Pregabalin: a new neuromodulator with broad therapeutic indications.
To review pregabalin's pharmacology, pharmacokinetics, efficacy, and adverse effects in the treatment of neuropathic pain, epilepsy, and anxiety. A MEDLINE search (1993-October 2005) for peer-reviewed English-language publications was performed. Abstracts from professional meetings were also included. Key terms were anxiety, diabetic neuropathy, epilepsy, neuropathic pain, postherpetic neuralgia, pregabalin, and seizures. Basic pharmacology data were extracted from animal studies; pharmacokinetic data were extracted from human studies. Multicenter, double-blind, placebo-controlled, parallel-group studies were included to describe the efficacy and adverse effects of pregabalin. Pregabalin is a new agent that exerts its pharmacodynamic effect by modulating voltage-gated calcium channels. Pregabalin has a linear pharmacokinetic profile. It is completely absorbed, not bound to plasma proteins, not metabolized, and eliminated unchanged through the kidneys. Doses must be adjusted in patients with renal insufficiency. Clinical trials showed that pregabalin is effective in neuropathic pain associated with postherpetic neuralgia, diabetic peripheral neuropathy, in partial epilepsy as adjunctive therapy, and in generalized and social anxiety disorders. The most common adverse effects were dizziness and somnolence. Few serious adverse effects were reported. Pregabalin should not be discontinued rapidly. Pregabalin is an effective and safe analgesic, antiepileptic, and anxiolytic medicine. It will provide a new treatment option for patients with neuropathic pain and partial epilepsy.


[Gerontology and endocrinology at the beginning of the 20th century: Dr. Voronoff (1866-1951)].
Rejuvenation by monkey testicle transplanting was terribly fashionable in Paris, between years 1925-1930. The manual miracles done by a group of very well-known surgeons, in Paris, (especially Serge Voronoff and Dartigues) rooted in the head of a too credulous public the idea according to it was possible to be made scientifically younger by genital graftings. The "Etude sur la vieillesse et la rajeunissement par la greffe" (1926), written by Voronoff, provided the clinical, histological and iconographical proofs of a such rejuvenation. The paper analyses that was put forward as "proofs", situated in the scientific and cultural context of the time. A possible link between youth, sexual vigour and animality sends back to a mythic history of gerontology and endocrinology, two medical fields which however became scientific specialties in the beginning of the twentieth century.


Age-friendly neighbourhoods and depression among older people in China: Evidence from China Family Panel Studies.
Older population with depression symptoms reached about 64 million in China. Under the World Health Organization's (WHO) age-friendly communities framework, this study explored relationships between neighbourhood environment characteristics and depressive symptoms among community-dwelling older adults in China. Data were obtained from the China Family Panel Studies (CFPS), a national multi-stage probability sample in China. The final analytic sample comprised 5,641 older adults in China. Neighbourhood environment characteristics were measured in three ways: objective facilities, interviewers' evaluation, and respondents' own perceptions on the neighbourhood environment. Depressive symptoms were measured by the 20-item version of the Center for Epidemiologic Studies Depression Scale (CES-D). Multilevel regression models were applied. Neighbourhoods with more exercise and recreational facilities, better interviewers' evaluations, and better objective respondents' perceptions on neighbourhood environment at a neighbourhood level were significantly negatively associated with depressive symptoms, but these association were influenced by respondents' demographic characteristics, socioeconomic status and respondents' own perceptions of neighbourhood environment at the individual level. On the other hand, respondents' subjective positive perceptions of neighbourhood environment at the individual level were also significantly negatively associated with depressive symptoms. The actual conditions of affordability, accessibility and utilization of public facilities and social services within neighbourhoods were not known. This research extended the current knowledge of the associations between neighbourhoods and mental health among older adults, to promote ageing in place in China. Great importance should be attached to the improvement of both physical and social aspects of the neighbourhoods to develop age-friendly communities.


Change in urinary markers of osteoclast activity following palliative radiotherapy for bone metastases.
To examine the effect of radiotherapy for bone metastases on urinary markers of osteoclast activity. Patients with radiological evidence of bone metastases planned for palliative radiotherapy were eligible for the study. A urine specimen was collected before and 1 month after radiotherapy to assess levels of calcium, creatinine, magnesium, phosphate, N-telopeptide and pyridinoline. The Brief Pain Inventory was completed in person at baseline and by telephone follow-up at 1 month after radiotherapy. Patients were classified as responders (complete or partial pain response) or non-responders (stable or progressive pain) to radiotherapy based on the International Bone Metastases Consensus Criteria for end point measurements. Absolute values of urine markers were compared between responders and non-responders, or between responders and patients with progression. Our study population consisted of 74 men and 51 women. A single 8 Gy or 20 Gy in five daily fractions were commonly employed. At the 1 month follow-up, all Brief Pain Inventory functional interference scores showed a highly significant decrease from baseline (P<0.01). From our study population, 58 (64%) were classified as responders and 57 (46%) as non-responders to radiotherapy. We compared the urinary markers between the responders and the non-responders. There were no statistically significant differences between the two groups either in terms of baseline markers or in terms of month 1 follow-up markers. There was no significant change from baseline to the 1 month follow-up in responders or in non-responders to radiotherapy. Baseline levels of urinary markers could not predict which patient would benefit from palliative radiotherapy.


Characterization of butyrate-metabolism in colorectal cancer to guide clinical treatment.
Colorectal cancer (CRC) is the third most prevalent one in the world among the most common malignant tumors. Numerous studies have shown that butyrate has demonstrated promise as an antitumor agent in a variety of human cancer types. However, butyrate remains understudied in CRC tumorigenesis and progression. In this study, we explored therapeutic strategies to treat CRC by examining the role of butyrate metabolism. First, from the Molecular Signature Database (MSigDB), we identified 348 butyrate metabolism-related genes (BMRGs). Next, we downloaded 473 CRC and 41 standard colorectal tissue samples from The Cancer Genome Atlas (TCGA) database and the transcriptome data of GSE39582 dataset from Gene Expression Omnibus (GEO) database. Then we evaluated the expression patterns of butyrate metabolism-related genes with difference analysis in CRC. Through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analysis, a prognostic model was constructed based on differentially expressed BMRGs. In addition, we discovered an independent prognostic marker for CRC patients. According to the expression levels and coefficients of identified BMRGs, the risk scores of all CRC samples were calculated. Utilizing differentially expressed genes in the high- and low-risk groups, we also constructed a Protein-Protein Interaction (PPI) network to visualize the interactions between proteins. Through the results of PPI network, we screened out differentially expressed target butyrate metabolism-related genes from ten hub genes. Finally, we performed clinical correlation analysis, immune cell infiltration analysis, and mutation analysis for these target genes. One hundred and seventy three differentially expressed butyrate metabolism-related genes were screened out in all the CRC samples. The prognostic model was established with univariate Cox regression and LASSO regression analysis. CRC patients' overall survival was significantly lower in the high-risk group than in the low-risk group for both training and validation set. Among the ten hub genes identified from the PPI network, four target butyrate metabolism-related genes were identified containing FN1, SERPINE1, THBS2, and COMP, which might provide novel markers or targets for treating CRC patients. Eighteen butyrate metabolism-related genes were used to develop a risk prognostic model that could be helpful for doctors to predict CRC patients' survival rate. Using this model, it is beneficial to forecast the response of CRC patients to immunotherapy and chemotherapy, thus making it easier to custom tailor cancer chemotherapy and immunotherapy to the individual patient.


Genome-wide association and transcriptome studies identify candidate genes and pathways for feed conversion ratio in pigs.
The feed conversion ratio (FCR) is an important productive trait that greatly affects profits in the pig industry. Elucidating the genetic mechanisms underpinning FCR may promote more efficient improvement of FCR through artificial selection. In this study, we integrated a genome-wide association study (GWAS) with transcriptome analyses of different tissues in Yorkshire pigs (YY) with the aim of identifying key genes and signalling pathways associated with FCR. A total of 61 significant single nucleotide polymorphisms (SNPs) were detected by GWAS in YY. All of these SNPs were located on porcine chromosome (SSC) 5, and the covered region was considered a quantitative trait locus (QTL) region for FCR. Some genes distributed around these significant SNPs were considered as candidates for regulating FCR, including TPH2, FAR2, IRAK3, YARS2, GRIP1, FRS2, CNOT2 and TRHDE. According to transcriptome analyses in the hypothalamus, TPH2 exhibits the potential to regulate intestinal motility through serotonergic synapse and oxytocin signalling pathways. In addition, GRIP1 may be involved in glutamatergic and GABAergic signalling pathways, which regulate FCR by affecting appetite in pigs. Moreover, GRIP1, FRS2, CNOT2, and TRHDE may regulate metabolism in various tissues through a thyroid hormone signalling pathway. Based on the results from GWAS and transcriptome analyses, the TPH2, GRIP1, FRS2, TRHDE, and CNOT2 genes were considered candidate genes for regulating FCR in Yorkshire pigs. These findings improve the understanding of the genetic mechanisms of FCR and may help optimize the design of breeding schemes.


Granulocyte-macrophage colony-stimulating factor and the immune system.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional cytokine currently used for the reversal of neutropenia associated with cytotoxic chemotherapy, bone marrow and haemopoietic stem cell transplantation. GM-CSF also modulates the function of differentiated white blood cells. In the context of local inflammatory responses, GM-CSF stimulates macrophages for antimicrobial and antitumor effects. GM-CSF further enhances healing and repair by its actions on fibroblasts and epidermal cells. GM-CSF is the pivotal mediator of the maturation and function of dendritic cells, the most important cell type for the induction of primary T cell immune responses. GM-CSF may enhance antibody dependent cellular cytotoxicity (ADCC) in several cell types, and the generation and cytotoxicity of natural killer (NK) cells. On this basis, GM-CSF may be useful for inducing or augmenting antibody responses to antimicrobial vaccines, to enhance killing of intracellular microorganisms, to accelerate epidermal and mucosal wound healing, and to stimulate protective immunity against tumors.


