Gut microbiota and obesity.
The human intestine harbors a complex bacterial community called the gut microbiota. This microbiota is specific to each individual despite the existence of several bacterial species shared by the majority of adults. The influence of the gut microbiota in human health and disease has been revealed in the recent years. Particularly, the use of germ-free animals and microbiota transplant showed that the gut microbiota may play a causal role in the development of obesity and associated metabolic disorders, and lead to identification of several mechanisms. In humans, differences in microbiota composition, functional genes and metabolic activities are observed between obese and lean individuals suggesting a contribution of the gut microbiota to these phenotypes. Finally, the evidence linking gut bacteria to host metabolism could allow the development of new therapeutic strategies based on gut microbiota modulation to treat or prevent obesity.


Is ultracision knife safe and efficient for breast capsulectomy? A preliminary study.
Silicone breast implants are used to a wide extent in the field of plastic surgery. However, capsular contracture remains a considerable concern. This study aimed to analyze the effectiveness and applicability of an ultracision knife for capsulectomy breast surgery. A prospective, single-center, randomized study was performed in 2009. The inclusion criteria specified female patients 20-80 years of age with capsular contracture (Baker 3-4). Ventral capsulectomy was performed using an ultracision knife on one side and the conventional Metzenbaum-type scissors and surgical knife on the collateral side of the breast. Measurements of the resected capsular ventral fragment, operative time, remaining breast tissue, drainage time, seroma and hematoma formation, visual analog scale pain score, and sensory function of the nipple-areola complex were assessed. In addition, histologic analysis of the resected capsule was performed. Five patients (median age, 59.2 years) were included in this study with a mean follow-up period of 6 months. Three patients had Baker grade 3 capsular contracture, and two patients had Baker grade 4 capsular contracture. The ultracision knife was associated with a significantly lower pain score, shorter operative time, smaller drainage volume, and shorter drainage time and resulted in a larger amount of remaining breast tissue. Histologic analysis of the resected capsule showed no apoptotic cells in the study group or control group. The results suggest that ventral capsulectomy with Baker grade 3 or 4 contracture using the ultracision knife is feasible, safe, and more efficient than blunt dissection and monopolar cutting diathermy and has a short learning curve. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.


Characterization of a novel MICA allele, MICA*012:05, by cloning and sequencing.
A new MICA allelic variant, MICA*012:05, has been identified in a Chinese Mongolian population. Following polymerase chain reaction-sequence-based typing (PCR-SBT), this new allele was further confirmed by cloning and sequencing. MICA*012:05 was linked to an HLA-A*24-C*01-B*55:02-DRB1*09 haplotype. MICA*012:05 differs from MICA*012:01 by a single synonymous C to T substitution at nucleotide position 269 in exon 3.


Accumulation of pro-cancer cytokines in the plasma fraction of stored packed red cells.
Perioperative blood transfusion has been linked to decreased survival in pancreatic cancer; however, the exact causal mechanism has not been elucidated. Allogeneic transfusions are known to expose patients to foreign cells and lipid mediators. We hypothesize that stored packed red cells (pRBCs) contain pro-cancer cytokines that augment tumor progression. We analyzed the plasma fraction of stored pRBCs for pro-cancer cytokines and evaluated the affect of both storage time and leukocyte reduction on these mediators. Chemiarray™ analysis for pro-cancer cytokines was performed on the acellular plasma fraction of stored leukocyte-reduced (LR) and non-leukocyte-reduced (NLR) pRBCs at day 1 (D.1-fresh) and day 42 (D.42-outdate) of storage. Elevated expression of monocyte chemotactic protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), angiogenin, tumor necrosis factor-alpha (TNF-α), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) was found. Specific enzyme-linked immunosorbent assay was performed for each of these factors in LR and NLR blood at D.1, day 28, and D.42. Data were analyzed by ANOVA. A p value ≤ 0.05 was considered significant; N ≥ 4 per group. Migration assays were performed using inhibitors of EGF (gefitinib) and PDGF (imatinib) on murine pancreatic adenocarcinoma cells (Pan02) exposed to D.1 and D.42 LR and NLR plasma. Proliferation assays were performed on Pan02 cells to test the inhibition of PDGF. MCP-1 levels increased with storage time in LR blood, 86.3 ± 6.3 pg/ml at D.1 vs. 121.2 ± 6.1 pg/ml at D.42 (p = 0.007), and NLR blood, 78.2 ± 7.3 pg/ml at D.1 vs. 647.8 ± 220.7 pg/ml at D.42 (p = 0.02). RANTES levels are lower in LR compared to NLR stored blood, 3.0 ± 1.9 vs. 15.8 ± 0.7 pg/ml at D.42 (p < 0.001), but similar in D.1 blood, 13.8 ± 1.8 pg/ml in LR vs. 12.0 ± 1.6 pg/ml in NLR. Angiogenin levels were different between LR and NLR blood, 0 pg/ml (undetectable) vs. 44.2 ± 3.7 pg/ml (p < 0.001). Storage time did not affect concentration. TNF-α levels were not different between LR and NLR blood, and there was no storage time effect on concentration. EGF and PDGF levels increased with storage time in NLR blood only, 216.4 ± 3.8 pg/ml at D.1 vs. 1,436.4 ± 238.6 pg/ml at D.42 for EGF (p = 0.001), and 61.6 ± 6.0 pg/ml at D.1 vs. 76.5 ± 1.7 pg/ml at D.42 (p = 0.003) for PDGF. Inhibition of EGF reduced migration in Pan02 cells treated with D.42 NLR blood, 245.9 ± 11.2 vs. 164.6 ± 10.6 cells/hpf (p < 0.001). Inhibition of PDGF had no effect on Pan02 migration and reduced cell proliferation in cells treated with D.42 NLR, 181.1 ± 1.5% over control vs. 157.5 ± 2.1% (p < 0.001). Pro-cancer cytokines that can augment tumor progression were identified in pRBCs. Some of these factors are present in fresh blood. The soluble factors identified herein may represent possible therapeutic targets to offset negative effects of transfusion. These data stress the need for efforts in cancer patients to reduce transfusion requirements if needed.


Hyper-methylated miR-203 dysregulates ABL1 and contributes to the nickel-induced tumorigenesis.
Nickel compounds have been found to be carcinogenic based upon epidemiological, animal and cell culture studies. Previous studies suggest that epigenetic mechanisms play a role in Nickel-induced carcinogenesis such as DNA methylation and histone modification. In this study, we investigated the role of microRNAs (miRNAs) in nickel-induced carcinogenesis. The expression of several miRNAs which may function as tumor suppressor genes revealed a strong downregulation of miR-203 in Ni3S2-transformed 16HBE cells (NSTCs). Meanwhile, we observed hypermethylation of CpGs in miR-203 promoter and first exon area, and proved that the hyper-methylated miR-203 was involved in the Nickel-induced tumorigenesis. Moreover, we identified that miR-203 may suppress the tumorigenesis at least in part through negatively regulating its target gene ABL1. Our findings indicate that DNA methylation-associated silencing of tumor suppressor miRNAs contributes to the development of Nickel-induced cancer.


