC is typically limited to supportive care and palliative medications. Curative treatment is still in the experimental stage. Recent research on patients with SC proved that antibodies against the group A streptococcus cross-react with epitopes of neurons in the basal ganglia, namely, intracellular tubulin and extracellular lysoganglioside. Therefore, immune modulating therapy by means of prednisone, plasma exchange and IVIG are mentioned in the literature as possible effective treatment. Beneficial effect of IVIG has been shown in several diseases with molecular mimicry as the underlying pathophysiology. In this paper, we describe two girls aged 11 and 13 years, respectively, who presented with SC having severe disabilities in their daily live. We treated both patients with IVIG 400 mg/kg/day for 5 days. Treatment was tolerated well and had a pronounced positive effect. Shortly after the drug was administered, all signs and symptoms disappeared in both patients. Based upon these patients, we highlight IVIG as a serious treatment option for SC.


Progress in Research on the Effect of Melatonin on Postoperative Cognitive Dysfunction in Older Patients.
Postoperative cognitive dysfunction (POCD) is a common complication of the central nervous system in elderly patients after operation. It will prolong the length of stay, reduce the independence and quality of daily life, and increase the risk of death. However, at present, there is a lack of safe and effective ideal drugs for the prevention and treatment of POCD. Melatonin is one of the hormones secreted by the pineal gland of the brain, which has the functions of regulating circadian rhythm, anti-inflammation, anti-oxidation, anti-apoptosis, and so on. Some recent studies have shown that MT can prevent and treat POCD by adjusting circadian rhythm, restoring cholinergic system function, neuroprotection, and so on. This article will introduce POCD, melatonin and the mechanism of melatonin on POCD, respectively, to provide a basis for clinical prevention and treatment of POCD in the elderly.


Microbead-separated thermionic energy converter with enhanced emission current.
The efficiency of thermionic energy converters is a strong function of the inter-electrode separation due to space-charge limitations. Here we demonstrate vacuum thermionic energy converters constructed using barium dispenser cathodes and thin film tungsten anodes, separated by size specific alumina microbeads for simple device fabrication and inter-electrode gap control. The current and device efficiency at the maximum power point are strongly dependent on the inter-electrode gap, with a maximum device efficiency of 0.61% observed for a gap on the order of 5 μm. Paths to further reductions in space charge and improved anode work function are outlined with potential for over an order of magnitude improvement in output power and efficiency.


[Clinicopathological characteristics and differential diagnosis of 6 cases of congenital granular cell tumor].
To provide references for the diagnosis and treatment of congenital granular cell tumor (CGCT), by comprehensive analysis of the clinical data, histopathological and immunohistochemical results. Patients with CGCT were involede, from March 2015 to November 2020, at the Department of Oral and Maxillofacial Surgery of the First Affiliated Hospital of Zhengzhou University. A total of 6 children, aged 3-16 days, 1 male and 5 female, 5 maxillary and 1 mandibular, with maximum tumor diameter of 6-70 mm, were included. The lesions of CGCT were single and connected to the alveolar ridge by a pedicle. The surface of the tumor was covered with a vascular network, and two cases had ulcers on the surface of the tumor. All 6 cases had the tumor removed surgically and there was no recurrence or metastasis in the follow-up visit. Although CGCT is rare, it is a benign tumor and generally does not recur or metastasize after surgery, and has a good prognosis. The prenatal imaging, clinical manifestations after delivery, pathological characteristics and immunohistochemical analyses may provide reference for early diagnosis and treatment of CGCT.


Sequence analysis and expression of the filamentous phage phi Lf gene I encoding a 48-kDa protein associated with host cell membrane.
One viral strand of phi Lf, a filamentous phage of Xanthomonas campestris pv.campestris, the open reading frame (ORF440) behind gene VI was identified as gene I. This gene codes for pI protein (440 aa, 48 kDa) which was shown to be membrane-bound in the phi Lf-infected host cell by Western blot analysis using the antibody raised against the protein expressed in Escherichia coli. Its predicted amino acid sequence has a nucleotide-binding motif in the N-terminal 97 aa and a membrane-spanning domain (aa 221 to 236). These structural features are characteristic of pIs of several filamentous phages which are transmembrane proteins required for phage assembly. Thus far, nine phi Lf genes have been identified which are organized in the order GII-gX-gV-gVII-gIX-gVIII-gIII-gVI-gI, similar to the genome organization of E. coli filamentous phages.


Laboratory investigation of systemic lupus erythematosus.
Diagnosis of systemic lupus erythematosus (SLE) requires documentation of multisystem involvement and the presence of antinuclear antibodies. In almost all cases of SLE, these autoantibodies are detected at significant titer with a sensitive screening test such as the fluorescent antinuclear antibody test. After other diagnostic possibilities, such as rheumatoid arthritis, have been excluded, several laboratory tests (hematocrit determination, complement tests, anti-native DNA assays) are available to monitor the response to therapy.


Altered phenotype and function of dendritic cells in children with type 1 diabetes.
The importance of dendritic cells (DC) in the activation of T cells and in the maintenance of self-tolerance is well known. We investigated whether alterations in phenotype and function of DC may contribute to the pathogenesis of Type 1 diabetes (T1DM). Mature DC (mDC) from 18 children with T1DM and 10 age-matched healthy children were tested. mDC, derived from peripheral blood monocytes cultured for 6 days in presence of interleukin (IL)-4 and granulocyte-macrophage colony stimulating factor (GM-CSF) and stimulated with lipopolysaccharide (LPS) for the last 24 h, were phenotyped for the expression of the co-stimulatory molecules B7.1 and B7.2. In six patients and six controls allogenic mixed leucocyte reaction (AMLR) was performed using mDC and cord blood-derived naive T cells at a DC/T naive ratio of 1 : 200. Proliferation was assessed on day 7 by [(3)H]-thymidine incorporation assay. Mature DC derived from patients showed, compared with controls, a reduced expression of B7.1 [mean of fluorescence intensity (MFI): 36.2 +/- 14.3 versus 72.9 +/- 34.5; P = 0.004] and B7.2 (MFI: 122.7 +/- 67.5 versus 259.6 +/- 154.1; P = 0.02). We did not find differences in the HLA-DR expression (P = 0.07). Moreover, proliferative response of allogenic naive T cells cultured with mDC was impaired in the patients (13471 +/- 9917.2 versus 40976 +/- 24527.2 cpm, P = 0.04). We also measured IL-10 and IL-12 concentration in the supernatant of DC cultures. Interestingly, we observed in the patients a sevenfold higher level of IL-10 (P = 0.07) and a ninefold lower level of IL-12 (P = 0.01). Our data show a defect in the expression of the co-stimulatory molecules and an impairment of DC priming function, events that might contribute to T1DM pathogenesis.