Mitophagy mechanisms in neuronal physiology and pathology during ageing.
Ageing in diverse species ranging from the simple nematode Caenorhabditis elegans to humans is associated with a marked decrease of neuronal function and increased susceptibility to neurodegeneration. Accumulating findings also indicate that alterations in neuronal functionality with age are associated with a decline in mitochondrial integrity and function. The rate at which a mitochondrial population is refreshed is determined by the coordination of mitochondrial biogenesis with mitophagy, a selective type of autophagy targeting damaged or superfluous mitochondria for degradation. Coupling of these opposing processes is crucial for maintaining cellular energy homeostasis, which eventually contributes to health span. Here, we focus on the role of mitophagy in nervous system function in the context of normal physiology and disease. First, we consider the progress that has been made over the last decade in elucidating the mechanisms that govern and regulate mitophagy, placing emphasis on the PINK1/Parkin-mediated mitophagy. We further discuss the contribution of mitophagy to the maintenance of neuronal homeostasis and health as well as recent findings implicating impaired mitophagy in age-related decline of the nervous system function and consequently in the pathogenesis of neurodegenerative diseases.


Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting.
Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system afflicting nearly three million individuals worldwide. Neuroimmune interactions between glial, neural, and immune cells play important roles in MS pathology and offer potential targets for therapeutic intervention. Here, we review underlying risk factors, mechanisms of MS pathogenesis, available disease modifying therapies, and examine the value of emerging technologies, which may address unmet clinical needs and identify novel therapeutic targets.


Capillary electrophoresis off-line matrix-assisted laser desorption/ionisation mass spectrometry of intact and digested proteins using cationic-coated capillaries.
Capillary electrophoresis (CE) was coupled off-line with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS) for the analysis of proteins and peptides. CE fractions were collected directly on a matrix-coated MALDI target, using a sheath-flow interface. Protein adsorption during CE separations was prevented by coating the capillaries with the physically adsorbed, cationic polymer PolyE-323. The CE/MALDI-MS system was used for the analysis of model proteins and peptides at physiological pH as well as analysis of proteins in tear fluid. Moreover, tryptic on-target digestion of the collected protein fractions, with subsequent MALDI-MS and MS/MS peptide analysis, was demonstrated.


Refugee mother-child dyads' hair cortisol, post-traumatic stress, and affectionate parenting.
Refugees are a special population who experience adversity before, during and after forced displacement. Hence, many of them show post-traumatic stress symptoms (PTSS). PTSS can be transmitted from the mother to the child and are associated with alterations in cortisol responses. Positive parenting practices, such as maternal affection, counteracts psychopathology in early childhood. The aim of this explorative study was to investigate how children's cortisol is associated with mothers' cortisol after forced displacement, and whether or not an association depends on maternal affection. A total of 42 Arabic-speaking mother-child dyads, who came to Germany as refugees from Syria or Iraq within the past four years, participated in the present cross-sectional study. All children were below the age of 5 years. We assessed children's and mothers' hair cortisol concentration (HCC) and PTSS. Additionally, we observed and objectively rated maternal affection during mother-child interactions. The association between mothers' and children's HCC, as well as their associations with maternal affection, depended on the difference between children's and mothers' HCC. Furthermore, this HCC difference significantly predicted children's PTSS. Hence, in order to understand the mechanisms underlying children's PTSS, it is essential to consider maternal variables and differential effects within samples. We discussed possible explanations for those findings.


In situ photothermal nano-vaccine based on tumor cell membrane-coated black phosphorus-Au for photo-immunotherapy of metastatic breast tumors.
Cancer vaccines which can activate antitumor immune response have great potential for metastatic tumors treatment. However, clinical translation of cancer vaccines remained challenging due to weak tumor antigen immunogenicity, inefficient in vivo delivery, and immunosuppressive tumor microenvironment. Nanomaterials-based photothermal treatment (PTT) triggers immunogenic cell death while providing in situ tumor-associated antigens for subsequent anti-tumor immunity. Here, an in situ photothermal nano-vaccine (designated as BCNCCM) based on cancer cell membrane (CCM) was explored by co-encapsulating immune adjuvant CpG oligodeoxynucleotide (ODN) loaded black phosphorus-Au (BP-Au) nanosheets together with an indoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919) by CCM, for the elimination of primary and metastatic breast tumors. The nano-vaccine could be delivered to tumor site selectively by CCM targeting and exhibit vaccine-like functions through the combined effect of in situ generated tumor-associate agents after PTT and immune adjuvant CpG, resulting in trigger of tumor-specific immunity. Furthermore, tumor inhibition was enhanced owing to the reversed immunosuppressive microenvironment mediated by IDO inhibitors. The nano-vaccine not only had good therapeutic effect on primary and metastatic tumors, but also could prevent tumor recurrence by producing systemic immune memory. Therefore, the photothermal nano-vaccine which coordinate in situ vaccine-like function and immune modulation may be a promising stragegy for photo-immunotherapy of metastatic tumors.


Nickel-catalyzed borylation of aryl cyclopropyl ketones with bis(pinacolato)diboron to synthesize 4-oxoalkylboronates.
Aryl cyclopropyl ketones undergo nickel-catalyzed borylative ring opening with bis(pinacolato)diboron to yield 4-oxoalkylboronates.


Effects of posture and sleep on the pharmacokinetics of paracetamol (acetaminophen) and its metabolites.
The effects of posture and sleep on the pharmacokinetics of paracetamol (acetaminophen) 500 mg and its metabolites were studied in 8 healthy men. The mean residence times for paracetamol or its metabolites were significantly altered by change in posture or by sleep, whereas other pharmacokinetic parameters were unchanged. The change in mean residence time is consistent with a faster absorption of paracetamol during ambulation. The present data suggest that the proposed posture-related changes in volume of distribution do not exist, and that there is no pharmacokinetic basis for a headache being relieved by taking paracetamol and lying down.


Age-associated changes in gene expression patterns in the liver.
Aging is one of the least clearly understood biological processes. Alteration of oxidation/reduction (redox) enzymes has been demonstrated with aging; however, a systematic analysis of expression patterns has not been performed. The liver plays a key role in homeostasis and detoxification; therefore alteration of hepatic gene expression with aging may affect outcome after surgery. The purpose of our study was to assess changes in gene expression patterns in aged livers from both rats and humans using gene array analysis. Total RNA was extracted from young (2-month-old) and aged (2-year-old) rat livers, as well as young (1-year-old) and aged (78-year-old) human livers. Gene expression patterns were compared using Affymetrix GeneChip arrays. The expression pattern of selected genes was confirmed by reverse transcription-polymerase chain reaction. A threefold or greater change in gene expression was noted in 582 genes in the aged rat livers and 192 genes in the aged human livers. Comparison of the genes that were increased with aging demonstrated some similar patterns of expression in the rat and human livers, particularly in members of the antioxidant family and the cytochrome P-450 genes. Our findings demonstrate changes in the expression pattern of genes in the liver with aging. Concomitant increases in the expression of important antioxidant and detoxifying genes were noted in the livers of both rats and humans. This induction pattern suggests a complex link between changing hepatic detoxification/redox capability and senescence.


Similarity searching in files of three-dimensional chemical structures: representation and searching of molecular electrostatic potentials using field-graphs.
This paper reports a method for the identification of those molecules in a database of rigid 3d structures with molecular electrostatic potential (MEP) grids that are most similar to that of a user-defined target molecule. The most important features of an MEP grid are encoded in field-graphs, and a target molecule is matched against a database molecule by a comparison of the corresponding field-graphs. The matching is effected using a maximal common subgraph isomorphism algorithm, which provides an alignment of the target molecule's field-graph with those of each of the database molecules in turn. These alignments are used in the second stage of the search algorithm to calculate the intermolecular MEP similarities. Several different ways of generating field-graphs are evaluated, in terms of the effectiveness of the resulting similarity measures and of the associated computational costs. The most appropriate procedure has been implemented in an operational system that searches a corporate database, containing ca. 173,000 3D structures.


Behavioural effects of peripherally injected interleukin-1: role of prostaglandins.
To investigate the possible mediation by prostaglandins of changes in behaviour induced by peripheral injection of interleukin-1 (IL-1), two types of behavioural tests were chosen, social exploration in mice and schedule-controlled behaviour in rats. Mice treated with 1 and 2.5 micrograms recombinant human IL-1 beta showed a time- and dose-dependent decrease in exploration of a juvenile conspecific. This effect was completely blocked by pretreatment with 10 mg/kg indomethacin or 10 mg/kg piroxicam, but not with 50 mg/kg aspirin. The disruption of operant responding induced by 5 micrograms IL-1 in rats was also suppressed by pretreatment with 5 mg/kg indomethacin or 10 mg/kg piroxicam. These results indicate that prostaglandins mediate the behavioural effects of peripherally injected IL-1.


PHYLOGENETIC STUDIES OF COADAPTATION: PREFERRED TEMPERATURES VERSUS OPTIMAL PERFORMANCE TEMPERATURES OF LIZARDS.
The view that behavior and physiological performance are tightly coadapted is a central principle of physiological ecology. Here, we test this principle using a comparative study of evolutionary patterns in thermal preferences and the thermal dependence of sprinting in some Australian skinks (Lygosominae). Thermal preferences (Tp ) differ strikingly among genera (range 24° to 35°C), but critical thermal maxima (CTMax) (range 38° to 45°C) and optimal temperatures for sprinting (To , 32° to 35°C) vary less. Diurnal genera have relatively high Tp , To , and CTMax. In contrast, nocturnal genera have low Tp but have moderate to high To and CTMax. Both nonphylogenetic and phylogenetic (minimum-evolution) approaches suggest that coadaptation is tight only for genera with high Tp . Phylogenetic analyses suggest that low Tp and, thus, partial coadaptation are evolutionarily derived, indicating that low thermal preferences can evolve, even if this results in reduced performance. In one instance, thermal preferences and the thermal dependence of sprinting may have evolved in opposite directions, a phenomenon we call "antagonistic coadaptation." We speculate on factors driving partial coadaptation and antagonistic coadaptation in these skinks.


Blood pressure regulation in third-trimester pregnant women receiving tocolytic terbutaline infusion.
Terbutaline (20 micrograms/min) was infused during 30 min in 17 women in whom a manual external manipulation of a breech presentation was going to be attempted. A significant increase in systolic (P = 0.003) and a decrease in diastolic blood pressure (P = 0.04) was noted at the end of the infusion but no change in mean arterial blood pressure was obtained. At the same time aldosterone serum levels had dropped significantly (P = 0.009) and plasma angiotensin II showed a marked increase (P less than 0.001) which continued during the next 30 min. All changes were normalized after the infusion. The angiotensin-converting enzyme activity remained unchanged, as did vasopressin plasma levels. The combined results of terbutaline provocation have been interpreted to mean that blood pressure regulation in third-trimester pregnant women is similar to that in nonpregnant individuals. The increase in dehydroepiandrosterone sulphate (P less than 0.05) noted at the end of infusion was suggested to be related to the blood pressure changes and was unrelated to fluctuations in serum cortisol. The latter steroid increased between 30 and 60 min, e.g. during the manual external manipulation, and was interpreted as being due to maternal stress.