Impaired platelet function in a patient with P2Y12 deficiency caused by a mutation in the translation initiation codon.
In this study, we have identified a patient (OSP-1) with a congenital P2Y12 deficiency showing a mild bleeding tendency from her childhood and examined the role of P2Y12 in platelet function. At low concentrations of agonists OSP-1 platelets showed an impaired aggregation to several kinds of stimuli, whereas at high concentrations they showed a specifically impaired platelet aggregation to adenosine diphosphate (ADP). ADP normally induced platelet shape change and failed to inhibit PGE1-stimulated cAMP accumulation in OSP-1 platelets. Molecular genetic analysis revealed that OSP-1 was a homozygous for a mutation in the translation initiation codon (ATG to AGG) in the P2Y12 gene. Heterologous cell expression of wild-type or mutant P2Y12 confirmed that the mutation was responsible for the deficiency in P2Y12. OSP-1 platelets showed a markedly impaired platelet spreading onto immobilized fibrinogen. Real-time observations of thrombogenesis under a high shear rate (2000 s(-1)) revealed that thrombi over collagen were small and loosely packed and most of the aggregates were unable to resist against high shear stress in OSP-1. Our data suggest that secretion of endogenous ADP and subsequent P2Y12-mediated signaling are critical for platelet aggregation, platelet spreading, and as a consequence, for stabilization of thrombus.


Activation of a T-box-Otx2-Gsc gene network independent of TBP and TBP-related factors.
Embryonic development relies on activating and repressing regulatory influences that are faithfully integrated at the core promoter of individual genes. In vertebrates, the basal machinery recognizing the core promoter includes TATA-binding protein (TBP) and two TBP-related factors. In Xenopus embryos, the three TBP family factors are all essential for development and are required for expression of distinct subsets of genes. Here, we report on a non-canonical TBP family-insensitive (TFI) mechanism of transcription initiation that involves mesoderm and organizer gene expression. Using TBP family single- and triple-knockdown experiments, α-amanitin treatment, transcriptome profiling and chromatin immunoprecipitation, we found that TFI gene expression cannot be explained by functional redundancy, is supported by active transcription and shows normal recruitment of the initiating form of RNA polymerase II to the promoter. Strikingly, recruitment of Gcn5 (also known as Kat2a), a co-activator that has been implicated in transcription initiation, to TFI gene promoters is increased upon depletion of TBP family factors. TFI genes are part of a densely connected TBP family-insensitive T-box-Otx2-Gsc interaction network. The results indicate that this network of genes bound by Vegt, Eomes, Otx2 and Gsc utilizes a novel, flexible and non-canonical mechanism of transcription that does not require TBP or TBP-related factors.


Concepts, questions and goals in general practice. Are you asking the right questions?
The author has developed a set of questions that can be used as a guide to planning a thoughtful consultation: one that will lead to improved diagnostic and management decisions.


Expression profiles of mRNA transcript variants encoding the human inhibitor of growth tumor suppressor gene family in normal and neoplastic tissues.
The INhibitor of Growth (ING) tumor suppressor gene family is important in regulating cell fate and reads the epigenetic code by interacting specifically with methylated histone H3. Several transcript variants are expressed from the five ING genes but nomenclature for these variants are not consistent in the literature, and very little is known regarding transcript variant expression in normal human tissues and during development. Here we propose a standardized nomenclature for human ING gene family transcript variants and present an expression analysis using real-time quantitative PCR. We establish the steady-state levels of eleven human ING mRNA transcript variants across several fetal, adult, and tumor tissues as well as in cancer-derived cell lines. Consistent with their roles as type II tumor suppressors, we find up to 10,000-fold reduction in many transcript variants in a subset of neoplastic cells. We also find considerable variation in expression levels in different tissues, with up to 1 million-fold higher expression of some ING transcripts in adult, compared to fetal counterparts, particularly in the brain cerebral cortex. These results show differential expression of specific subsets of ING1-5 transcript variants in tissues that may influence the degree to which these variants contribute to epigenetic regulation in cancer and development.


Self-Curing Glass Ionomer Cement Covered by Photopolymerizable Adhesive for Protection of Mucoperiosteal or Gingival Flap Sutures in Canine Oral Surgery.
Periodontal disease is one of the main affections of the oral cavity of dogs. Its main complication is the formation of periapical abscess, which, when affecting the maxillary canine teeth, can lead to the formation of oronasal fistulae. The objective of this study was to evaluate the efficiency of self-curing glass ionomer cement, covered by photopolymerizable adhesive, as a protective element for mucoperiosteal or gingival flap sutures in oral surgery of dogs. We studied 15 dogs from the clinical routine of the dental service of a teaching veterinary hospital, which needed oral surgeries to correct oronasal fistulae, defects or oral cavity communications, regardless of the causal agent. Group one (G1) was composed of seven animals that presented oronasal fistulae after the extraction of maxillary canine teeth compromised by severe periodontal disease. These fistulae were reduced by the double-mucoperiosteal-flap technique, 15 days after the dental extraction. Group two (G2) was composed of five other dogs that presented oronasal fistulae after the extraction of maxillary canine teeth compromised by severe periodontal disease. In this group, the fistulae were reduced by the single-flap technique, immediately after the dental extraction. Group three (G3) was composed of three animals, two of which presented oronasal fistulae due to maxillary fracture and the third one after excision of oral neoplasia. In all groups, simple interrupted sutures were used with 3.0 nylon, and a thin layer of self-curing glass ionomer cement was applied immediately over the operated area. After cement's settling time, a thin layer of photopolymerizable adhesive was applied to the already polymerized cement. In G1, the protective cement was removed on average at 15 (±2) postoperative days, in G2 at 6 (±1) days and in G3 at 11 (±9) days. In the postoperative period, the animals received antibiotics and anti-inflammatory drugs, and they received their usual dry dog food diet. No Elizabethan collar or any other protective measure was used for suturing or the surgical wound. The result was healing of 100% of the oronasal fistulae, without suture dehiscence or the need for new surgical interventions. Thus, it was concluded that the use of self-curing glass ionomer cement covered by photopolymerizable adhesive was fully satisfactory, providing protection of sutures and surgical wounds and showing the potential for routine use in oral surgery in dogs.


Association between mean arterial pressure during the first 24 hours and hospital mortality in patients with cardiogenic shock.
The optimal MAP target for patients with cardiogenic shock (CS) remains unknown. We sought to determine the relationship between mean arterial pressure (MAP) and mortality in the cardiac intensive care unit (CICU) patients with CS. Using a single-center database of CICU patients admitted between 2007 and 2015, we identified patients with an admission diagnosis of CS. MAP was measured every 15 min, and the mean of all MAP values during the first 24 h (mMAP24) was recorded. Multivariable logistic regression determined the relationship between mMAP24 and adjusted hospital mortality. We included 1002 patients with a mean age of 68 ± 13.7 years, including 36% females. Admission diagnoses included acute coronary syndrome in 60%, heart failure in 74%, and cardiac arrest in 38%. Vasoactive drugs were used in 72%. The mMAP24 was higher (75 vs. 71 mmHg, p < 0.001) among hospital survivors (66%) compared with non-survivors (34%). Hospital mortality was inversely associated with mMAP24 (adjusted OR 0.9 per 5 mmHg higher mMAP24, p = 0.01), with a stepwise increase in hospital mortality at lower mMAP24. Patients with mMAP24 < 65 mmHg were at higher risk of hospital mortality (57% vs. 28%, adjusted OR 2.0, 95% CI 1.4-3.0, p < 0.001); no differences were observed between patients with mMAP24 65-74 vs. ≥ 75 mmHg (p > 0.1). In patients with CS, we observed an inverse relationship between mMAP24 and hospital mortality. The poor outcomes in patients with mMAP24 < 65 mmHg provide indirect evidence supporting a MAP goal of 65 mmHg for patients with CS.