Evaluation of noncovalent interactions between peptides and polyether compounds via energy-variable collisionally activated dissociation.
Energy-variable collisionally activated dissociation (CAD) was used to analyze noncovalent interactions of protonated peptide/polyether complexes in a quadrupole ion trap complexes were formed with a series of four polyether host molecules and thirteen peptide molecules. Comparison of dissociation thresholds revealed correlations between the gas-phase basicities of the peptides and polyether molecules and the onset of dissociation. The dissociation thresholds of complexes containing the tripeptides or pentapeptides were inversely proportional to the gas-phase basicities of the sites of protonation of the peptides. Intramolecular hydrogen bonding of the pentapeptides affected the observed dissociation thresholds as well. The dissociation thresholds also scaled proportionally to the gas-phase basicities of the polyethers in the complexes, and the importance of the conformational flexibility of the polyether ligand was confirmed for one of the histidine-containing tripeptide complexes.


Electro-hyperthermia up-regulates tumour suppressor Septin 4 to induce apoptotic cell death in hepatocellular carcinoma.
Modulated electro-hyperthermia (mEHT) has been shown to be effective against various types of human tumours, including hepatocellular carcinoma (HCC). Here we aimed to investigate the molecular mechanism underlying the cytotoxic effects of mEHT to HCC cells. Human liver cancer cell lines, Huh7 and HepG2, were treated with mEHT (42 °C/60 min) three times at 2-day intervals. Growth inhibition and apoptotic induction were evaluated using MTS, microscopic analysis, a clonogenic assay, annexin V/PI staining and a ccK18 ELISA. Global changes in gene expression were examined using RNA sequencing to obtain insights into molecular changes in response to mEHT. For in vivo evaluation of mEHT we used HepG2 HCC xenografts grown in nude mice. mEHT suppressed HCC cell proliferation and long-term colony formation through induction of apoptosis. The growth inhibitory effects are induced through a subset of molecular changes. Notably the expression level of septin 4 (SEPT4) (involved in pro-apoptotic activity and growth suppression) was up-regulated, whereas a key regulator of invasiveness G-Protein coupled receptor 64 (GPR64) was repressed. Subsequent Western blotting confirmed that the common increase in tumour suppressor SEPT4 in both Huh7 and HepG2 cells is accompanied by the restoration of cyclin-dependent kinase (CDK) inhibitor p21 and decrease in pro-caspase 7 and pro-caspase 3, thereby accelerating apoptotic signalling in HCC cells. Additionally, mEHT significantly inhibited the growth of human HCC xenografts in nude mice. These findings suggest that apoptotic cell death induced by mEHT is mediated by the up-regulation of tumour suppressor SEPT4 in human HCC cells.


Ondansetron does not inhibit the analgesic effect of alfentanil.
5-Hydroxytryptamine (5-HT) causes antinociception via presynaptic 5-HT3 (5-HT subtype 3) receptors on primary afferent nociceptive neurones in the spinal cord dorsal horn. Therefore, ondansetron (a 5-HT3 receptor antagonist) may increase the perception of a noxious stimulus or decrease the effects of concurrently administered antinociceptive drugs. Using a randomized, double-blind, crossover study design, we have tested this hypothesis in eight healthy volunteers who, on three different days, received either ondansetron and placebo, ondansetron and alfentanil or placebo and alfentanil. Experimental pain was induced with heat, cold, mechanical pressure and electrical stimulation. Ondansetron alone did not change the response to any of the experimental tests, but alfentanil and the combination ondansetron-alfentanil significantly changed the response compared with ondansetron alone. There was no difference between alfentanil alone and the combination ondansetron-alfentanil. We conclude that ondansetron does not change the response to pressure, heat, cold or electrical nociceptive stimuli or antagonize the analgesic effect of alfentanil.


Keratoconus managed with intacs: one-year results.
To describe the visual outcome of keratoconus managed with Intacs implantation (Addition Technology Inc, Fremont, Calif) and to define criteria that predict good outcome. This retrospective, nonrandomized, comparative, consecutive case series studied 58 eyes of 43 patients with keratoconus managed by Intacs implantation. The outcome measures were analyzed pre-Intacs and 1 year post-Intacs. Preoperative parameters were correlated with outcome. Uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), manifest refraction, videokeratography, and patient questionnaires. Intacs were implanted in all eyes with no intraoperative complications. Six eyes underwent additional Intacs surgery. Post-Intacs, the mean +/- SD UCVA improved from less than 20/200 +/- 0.1 line to 20/50(-3) +/- 3.1 lines, the mean +/- SD BSCVA was unchanged at 20/32 +/- 2.0 lines, the mean +/- SD spherical equivalent improved from -3.88 +/- 1.64 to -1.04 +/- 1.51 diopters (D), and the mean +/- SD astigmatism improved from 3.34 +/- 2.23 to 1.97 +/- 1.51 D. Twenty-five eyes had a good outcome (UCVA> or =20/40). Multiple regression selected BSCVA, astigmatism, and spherical myopia as the preoperative predictors of outcome. Intacs improve myopia and regular astigmatism in keratoconus. Milder keratoconus (BSCVA>20/32(-2) and astigmatism<3.50 D) and significant spherical myopia (>-1.75) predict better outcome.