Adverse reactions to immunization with newer vaccines in the very preterm infant.
To study the frequency and types of adverse reactions to currently available vaccines in very preterm infants. Case notes were obtained for very preterm infants < or =30 weeks' gestational age who received their first immunization at the Royal Women's Hospital, Melbourne, during 1999-2003. Data were extracted for the time periods 48 h before and 48 h after immunizations, with the data extraction blinded as to whether the period being evaluated was pre- or post-immunization. Data collected focused on the frequency and severity of apnoea, respiratory support, fever and clinical consequences of adverse reactions. A total of 48 very preterm infants were immunized during the period; 37 infants had Comvax (Haemophilus influenzae type B and hepatitis B vaccine), Infanrix (diphtheria, tetanus and acellular pertussis vaccine) and inactivated poliomyelitis vaccine, and 11 infants had Comvax and Infanrix only. Their mean (SD) gestational age at birth was 26.4 (1.7) weeks with mean birthweight of 872 (235) g. The mean postnatal age at immunization was 76 (20) days. Low-grade fever (>37.5 degrees C per axilla) occurred in 16 (33%) infants after immunization, but none before immunization (P < 0.001). There was no substantial change in recorded apnoea. No serious adverse events were noted. Four (8%) infants underwent a septic work up post-immunization. The C-reactive protein was increased in all four infants, but other tests for sepsis were negative. Fever remains a common adverse event following immunization of the preterm infant in spite of the development of a new generation of vaccines.


Effect of adding byproducts of chicken slaughter on the quality of sausage over storage.
The use of byproducts generated by the food industry is a strategy that can have advantages in economic, technological, nutritional, and environmental terms. The aim of this study was to evaluate the influence of the addition of byproducts of chicken slaughter (skin and abdominal fat) on the quality of fresh sausage stored under freezing. Partial chemical characterization of the byproducts was performed. Three batches of chicken sausage were prepared with skin, abdominal fat, and with skin and abdominal fat added; thereafter were stored for 135 d in freezer. Partial chemical composition, physical characteristics, microbiological quality, and product acceptance were determined. Skin and abdominal fat are rich sources of fat. However, the addition of skin provided to sausage higher protein content, hardness, water retention capacity, and less cooking loss compared to added abdominal fat treatments. In contrast, the addition of abdominal fat provided higher lipid content to the sausages and displaying higher acceptability. The addition of byproducts in fresh sausage manufacture would be a great strategy to increase the chicken sausage value, with physicochemical quality improvement, and without sensory acceptability issues.


Characterizing the phenotype of drug-resistant childhood epilepsy associated with leukemia: A case series.
Children with leukemia are at risk for epilepsy due to primary disease or neurotoxic therapies. We describe the phenotypes of drug-resistant epilepsy in 10 children with history of leukemia. Of 10 cases, 6 had features of Lennox-Gastaut syndrome, and 4 had focal epilepsy. Mean age of epilepsy onset was 5 years in Lennox-Gastaut cases and 6.5 years in focal epilepsy cases. Mean latency between leukemia diagnosis and seizure onset was about 3 years. Brain MRI of 2 patients with epileptic encephalopathy had structural abnormalities - unclear if causative for epilepsy, and 4 had no overt structural abnormalities. In focal epilepsy group, 3 had temporal lobe epilepsy and one had fronto-temporal localization. All 10 patients had received intrathecal chemotherapy; 2 also had received whole brain irradiation. Seizures were poorly controlled in the epileptic encephalopathy group. Three underwent corpus callosotomy with variable response. Two patients with temporal lobe epilepsy had temporal lobectomy with Engel 1 outcome at 2 year follow-up in both. Two phenotypes of refractory epilepsy were observed in children with previous history of leukemia, focal epilepsy and epileptic encephalopathy. Children with temporal lobe epilepsy had good response to temporal lobectomy; response to palliative surgery was variable.


Investigating fatty liver disease-associated adverse outcome pathways of perfluorooctane sulfonate using a systems toxicology approach.
Adverse outcome pathway (AOP) frameworks help elucidate toxic mechanisms and support chemical regulation. AOPs link a molecular initiating event (MIE), key events (KEs), and an adverse outcome by key event relationships (KERs), which assess the biological plausibility, essentiality, and empirical evidence involved. Perfluorooctane sulfonate (PFOS), a hazardous poly-fluoroalkyl substance, demonstrates hepatotoxicity in rodents. PFOS may induce fatty liver disease (FLD) in humans; however, the underlying mechanism remains unclear. In this study, we evaluated the toxic mechanisms of PFOS-associated FLD by developing an AOP using publicly available data. We identified MIE and KEs by performing GO enrichment analysis on PFOS- and FLD-associated target genes collected from public databases. The MIEs and KEs were then prioritized by PFOS-gene-phenotype-FLD networks, AOP-helpFinder, and KEGG pathway analyses. Following a comprehensive literature review, an AOP was then developed. Finally, six KEs for the AOP of FLD were identified. This AOP indicated that toxicological processes initiated by SIRT1 inhibition led to SREBP-1c activation, de novo fatty acid synthesis, and fatty acid and triglyceride accumulation, culminating in liver steatosis. Our study provides insights into the toxic mechanism of PFOS-induced FLD and suggests approaches to assessing the risk of toxic chemicals.


A cytochrome b-glucose dehydrogenase chimeric enzyme capable of direct electron transfer.
The development of third generation biosensors depends on the availability of direct electron transfer (DET) capable enzymes. A successful strategy is to fuse a cytochrome domain to an enzyme to fulfil the function of a built-in redox mediator between the catalytic center and the electrode. In this study, we fused the cytochrome domain of Neurospora crassa CDH IIA (NcCYT) N-terminally to glucose dehydrogenase from Glomerella cingulata (GcGDH) to generate the chimeric enzyme NcCYT-GcGDH in a large amount for further studies. Heterologous expression in P. pastoris and chromatographic purification resulted in 1.8 g of homogeneous chimeric enzyme. Biochemical and electrochemical characterization confirmed that the chimeric enzyme is catalytically active, able to perform interdomain electron transfer (IET) and direct electron transfer (DET) via the fused cytochrome domain. The midpoint redox potential of the fused b-type cytochrome is 91 mV vs. SHE at pH 6.5 and the specific current obtained on a porous graphite electrode is 2.3 μA cm-2. The high current obtained on this simple, unmodified electrode at a rather low redox potential is a promising starting point for further optimization. The high yield of NcCYT-GcGDH and its high specific activity supports the application of the chimeric enzyme in bioelectrocatalytic applications.


Plasma beta-endorphin and insulin concentrations in relation to body fat and nutritional parameters in overweight and obese prepubertal children.
To investigate the relationship between plasma beta-endorphin (beta-end) and insulin concentrations and 1) body fat, and 2) nutritional parameters in overweight or obese prepubertal children. Cross-sectional study on plasma beta-end and insulin concentrations, body fat, indirect parameters of appetite namely daily energy and macronutrient intake. 143 (67 boys and 76 girls) overweight or obese children (group I) and 48 (27 boys and 21 girls) healthy children with normal parameters of somatic development (group II). Age: 5.8-9.6 y. Weight, height and subcutaneous skinfold thicknesses, plasma beta-end and insulin concentrations, diet history for energy and macronutrient intake. Group I was characterised by significantly higher average concentrations of beta-end and insulin in comparison to the control group. The analysis of these concentrations in the subgroups in relation to the percentage of body fat indicates that beta-end concentrations increased more than insulin concentrations with increasing fatness. A significantly positive correlation between beta-end and insulin levels was only noted in group I. Also, only in this group was there a significant positive correlation between beta-end levels and energy and macronutrient intake. In both groups the percentage of energy intake which was fat, correlated positively with beta-end concentrations. Furthermore energy and fat intakes showed a significant positive correlation with insulin levels in both groups. beta-endorphin and insulin concentrations in overweight and obese prepubertal children are not only higher than in non-obese children but also are positively correlated with each other and with the percentage of body fat. The relationship between plasma beta-end levels and food intake shows that the beta-end level may be able to be used as an indicator of appetite in overweight and obese prepubertal children whose food intake is not restricted.


Cladribine treatment for highly active multiple sclerosis: Real-world clinical outcomes for years 3 and 4.
Cladribine is an effective immunomodulatory treatment used for relapsing forms of multiple sclerosis (MS). To describe the clinical outcomes and rates of no evidence of disease activity (NEDA) in patients with highly-active disease treated with 2 years cumulative dose of cladribine, for years 3 and 4. We used the Sheba Multiple Sclerosis computerized data registry to retrospectively evaluate year-3 and year-4 clinical outcomes and NEDA-2 rates in highly active RRMS patients who completed the 2-dose 2-year cladribine treatment protocol (3.5 mg/kg cumulative dose over 2 years). The first week of treatment in year 1 was considered as baseline. Data analyses were performed using Python (version 3.0) and SAS® (version 9.4 SAS Institute, Cary, NC). Among 128 patients with highly-active MS that received cladribine treatment, 61 patients, 43 females, were studied for year-3 clinical outcomes, and 35 patients, 23 females, also for year-4. At the initiation of cladribine treatment, the mean ± SD age was 39.6 ± 10.74 years (45.9% of the patients were between 18 and 40 years), disease duration 12.7 ± 9.08 years, Expanded Disability Status Scale (EDSS) 3.7 ± 1.86 (54% had EDSS score > 3.0), and the annual relapse rate was 1.6 ± 0.9. The annual relapse rate decreased to 0.36 in year-3 and was 0.17 in year-4; 68.9% (42/61) of the patients were relapse-free in year-3, and 82.9% (29/35) were relapse-free in year-4. Disability at year-3 was 3.1 ± 2.07; 83.6% (51/61) of the patients remained neurologically stable (33, 54.1%) or improved (18, 29.5%). In year-4, EDSS was 3.2 ± 1.91, and 85.7% (30/35) of the patients remained stable (20, 57.1%) or improved (10, 28.6%). NEDA-2 was achieved for 59.0% (36/61) of patients in year-3, and for 74.3% (26/35) in year-4 of cladribine treatment. In the real-world cladribine proved to be clinically effective in year-3 and year-4 of treatment in the majority of highly active RRMS patients.