Diabetic retinopathy and the role of Omega-3 PUFAs: A narrative review.
Diabetes mellitus has been a major cause of concern for the past few decades. As the number of diabetic patients increases, so too does the occurrence of its complications. Diabetic retinopathy (DR) is one of these and constitutes the most common cause of blindness amongst working-age individuals. Chronic exposure to a hyperglycaemic environment remains the driving force of a cascade of molecular events that disrupt the microvasculature of the retina and if left untreated can lead to blindness. In this review, we identify oxidative stress as a major implication in the pathway to the development of DR and speculate that it plays a central role especially in the early stages of the disease. Cells lose their antioxidant capacity under a hyperglycaemic state, free radicals are formed and eventually apoptosis ensues. The polyol pathway; advanced glycation end-product formation; the protein kinase C pathway, and the hexosamine pathway are found to contribute to the increase in oxidative stress observed in diabetic patients. We also investigate the use of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in DR. These molecules possess antioxidant and anti-inflammatory properties and have been previously investigated for use in other ocular pathologies with promising results. In this review we present the latest findings in pre-clinical and clinical studies for the use of ω-3 PUFAs in DR. We hypothesise that ω-3 PUFAs could be beneficial for DR in ways of reducing the oxidative stress and limiting the progression of the disease that threatens the eyesight of the patient, in conjunction with conventional therapy.


Nystagmus-related FRMD7 gene influences the maturation and complexities of neuronal processes in human neurons.
Idiopathic congenital nystagmus (ICN) is an oculomotor disorder caused by the defects in the ocular motor control regions of the brain. Mutations in FRMD7, a member of the FERM family of proteins, associated with cytoskeletal dynamics, are the most frequent causes of X-linked ICN. Previous studies illustrated that FRMD7 is involved in the elongation of neurites during neuronal development; however, almost all the studies were performed on mice cell models. The complexity in the human neuronal network might suggest a unique vulnerability of human neurons to FRMD7 mutations. Herein, we successfully established human neuronal cell models with FRMD7 mutations, from fibroblasts-reprogrammed neurons (iNs). In these neurons, the complexity of the neuronal processes was measured by the induced ratio, total neurite length, the number of terminals, and the number of maturation neurons. The complexity of the neuronal processes was greatly reduced during various reprogramming stages in the presence of FRMD7 mutations. Consistently, the expression of the three main Rho GTPases was significantly increased by FRMD7 mutations. Interestingly, a slightly diverse phenotype is observed in different derived neurons. We established ideal human neuron models and confirmed that the mutation in FRMD7 influences the maturation and complexities of neuronal processes, which might be involved with the Rho GTPase signaling.


[Study on PLB induction and proliferation of Dendrobium officinale].
To study on the optimal medium ingredients for PLB induction and proliferation of Dendrobium officinale. Seed embryos of Dendrobium officinale were cultivated in MS medium as the basic medium, along with different plant hormones like 6-BA, NAA,2,4-D and KT or their combinations added with organic additives like PE, BE, AE and CM. BA and NAA combination was not conductive to germination and the germination ratio was even lower than that of MS medium; 10% PE and CM was beneficial to PLB induction; 2,4-D was not conductive to growth and proliferation; A certain concentration of BA, KT and NAA was beneficial to PLB proliferation; KT at 1.0 mg/L recorded the highest 40 d PLB proliferation times at 9.0; PE, CM and AE could promote the PLB proliferation at different levels, among which 10% CM was the most effective. The optimized medium ingredients suitable for PLB induction are MS +10% CM +1.0g/L AC; The optimized medium ingredients suitable for PLB proliferation are MS + 1.0 mg/L KT + 0.2 mg/L NAA + 10% CM.


Pregabalin and gabapentin for the treatment of sciatica.
Whilst pregabalin (PGB) and gabapentin (GBP) are both used to treat neuropathic pain, their relative role in sciatica is unclear. Our aim was to extensively review the roles of PGB and GBP in treating sciatica. The efficacy, side effects (SE) profile and cost of PGB and GBP in neuropathic pain states were reviewed with special reference to sciatica. Eleven articles matched the criteria: seven systematic reviews, one retrospective cross-sectional study, one placebo-controlled-crossover study, one randomized placebo-controlled double-blind study and one case report. GBP and PGB appeared to demonstrate comparable efficacy and SE. However, the amount and quality of evidence was low, and only indirect comparisons were available. Importantly, no direct "head-to-head" study existed. Globally, costs varied widely (by up to 31 times) and unpredictably (PGB cheaper than GBP, or vice versa). Formulary regulator rulings were globally disparate; however, many exclusively favoured the more expensive drug (whether GBP or PGB). No studies assessed PGB-GBP interchange. Weak evidence suggests that efficacy and SE with GBP and PGB are probably similar; however, firm conclusions are precluded. Despite weak data, and having cited minor titration, but definite cost, advantages, UK National Institute for Health and Clinical Excellence favoured PGB over GBP. Given that no evidence supports unhindered PGB-GBP interchange, neither drug should probably be favoured. Prospective "head-to-head" studies are urgently required to provide robust evidence-based knowledge for choice of GBP or PGB in sciatica.


Prevention of preharvest aflatoxin contamination through genetic engineering of crops.
Current practices on prevention of aflatoxin contamination of crop species include time consuming, expensive agronomic practices. Of all the methods available to-date, conventional breeding and/or genetic engineering to develop host plant-based resistance to aflatoxin-producing fungi appear to be valuable for several reasons. However, breeding for disease-resistant crops is very time consuming, especially in tree crops, and does not lend itself ready to combat the evolution of new virulent fungal races. Moreover, availability of known genotypes with natural resistance to mycotoxin-producing fungi is a prerequisite for the successful breeding program. While it is possible to identify a few genotypes of corn or peanuts that are naturally resistant toAspergillus we do not know whether these antifungal factors are specific toA. flavus. In crops like cotton, there are no known naturally resistant varieties toAspergillus. Availability of transgenic varieties with antifungal traits is extremely valuable as a breeding tool. Several antifungal proteins and peptides are available for genetic engineering of susceptible crop species, thanks to the availability of efficient modern tools to understand and evaluate protein interactions by proteomics of host, and genomics and field ecology of the fungus. Transgenic approaches are being undertaken in several industry and academic laboratories to prevent invasion byAspergillus fungi or to prevent biosynthesis of aflatoxin. Recent trends in reducing aflatoxin contamination through genetic engineering of cultivated crop species with antifungal proteins are summarized in this report.