Bilateral iliac vein thrombosis after seat belt-related trauma revealing hypoplasia of the inferior vena cava--a case report.
Hypoplasia of the inferior vena cava can be revealed by a deep venous thrombosis of the lower limbs. Associated precipitating factors or clotting defects leading to thrombosis are frequently observed. A case of bilateral iliac veins thrombosis occurring after a motor vehicle accident with seat belt injury is reported, revealing hypoplasia of the inferior vena cava. This young man was totally asymptomatic up to the crash, and did not have coagulation abnormalities. The patient had a very good outcome after anticoagulant treatment with complete regression of venous thromboses. Hypoplasia of the inferior vena cava was a predisposing anatomic abnormality that led to thrombosis, but seat belt trauma was probably the precipitating factor. This observation should be kept in mind in the evaluation of a deep venous lower limb thrombosis.


Evaluation of Kampo medicines used to treat rheumatoid arthritis in collagen-induced arthritic and pX transgenic mice.
Abstract To evaluate the usefulness of Kampo medicines (traditional herbal medicines) used clinically for the treatment of rheumatoid arthritis (RA), we selected eight of them and examined their effects on collagen-induced arthritic and pX transgenic mice. Among these, Dai-bofu-to, Kanzo-bushi-to, and Makyo-yokkan-to significantly reduced the severity of arthritis in collagen-induced arthritis (CIA) mice. The onset of arthritis was delayed by three Kampo medicines, but only the effect of Makyo-yokkan-to was statistically significant. In addition, three Kampo medicines suppressed the arthropathy of pX transgenic mice, which had developed spontaneously. The onset of arthritis was delayed by 10.7, 8.3, and 15.4 days following treatment with Dai-bofu-to, Kanzo-bushi-to, and Makyo-yokkan-to, respectively. A study of the underlying mechanism showed that Kanzo-bushi-to decreased serum antitype II collagen antibody levels, suggesting that Kanzo-bushi-to possesses immunomodulating activity. This study shows that some Kampo medicines are effective in an induced or spontaneously developed arthritis animal model of human RA.


Aberrant expression of MUC1 mucin in pediatric inflammatory bowel disease.
Mucin 1 (MUC1) glycoprotein is normally expressed at low levels on the luminal side of healthy colonic epithelial cells. In colon cancer and other epithelial tumors, MUC1 is overexpressed and hypoglycosylated. Antibodies specific for this "tumor form" of MUC1 are found in cancer patients. We hypothesized that MUC1 expression might be altered in chronic inflammation, such as in inflammatory bowel disease (IBD). Furthermore, we hypothesized that these alterations might induce antibody responses. The aims of this study were to characterize MUC1 expression in IBD and to examine whether pediatric patients with IBD have an MUC1-specific antibody. Colon biopsies were examined for MUC1 expression by immunochemistry using anti-MUC1 antibodies that detect normal or abnormal forms of MUC1. Sera were analyzed by Enzyme Linked Immunosorbent Assay (ELISA) for evidence of anti-MUC1 antibody. We found marked overexpression of MUC1 in IBD, most of which was hypoglycosylated. On colon specimens from healthy age-matched controls, we found low levels of luminal MUC1 and no alteration in its glycosylation. We detected antibody to MUC1 in sera of IBD patients as well as controls, and in a limited number of IBD samples examined longitudinally, we could correlate the rise and fall of antibody levels with clinical disease severity. MUC1 is overexpressed and hypoglycosylated in pediatric IBD and may play an important role in the pathogenesis of IBD, and thus warrants further study as a potential therapeutic target. Similarly, antibodies to MUC1 may influence IBD and should be explored as potential diagnostic or prognostic markers.


Structural and functional comparison of HemN to other radical SAM enzymes.
Radical SAM enzymes have only recently been recognized as an ancient family sharing an unusual radical-based reaction mechanism. This late appreciation is due to the extreme oxygen sensitivity of most radical SAM enzymes, making their characterization particularly arduous. Nevertheless, realization that the novel apposition of the established cofactors S-adenosylmethionine and [4Fe-4S] cluster creates an explosive source of catalytic radicals, the appreciation of the sheer size of this previously neglected family, and the rapid succession of three successfully solved crystal structures within a year have ensured that this family has belatedly been noted. In this review, we report the characterization of two enzymes: the established radical SAM enzyme, HemN or oxygen-independent coproporphyrinogen III oxidase from Escherichia coli, and littorine mutase, a presumed radical SAM enzyme, responsible for the conversion of littorine to hyoscyamine in plants. The enzymes are compared to other radical SAM enzymes and in particular the three reported crystal structures from this family, HemN, biotin synthase and MoaA, are discussed.


An accurate molecular structure of phenyl, the simplest aryl radical.
The phenyl radical (C6H5(·)) is the prototypical σ-type aryl radical and one of the most common aromatic building blocks for larger ring molecules. Using a combination of rotational spectroscopy of singly substituted isotopic species and vibrational corrections calculated theoretically, an extremely accurate molecular structure has been determined. Relative to benzene, the phenyl radical has a substantially larger C-Cipso-C bond angle [125.8(3)° vs. 120°], and a shorter distance [2.713(3) Å vs. 2.783(2) Å] between the ipso and para carbon atoms.


The approach to chronic cough in childhood.
Chronic cough is a fairly common pediatric complaint. Usually, it is secondary to irritation of the airways following a respiratory viral infection. In these cases, the cough tends to diminish over time. There may, however, be a subsequent development of bronchial hyperreactivity. Asthma is common in the pediatric population. From 50% to 90% of chronic coughers may have hyperreactive airways. In the absence of a pulmonary function laboratory to test for this, a trial of bronchodilator therapy is warranted. Other conditions discussed may also cause chronic cough and a thorough history and physical examination with some simple radiologic investigations can help pinpoint the cause. Specific therapy can then be used to manage the problem. In addition to specific therapy, care must be taken to explain to the parents and patient the physiology of the cough and why it is present. Anxieties and fears should be dealt with in a caring and direct manner. Occasionally, non-specific therapy is needed to allow the parents and child some rest and relief.