The impact of the COVID-19 pandemic on presentations of self-harm over an 18-month period to a tertiary hospital.
To examine and compare rates and methods of self-harm presenting to a tertiary referral hospital during an 18-month period since the onset of the COVID-19 pandemic with a similar period immediately prior to the pandemic onset. Data from an anonymized database compared rates of self-harm presentations and methods employed between 1st March 2020 and 31st August 2021 to a similar time-frame prior to the onset of the COVID-19 pandemic. A 9.1% increase in presentations with self-harm was noted since the onset of the COVID-19 pandemic. Periods of more stringent restrictions were associated with higher levels of self-harm (daily rate of 2.10 v 0.77). A higher lethality of attempt was demonstrated post-COVID-19 onset (χ2 = 15.38, p < 0.001). Fewer individuals presenting with self-harm were diagnosed with an adjustment disorder since the onset of the COVID-19 pandemic (n = 84, 11.1%, v. n = 112, 16.2%, χ2 = 7.898, p = 0.005), with no other differences pertaining to psychiatric diagnosis noted. More patients actively engaged with mental health services (MHS) presented with self-harm (n = 239 (31.7%) v. n = 137, (19.8%), χ2 = 40.798, p ≤ 0.001) since the onset of the COVID-19 pandemic. Despite an initial reduction, an increase in rates of self-harm has occurred since the onset of the COVID-19 pandemic with higher rates evident during periods of higher government mandated restrictions. An increase in active patients of MHS presenting with self-harm potentially relates to reduced availability of supports and particularly group activities. The recommencement of group therapeutic interventions for individuals attending MHS in particular is warranted.


Freeze-thawing impairs the motility, plasma membrane integrity and mitochondria function of boar spermatozoa through generating excessive ROS.
Cryopreservation is an efficient way to store spermatozoa and is closely associated with the quality of sperm after the freeze-thaw process. During freeze-thaw cycling, excessive reactive oxygen species (ROS) are produced, and the effects of ROS on boar sperm during cryopreservation have not been identified. In this study, we evaluated the quality of boar spermatozoa in different steps of cryopreservation (extension, cooling, and thawing for 30 min and 240 min) with or without boar-sperm antioxidant (N-acetylcysteine (NAC)). The ROS levels, sperm motility, plasma membrane integrity, mitochondrial activity, sperm chromatin structure, ATP content, and sperm apoptosis were assayed. After thawing, the ROS level and sperm apoptosis were significantly increased, and the sperm motility, plasma membrane integrity, mitochondrial activity, sperm chromatin structure, and ATP content were significantly impaired compared with those at the extension period and cooling period. Moreover, the addition of N-acetyl L-cysteine (NAC) reversed these changes. The freeze-thawing of boar spermatozoa impaired their motility, plasma membrane, mitochondrial activity, sperm chromatin structure and apoptosis by producing excessive ROS. Thus, the downregulation of ROS level by antioxidants, especially the NAC, is important for manufacturing frozen pig sperm to increase reproductive cells and livestock propagation, as well as to improve the application of frozen semen in pigs worldwide.


Live-cell imaging of endogenous Ras-GTP illustrates predominant Ras activation at the plasma membrane.
Ras-GTP imaging studies using the Ras-binding domain (RBD) of the Ras effector c-Raf as a reporter for overexpressed Ras have produced discrepant results about the possible activation of Ras at the Golgi apparatus. We report that RBD oligomerization provides probes for visualization of endogenous Ras-GTP, obviating Ras overexpression and the side effects derived thereof. RBD oligomerization results in tenacious binding to Ras-GTP and interruption of Ras signalling. Trimeric RBD probes fused to green fluorescent protein report agonist-induced endogenous Ras activation at the plasma membrane (PM) of COS-7, PC12 and Jurkat cells, but do not accumulate at the Golgi. PM illumination is exacerbated by Ras overexpression and its sensitivity to dominant-negative RasS17N and pharmacological manipulations matches Ras-GTP formation assessed biochemically. Our data illustrate that endogenous Golgi-located Ras is not under the control of growth factors and argue for the PM as the predominant site of agonist-induced Ras activation.


Children's reasoning about the efficiency of others' actions: The development of rational action prediction.
The relative efficiency of an action is a central criterion in action control and can be used to predict others' behavior. Yet, it is unclear when the ability to predict on and reason about the efficiency of others' actions develops. In three main and two follow-up studies, 3- to 6-year-old children (n = 242) were confronted with vignettes in which protagonists could take a short (efficient) path or a long path. Children predicted which path the protagonist would take and why the protagonist would take a specific path. The 3-year-olds did not take efficiency into account when making decisions even when there was an explicit goal, the task was simplified and made more salient, and children were questioned after exposure to the agent's action. Four years is a transition age for rational action prediction, and the 5-year-olds reasoned on the efficiency of actions before relying on them to predict others' behavior. Results are discussed within a representational redescription account.


The advances of topology optimization techniques in orthopedic implants: A review.
Metal implants are widely used in the treatment of orthopedic diseases. However, owing to the mismatched elastic modulus of the bone and implants, stress shielding often occurs clinically which can result in failure of the implant or fractures around the implant. Topology optimization (TO) is a technique that can provide more efficient material distribution according to the objective function under the special load and boundary conditions. Several researchers have paid close attention to TO for optimal design of orthopedic implants. Thanks to the development of additive manufacturing (AM), the complex structure of the TO design can be fabricated. This article mainly focuses on the current stage of TO technique with respect to the global layout and hierarchical structure in orthopedic implants. In each aspect, diverse implants in different orthopedic fields related to TO design are discussed. The characteristics of implants, methods of TO, validation methods of the newly designed implants, and limitations of current research have been summarized. The review concludes with future challenges and directions for research. Wang TO design of global layout and local structure of implants in diverse fields of orthopedic.


Thermo-reversible injectable gel based on enzymatically-chopped low molecular weight methylcellulose for exenatide and FGF 21 delivery to treat types 1 and 2 diabetes.
Diabetes is the fastest growing metabolic disease that fails to utilize glucose properly due to insulin deficiency or insulin resistance. Although several limited studies demonstrated non-invasive means of protein delivery, major hurdles for commercial success such as short half-life, enzymatic degradation and low bioavailability still remain to overcome. Methylcellulose (MC), a hydrophobically-modified cellulose derivative, forms temperature reversible gel in aqueous solution. However, as the gelling temperature of MC is higher than body temperature, it should be lowered to below body temperature for practical clinical application. In order to decrease gelling temperature and increase bio-compatibility and bio-elimination of MC, the molecular weight of MC was decreased using enzymatic degradation method and confirmed by gel permeation chromatography. Bio-elimination of low molecular weight (LMw) MC was confirmed with non-invasive live image and ex vivo experiment. The exenatide and FGF 21 were physically loaded 100% into LMwMC-based thermo-reversible gel and slowly released from gel with no initial bursts. Exenatide-loaded LMwMC gel showed reduction of blood glucose level for a week in type 1 diabetic animal model. FGF 21-loaded LMwMC gel reduced glucose level to normal condition and maintained over 10 days in type 2 diabetic animal model. LMwMC-based thermo-reversible and injectable hydrogel provides a strong potential to be efficient protein drug delivery system for the treatment of type 1 and type 2 diabetes.


The composition of upstream open reading frames (uORF) in four genes from Trypanosoma cruzi typical strains.
Upstream open reading frames (uORF) are small open reading frames located in the 5' untranslated region (5' utr) of a mature mRNA. We analysed in four strains representing the Trypanosoma cruzi groups Tc I, Tc II, Tc IV and Tc VI the uORF present in 5' utr sequences of four genes: P-type H+-ATPase 1, DEAD/H RNA helicase, casein kinase 1.1 and ferredoxin-NADP+ reductase. A segment in the 5' utr at each of these genes encompassing one or more uORF was PCR amplified and sequenced. An analysis of these sequences reveals that the uORF in T. cruzi show minor variations; however, these nucleotide substitutions mirror the divergence of T. cruzi strains into major groups.


Oxygenation Profiles of Human Blood, Cell Culture Medium, and Water for Perfusion of 3D-Bioprinted Tissues using the FABRICA Bioreactor Platform.
Persistent and saturated oxygen distribution from perfusion media (i.e., blood, or cell culture media) to cells within cell-dense, metabolically-active biofabricated tissues is required to keep them viable. Improper or poor oxygen supply to cells within the tissue bulk severely limits the tissue culturing potential of many bioreactors. We added an oxygenator module to our modular FABRICA bioreactor in order to provide stable oxygenation to biofabricated tissues during culture. In this proof of concept study of an oxygenated and perfused bioreactor, we characterized the oxygenation of water, cell culture medium, and human blood in the FABRICA as functions of augmenting vacuum (air inlet) pressure, perfusion (volumetric flow) rate, and tubing/oxygenator components. The mean oxygen levels for water and cell culture media were 27.7 ± 2.1% and 27.6 ± 4.1%, respectively. The mean oxygen level for human blood was 197.0 ± 90.0 mmHg, with near-physiologic levels achieved with low-permeability PharMed tubing alone (128.0 ± 14.0 mmHg). Hematologic values pre- and post-oxygenation, respectively were (median ± IQR): Red blood cell: 6.0 ± 0.5 (106/μL) and 6.5 ± 0.4 (106/μL); Hemoglobin: 17.5 ± 1.2 g/dL and 19.2 ± 3.0 g/dL; and Hematocrit: 56.7 ± 2.4% and 61.4 ± 7.5%. The relative stability of the hematologic parameters indicates that blood function and thus blood cell integrity were maintained throughout oxygenation. Already a versatile research tool, the now oxygenated FABRICA provides easy-to-implement, in vivo-like perfusion and stable oxygenation culture conditions in vitro semi-independently of one another, which means the bioreactor has the potential to serve as a platform for investigating the behavior of 3D tissue models (regardless of biofabrication method), performing drug toxicity-testing, and testing pharmaceutical efficacy/safety.


Current advancements and future perspectives of long noncoding RNAs in lipid metabolism and signaling.
The investigation of lncRNAs has provided a novel perspective for elucidating mechanisms underlying diverse physiological and pathological processes. Compelling evidence has revealed an intrinsic link between lncRNAs and lipid metabolism, demonstrating that lncRNAs-induced disruption of lipid metabolism and signaling contribute to the development of multiple cancers and some other diseases, including obesity, fatty liver disease, and cardiovascular disease. The current review summarizes the recent advances in basic research about lipid metabolism and lipid signaling-related lncRNAs. Meanwhile, the potential and challenges of targeting lncRNA for the therapy of cancers and other lipid metabolism-related diseases are also discussed. Compared with the substantial number of lncRNA loci, we still know little about the role of lncRNAs in metabolism. A more comprehensive understanding of the function and mechanism of lncRNAs may provide a new standpoint for the study of lipid metabolism and signaling. Developing lncRNA-based therapeutic approaches is an effective strategy for lipid metabolism-related diseases.