How did rehabilitation professionals act when faced with the Great East Japan earthquake and disaster? Descriptive epidemiology of disability and an interim report of the relief activities of the ten Rehabilitation-Related Organizations.
Inter-organizational coordination is important for rehabilitation disaster relief. The 2011 Great East Japan Earthquake and Disaster was unprecedented, being geographically widespread and multifaceted. Faced with the crisis, rehabilitation professionals established the 10 Rehabilitation-Related Organizations of Rehabilitation Support Service (10-RRO). The objectives of this paper are to provide descriptive epidemiology and assess the activities of 10-RRO. Descriptive. Epidemiological data on disability were collected, mainly from official sources. Relief activities were reviewed from daily reports, and the preparedness, initial response and functioning of 10-RRO were assessed with a questionnaire directed at 36 executives of individual organizations. The disaster was characterized by a very low ratio of injuries to death of 0.372, and an odds ratio of deaths among disabled persons of 2.32. 10-RRO provided relief activities at 3 shelters. The total number of dispatch days ranged from 107 to 146, and the cumulative number of professionals and evacuees served was 1,202 and 7,300, respectively. Support activities included prevention of immobilization, daily life support, environmental improvement and transition to temporary housing. The questionnaire survey revealed poor preparedness, satisfactory initial response and support activities, and problems of data collection and advocacy. The disaster was characterized by minimal trauma and a great need for preventing immobilization. This first collaborative endeavour was successful.


Maternal transfer and biodistribution of citrate and luminogens coated silver nanoparticles in medaka fish.
Given the wide applications of silver nanoparticles (AgNPs), it is necessary to evaluate their potentially adverse long-term effects. In this study, we performed a 100-day exposure of medaka fish to citrate and luminogens coated AgNPs and investigated the maternal transfer potentials and biodistribution of AgNPs. Following long-term AgNPs exposure, AgNPs were mainly distributed in the liver, followed by gills, intestine, and brain, but were also detected in the ovary and strongly colocalized with the dissolved Ag+. The quantified transfer efficiency of different Ag species was 1.56-5.07%. Long-term exposure of medaka to small size of AgNPs (20 nm) reduced the hatching rate attributable to the accumulation of AgNPs and their dissolved Ag+. The maternally transferred AgNPs were mainly concentrated in the Kupffer's vesicle of embryos, while their dissolved Ag+ was almost homogeneously distributed in the embryos. In contrast, the newly accumulated AgNPs were mainly absorbed at the chorion of embryos. During initial larval development, the maternally transferred AgNPs and their dissolved Ag+ were consistently concentrated in intestine. Significant dissolution of maternally transferred AgNPs occurred during larval development. Our results showed that long-term exposure to AgNPs caused distinct biodistribution in the next generation of medaka, and may have implications for assessing their potential adverse effects.


Ruptured left ventricular pseudoaneurysm in the mediastinum following acute myocardial infarction: a case report.
Left ventricular pseudoaneurysm is an uncommon complication after transmural acute myocardial infarction (AMI). Here we describe the case of a 43-year-old man who presented with AMI and chest distress despite the normal appearance of his coronary artery during coronary angiography. Timely thrombolytic therapy was administered. Echocardiography, and cardiac computed tomography showed a ventricular pseudoaneurysm, and direct visualization at the time of surgery showed that it had ruptured in the mediastinum instead of the pericardium. The survival rate of patients with ventricular pseudoaneurysm rupture is low. The rupture of ventricular pseudoaneurysm in the mediastinum is rare; therefore, this case is noteworthy.


Plasma metabolomics and network pharmacology identified glutamate, glutamine, and arginine as biomarkers of depression under Shuganjieyu capsule treatment.
Depression is a psychiatric disorder and confers an enormous burden on society. Mild to moderate forms of depression (MMD) are particularly common. Our previous studies showed that the Shuganjieyu (SGJY) capsule might improve depressive and cognitive symptoms in patients with MMD. However, biomarkers evaluating the efficacy of SGJY and the underlying mechanism remains unclear. The aim of the present study was to discover efficacy biomarkers and explore the underlying mechanisms of SGJY as antidepression treatment. Twenty-three patients with MMD were recruited and administered with SGJY for 8 weeks. Results showed that the content of 19 metabolites changed significantly in the plasma of patients with MMD, among which 8 metabolites improved significantly after SGJY treatment. Network pharmacology analysis showed that 19 active compounds, 102 potential targets, and 73 enzymes were related to the mechanistic action of SGJY. Through a comprehensive analysis, we identified four hub enzymes (GLS2, GLS, GLUL, and ADC), three key differential metabolites (glutamine, glutamate, and arginine), and two shared pathways (alanine, aspartate, and glutamate metabolism; and arginine biosynthesis). Receiver operating characteristic curve (ROC) analysis showed that the three metabolites had a high diagnostic ability. The expression of hub enzymes was validated using RT-qPCR in animal models. Overall, glutamate, glutamine, and arginine may be potential biomarkers for evaluating the efficacy of SGJY. The present study provides a new strategy for pharmacodynamic evaluation and mechanistic study of SGJY, and offers new information for clinical practice and treatment research.


Non-inferiority Testing for Risk Ratio, Odds Ratio and Number Needed to Treat in Three-arm Trial.
Three-arm non-inferiority (NI) trial including the experimental treatment, an active reference treatment, and a placebo where the outcome of interest is binary are considered. While the risk difference (RD) is the most common and well explored functional form for testing efficacy (or effectiveness), however, recent FDA guideline suggested measures such as relative risk (RR), odds ratio (OR), number needed to treat (NNT) among others, on the basis of which NI can be claimed for binary outcome. Albeit, developing test based on these different functions of binary outcome are challenging. This is because the construction and interpretation of NI margin for such functions are non-trivial extensions of RD based approach. A Frequentist test based on traditional fraction margin approach for RR, OR and NNT are proposed first. Furthermore a conditional testing approach is developed by incorporating assay sensitivity (AS) condition directly into NI testing. A detailed discussion of sample size/power calculation are also put forward which could be readily used while designing such trials in practice. A clinical trial data is reanalyzed to demonstrate the presented approach.


AQP1 expression alterations affect morphology and water transport in Schwann cells and hypoxia-induced up-regulation of AQP1 occurs in a HIF-1α-dependent manner.
Aquaporin-1 (AQP1) is the principle water channel in the peripheral nervous system (PNS) and is specifically localized to Schwann cells in the PNS. However, the pathophysiological role of AQP1 in peripheral nerves is poorly understood. Here, we utilized RNA interference by lentiviral transduction to specifically down-regulate AQP1 expression and a lentiviral overexpression protocol to up-regulate AQP1 expression, in primary Schwann cell cultures. AQP1 gene silencing resulted in a cell shrinkage phenotype, while AQP1 gene overexpression caused a cell swelling phenotype, as validated by cell volume determinations. Secondly, we utilized an in vitro hypoxia model in Schwann cells to mimic in vivo facial nerve injury. We demonstrated that AQP1 expression was induced within 8h following hypoxia injury in vitro, and that AQP1 knockdown (KD) caused the cells to resist edema following hypoxia. Finally, we investigated the hypoxic regulation of the AQP1 gene, as well as the involvement of Hypoxia-inducible factor-1α (HIF-1α) in AQP1 modulation and we found that KD of HIF-1α decreased hypoxia-dependent induction of endogenous AQP1 expression at both the mRNA and protein levels. Taken together, these results indicate that (1) AQP1 is an important factor responsible for the fast water transport of cultured Schwann cells and is involved in cell plasticity; (2) AQP1 alterations may be a primary factor in hypoxia-induced peripheral nerve edema; (3) HIF-1α participates in the hypoxic induction of the AQP1 gene; (4) AQP1 inhibition might provide a new therapeutic alternative for the treatment of some forms of peripheral nerve edema.