Restoration of active transport of solutes and oxidative phosphorylation by naphthoquinones in irradiated membrane vesicles from Mycobacterium phlei.
Irradiation of the inverted membrane vesicles of Mycobacterium phlei with light at 360 nm inactivated the natural menaquinone [MK(9)(II-H)] and resulted in a loss of substrate oxidation, pH gradient, membrane potential, active transport of proline or calcium ions, and oxidative phosphorylation. Restoration of the protonmotive force and active transport occurred on addition of naphthoquinones such as vitamin K(1), menadione, or lapachol to the irradiated membrane vesicles. However, coupled phosphorylation was restored only by vitamin K(1). Menadione and lapachol did not act as uncoupling agents. The magnitude of the pH gradient and membrane potential in the quinone-restored system was a reflection of the rate of oxidation and was correlated with the rate of uptake of proline or Ca(2+). These results are consistent with the chemosmotic hypothesis proposed for the energy transducing mechanism for active transport and further demonstrate that the complete respiratory chain is not required to drive active transport. In contrast, the data suggest that in addition to the driving force (protonmotive force) necessary to establish oxidative phosphorylation, a specific spatial orientation of the respiratory components, such as the naphthaquinones, is essential for the utilization of the proton gradient or membrane potential or both. Bypass of electrons from the respiratory chain with menadione may explain the inability of this quinone to restore oxidative phosphorylation; however, lapachol restores oxidation by the same electron transport pathway as the natural menaquinone but fails to restore phosphorylation. Because all three quinones restore the protonmotive force, other factors that are discussed must be considered in understanding the mechanism of oxidative phosphorylation.


Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period.
During pregnancy, the maternal endocrine pancreas undergoes, as a consequence of placental lactogens and prolactin (PRL) action, functional changes that are characterized by increased glucose-induced insulin secretion. After delivery, the maternal endocrine pancreas rapidly returns to non-pregnant state, which is mainly attributed to the increased serum levels of glucocorticoids (GCs). Although GCs are known to decrease insulin secretion and counteract PRL action, the mechanisms for these effects are poorly understood. We have previously demonstrated that signal transducer and activator of transcription 3 (STAT3) is increased in islets treated with PRL. In the present study, we show that STAT3 expression and serine phosphorylation are increased in pancreatic islets at the end of pregnancy (P19). STAT3 serine phosphorylation rapidly returned to basal levels 3 days after delivery (L3). The expression of the sarcoendoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2), a crucial protein involved in the regulation of calcium handling in beta-cells, was also increased in P19, returning to basal levels at L3. PRL increased SERCA2 and STAT3 expressions and STAT3 serine phosphorylation in RINm5F cells. The upregulation of SERCA2 by PRL was abolished after STAT3 knockdown. Moreover, PRL-induced STAT3 serine phosphorylation and SERCA2 expression were inhibited by dexamethasone (DEX). Insulin secretion from islets of P19 rats pre-incubated with thapsigargin and L3 rats showed a dramatic suppression of first phase of insulin release. The present results indicate that PRL regulates SERCA2 expression by a STAT3-dependent mechanism. PRL effect is counteracted by DEX and might contribute to the adaptation of maternal endocrine pancreas during the peripartum period.


Effects of practice on recognition memory of mildly mentally retarded adults.
The effect of practice on recognition memory of mildly mentally retarded adults was investigated in two experiments using the Sternberg (1969) memory scanning paradigm. In Experiment 1, the slope and zero intercept for item-recognition functions under both fixed- and varied-set procedures decreased over seven sessions of practice among retarded adults and nonretarded children, remaining relatively constant among nonretarded adults. Because performance of only retarded subjects had not yet reached asymptote, Experiment 2 provided these subjects with additional practice at the same task (varied-set procedure only). After extended practice, slopes in the retarded group were near those for both nonretarded groups; therefore, although the generally poorer performance of retarded adults in this task may reflect some structural impairment, the initial level of deficiency is reduced by practice.


Nephrotic syndrome associated with Schistosoma mansoni infection.
A case of nephrotic syndrome in which Schistosoma mansoni infection associated with membranoproliferative glomerulonephritis type 1 is reported. In endemic areas glomerulopathy secondary to Schistosoma mansoni has been described. Although not commonly seen in mainland United States, Schistosoma mansoni infection should be considered in the differential diagnosis of proteinuria in persons who have visited or are from endemic regions.


Prostate Cancer Screening in a New Era of Genetics.
Men who inherit pathogenic germline mutations in BRCA2 and BRCA1 are at increased risk of developing aggressive prostate cancer, and those with germline mutations in other DNA repair genes such as ATM, CHEK2, and MSH2/MSH6 may also have increased risks. Although clinically important, there is lack of specific guidance regarding management strategies for men at increased risk owing to germline mutation status or family history of aggressive prostate cancer. We review prostate cancer genetic risk factors and the ongoing IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) screening study. Pending results of IMPACT and unified guidelines, there are areas of uncertainty and need for further study. Ongoing and future research will be critical for optimizing prostate cancer screening approaches for men at the highest risk for aggressive prostate cancer. In the interim, we propose a practical approach to prostate cancer screening for men with a germline mutation in a known/suspected moderate to high-penetrance cancer predisposition gene (eg, BRCA1/2), and/or men with a first- or second-degree relative with metastatic prostate cancer (regardless of genetic testing): baseline prostate-specific antigen and digital rectal exam by experienced providers at age 40 years or 5 years earlier than age of diagnosis of the youngest first- or second-degree relative with metastatic prostate cancer, whichever is earlier. Then, based on age, digital rectal exam, and prostate-specific antigen, we suggest consideration of magnetic resonance imaging, biopsy, and/or continued monitoring.