Decomposition of individual-specific and individual-shared components from resting-state functional connectivity using a multi-task machine learning method.
Resting-state functional connectivity (RSFC) can be used for mapping large-scale human brain networks during rest. There is considerable interest in distinguishing the individual-shared and individual-specific components in RSFC for the better identification of individuals and prediction of behavior. Therefore, we propose a multi-task learning based sparse convex alternating structure optimization (MTL-sCASO) method to decompose RSFC into individual-specific connectivity and individual-shared connectivity. We used synthetic data to validate the efficacy of the MTL-sCASO method. In addition, we verified that individual-specific connectivity achieves higher identification rates than the Pearson correlation (PC) method, and the individual-specific components observed in 886 individuals from the Human Connectome Project (HCP) examined in two sessions over two consecutive days might serve as individual fingerprints. Individual-specific connectivity has low inter-subject similarity (-0.005±0.023), while individual-shared connectivity has high inter-subject similarity (0.822±0.061). We also determined the anatomical locations (region or subsystem) related to individual attributes and common features. We find that individual-specific connectivity exhibits low degree centrality in the sensorimotor processing system but high degree centrality in the control system. Importantly, the individual-specific connectivity estimated by the MTL-sCASO method accurately predicts behavioral scores (improved by 9.4% compared to the PC method) in the cognitive dimension. The decomposition of individual-specific and individual-shared components from RSFC provides a new approach for tracing individual traits and group analysis using functional brain networks.


Clinical results and radiologic findings after cementless implantation of PCA stems in total hip replacement.
The results of radiologic and clinical follow-up of 81 PCA (porous coated anatomie) hip joint prostheses implanted in our clinic between 1986 and 1988 are presented. One of the prostheses had to be explanted because of aseptic loosening after 2.5 years' implantation. Contrary to the fixation concept of the prosthesis, which requires both proximal osseointegration and free axial shifting of the distal part of the prosthesis, our follow-up radiographs showed proximal lysis of 2 mm and more as well as distal hypersclerosis of 3 mm and more in the form of endosteal bone formation in 70% of cases 3 years after implantation. On the basis of our data, the question whether these bone reactions will finally lead to aseptic loosening of the implant cannot be answered yet.


Correlation between calcium, water contents and ultrasonographic appearance of atherosclerotic lesions of carotid artery lesions.
We tested the hypothesis whether there is a correlation between the echogenicity and calcium and water contents of carotid plaques. Ninety carotid befurcations from 45 deceased patients were removed during autopsy. Thirty-four plaques were categorized as homogenous echolucent (HEL), homogenous echogenic (HEG) and heterogenous (HE) plaques based on premortem B-mode image. Water content was expressed in % of wet weight. Ca was determined by proton-induced X-ray emission and expressed in ppm. Relative optical density of the B-mode images was analyzed offline using a computer program. HEL plaques had lower Ca content (medians and IQRs: 6,145 [4,465-6,536 ppm]) compared to HEG (74,100 [15,300-1,44,500-ppm]), P ≤ 0.001). HE plaques showed an intermediate calcium content (7,310 [4,840-9,920 ppm]) that was statistically not different from echolucent plaques. Water content of HEG plaques was statistically not different from HEL and HE (HEG:53.5 [35.5-64%], HEL: 73.5 [69.7-78.5%], HE: 70.6 [67.4-73.9%]). HEG plaques had the highest relative optical densities (196 [188-217%]). HEL and HE had similar relative optical densities (HEL: 176 [164-187%], HE: 164 [144-188%], respectively). A significant positive correlation was found between the Ca content and relative optical density of plaques. Echogenicity of carotid plaques increases along with their calcium content. Water content may be an important factor in differentiation of different plaques.


HSPs drive dichotomous T-cell immune responses via DNA methylome remodelling in antigen presenting cells.
Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91. Global DNMT-dependent epigenetic modifications lead to changes in protein expression within these antigen-presenting cells. Specifically, pDCs upregulate neuropilin-1 to enable the long term interactions of pDCs with Treg cells, thereby enhancing suppression of Th1 anti-tumour immunity. Our study defines a CD91-dependent mechanism through which gp96 controls dichotomous immune responses relevant to the therapy of cancer and autoimmunity.


Mechanisms of selective copper removal by tetrathiomolybdate from metallothionein in LEC rats.
Copper (Cu) was selectively removed from metallothionein (MT) in the liver of LEC rats (Long-Evans rats with a cinnamon-like coat color) in vivo and in vitro by tetrathiomolybdate (TTM). Female LEC rats were injected intraperitoneally with TTM at a dose of 10 mg/kg body weight for 8 consecutive days. More than 2/3 of the Cu accumulating in the liver was removed by TTM treatment 24 h after the last injection. Although most Cu was bound to MT in the soluble fraction before TTM treatment, the Cu remaining in the liver was present almost exclusively in the non-soluble fraction together with molybdenum (Mo). Cu,Zn,Cd-MT was separated from the liver of LEC rats that had been injected with cadmium (Cd) and reacted with TTM at mol ratios of 0, 0.25, 0.50, 1.0, 2.0 and 4.0 to Cu bound to MT for 10 min at 37 degrees C. When TTM was added at a mol ratio of less than 1.0, a Cu,Zn,Cd-MT/TTM complex was detected, while addition of TTM at a mol ratio of greater than 1.0 selectively removed Cu from MT and produced a Cu/TTM complex via liberation of Zn,Cd-MT from the Cu,Zn,Cd-MT/TTM complex. Excessive TTM appeared to facilitate polymerization of the Cu/TTM complex to insoluble polymers. The dose-related formation of differing MT/TTM complexes explains the findings observed in vivo.


Raphe dorsalis-spinal cord cografts in oculo: electrophysiological evidence for an excitatory serotonergic innervation of transplanted spinal neurons.
Intraocular replicas of descending serotonergic bulbospinal pathways were constructed by means of sequential intraocular grafting of nucleus raphe dorsalis and spinal cord. Using extracellular recordings we have studied the functional connections between such double grafts. Superfusion of single spinal cord grafts with serotonin causes an increase in spontaneous activity. This excitation is reversibly blocked by the specific 5-hydroxytryptamine (5-HT) antagonist metergoline. Stimulation of the raphe part of nucleus raphe dorsalis-spinal cord double grafts causes a long-lasting excitation of the spinal neurons similar to that seen in single spinal cord grafts given serotonin. The electrically induced excitation could also be reversibly blocked with metergoline. It is concluded that serotonin-containing nerves from grafts of nucleus raphe dorsalis are not only morphologically organotypic, but also form functional contacts with neurons in cografted spinal cord. The results further support an excitatory or modulatory role of the descending spinal serotonergic pathways and demonstrate that functional contacts can be established between isolated CNS grafts when 5-HT fibers invade immature or mature spinal cord tissue.


Bidirectional Shifting Effects of the Sound Intensity on the Best Frequency in the Rat Auditory Cortex.
Frequency and intensity are two independent attributes of sound stimuli. Psychoacoustic studies have found that the sound intensity can affect the perception of frequency; however, the underlying neuronal mechanism remains largely unknown. To investigate if and how the sound level affects the frequency coding for auditory cortical neurons, we recorded the activities of neuronal ensembles and single neurons, as well as the synaptic input evoked by pure tones of different frequency and intensity combinations, in layer 4 of the rat primary auditory cortex. We found that the best frequency (BF) shifted bidirectionally with the increases in intensity. Specifically, the BF of neurons with a low characteristic frequency (CF) shifted lower, whereas the BF of neurons with a higher CF shifted higher. Meanwhile, we found that these shifts in the BF can lead to the expansion of high- and low-frequency areas in the tonotopic map, increasing the evenness of the BF distribution at high intensities. Our results revealed that the frequency tuning can bidirectionally shift with an increase in the sound intensity at both the cellular and population level. This finding is consistent with the perceptual illusions observed in humans and could provide a potential mechanism for this psychoacoustic effect.


Effects of TDP-43 overexpression on neuron proteome and morphology in vitro.
TDP-43 is pathologically and genetically with associated amyotrophic lateral sclerosis and frontotemporal lobar degeneration. These diseases are characterized by significant neurite defects, including cytoskeletal pathology. The involvement of TDP-43 in the degeneration of neurons in these diseases are not yet well understood, however accumulating evidence shows involvement in neurite outgrowth, remodelling and in regulation of many components of the neuronal cytoskeleton. In order to investigate how alterations to TDP-43 expression levels may exert effects on the neuronal cytoskeleton, primary cortical neurons from transgenic mice overexpressing one or two copies of human wildtype TDP-43 under the prion promoter were examined. Label-free quantitative proteomic analysis, followed by functional annotation clustering to identify protein families that clustered together within up- or down-regulated protein groups, revealed that actin-binding proteins were significantly more abundant in neurons overexpressing TDP-43 compared to wildtype neurons. Morphological analysis demonstrated that during early development neurons expressing one copy of human TDP-43 had an increased number of neurite branches and alterations to growth cone morphology, while no changes were observed in neurons expressing two copies of TDP-43. These developmental processes require specific expression and organization of the cytoskeleton. The results from these studies provide further insight into the normal function of TDP-43 and how alterations in TDP-43 expression may impact the cytoskeleton.


Profiles of gut microbiota in obese-insulin-resistant rats treated with biotics.
Our previous studies demonstrated the beneficial effects of the probiotic Lactobacillus paracasei HII01, prebiotic xylooligosaccharide (XOS), and synbiotics on several parameters in high-fat diet (HFD)-induced obese rats. However, the gut microbiota composition in these rats has not been investigated. Therefore, this study aimed to investigate the impact of biotic therapies on gut microbiota in HFD-induced obese-insulin-resistant rats. Male Wistar rats were fed with a normal diet (ND, n = 5) and a HFD (n = 20) for 24 weeks. At week 13, HFD-fed rats were given either a probiotic (L. paracasei, HF-Pro, n = 5), prebiotic (XOS, HF-Pre, n = 5), synbiotic (XOS + L. paracasei, HF-Syn, n = 5), or vehicle (HF-V, n = 5) for 12 weeks. ND-fed rats received vehicle (ND-V, n = 5). At week 24, all rats were decapitated, and metabolic parameters and gut microbiota were analyzed. HF-V rats developed an obese-insulin-resistant condition as indicated by impaired metabolic parameters. The prebiotic and synbiotic restored those metabolic parameters to the same level of ND-V rats. The gut microbiota composition of ND-V and HF-V rats differed as indicated by beta diversity. Verrucomicrobia in ND-V rats and Firmicutes and Proteobacteria in HF-V rats were dominant. Interestingly, Verrucomicrobia was also prominent in the HF-Syn rats. HF-Pre rats showed a distinct gut microbiota the predominant family being Ruminococcaceae. The changes in gut microbiota after HFD consumption included increased Firmicutes and Proteobacteria. The treatment with the prebiotic and synbiotic showed an association with the increase in Ruminococcaceae and Verrucomicrobia, respectively. These changes in gut microbiota due to biotics may mediate the beneficial effects on metabolic parameters.