[On the Population Genetic Portrait of Kaluga, Acipenser dauricus Georgi, 1775 Analysis of Sequence Variation in the Mitochondrial DNA Control Region].
The variability of the mtDNA D-loop was examined in kaluga endemic to the Amur River, which is classified as critically endangered by the IUCN Red List of Threatened species. Sequencing of the D-loop fragment (819 bp) in 122 kaluga specimens collected in Lower Amur revealed 27 unique genotypes. The sample was characterized by a relatively low level of haplotypic (0.927) and nucleotide (0.0044) diversity. No considerable deviations from the neutral mutation model of DNA polymorphism were observed. Overall, the mismatch distribution patterns and the results of testing of simple demographic models (sudden demographic expansion and exponential population growth) pointed to a past increase in the number of kaluga sturgeons. According to the Bayesian skyline, the kaluga population doubled over the last two to three thousand years. The number of mature females in the modern kaluga population and the assessment of their long-term effective population size (Nef) are roughly at the same level (about three thousand individuals), which confirms the validity of assigning kaluga to the category of species on the brink of extinction.


Investigating the genetic components of tuber bruising in a breeding population of tetraploid potatoes.
Tuber bruising in tetraploid potatoes (Solanum tuberosum) is a trait of economic importance, as it affects tubers' fitness for sale. Understanding the genetic components affecting tuber bruising is a key step in developing potato lines with increased resistance to bruising. As the tetraploid setting renders genetic analyses more complex, there is still much to learn about this complex phenotype. Here, we used capture sequencing data on a panel of half-sibling populations from a breeding programme to perform a genome-wide association analysis (GWAS) for tuber bruising. In addition, we collected transcriptomic data to enrich the GWAS results. However, there is currently no satisfactory method to represent both GWAS and transcriptomics analysis results in a single visualisation and to compare them with existing knowledge about the biological system under study. When investigating population structure, we found that the STRUCTURE algorithm yielded greater insights than discriminant analysis of principal components (DAPC). Importantly, we found that markers with the highest (though non-significant) association scores were consistent with previous findings on tuber bruising. In addition, new genomic regions were found to be associated with tuber bruising. The GWAS results were backed by the transcriptomics differential expression analysis. The differential expression notably highlighted for the first time the role of two genes involved in cellular strength and mechanical force sensing in tuber resistance to bruising. We proposed a new visualisation, the HIDECAN plot, to integrate the results from the genomics and transcriptomics analyses, along with previous knowledge about genomic regions and candidate genes associated with the trait. This study offers a unique genome-wide exploration of the genetic components of tuber bruising. The role of genetic components affecting cellular strength and resistance to physical force, as well as mechanosensing mechanisms, was highlighted for the first time in the context of tuber bruising. We showcase the usefulness of genomic data from breeding programmes in identifying genomic regions whose association with the trait of interest merit further investigation. We demonstrate how confidence in these discoveries and their biological relevance can be increased by integrating results from transcriptomics analyses. The newly proposed visualisation provides a clear framework to summarise of both genomics and transcriptomics analyses, and places them in the context of previous knowledge on the trait of interest.


Echocardiography and fetal heart sounds in the diagnosis of fetal heart block.
A 32-week fetus was demonstrated phonocardiographically and echocardiographically to have a regular atrial rate of 150 per minute and a regular ventricular rate of 39 per minute, indicating complete heart block. The diagnosis was suspected when two groups of heart sounds at two distinct rates were heard on auscultation, and was confirmed by the postnatal ECG. The maternal history was significant for the presence of systemic lupus erythematosus. The basis for the echocardiographic diatnosis of complete heart block, the presence of atrial heart sounds in complete heart block, and the relationship of maternal SLE to congenital heart block are discussed.


A high-throughput 3-D composite dielectrophoretic separator.
Dielectrophoresis has great potential to offer a range of diverse fields from bioprocessing to clinical medicine, but is hampered by low throughput rates to the micrometer scale of the electrodes required to generate highly nonuniform fields. Here we describe a novel approach to electrode construction, using a drilled laminated structure to form channels bearing electrodes 30 microm across and 150 microm apart. Since these electrodes appear along all sides of the drilled bore, the trapping efficiency is improved over conventional devices. We have developed and demonstrated a separator capable of sorting a 50:50 mixture of viable and nonviable yeast cells into an 86:14 mixture at 25 mLhr(-1).


Long-term safety of dichloroacetate in congenital lactic acidosis.
We followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies of the E1α subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or respiratory chain complexes I (1 patient), IV (3 patients) or I+IV (1 patient) who received oral dichloroacetate (DCA; 12.5 mg/kg/12 h) for 9.7 to 16.5 years. All subjects originally participated in randomized controlled trials of DCA and were continued on an open-label chronic safety study. Patients (1 adult) ranged in age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean ± SD: 23.5 ± 10.9 years). Subjects were either normal or below normal body weight for age and gender. The 3 PDC deficient patients did not consume high fat (ketogenic) diets. DCA maintained normal blood lactate concentrations, even in PDC deficient children on essentially unrestricted diets. Hematological, electrolyte, renal and hepatic status remained stable. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of DCA in 3 patients, although symptomatic worsening of peripheral neuropathy did not occur. We conclude that chronic DCA administration is generally well-tolerated in patients with congenital causes of lactic acidosis and is effective in maintaining normal blood lactate levels, even in PDC-deficient children not consuming strict ketogenic diets.


Double-blind, multicenter, prospective randomized study of trospectomycin vs. Clindamycin, both with aztreonam, in non-community acquired obstetric and gynecologic infections.
The purpose of this study was to compare the clinical efficacy and safety of trospectomycin sulfate with that of clindamycin phosphate, both with aztreonam, for the treatment of obstetric and gynecologic infections. In a double-blind, multicenter, prospective randomized study, 579 patients with either endometritis following cesarean delivery or pelvic cellulitis following hysterectomy were enrolled and received medication. Administered was either trospectomycin sulfate 500 mg IV every 8 h or clindamycin phosphate 900 mg IV every 8 h in a 1:1 randomization ratio. Both groups of patients received aztreonam 1 g IV every 8 h. The patients were followed for clinical responses and side effects. The cure rate for the trospectomycin sulfate arm was 91.8% and for clindamycin phosphate arm it was 88.4% (P = 0.218). The adverse events were similar in both groups. Trospectomycin was as effective as clindamycin, when both were combined with aztreonam, in treatment of obstetric and gynecologic infections.


Effects of calcium-antagonistic coronary vasodilators, nifedipine and verapamil, on ventricular automaticity of the dog.
In isolated, blood-perfused canine papillary muscles intra-arterial injection of calcium-antagonistic coronary vasodilators, nifedipine and verapamil, produced a dose-related decrease in force of contraction. The ventricular rate of about 40 beats/min was not significantly changed by nifedipine even in doses which profoundly decreased the force of contraction. Verapamil changed the ventricular rate in a biphasic manner, but the changes remained as small as about 10% of the basal rate in doses which markedly suppressed the force of contraction. Calcium chloride elicited an increase in force of contraction but depressed automaticity. The present results show that in response to nifedipine, verapamil and calcium ions, ventricular automaticity has characteristics different from those of the sinus node.


Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients.
Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma. From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy. Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05). (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.


RNA-loaded CD40-activated B cells stimulate antigen-specific T-cell responses in dogs with spontaneous lymphoma.
Cell-based vaccination strategies to induce functional tumor-specific T cells in cancer patients have focused on using autologous dendritic cells. An alternative approach is to use RNA-loaded CD40 activated B cells (CD40-B) that are highly efficient antigen-presenting cells capable of priming naive T cells, boosting memory T-cell responses and breaking tolerance to tumor antigens. The use of tumor RNA as the antigenic payload allows for gene transfer without viruses or vectors and permits major histocompatibility complex (MHC)-independent, multiple-antigen targeting. Here, we use CD40L transfected K562 cells to generate functional CD40-B cells from the peripheral blood of humans and dogs. Testing of RNA-loaded CD40-B cells in dogs allows not only for its development in veterinary medicine but also for determination of its safety and efficacy in a large animal model of spontaneous cancer prior to initiation of human clinical trials. We found that CD40-B cells from healthy humans, healthy dogs and tumor-bearing dogs express increased levels of immune molecules such as MHC and CCR7. Moreover, RNA-loaded CD40-B cells induce functional, antigen-specific T cells from healthy dogs and dogs with lymphoma. These findings pave the way for immunotherapy trials using tumor RNA-loaded CD40-B cells to stimulate antitumor immunity in a large animal model of spontaneous neoplasia.


Quality of everyday life in long stay institutions for the elderly. An observational study of long stay hospital and nursing home care.
The observational study reported here was part of a wider evaluation of long stay care for elderly people. The observational study showed that it was essential not to rely on interview material alone. Qualitative techniques provided insights into behaviours, moods and interactions which would have been difficult to measure using traditional survey techniques. The data collected was analysed in relation to the theory of the total institution and disengagement theory. Although the survey data presented evidence of block treatment of individuals in both long stay hospital wards and smaller nursing homes for the elderly, the observational study showed that only the ward setting conformed closely to Goffman's concept of the total institution. In addition, the study indicated that involvement in activities and interaction with others promotes positive feelings among elderly people, and questions the validity of disengagement theory.


Mothers' physical interventions in toddler play in a low-income, African American sample.
This mixed method study examined 28 low-income African American mothers' physical interventions in their 14-month-old toddlers' play. Inductive methods were used to identify six physical intervention behaviors, the affect accompanying physical interventions, and apparent reasons for intervening. Nonparametric statistical analyses determined that toddlers experienced physical intervention largely in the context of positive maternal affect. Mothers of boys expressed highly positive affect while physically intervening more than mothers of girls. Most physically intervening acts seemed to be motivated by maternal intent to show or tell children how to play or to correct play deemed incorrect. Neutral affect was the most common toddler affect type following physical intervention, but boys were more likely than girls to be upset immediately after physical interventions. Physical interventions intended to protect health and safety seemed the least likely to elicit toddler upset.


Homocysteine Exposure Impairs Myocardial Resistance to Ischaemia Reperfusion and Oxidative Stress.
Hyperhomocysteinaemia is recognised as a strong independent risk factor for developing cardiovascular disease. This study investigated how an acute homocysteine dose affected cardiac performance during ischaemia reperfusion and cardiomyocyte contractility and morphology under normal conditions and during oxidative stress. Cardiac function was measured in isolated and perfused rat hearts before and after 40 minutes' global normothermic ischaemia. Where used, 0.1 mM L-homocysteine was present prior to, and throughout ischaemia, before wash out after 10 minutes' reperfusion. Calcium transients under normal conditions and changes in contractile synchronicity during oxidative stress (exposure to 0.2 mM H2O2) were measured in freshly isolated rat cardiomyocytes incubated for 60 minutes ± 0.1 mM L-homocysteine. During ischaemia reperfusion 0.1 mM L-homocysteine significantly reduced the rate pressure product during reperfusion (10,038 ± 749 vs. 5955 ± 567 mmHg bpm, p < 0.001), but did not affect time to ischaemic contracture. Incubation of freshly isolated cardiomyocytes with 0.1 mM L-homocysteine significantly decreased the amplitude of the calcium transient and slowed the time to half relaxation. These findings suggest that homocysteine exposure affected myocardial recovery from ischaemia and contractile homeostasis although the exact mechanisms for these changes remain to be determined.


Duodeno-renal fistula due to a nasogastric tube in a neonate.
Major complications due to nasogastric tubes (NGT) are uncommon. Esophageal and duodenal perforations have been described. We describe a newborn in whom a NGT led to a duodenal perforation, causing duodeno-renal fistula.


Maternal hepatic and embryonic effects of 1,2,4-trichlorobenzene in the rat.
The possible maternal hepatic and reproductive effects of 1,2,4-trichlorobenzene (TCB) were assessed in rats given 0, 36, 120, 360, and 1200 mg/kg/day of TCB on Days 9-13 of gestation. The animals were sacrificed on Day 14 of pregnancy. Maternal deaths (2/9 rats, 6/6 rats) were recorded in the 360 and 1200 mg/kg/day treatment groups and body weight gain was significantly decreased in the 360 mg/kg/day TCB group. Maternal liver weight, liver/body weight ratio, and hepatic microsomal protein content were unaffected by TCB treatment. Although Day 14 NADPH-cytochrome c reductase activity was affected only at 360 mg/kg/day TCB, the maternal hepatic microsomal cytochrome P-450 content was significantly increased by administration of both 120 and 360 mg/kg/day of TCB. Hepatic microsomal aminopyrine N-demethylase, ethoxyresorufin O-deethylase, and UDP-glucuronyl transferase activity towards p-nitrophenol were also increased at 120 and 360 mg/kg TCB. Glutathione S-transferase activity to 1-chloro-2,4-dinitrobenzene and 1,2 dichloro-4-nitrobenzene were both increased by pretreatment with TCB. Although pretreatment with 360 mg/kg/day TCB did not increase resorptions, embryolethality, or teratogenicity, embryonic development was significantly retarded by all four growth criteria used (head length, crown-rump length, somite number, and protein content).


The Relationship between Social Support and Secondary Posttraumatic Growth among Health Care Providers Working with Trauma Victims-The Mediating Role of Cognitive Processing.
Individuals, who help trauma victims as part of their professional responsibilities, may experience positive effects of their work, occurring in the form of Secondary Posttraumatic Growth (SPTG). Its determinants include environmental factors such as social support, and individual characteristics, particularly cognitive processing of the trauma. The purpose of this study was to determine the associations between SPTG and social support and cognitive processing of trauma, also considered as a mediator, in a group of medical personnel exposed to secondary trauma. The results of 408 participants, paramedics and nurses, were analyzed. Three measurement tools were used: the Secondary Posttraumatic Growth Inventory, the Social Support Scale measuring four sources of support and the Cognitive Trauma Processing Scale to assess five cognitive coping strategies. The results indicated that SPTG was positively related to social support and cognitive coping strategies. Cognitive coping strategies act as a mediator in the relationship between social support and SPTG. Despite their exposure to secondary traumatization, paramedics and nursing staff experience positive consequences of their work related to helping injured people. In order to promote growth after trauma, it is advisable to encourage medical representatives to use social support and primarily positive coping strategies.