Effect of increasing levels of threonine relative to lysine on the performance and meat quality of finishing pigs.
The present study aimed to evaluate the effects of varying standardized ileal digestible lysine:threonine (SID Lys:Thr) ratio in the diet on the performance and meat quality of finishing pigs. In total 192 crossbred pigs ([Landrace×Yorkshire]×Duroc, 17 weeks old), with an initial body weight (BW) of 70.6±3.9 kg were used in an 8-wk trial. Pigs were randomly allotted to one of six dietary treatments based on their initial BW and sex (8 replications; 4 pigs per pen, 2 barrows and 2 gilts). The pigs in the 6 treatments were fed diets having different SID Lys:Thr ratios such as 1:0.65, 1:0.66, 1:0.67, 1:0.68, 1:0.69, and 1:0.70. A linear increment (p<0.05) in average daily gain (ADG) and trends in reduction in feed conversion ratio (FCR) were observed during day 29 to 56 of the experiment and the apparent total tract digestibility (ATTD) of dry matter tended to increase linearly (p = 0.094) at the end of the experiment (day 56) with the increase in the dietary SID Lys:Thr ratios. The backfat thickness and lean percentage increased (linear effect, p<0.05) on day 28. In addition, at day 56, a linear (p<0.05) increment in lean percentage was observed. Significant quadratic responses (p = 0.02) for pH and drip loss at day 7 (p = 0.02), a linear increase (p<0.05) in cooking loss and drip loss at day 7, and a trend in quadratic response (p = 0.07) in the lightness of meat color (L*) were observed, whereas other meat quality indices were unaffected by varying the SID Lys:Thr ratios. The SID Lys:Thr ratio for maximum ADG, minimum FCR and enhanced digestibility was found to be 0.70. However, for carcass trait and meat quality, the SID Lys:Thr ratio of 0.65 was enough.


Anesthetic efficacy of lidocaine/meperidine for inferior alveolar nerve blocks.
The authors, using a crossover design, randomly administered, in a single-blind manner, inferior alveolar nerve blocks using 36 mg of lidocaine with 18 microg of epinephrine or a combination of 36 mg of lidocaine with 18 microg epinephrine plus 36 mg meperidine with 18 microg of epinephrine, at 2 separate appointments, to 52 subjects. An electric pulp tester was used to test for anesthesia, in 4-minute cycles for 60 minutes, of the molars, premolars, and central and lateral incisors. Anesthesia was considered successful when 2 consecutive 80 readings were obtained within 15 minutes and the 80 reading was continuously sustained for 60 minutes. Using the lidocaine solution, successful pulpal anesthesia ranged from 8 to 58% from the central incisor to the second molar. Using the lidocaine/meperidine solution, successful pulpal anesthesia ranged from 0 to 17%. There was a significant difference (P < .05) between the lidocaine and lidocaine/meperidine solutions for the lateral incisors through the second molars. We conclude that the addition of meperidine to a standard lidocaine solution does not increase the success of the inferior alveolar nerve block.


Pancreatic enzyme stimulation of intestinal chloride secretion.
Mucosal addition of pancreatic enzymes (i.e., chymotrypsinogen and amylase) to a short-circuited Ussing chamber containing a section of stripped rabbit ileum greatly increases short-circuit current (SCC). SCC increases slowly, requiring several hours to reach peak response to enzyme addition. Serosal addition of enzyme or mucosal addition of albumin produces no such response. Chloride flux in the absence of enzyme conforms to behavior predicted for predominantly paracellular movement. Chymotrypsinogen in the mucosal bath augments serosal-to-mucosal chloride flux in a manner consistent with an intracellular pathway. The chloride secretion produced by enzyme addition is of similar magnitude to the additional increment in SCC.


Blood lactate levels during cardiopulmonary bypass for valvular heart surgery.
Cardiopulmonary bypass (CPB) is widely used to maintain systemic perfusion and oxygenation during open-heart surgery. Tissue hypoperfusion with resultant lactic acidosis during CPB, may occur during hypothermia, extreme haemodilution, low flow CPB, and excessive neurohormonal activation. There has been no documentation of the correlation between blood lactate level elevations in the perioperative period, and its relation to preoperative New York Heart Association (NYHA) classification and the use of ionotropic support during weaning from CPB, duration of postoperative ventilatory support and perioperative mortality. We studied the perioperative blood lactate levels in 82 patients undergoing valvular heart surgery. Arterial blood samples were collected at different stages of CPB. The observed mean baseline lactate levels were 1.9+/-0.8 mmol/L (normal range of 0.9 to 1.7 mmol/L). The mean circulating lactate levels at 15 min and 45 min after institution of CPB increased to 7.01+/-2.6 mmol/L and 9.92+/-3.5 mmol/L. A progressive decline in the mean lactate level, was seen during rewarming (at 35 degrees C), immediately off-bypass, 24 hours and 48 hours postoperatively with mean lactate levels being 7.01+/-3.2 mmol/L, 4.75+/-1.01 mmol/L, 3.06+/-1.1 mmol/L, and 2.10+/-1.05 mmol/L respectively. Comparison of mean lactate levels in NYHA class I, II, III, and IV patients showed that in the intraoperative period and immediately after CPB, the elevation in lactate levels were statistically significant (p< 0.001) in patients in NYHA Class IV. However the values, in all classes, were similar at 24 and 48 hours after CPB. Also, patients with lactate levels >4 mmol/ L required prolonged inotropic and ventilatory support.


MR angiography of the thoracic aorta.
MR angiography is a powerful tool in evaluating the complete spectrum of congenital and acquired diseases of the thoracic aorta. The use of gadolinium-chelates in conjunction with rapid three-dimensional sequences performed with breath holding provides robust image quality with multiple display options. As a result of technological advances in hardware, software, and pulse sequence implementation combined with innovative use of contrast agents, MR angiography is poised to replace conventional catheter angiography of the thoracic aorta for many indications.


The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits.
Diabetes encompasses a heterogeneous group of diseases, each with a substantial genetic component. We review the division of diabetes into different subtypes based on clinical phenotype, the fruitful pursuit of genes underlying monogenic forms of the disease, the successes and drawbacks of whole-genome linkage scans in type 1 and type 2 diabetes, and the recent identification of several diabetes genes by large association studies. We use the lessons learned from this extensive body of evidence to illustrate general implications for the genetic analysis of complex traits.