Delayed build-up of Arctic ice sheets during 400,000-year minima in insolation variability.
Knowledge of the past variability of climate at high northern latitudes during astronomical analogues of the present interglacial may help to inform our understanding of future climate change. Unfortunately, long-term continuous records of ice-sheet variability in the Northern Hemisphere only are scarce because records of benthic (18)O content represent an integrated signal of changes in ice volume in both polar regions. However, variations in Northern Hemisphere ice sheets influence the Siberian High (an atmospheric pressure system), so variations in the East Asian winter monsoon (EAWM)--as recorded in the aeolian dust deposits on the Chinese Loess Plateau--can serve as a useful proxy of Arctic climate variability before the ice-core record begins. Here we present an EAWM proxy record using grain-size variations in two parallel loess sections representative of sequences across the whole of the Chinese Loess Plateau over the past 900,000 years. The results show that during periods of low eccentricity and precessional variability at approximately 400,000-year intervals, the grain-size-inferred intensity of the EAWM remains weak for up to 20,000 years after the end of the interglacial episode of high summer monsoon activity and strong pedogenesis. In contrast, there is a rapid increase in the EAWM after the end of most other interglacials. We conclude that, for both the 400,000-year interglacials, the weak EAWM winds maintain a mild, non-glacial climate at high northern latitudes for much longer than expected from the conventional loess and marine oxygen isotope records. During these times, the less-severe summer insolation minima at 65° N (ref. 4) would have suppressed ice and snow accumulation, leading to a weak Siberian High and, consequently, weak EAWM winds.


Colon cancer in the young: contributing factors and short-term surgical outcomes.
The incidence in young patients has increased significantly over the last few decades. The aim of this study is to evaluate demographic and tumor characteristics of young patients and analyze the short-term surgical outcomes of patients undergoing surgery. We performed a 2-year review (2015-2016) of the ACS-NSQIP and included all patients with CC who underwent surgical management. Patients were stratified into two groups: early-onset CC (< 50 years old) and late-onset CC (≥ 50 years old). Outcome measures were hospital length of stay, 30-day complications, mortality, and readmission. We included a total of 15,957 patients in the analysis. Mean age was 65 ± 13 years, and 52% were male. Overall 10% of the patients had early-onset CC. Patients with early-onset CC were more likely to be black (11% vs 7%, p = 0.04) and Hispanic (8% vs 4%, p = 0.02). Additionally, they presented with a more aggressive tumor and higher TNM staging. Patients with early onset CC had lower 30-day complications (18% vs 22%, p = 0.02), shorter hospital length of stay (6[3-8] vs 8[5-11], p = 0.03) and lower 30-day mortality (0.4% vs 1.8%, p = 0.04) compared to their counterparts. However, there was no difference between the two groups regarding 30-day readmission. On regression analysis, there was no difference between the two groups regarding study outcomes. Racial disparity does exist in the incidence of colon cancer in the young with higher incidence in blacks. Younger patients with CC tend to have better surgical outcomes on univariate analysis. On regression analysis, the surgical outcomes between the two groups are comparable.


Generation of superoxide anion in chloroplasts of Arabidopsis thaliana during active photosynthesis: a focus on rapidly induced genes.
The antioxidant defense system involves complex functional coordination of multiple components in different organelles within the plant cell. Here, we have studied the Arabidopsis thaliana early response to the generation of superoxide anion in chloroplasts during active photosynthesis. We exposed plants to methyl viologen (MV), a superoxide anion propagator in the light, and performed biochemical and expression profiling experiments using Affymetrix ATH1 GeneChip microarrays under conditions in which photosynthesis and antioxidant enzymes were active. Data analysis identified superoxide-responsive genes that were compared with available microarray results. Examples include genes encoding proteins with unknown function, transcription factors and signal transduction components. A common GAAAAGTCAAAC motif containing the W-box consensus sequence of WRKY transcription factors, was found in the promoters of genes highly up-regulated by superoxide. Band shift assays showed that oxidative treatments enhanced the specific binding of leaf protein extracts to this motif. In addition, GUS reporter gene fused to WRKY30 promoter, which contains this binding motif, was induced by MV and H(2)O(2). Overall, our study suggests that genes involved in signalling pathways and with unknown functions are rapidly activated by superoxide anion generated in photosynthetically active chloroplasts, as part of the early antioxidant response of Arabidopsis leaves.


Ferritin in cancer therapy: A pleiotropic tumoraffin nanocage-based transport.
Ferritin, a ubiquitously distributed iron storage protein, can specifically target tumor cells through transferrin receptor 1. Due to its rearrangeable nanocage structure, ferritin can be loaded with anticancer drugs. Combined with amino acid modifications on the outer- and/or inner-spaces of the nanocage, ferritins can be further coupled with antigens, antibodies, and nucleotide sequences. Since ferritin is naturally presented in the human body, when used in vivo, ferritin exhibits good biocompatibility, and no immunogenic response occurs. These makes ferritin an ideal nanocarrier which shows broad application prospects in cancer therapy. In this study, to find articles, a search was made in PubMed with the keywords ferritin, drug delivery, drug delivery, and cancer treatment. According to the investigation, some studies suggest that ferritin can be loaded with drugs and targeted for delivery to tumor tissue. Therefore, ferritin nanocarriers loaded with drugs can be used in chemotherapy, photodynamic therapy (PDT), photothermal therapy (PTT) and immunotherapy. Importantly, the specific targeting of ferritin nanocarriers to tumor cells increases the effectiveness of related therapies and reduces side effects. We conclude in this paper that the superior properties of ferritin nanocarriers as an emerging drug delivery system make them a promising cancer treatment strategy. In the future, it is worth conducting clinical trials to further investigate the safety and efficacy of ferritin nanocarriers in patients.


Changes in Stereotypical Behavior Following Chlorpromazine Termination: Polypharmcy Effects on Response Class Membership.
A paucity of information exists relating to the possible biological and environmental interactions influencing the occurrence of stereotypical behavior. In particular, there is limited research on the effects of psychotropic medication use on stereotypy presentation in individuals diagnosed with developmental disabilities such as intellectual disability and autism spectrum disorder. We studied the stereotypy of a man with autism spectrum disorder and intellectual disability across 2 years. The topographies of stereotypical behavior included walking in circles, head tapping, arm flinging, and object stereotypy. These behaviors were observed weekly while the participant received daily dosages of 25 mg of chlorpromazine, 1.5 mg of lorazepam, and 2,500 mg of divalproex. At Week 75, chlorpromazine was discontinued while the other drugs and dosages were maintained. We observed a statistically significant decrease in walking in circles, but no changes in the other topographies of stereotypy. The results suggest that the gross motor activity was differentially affected by the chlorpromazine discontinuation and also suggests that alterations in dopamine receptor binding may have selectively influenced changes in stereotypical responding.


Decolorization and phytotoxicity reduction of reactive blue 40 dye in real textile wastewater by active consortium: Anaerobic/aerobic algal-bacterial-probiotic bioreactor.
The textile dyeing and printing industries has led to extensive environmental pollution and severely threatens ecosystems. The best microbial species for such application was selected among the isolated bacterial populations by conducting CI Reactive Blue 40 (CI RB 40) batch degradation studies with the bacterial-algal-probiotic strains. In this study, three suitable species (Pseudomonas putida, Chlorella and Lactobacillus plantarum) were applied to degrade and detoxify CI RB 40, a reactive diazo dye in Real Textile Wastewater, used in textile dyeing industry worldwide. Process parameters were optimized using Response Surface Methodology and under the optimum conditions (e.g., inoculum size of 10%), temperature of 35 °C, 150 ppm, and time of 6 days). The maximum COD and color removal efficiencies, when tested with 1000 ppm of dye using batch reactors were found to be 89% and 99%, respectively. Our results showed also that bacteria had a high decolorization capacity. The regression analysis revealed a good match of the experimental data to the second-order polynomial with a high coefficient of determination (R2). UV-Visible and FTIR spectroscopy analysis confirmed the biodegradation of CI RB 40. Finally, toxicity of CIRB 40 before and after biodegradation was studied and the detoxification of CIRB 40 dye solution after biodegradation process was confirmed.


Prevention and early identification of elder abuse.
Elder abuse is a public health problem growing more pervasive despite being grossly underreported and underdetected. Annually, many vulnerable older adults suffer various forms of abuse threatening their overall health, quality of life, and survival. To better protect our aging population, we must overcome obstacles such as ageism, lack of geriatric health professional training, and low screening practices in clinical settings. Addressing these challenges is not sufficient for eliminating the abuse of older adults, but it is necessary for diminishing the potential for abuse and the associated negative health outcomes.


Complete Genome Assembly of Pantoea stewartii subsp. stewartii DC283, a Corn Pathogen.
The phytopathogen Pantoea stewartii subsp. stewartii DC283 causes Stewart's wilt disease in corn after transmission from the corn flea beetle insect vector. Here, we report that the complete annotated genome of P. stewartii DC283 has been fully assembled into one circular chromosome, 10 circular plasmids, and one linear phage.


A non-equilibrium state of deoxyhaemoglobin. Temperature-dependence and oxygen binding.
After reduction of human methaemoglobin by solvated electrons a non-equilibrium low-spin state of deoxyhaemoglobin is formed which has the characteristic haemochrome spectrum. This haemochrome state is ascribed to a weakly 6-coordinated structure of the haem, which is stabilised by the protonated distal histidine. Oxygen binding is not inhibited by the presence of the weak interaction in the haemochrome state. From the pH dependence of the biphasic behaviour of the oxygen binding a pK of about 8.8 is obtained which is ascribed to the deprotonation of the distal histidine which is in the proximity of a negative ion. A model is proposed to explain the complex spin-equilibria observed in methaemoglobin. The enthalpy of activation of the decay of the haemochrome state is about 53 kJ x mol(-1) and increases to 90 kJ x mol(-1) in the presence of 1 M methanol, indicating a strong interaction between methanol and haemoglobin. Around pH 8.4 the rate constant of the binding of oxygen to the haemochrome state is so high that it may well be diffusion controlled.