Chemical constituents from the leaves of Psidium guajava.
Five constituents including one new pentacyclic triterpenoid guajanoic acid (1) and four known compounds beta-sitosterol (2), uvaol (3), oleanolic acid (4), and ursolic acid (5) have been isolated from the leaves of Psidium guajava. The new constituent 1 has been characterized as 3beta-p-E-coumaroyloxy-2alpha-methoxyurs-12-en-28-oic acid through 2D NMR techniques and chemical transformations. This is the first report of isolation of compound 3 from the genus Psidium.


Time to develop chronic kidney disease in an Ecuadorian Type 2 Diabetes Mellitus cohort: Survival analysis in primary care.
Chronic Kidney Disease (CKD) represents a high burden to health systems. However, the survival time for CKD in a Type 2 Diabetes Mellitus (T2DM) population is unknown. Determine the risk factors, survival time and the incidence rate of CKD in T2DM. Retrospective clinical cohort study (follow up 10 years). 513 patients with T2DM were included. Numerical variables were compared using the mean difference. Chi squared and odds ratios were calculated for categorical variables. Survival analysis was done through life tables and Kaplan-Meier. The mean difference between the group that developed CKD and those who did not, was significant in: age, age at diagnosis of T2DM and years with T2DM. Risk factors for developing CKD were: the presence of hypertension, albuminuria, retinopathy, high triglycerides and high HbA1c. The incidence rate was 32.07 per 1000 person-years of follow-up and 207 (40.4%) of patients developed CKD during the study. The median for developing CKD was 20.52 years of disease with an increasing risk with time. Half of the patients with T2DM will develop CKD by the second decade of disease. Time, arterial hypertension, retinopathy, albuminuria and triglycerides are factors associated with CKD in patients with T2DM.


Identification and in silico analysis of functional SNPs of the BRCA1 gene.
Single-nucleotide polymorphisms (SNPs) play a major role in the understanding of the genetic basis of many complex human diseases. Also, the genetics of human phenotype variation could be understood by knowing the functions of these SNPs. It is still a major challenge to identify the functional SNPs in a disease-related gene. In this work, we have analyzed the genetic variation that can alter the expression and the function of the BRCA1 gene using computational methods. Of the total 477 SNPs, 65 were found to be nonsynonymous (ns) SNPs. Among the 14 SNPs in the untranslated region, 4 were found in the 5' and 10 were found in the 3' untranslated region (UTR). It was found that 16.9% of the nsSNPs were damaging, by both the SIFT and the PolyPhen servers. The UTR Resource tool suggested that 2 of 4 SNPs in the 5' UTR and 3 of 10 SNPs in the 3' UTR might change the protein expression levels. We identified major mutations from proline to serine at positions 1776 and 1812 of the native protein of the BRCA1 gene. From a comparison of the stabilizing residues of the native and mutant proteins, we propose that an nsSNP (rs1800751) could be an important candidate for the breast cancer caused by the BRCA1 gene.


Revascularization of skeletal muscle transplanted into the hamster cheek pouch: electron microscopy.
Revascularization of bundles of skeletal muscle fibers transplanted into the cheek pouch of hamsters was examined previously by intravital and light microscopy. Some blood vessels survived the ischemia of transplantation and revascularization resulted from the growth of surviving vessels. We have now examined the cellular events of graft revascularization by electron microscopy (EM). Approximately 20 skeletal muscle fibers were autografted into the hamster cheek pouch. Segments of the graft were prepared for EM from 0.5 to 5 days after transplantation. At 0.5 day, the endothelial cells of surviving blood vessels had short processes extending from them. By 1.0 day, some endothelial cells had separated. At 1.5 days, many endothelial cells were undergoing mitosis. Blood vessels at 2 to 2.5 days were of narrow diameter and most were densely packed with erythrocytes. Circulation was reestablished between 2.5 and 3 days. The fine structure of the blood vessels changed little after 3 days except for a decrease in the number of vesicles in the endothelial cell cytoplasm and the formation of normal endothelial cell injections. After 5 days, blood vessels were larger in diameter, but otherwise similar to control capillaries. We conclude that, despite the initial absence of circulation, surviving blood vessels underwent a rapid, orderly sequence of growth.


Suture technicians in a children's hospital emergency department.
A program that employs technicians for suturing lacerations is presented. Careful selection of the candidates, intensive training, and ongoing monitoring of their activities have been major factors in the success of the program. The curriculum of a course for suture technicians and their job description are discussed.


Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior and physiology.
Mescaline and phencyclidine (PCP) are potent hallucinogenic agents affecting human and animal behavior. As their psychotropic effects remain poorly understood, further research is necessary to characterize phenotypes they evoke in various animal models. Zebrafish (Danio rerio) are rapidly emerging as a new model organism for neuroscience research. Here, we examine the effects of mescaline (5-20mg/l) and PCP (0.5-3mg/l) in several zebrafish paradigms, including the novel tank, open field and shoaling tests. Mescaline and PCP dose-dependently increased top activity in the novel tank test, also reducing immobility and disrupting the patterning of zebrafish swimming, as assessed by ethograms. PCP, but not mescaline, evoked circling behavior in the open field test. At the highest doses tested, mescaline markedly increased, while PCP did not affect, zebrafish shoaling behavior. Finally, 20mg/l mescaline did not alter, and 3mg/l PCP elevated, whole-body cortisol levels. Overall, our studies indicate high sensitivity of zebrafish models to hallucinogenic compounds with complex behavioral and physiological effects.


MedML: Fusing medical knowledge and machine learning models for early pediatric COVID-19 hospitalization and severity prediction.
The COVID-19 pandemic has caused devastating economic and social disruption. This has led to a nationwide call for models to predict hospitalization and severe illness in patients with COVID-19 to inform the distribution of limited healthcare resources. To address this challenge, we propose a machine learning model, MedML, to conduct the hospitalization and severity prediction for the pediatric population using electronic health records. MedML extracts the most predictive features based on medical knowledge and propensity scores from over 6 million medical concepts and incorporates the inter-feature relationships in medical knowledge graphs via graph neural networks. We evaluate MedML on the National Cohort Collaborative (N3C) dataset. MedML achieves up to a 7% higher AUROC and 14% higher AUPRC compared to the best baseline machine learning models. MedML is a new machine learnig framework to incorporate clinical domain knowledge and is more predictive and explainable than current data-driven methods.


Identification of a novel phylogenetic lineage of Alternaria alternata causing citrus brown spot in China.
Alternaria alternata sensu lato, casual agent of citrus brown spot, first identified in Yunnan province in 2010 and subsequently found in Zhejiang, Hunan, Guangdong provinces, Chongqing municipality andGuangxi autonomous region in China. During 2010-2012, 86 isolates were collected from diseased citrus, of which 85 % isolates were pathogenic to Ponkan tangerine. Phylogenetic analyses of Chinese and worldwide isolates using partial sequences of an endopolygalacturonase gene (endoPG) and combined dataset ofendoPG and two anonymous loci (OPA1-3, OPA2-1) found that Chinese isolates fell into two of three previously described clades. One clade ('clade 3') contained isolates from Turkey and Israel, and the other clade ('clade 1') contained isolates from Florida, USA. None of the isolates from China fell into the last previously described clade ('clade 2'). However, 24 isolates from Hunan, Guangdong and Guangxi fell into a fourth clade ('clade 4') not previously reported to be associated with citrus brown spot. This clade included multilocus haplotypes known to infect Japanese pear and strawberry. The observation that Chinese brown spot isolates fell into only two of three known worldwide lineages suggests that this fungus may not have co-evolved with its host in China but elsewhere in Southeast Asia and introduced to China.