Genomic amplification of HPV, h-TERC and c-MYC in liquid-based cytological specimens for screening of cervical intraepithelial neoplasia and cancer.
Cervical cancer is one of the most prevalent female cancer types in developing countries. ThinPrep cytological test (TCT) and human papillomavirus (HPV) detection are canonical screening methods for cervical cancer currently. However, there are limitations to these techniques. The aim of the present study was to identify efficient and practical methods for the screening of cervical intraepithelial neoplasia (CIN) and carcinoma. Residual PreservCyt specimens were obtained from 1,000 women who were admitted between August 2013 and December 2015. TCT, human telomerase RNA component (h-TERC) fluorescent in situ hybridization (FISH), MYC-specific FISH and surface plasmon resonance (SPR)-HPV genotyping were performed, followed by histopathology for those patients with positive results in any of the four tests. As a result, 106, 64, 56 and 112 patients were positive in the TCT, h-TERC, c-MYC and SPR-HPV tests, respectively, resulting in 213 being scheduled for histopathology; inflammation was identified in 159 patients, CIN I in 31, CIN II in 14, CIN III in seven and invasive cervical cancer in two patients. Using histopathology as the gold standard, TCT exhibited the highest sensitivity (87.04%), while h-TERC analysis had the highest specificity (81.76%). Parallel tests demonstrated that the Youden's index of TCT + h-TERC was the highest (0.49), while the serial analysis reported that TCT + HPV had the highest Youden's index (0.53) compared with any of the biomarkers alone (TCT, 0.50; HPV, 0.29; h-TERC, 0.47). In conclusion, dual positive TCT and HPV may be an efficient approach for basic screening of cervical lesions. h-TERC amplification may serve as an auxiliary test to improve the specificity.


A novel small molecule compound possesses immunomodulatory properties on bone marrow-derived dendritic cells via TLR7 signaling pathway and alleviates the development of SLE.
Dendritic cells (DCs) play an important role in the development and maintenance of immune tolerance. Activation of TLR7, which is expressed in DCs, is thought to contribute to the complex pathophysiology of systemic lupus erythematosus (SLE). In this study, we analyzed the in vitro and in vivo function of a novel small-molecule compound, FC-99, which was previously reported to have immunomodulatory functions. We found that FC-99 inhibited the expression of CD40 and inflammatory mediators (IL-6, IL-12, and CXCL-10), as well as R848-induced phosphorylation of IκB-α. We also present evidence that FC-99 is remarkably efficacious in the treatment of murine lupus. Interestingly, FC-99 affected the maturation and percentage of DCs in lupus-prone mice. Therefore, FC-99 may serve as a potential drug candidate for treatment of SLE.


Volumetric determination of apolipoprotein stoichiometry of circulating HDL subspecies.
Although HDL is inversely correlated with coronary heart disease, elevated HDL-cholesterol is not always protective. Additionally, HDL has biological functions that transcend any antiatherogenic role: shotgun proteomics show that HDL particles contain 84 proteins (latest count), many correlating with antioxidant and anti-inflammatory properties of HDL. ApoA-I has been suggested to serve as a platform for the assembly of these protein components on HDL with specific functions - the HDL proteome. However, the stoichiometry of apoA-I in HDL subspecies is poorly understood. Here we use a combination of immunoaffinity chromatography data and volumetric analysis to evaluate the size and stoichiometry of LpA-I and LpA-I,A-II particles. We conclude that there are three major LpA-I subspecies: two major particles, HDL[4] in the HDL3 size range (d = 85.0 ± 1.2 Å) and HDL[7] in the HDL2 size range (d = 108.5 ± 3.8 Å) with apoA-I stoichiometries of 3 and 4, respectively, and a small minor particle, HDL[1] (d = 73.8 ± 2.1Å) with an apoA-I stoichiometry of 2. Additionally, we conclude that the molar ratio of apolipoprotein to surface lipid is significantly higher in circulating HDL subspecies than in reconstituted spherical HDL particles, presumably reflecting a lack of phospholipid transfer protein in reconstitution protocols.


Modeling of flow in a straight stented and nonstented side wall aneurysm model.
We investigated the changes of flow patterns in a blood vessel with a side wall aneurysm resulting from placement of a stent. Local hemodynamics can be markedly altered by placing an intravascular stent, which covers the orifice of the aneurysm. The alternations in flow patterns can lead to flow stasis in the aneurysmal pouch and promote the formation of a stable thrombus. Furthermore, a porous stent can serve as substrate for neointimal growth and subsequently induce a remodeling of the diseased arterial segment. To examine changes in local hemodynamics due to stent placement, a stented and nonstented aneurysm model was investigated computationally in a three-dimensional configuration using a finite element fluid dynamics program. The finite element model was studied under incompressible, pulsatile, viscous, Newtonian conditions. The fluid dynamic similarity parameter, i.e., the maximum/minimum Reynolds number, was set at about 240/25 based on cross-sectional average instantaneous flow. The Womersley number was set to 2.5. These values are representative of large cerebral arteries. The results of the stented versus the nonstented model show substantial difference sin flow patterns inside the aneurysmal pouch. Flow activity inside the stented aneurysm model is significantly diminished and flow inside the parent vessel is less undulated and is directed past the orifice. A high-pressure zone at the distal neck and the dome of the aneurysm prior to stenting decreases after stent placement. However, elevated pressure values are found at the stent filaments facing the current. Higher shear rates are observed at the distal aneurysmal neck after stenting, but are confined to a smaller region and are unidirectional compared to the nonstented model.


Molecular characterization of the hydroxylase HmtN at 1.3 Å resolution.
Himastatin is a novel antibiotic with antitumor and antibacterial activity. In the himastatin biosynthesis pathway, HmtN is responsible for the hydroxylation of the piperazic acid (Pip) motif. Herein, we present the crystal structures of HmtN (1.3 Å), which is the first structure for a cytochrome P450 involved in the hydroxylation of cyclohexadepsipeptide during himastatin biosynthesis. Structure analysis indicated that almost all the surface of HmtN has negative electrostatic potential, only small patches of positive electrostatic potential can be found. It is worth noting that almost the entire active site of HmtT is negatively charged, while HmtN active site is composed of positive and negative charge. This may be relevant to their specific substrate recognition and different catalytic function. In addition, three channels were observed in HmtN crystal structure; channel 3 may be essential for substrate ingress and egress from the active site to the surface, while channel 1 and channel 2 may be the solvent and water pathway, respectively.


Task performance with visual acuity while wearing a respiratory mask.
Forty-six subjects were required to perform a console-monitoring and two hand-eye coordination tasks while wearing masks with lenses clouded to give seven levels of visual acuity. The console-monitoring task performance was found to be the most sensitive to visual acuity, followed by the random hand-eye coordination task. These results can be used to help predict performance degradation when lenses become clouded due to condensation or particulate deposition.