Quantitative mapping of specific proteins in biological tissues by laser ablation-ICP-MS using exogenous labels: aspects to be considered.
Laser ablation (LA) coupled with inductively coupled plasma mass spectrometry (ICP-MS) is a versatile tool for direct trace elemental and isotopic analysis of solids. The development of new strategies for quantitative elemental mapping of biological tissues is one of the growing research areas in LA-ICP-MS. On the other hand, the latest advances are related to obtaining not only the elemental distribution of heteroatoms but also molecular information. In this vein, mapping of specific proteins in biological tissues can be done with LA-ICP-MS by use of metal-labelled immunoprobes. However, although LA-ICP-MS is, in principle, a quantitative technique, critical requirements should be met for absolute quantification of protein distribution. In this review, progress based on the use of metal-labelled antibodies for LA-ICP-MS mapping of specific proteins is reported. Critical requirements to obtain absolute quantitative mapping of specific proteins by LA-ICP-MS are highlighted. Additionally, illustrative examples of the advances made so far with LA-ICP-MS are provided. Graphical abstract In the proposed critical review, last advances based on the use of metal-labelled antibodies and critical requirements for LA-ICP-MS quantitative mapping of specific proteins are tackled.


Light and electron microscopic observations on a ganglioneuroma.
This report describes some additional morphologic observations on a mediastinal ganglioneuroma. The neoplastic neurons contained argentaffin cytoplasmic granules presumably representing neurosecretory granules. Cytoplasmic inclusions resembling Pick's bodies were frequently observed in the neuronal components of the tumor. These inclusions consisted of neurofilaments mixed with a variable number of microtubules, dense core vesicles and other organelles. These findings expand the range of conditions in which Pick's bodies are found.


Clinical Characteristics of Fibromyalgia in a Chronic Pain Population.
To compare fibromyalgia (FM) characteristics among patients identified in a community-based chronic pain cohort based on traditional International Classification of Diagnoses 9th revision (ICD-9) diagnostic coding, with that of patients identified using a novel predictive model. This retrospective study used data collected from July 1999 to February 17, 2015, in multiple chronic pain clinics in the United States. Patients were assigned to the FM case group based on specific inclusion criteria using ICD-9 codes or, separately, from results of a novel FM predictive model that was developed using random forest and logistic regression techniques. Propensity scoring (1:1) matched FM patients (cases) to nonmalignant chronic pain patients without FM (controls). Patient-reported measures (eg, pain, fatigue, quality of sleep) and clinical characteristics (ie, comorbidities, procedures, and regions of pain) were outcomes for analysis. Nine ICD-9 clinical modification diagnoses had odds ratios with large effect sizes (Cohen's d > 0.8), demonstrating the magnitude of the difference between the FM and matched non-FM cohorts: chronic pain syndrome, latex allergy, muscle spasm, fasciitis, cervicalgia, thoracic pain, shoulder pain, arthritis, and cervical disorders (all P < 0.0001). Six diagnoses were found to have a moderate effect size (Cohen's 0.5 < d > 0.8): cystitis, cervical degeneration, anxiety, joint pain, lumbago, and cervical radiculitis. The identification of multiple comorbidities, diagnoses, and musculoskeletal procedures that were significantly associated with FM may facilitate differentiation of FM patients from other conditions characterized by chronic widespread pain. Predictive modeling may enhance identification of FM patients who may otherwise go undiagnosed.


Relationship of critical velocity to marathon running performance.
The purpose of this investigation was to evaluate the critical velocity (CV) test for prediction of marathon running performance. Twelve subjects [mean age (SD) = 29 (4) years; mean body mass = 63 (13) kg] were tested for CV and completed the 1994 New York City Marathon. The CV (m.s-1) was determined from times to exhaustion at four treadmill running velocities. In addition, peak oxygen consumption (VO2peak; ml.kg-1.min-1) and ventilatory threshold (Thvent) were determined from an incremental treadmill test. The Thvent was calculated using bi-segmental linear regression and was expressed as the velocity (m.s-1) at Thvent. Separate simple linear regression analyses showed that marathon time [MT; mean (SD) = 231.9 (27.4) min] correlated more highly with CV [MT = 445.3 - 50.3 (CV); r2 = 0.76, SEE = 14.1 min] than either VO2peak [MT = 390.7-2.7 (VO2peak); r2 = 0.51, SEE = 20.1 min] or Thvent [MT = 353.5 - 30.1 (Thvent) r2 = 0.28, SEE = 27.4 min]. A stepwise regression analysis resulted in CV (entered first) and Thvent being included in the prediction equation [MT = 443.5-78.9 (CV) + 34.3 (Thvent). R2 = 0.88, SEE = 10.7 min], while VO2peak was not included. These preliminary data indicate that the CV test may be an attractive field test for assessing marathon performance capabilities.


RBM15 condensates modulate m6A modification of STYK1 to promote tumorigenesis.
RBM15 expression is recurrently upregulated in several types of malignant tissues, and its high expression level is typically associated with poor prognosis. However, whether and how RBM15 is involved in the tumor progression remains unclear. In this study, we found that overexpressing RBM15 in NIH3T3 cells was able to enhance proliferation rate in vitro and induced subcutaneous tumor formation in vivo. Moreover, we imaged the subcellular localization of RBM15 with our home-built structured illumination super-resolution microscopy, and revealed that RBM15 formed substantial condensates dispersed in the nucleus, undergoing dynamic fusion and fission activities. These condensates were partially colocalized with m6A-modified transcripts in the nucleus. In addition, we confirmed that RBM15 formed "liquid-like" droplets in a protein/salt concentration-dependent manner in vitro, and the addition of RNA further enhanced its phase-separation propensity. To identify downstream targets of RBM15, we performed meRIP-seq and RNA-seq, revealing that RBM15 preferentially bound to and promoted the m6A modification on the mRNA of Serine/threonine/tyrosine kinase 1 (STYK1), thereby enhancing its stability. The upregulated STYK1 expression caused MAPK hyperactivation, thereby leading to oncogenic transformation of NIH3T3 cells.


Educational Activity for the Radiation Emergency System in the Northern Part of Japan: Meeting Report on "The 3rd Educational Symposium on Radiation and Health (ESRAH) by Young Scientists in 2016".
In the northern part of Japan, close cooperation is essential in preparing for any possible emergency response to radiation accidents because several facilities, such as the Low-Level Radioactive Waste Disposal Facility, the MOX Fuel Fabrication Plant and the Vitrified Waste Storage Center, exist in Rokkasho Village (Aomori Prefecture). After the accident at Fukushima Daiichi Nuclear Power Plant in 2011, special attention should be given to the relationship between radiation and human health, as well as establishing a system for managing with a radiation emergency. In the area of Hokkaido and Aomori prefectures in Japan, since 2008 an exchange meeting between Hokkaido University and Hirosaki University has been held every year to have opportunities to discuss radiation effects on human health and to collect the latest news on monitoring environmental radiation. This meeting was elevated to an international meeting in 2014 titled "Educational Symposium on Radiation and Health (ESRAH) by Young Scientists". The 3rd ESRAH meeting took place in 2016, with the theme "Investigating Radiation Impact on the Environmental and Health". Here we report the meeting findings on the continuing educational efforts after the Fukushima incident, what was accomplished in terms of building a community educational approaches, and future goals.


Lactic acid fermentation of food waste as storage method prior to biohydrogen production: Effect of storage temperature on biohydrogen potential and microbial communities.
This study aims to investigate the impact of utilizing lactic acid fermentation (LAF) as storage method of food waste (FW) prior to dark fermentation (DF). LAF of FW was carried out in batches at six temperatures (4 °C, 10 °C, 23 °C, 35 °C, 45 °C, and 55 °C) for 15 days followed by biological hydrogen potential (BHP) tests. Different storage temperatures resulted in different metabolites distribution, with either lactate or ethanol being dominant (159.2 ± 20.6 mM and 234.4 ± 38.2 mM respectively), but no negative impact on BHP (averaging at 94.6 ± 25.1 mL/gVS). Maximum hydrogen production rate for stored FW improved by at least 57%. Microbial analysis showed dominance of lactic acid bacteria (LAB) namely Lactobacillus sp., Lactococcus sp., Weisella sp., Streptococcus sp. and Bacillus sp. after LAF. Clostridium sp. emerged after DF, co-existing with LAB. Coupling LAF as a storage method was demonstrated as a novel strategy of FW management for DF, for a wide range of temperatures.


Trans-regulation of thoracic homeotic selector genes of the Antennapedia and bithorax complexes by the trithorax group genes: absent, small, and homeotic discs 1 and 2.
Genes of the trithorax group appear to be required for the maintenance of expression of the homeotic selector genes of the Antennapedia and bithorax complexes. According to genetic criteria, the Drosophila melanogaster genes absent, small, or homeotic discs 1 and 2 (ash1 and ash2) are members of the trithorax group. In this paper we examine the consequences of ash1 and ash2 mutations on the expression of homeotic selector genes in imaginal discs. The results of these experiments demonstrates that both ash1 and ash2 are trans-regulatory elements of homeotic selector gene regulation. Hypomorphic ash1 mutations cause variegated expression of Antennapedia, Sex combs reduced, Ultrabithorax, and engrailed. Complete loss of ash2 activity causes the loss of expression of Sex combs reduced in first leg imaginal discs, loss of expression of Ultrabithorax in third leg discs, and a late-patterned loss of expression of Ultrabithorax within haltere discs, yet has no effect on engrailed or Antennapedia expression. These results suggest that the range and action of trithorax group genes is varied and complex and argue against any model in which all of the products of the trithorax group act together in a single mechanism or complex.


An insertion mutation of the bovine Fii gene is responsible for factor XI deficiency in Japanese black cattle.
Factor XI deficiency in Japanese black cattle is an hereditary mild bleeding disorder with an autosomal recessive mode of inheritance. To characterize the molecular lesion causing factor XI deficiency in cattle, we isolated an entire coding region of the bovine F11 gene, which comprises 15 exons and 14 introns, and determined its nucleotide sequences. Comparison of the nucleotide sequences of the F11 gene between affected and unaffected animals revealed an insertion of 15 nucleotides in exon 9 of the affected animals. The insertion results in a substitution of one amino acid with six amino acids in a highly conserved amino acid sequence in the fourth apple domain of factor XI protein. Genotyping of the F11 gene in 109 Japanese black cattle revealed that the insertion clearly corresponded to the factor XI activities of the animals. We therefore concluded that the insertion of 15 nucleotides in the F11 gene is the causative mutation for factor XI deficiency in Japanese black cattle. Genotyping of the F11gene by detecting the insertion will be an effective DNA-based diagnostic system to prevent incidence of the disease.