Clinical spectrum and pleiotropic nature of CDH1 germline mutations.
CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer-the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype-phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin's pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.


Femtosecond laser fabrication of volume-phase gratings in CdSxSe1-x-doped borosilicate glass at a low repetition rate.
Volume-phase gratings (VPGs) were fabricated in CdSxSe1-x quantum-dot-doped borosilicate glass at a low repetition rate (800 nm, 140 fs, 1 kHz). The VPGs were designed based on rigorous coupled wave analysis simulations. Results indicate that the inscribed thickness (L) is the key parameter to maximize the diffraction efficiency at order 1. Microscope images of the cross sections and diffraction efficiency measurements were taken in order to characterize the modification of the material at different laser-inscription parameters. A maximum VPG diffraction efficiency of 67% (at order 1) was achieved. Also, a refractive index change of Δn=2.25·10-3 is estimated from these VPG diffraction efficiency measurements. The measurements regarding polarization-insensitive diffraction efficiency showed that the birefringence produced in the substrate is negligible.


Efficacy and short-term outcomes of preoperative chemoradiotherapy with intermittent oral tegafur-uracil plus leucovorin in Japanese rectal cancer patients: a single center experience retrospective analysis.
Various types of preoperative chemoradiotherapy (CRT) have been established for rectal cancer; thus, Physicians will need to refine the selection of appropriate preoperative CRT for different patients since there are various treatment regimens. Oral tegafur-uracil (UFT) plus leucovorin (LV) is commonly used to treat rectal cancer in Japan. Oral chemotherapy offers patients many potential advantages. Since 2008, we have been performing preoperative CRT with intermittent oral UFT plus LV in locally advanced rectal cancer patients to prevent postoperative local recurrence. Here, in a retrospective analysis, we evaluated the efficacy and short-term outcomes of preoperative CRT with intermittent oral UFT plus LV. We analyzed data from 62 patients with locally advanced rectal cancer, including 31 patients who underwent preoperative CRT between 2009 and 2013 (the CRT group) and 31 patients who were treated with surgery alone between 2001 and 2008 (the non-CRT group). Clinicopathologically, both groups included patients with rectal cancer at clinical tumor stages III-IV or clinical node stages 0-III. In the CRT group, curative operations were performed ≥8 weeks after CRT. Patients were concomitantly treated with 2 cycles of oral UFT (300 mg/m2/day, days 1-14 and 29-42) plus LV (75 mg/day, days 1-14 and 29-42) and 45 Gy of radiotherapy. Chemotherapy was repeated every 28 days, followed by a 2-week break. The completion rate of CRT was high at 94% (n = 29/31). The downstaging rate of CRT was 61% (n = 19/31). The pathological complete response rate was 6.5% (n = 2/31). Significant differences were observed in the 3-year local recurrence rate between the two groups (P < 0.05). Preoperative CRT with intermittent oral UFT plus LV appears to be a tolerable and effective treatment for Japanese patients with rectal cancer. A further investigation of a diversification of preoperative CRT for Japanese rectal cancer patients is required.


The association between chronic airflow obstruction and poverty in 12 sites of the multinational BOLD study.
Poverty is strongly associated with mortality from COPD, but little is known of its relation to airflow obstruction.In a cross-sectional study of adults aged ≥40 years from 12 sites (N=9255), participating in the Burden of Obstructive Lung Disease (BOLD) study, poverty was evaluated using a wealth score (0-10) based on household assets. Obstruction, measured as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) (%) after administration of 200 μg salbutamol, and prevalence of FEV1/FVC<lower limit of normal were tested for association with poverty for each site, and the results were combined by meta-analysis.Mean wealth scores ranged from 4 in Blantyre (Malawi) and Kashmir (India) to 10 in Riyadh (Saudi Arabia), and the prevalence of obstruction, from 16% in Kashmir to 3% in Riyadh and Penang (Malaysia). Following adjustments for age and sex, FEV1/FVC increased by 0.36% (absolute change) (95%CI: 0.22, 0.49; p<0.001) per unit increase in wealth score. Adjustments for other confounders reduced this effect to 0.23% (0.11, 0.34), but even this value remained highly significant (p<0.001). Results were consistent across sites (I2=1%; phet=0.44). Mean wealth scores explained 38% of the variation in mean FEV1/FVC between sites (r2=0.385, p=0.031).Airflow obstruction is consistently associated with poverty at individual and community levels across several countries.


Biomarkers of Brain Damage and Postoperative Cognitive Disorders in Orthopedic Patients: An Update.
The incidence of postoperative cognitive dysfunction (POCD) in orthopedic patients varies from 16% to 45%, although it can be as high as 72%. As a consequence, the hospitalization time of patients who developed POCD was longer, the outcome and quality of life were worsened, and prolonged medical and social assistance were necessary. In this review the short description of such biomarkers of brain damage as the S100B protein, NSE, GFAP, Tau protein, metalloproteinases, ubiquitin C terminal hydrolase, microtubule-associated protein, myelin basic protein, α-II spectrin breakdown products, and microRNA was made. The role of thromboembolic material in the development of cognitive decline was also discussed. Special attention was paid to optimization of surgical and anesthetic procedures in the prevention of postoperative cognitive decline.


THE CONTROVERSIAL AND DYNAMIC OVARY.
The ovaries from 75 females ranging in age from the newborn to 96 years were subjected to histologic scrutiny. Ageing phenomena comprising the gonad's life-long metamorphosis were documented. The cause of menopausal ovarian failure is twofold: (1) Ovarian vessel wall thickening and hyalinization as the cardiovascular system ages reduces perfusion of the gonad. (The blood supply of the ovaries is well designed to permit mobility but longevity of function is sacrificed.) (2) Gradual replacement of egg- and hormone-producing cells by fibrous tissue. This scar tissue accumulates as a result of ovulation and pregnancy and is less efficiently removed from the ovary in the later fertile years. By inhibiting ovulation, the oral contraceptives will likely delay the natural senescence of the ovary. More basic research is indicated to elucidate the mechanism of oogenesis.