Non-technical skills: a review of training and evaluation in urology.
With non-technical skills (NTS) deficits being recognised as a major cause for error in surgery, there is an increasing interest in their training and evaluation. A growing number of training courses are emerging and some NTS curricula have also been created. Many different training methods are described in the literature but there is still uncertainty with regards to their optimum combination within a curriculum. A literature review of the electronic database Medline was performed. All articles published before December 2018 were screened by abstract and included if deemed relevant by the author. The included articles' reference lists were also screened for further relevant studies. Simulation training is accepted as the most effective way to train NTS. Within simulation training, it is shown that the 'igloo' full immersion/distributed simulation environment is appropriate for teaching NTS in urological scenarios where a designated operating room or space is not available. The use of multiple settings, for example wards and clinics as well as the operating room, is advantageous, as is training in an interprofessional team. Classroom teaching also plays a role in NTS training as an adjunct to simulation, with evidence that it improves some parameters of NTS. All levels, including qualified surgeons, benefit from NTS training; however, adaptation to both trainee level and specialty is important. Although less time consuming, training juniors and seniors together mainly benefits juniors, and training NTS at the same time as technical skills detracts from the quality of teaching. Debriefing is an important part of training and should be well structured; there are many debriefing models in existence, allowing for choice of method based on examiner preference and participant demographic. Furthermore, examiners should be well briefed in their task and trained in NTS assessment. To move forward, studies should combine tried and tested learning techniques into a curriculum covering all training levels, which should then be validated and followed up long term to ensure a positive impact on patient safety.


Correlation between expression of MUC1 core protein and outcome after surgery in mass-forming intrahepatic cholangiocarcinoma.
It has been reported that MUC1 is an important prognostic factor in several cancers. This study investigated the importance of MUC1 as a prognostic factor in mass-forming intrahepatic cholangiocarcinoma (m-ICC). In 50 patients with m-ICC who had undergone hepatectomy, expression of MUC1 was investigated. Expression of MUC1 was examined by immunohistochemical staining with monoclonal antibody HMPV, which recognizes the MUC1 core peptide. The immunohistochemical staining patterns of MUC1 were classified into three types: ductal type (the luminal surface membrane of neoplastic cells was stained), cytoplasmic type (the cytoplasm of neoplastic cells was stained dominantly), and negative type. Expression of MUC1 was detected immunohistochemically in 38 (76%) of 50 cases of m-ICC (ductal type, 18; cytoplasmic type, 20; and negative type, 12). Seventy-five percent of patients with lymph node metastasis had the cytoplasmic type MUC1 expression. Lymph node dissection was performed in only 20 patients, but significant correlation was demonstrated between MUC1 expression and lymph node metastasis (P = 0.0227). The location of MUC1 expression correlated with surgical outcome in m-ICC. Patients with the cytoplasmic type expression showed significantly lower survival rates. Univariate analysis revealed that MUC1 expression was a statistically significant risk factor affecting outcome in m-ICC (P = 0.0028). Furthermore, expression of MUC1 was found to be a statistically significant independent risk factor in multivariate analysis (P = 0.0063). The results suggest that evaluation of MUC1 expression may be very useful in predicting the surgical outcome in m-ICC.


Diffusion-Weighted Zonal Oblique Multislice-EPI Enhances the Detection of Small Lesions with Diffusion Restriction in the Brain Stem and Hippocampus: A Clinical Report of Selected Cases.
Diffusion restriction is the morphologic hallmark of acute ischemic infarcts and excitotoxic brain injury in various cerebral pathologies. Diffusion restriction is visible as hyperintensity on DWI and as hypointensity on ADC maps. Due to the vicinity of multiple anatomic structures in the brain stem and hippocampus, very small lesions with diffusion restriction may result in severe clinical symptomatology, but these small lesions easily go undetected on standard cerebral DWI due to insufficient spatial resolution, T2* blurring, and image artifacts caused by susceptibility-related image distortions. Diffusion-weighted zonal oblique multislice-EPI with reduced FOV acquisition permits a considerable increase in spatial resolution and enhances the visualization of very small pathologic lesions in the brain stem and hippocampus. Improved performance in the depiction of different pathologic lesions with diffusion restriction in the brain stem and hippocampus using this sequence compared with standard DWI in selected cases is presented.


Photochemically derived 1-aminonorbornanes provide structurally unique succinate dehydrogenase inhibitors with in vitro and in planta activity.
Agrochemical fungicidal leads have been prepared from photochemically derived 1-aminonorbornane building blocks. The unique 1-aminonorbornane core is generated via direct excitation of a Schiff base precursor, leveraging the N-centered radical character of the excited state species to facilitate a series of radical reactions that construct the norbornane core. This process requires no exogenous reagents, only solvent and photons; thus, it represents an exceptionally simple and efficient means of generating the key building blocks. These (hetero) arene-fused 1-aminonorbornanes are unprecedented in both the agrochemical and pharmaceutical discovery literature; therefore, photochemical advances have provided the unique opportunity to explore the functional utility of novel chemical space. Toward this end, the 1-aminonorbornanes were used to generate next-generation succinate dehydrogenase inhibitors. In vitro fungicidal activity is demonstrated against three fungal plant pathogens affecting field crops, specifically: Fusarium graminearum, Sclerotinia sclerotiorum, and Macrophomina phaseolina. The in vitro performance against F. graminearum was shown to translate into a greenhouse setting. The discovery of in planta fungicidal activity illustrates the interdisciplinary value available via photochemical innovation.


The protective activity of Conyza blinii saponin against acute gastric ulcer induced by ethanol.
Conyza blinii H.Lév., is a type of natural plant. Its dried overground section is used to treat infections and inflammations in traditional Chinese medicine. Triterpenoidal saponins have a wide range of bioactivities, for instance, anti-cancer, anti-virus and anti-anaphylaxis. Conyza blinii saponin (CBS), mainly composed of triterpenoidal saponins, is the total saponin of Conyza blinii H.Lév. It has been reported that CBS also has gastric mucous membrane protection activity. This study aims to test CBS׳s protective activity of gastric׳s mucous membrane against ethanol. This investigation may lead to the development of novel drug from natural products as anti-ulcer agent, or as gastric mucous protective against chemical damage. CBS (Conyza blinii saponin) is the total saponin of Conyza blinii H.Lév., which was obtained as described previously. We tested the protective activity of CBS against ethanol-induced ulcer. Thirty six rats were grouped randomly as 'NORMAL', 'CONTROL', 'MODEL', 'LOW DOSE', 'MEDIUM DOSE' and 'HIGH DOSE'. The 'NORMAL' group were rats with no pathological model established within it. The 'CONTROL' group was administrated with colloidal bismuth subcitrate, while 'MODEL' group was not given any active agents apart from absolute ethanol in order to obtain gastric ulcer model. The three 'DOSE' groups were treated with different concentrations of CBS (5, 10, 20mg/mL) before administration followed by absolute ethanol. All rats were sacrificed after the experiment to acquire the gastric tissue. The ulcer index (UI), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured to monitor the activity of CBS. Besides, the rat gastric tissue was made to paraffin section and stained using the Hematoxylin-Eosin (HE) method. The histopathology examination was carried out to examine CBS efficacy in terms of gastric mucous protection. We found that CBS had a profound protection activity against acute gastric ulcer induced by ethanol and this activity displayed a concentration-dependent manner. The efficacy of 10 and 20mg/mL CBS was comparable with colloidal bismuth subcitrate (P<0.05). All three level of CBS tested were able to significantly reduce UI, MDA and enhance SOD level (P<0.05). It was deduced that the mechanism for such activity would be anti-lipid peroxidation, facilitating free radicals clearance. In addition , histopathology examination of the gastric mucous membrane supported the same conclusion, that CBS can efficiently suppress the inflammatory reactions, bleeding and protect the gastric mucosa.


Tetanic uterine contraction may be a cause of persistent fetal bradycardia after fetal blood sampling by ultrasound-guided cordocentesis.
Persistent fetal bradycardia necessiating emergency cesarean section is uncommon but a serious complication of ultrasound-guided cordocentesis. The cause of this complication, however, is not completely known. Reported here is a case of tetanic uterine contraction after fetal blood sampling via cordocentesis.


Mutational spectrum of Smith-Lemli-Opitz syndrome.
Smith-Lemli-Opitz syndrome (SLOS; OMIM #270400) is an autosomal recessive malformation syndrome characterized by a large spectrum of morphogenic and congenital anomalies. SLOS is caused by mutations in the DHCR7 gene, which encodes 7-dehydrocholesterol reductase, the enzyme that catalyzes the final step in cholesterol biosynthesis. We report on 154 currently known mutations in DHCR7 identified in patients affected with SLOS and discuss their coding consequences. These 154 mutations include 130 missense, 8 nonsense, 8 deletions, 2 insertions, 1 indel, and 5 splice site mutations. Using information available from published case reports and from patients identified in our clinical diagnostic laboratory, we analyzed correlations between genotype, clinical presentation and 7-dehydrocholesterol level.


Influence of arterial occlusion on hematocrit and plasma protein concentration of femoral venous blood in rabbit.
The changes of venous outflow (Qv), hematocrit (Hct), total plasma protein (Tp), electrolytes, crystalloid osmolality, PO2, PCO2, and pH were simultaneously measured in hindlimb preparation of anesthetized rabbits during 5 min occlusion of the femoral artery and the abdominal aorta and during the reactive hyperemia. During the occlusion of the femoral artery, Qv decreased to 66.4% at the end of the occlusion. Hct and Tp decreased slightly and then tended to progressively increase. PO2 showed an increasing trend following an initial decrease. During the occlusion of the aorta, Qv showed a continuous drop to 38.0%, while Hct and Tp declined to 95.4 and 93.8%, respectively. Qv, Hct, and Tp showed increase after the release of the occlusion of the femoral artery and the aorta. Crystalloid osmolality and K+ were observed to rise slightly. From these results it was suggested (1) that the increase of Hct and Tp which represents the hemoconcentration occurred during the reactive hyperemia and during the occlusion of the femoral artery, while the hemodilution occurred during the aortic occlusion, and (2) that the gradual increase of Hct and Tp during the occlusion of the femoral artery would be caused by the collateral blood flow.