Hemoglobin variant (hemoglobin Aalborg) mimicking interstitial pulmonary disease.
Hemoglobin Aalborg is a moderately unstable hemoglobin variant with no affiliation to serious hematological abnormality or major clinical symptoms under normal circumstances. Our index person was a healthy woman of 58, not previously diagnosed with hemoglobinopathy Aalborg, who developed acute respiratory failure after a routine cholecystectomy. Initially she was suspected of idiopathic interstitial lung disease, yet a series of tests uncovered various abnormal physiological parameters and set the diagnosis of hemoglobinopathy Aalborg. This led us to examine a group of the index person's relatives known with hemoglobinopathy Aalborg in order to study whether the same physiological abnormalities would be reencountered. They were all subjected to spirometry and body plethysmography, six-minute walking test, pulse oximetry, and arterial blood gas samples before and after the walking test. The entire study population presented the same physiological anomalies: reduction in diffusion capacity, and abnormalities in P(a)O2 and p50 values; the latter could not be presented by the arterial blood gas analyzer; furthermore there was concordance between pulse oximetry and arterial blood gas samples regarding saturation. These data suggest that, based upon the above mentioned anomalies in physiological parameters, the diagnosis of hemoglobinopathy Aalborg should be considered.


Antiviral activity of benzimidazole derivatives. II. Antiviral activity of 2-phenylbenzimidazole derivatives.
Seventy-six 2-phenylbenzimidazole derivatives were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. The most commonly affected viruses were, in decreasing order, CVB-2, BVDV, Sb-1, HSV-1, and YFV, while HIV-1 and VSV were not affected, and RSV, VV and Reo-1 were only susceptible to a few compounds. Thirty-nine compounds exhibited high activity (EC(50)=0.1-10microM) against at least one virus, and four of them were outstanding for their high and selective activity against VV (24, EC(50)=0.1microM) and BVDV (50, 51, and 53 with EC(50)=1.5, 0.8, and 1.0microM, respectively). The last compounds inhibited at low micromolar concentrations the NS5B RdRp of BVDV and also of HCV, the latter sharing structural similarity with the former. The considered compounds represent attractive leads for the development of antiviral agents against poxviruses, pestiviruses and even HCV, which are important human and veterinary pathogens.


Development of an internally braced prosthesis for total talus replacement.
Total loss of talus due to trauma or avascular necrosis, for example, still remains to be a major challenge in foot and ankle surgery with severely limited treatment options. Implantation of a custom made total talar prosthesis has shown promising results so far. Most important factors for long time success are degree of congruence of articular surfaces and ligamentous stability of the ankle. Therefore, our aim was to develop an optimized custom made prosthesis for total talus replacement providing a high level of primary stability. A custom made hemiprosthesis was developed using computed tomography and magnetic resonance imaging data of the affected and contralateral talus considering the principles and technology for the development of the S.T.A.R. prosthesis (Stryker). Additionally, four eyelets for fixation of artificial ligaments were added at the correspondent footprints of the most important ligaments. Two modifications can be provided according to the clinical requirements: A tri-articular hemiprosthesis or a bi-articular hemiprosthesis combined with the tibial component of the S.T.A.R. total ankle replacement system. A feasibility study was performed using a fresh frozen human cadaver. Maximum range of motion of the ankle was measured and ligamentous stability was evaluated by use of standard X-rays after application of varus, valgus or sagittal stress with 150 N. Correct implantation of the prosthesis was technically possible via an anterior approach to the ankle and using standard instruments. Malleolar osteotomies were not required. Maximum ankle dorsiflexion and plantarflexion were measured as 22-0-28 degrees. Maximum anterior displacement of the talus was 6 mm, maximum varus tilt 3 degrees and maximum valgus tilt 2 degrees. Application of an internally braced prosthesis for total talus replacement in humans is technically feasible and might be a reasonable procedure in carefully selected cases with no better alternatives left.


NlpD links cell wall remodeling and outer membrane invagination during cytokinesis in Escherichia coli.
Cytokinesis in gram-negative bacteria requires the constriction of all three cell envelope layers: the inner membrane (IM), the peptidoglycan (PG) cell wall and the outer membrane (OM). In order to avoid potentially lethal breaches in cell integrity, this dramatic reshaping of the cell surface requires tight coordination of the different envelope remodeling activities of the cytokinetic ring. However, the mechanisms responsible for this coordination remain poorly defined. One of the few characterized regulatory points in the envelope remodeling process is the activation of cell wall hydrolytic enzymes called amidases. These enzymes split cell wall material shared by developing daughter cells to facilitate their eventual separation. In Escherichia coli, amidase activity requires stimulation by one of two partially redundant activators: EnvC, which is associated with the IM, and NlpD, a lipoprotein anchored in the OM. Here, we investigate the regulation of amidase activation by NlpD. Structure-function analysis revealed that the OM localization of NlpD is critical for regulating its amidase activation activity. To identify additional factors involved in the NlpD cell separation pathway, we also developed a genetic screen using a flow cytometry-based enrichment procedure. This strategy allowed us to isolate mutants that form long chains of unseparated cells specifically when the redundant EnvC pathway is inactivated. The screen implicated the Tol-Pal system and YraP in NlpD activation. The Tol-Pal system is thought to promote OM invagination at the division site. YraP is a conserved protein of unknown function that we have identified as a new OM-localized component of the cytokinetic ring. Overall, our results support a model in which OM and PG remodeling events at the division site are coordinated in part through the coupling of NlpD activation with OM invagination.


Characteristics of Finger Tapping Are Not Affected by Heavy Strength Training.
The authors investigated the effects of 2 weeks of heavy index finger strength training on characteristics of freely chosen finger tapping including tapping frequency, tap force, and finger displacement. One group (n = 12) performed index finger extension and flexion strength training. A control group (n = 12) performed no intervention. Results showed that the training group increased strength in both extension (19.5 ± 22.2%, p = .015) and flexion (9.4 ± 9.8%, p = .001) from pretest to posttest. Furthermore, training did not affect the frequency and the pattern of the tapping movement (Fs = 0.004-3.441, ps = .077-.954). The present results are in contrast to previous findings of reduced movement frequency and altered movement pattern during ergometer pedaling after strength training. This difference may be explained by the dissimilarity between the 2 tasks.