The Role of Lipidomics in Autism Spectrum Disorder.
Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome commonly diagnosed in early childhood; it is usually characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal with loss in communication skills. Its development may be affected by a variety of environmental and genetic factors. Trained physicians diagnose and evaluate the severity of ASD based on clinical evaluations of observed behaviors. As such, this approach is inevitably dependent on the expertise and subjective assessment of those administering the clinical evaluations. There is a need to identify objective biological markers associated with diagnosis or clinical severity of the disorder. Several important issues and concerns exist regarding the diagnostic competence of the many abnormal plasma metabolites produced in the different biochemical pathways evaluated in individuals with ASD. The search for high-performing bio-analytes to diagnose and follow-up ASD development is still a major target in medicine. Dysregulation in the oxidative stress response and proinflammatory processes are major etiological causes of ASD pathogenesis. Furthermore, dicarboxylic acid metabolites, cholesterol-related metabolites, phospholipid-related metabolites, and lipid transporters and mediators are impaired in different pathological conditions that have a role in the ASD etiology. A mechanism may exist by which pro-oxidant environmental stressors and abnormal metabolites regulate clinical manifestations and development of ASD.


Detection of enteroviruses in urban sewage by next generation sequencing and its application in environmental surveillance.
Environmental surveillance has been used successfully in monitoring enterovirus (EV) circulation; however cell culture method may introduce a selective bias in those EV strains that are recovered from the environment. In this study, urban sewage samples were collected monthly in Jinan, China in 2018 and concentrated via membrane adsorption/elution method. A P1 seminested RT-PCR (RT-snPCR) and NGS method was developed, by which amplicons of 4000 nucleotide in length covering the entire P1 region of EVs were obtained from sewage concentrates and were further analyzed by next generation sequencing (NGS). In addition, for each sewage concentrate, two other assays - cell culture and NGS based partial VP1 amplicon sequencing - were conducted in parallel and compared. The results showed that the P1 RT-snPCR and NGS method generated the most data, with 32 serotypes identified belonging to species EV-A (n = 11), EV-B (n = 14), and EV-C (n = 7). These serotypes covered all those detected from the methods of cell culture (n = 10) and partial VP1 amplicon sequencing (n = 16). EV serotypes from acute flaccid paralysis surveillance correlated with those from sewage. Phylogenetic analysis on coxsackievirus B5, a common pathogen of meningitis, revealed close genetic relationship between environmental and clinical sequences. These results demonstrate sewage contains different EVs related to a variety of diseases. Traditional cell culture method underestimates the existence of some serotypes. NGS based environmental surveillance provides data which are consistent with those from clinical diseases, greatly improves our understanding on the actual circulation in the population, and should be encouraged for public health surveillance.


The effect of oxidant stress on diamide-treated human granulocytes.
The role of sulfhydryls in the protection of human polymorphonuclear neutrophils against extracellular oxidant attack was investigated by simultaneously exposing polymorphonuclear neutrophils to the thiol-oxidizing agent diamide and the oxidant-generating system xanthine-xanthine oxidase. Neither diamide nor the oxidants generated by the xanthine-xanthine oxidase system alone impaired the burst in chemiluminescence, hexose monophosphate shunt activity or formate oxidation normally seen during polymorphonuclear neutrophil phagocytosis. Incubation of the polymorphonuclear neutrophils simultaneously with diamide and xanthine-xanthine oxidase markedly impaired polymorphonuclear neutrophil phagocytosis, hexose monophosphate shunt activity, chemiluminescence and formate oxidation. Although the polymorphonuclear neutrophils exposed to diamide and xanthine-xanthine oxidase did not respond to a variety of phagocytizable stimuli, trypan blue exclusion was normal and hexose monophosphate shunt activity could be stimulated by diamide. The damaging effect of the diamide xanthine-xamthine oxidase system could be blocked by the addition of superoxide dismutase or catalase, but not by hydroxyl radical or singlet oxygen scavengers. We hypothesize that an unidentified population of thiols may play a role in protecting the polymorphonuclear neutrophil from endogenously derived oxidants.


Antibiotic exposure within six months before systemic therapy was associated with lower cancer survival.
The objective of the study was to quantify associations between cancer survival and antibiotic exposure before systemic anticancer therapy. This population-based cohort study compares cause-specific survival according to antibiotic exposure before non-immune checkpoint inhibitor (ICI) systemic therapy in patients diagnosed with single primary cancers in New South Wales between 2013 and 2016. Proportional hazards regression was used to control for confounding, with no antibiotic exposure in the six months before non-ICI systemic therapy serving as the comparator. After adjusting for tumour spread, cancer site, age, sex and comorbidity, people having antibiotic exposure within 180 days before non-ICI systemic therapy had poorer cancer survival (hazard ratios ranging from 1.21 [95% confidence interval: 1.06-1.39] to 1.58 [1.34-1.87]) for shorter periods since antibiotic exposure (P < .0001). Similarly, poorer survival trends applied for localized and metastatic cancer. Of six prevalent cancers studied, lung and breast primaries showed the strongest associations of lower survival with prior antibiotic exposure. Antibiotic exposure within 180 days before non-ICI systemic cancer treatment is associated with poorer survival. If confirmed in other studies, it provides another reason for vigilant antibiotic stewardship.


Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila.
In mammals, members of the tumor necrosis factor (TNF) family play an important role in the regulation of cellular proliferation, differentiation and programmed cell death. We describe isolation and characterization of an orthologous ligand/receptor axis in Drosophila. The ligand, designated Eiger, is a type II membrane glycosylated protein, which can be cleaved at residue 145 and released from the cell surface as a soluble factor, thereby representing the first potential cytokine to be described in Drosophila. Eiger exists in two alternatively spliced isoforms, Eiger long (Eiger-L) and Eiger short (Eiger-s), both of which are expressed throughout development and in the adult. We also describe the isolation and characterization of a novel Drosophila member of the TNF receptor family, designated Wengen, which is a type I membrane protein that can physically interact with the recently described TRAF2 homolog dTRAF2. Both Eiger and Wengen are expressed in distinctive patterns during embryogenesis and Eiger is responsive to genotoxic stress. Forced expression of Eiger-L, Eiger-s or Wengen, caused apoptotic cell death which could be rescued by caspase inhibitors or the JNK phosphatase Puckered. In addition, Eiger-induced cell killing was attenuated by RNAi-mediated suppression of Wengen. Our results illustrate that Eiger and Wengen represent proximal components of an evolutionarily conserved TNF-like signaling pathway in Drosophila.


A self-activating nanovesicle with oxygen-depleting capability for efficient hypoxia-responsive chemo-thermo cancer therapy.
Hypoxia-activated prodrugs (HAPs) promise to mitigate side effects of conventional chemotherapy and to enable precise medication treatment. One challenge facing HAPs-based chemotherapy is prodrug failure in normoxic tumor region. However, current strategies to enhance tumor hypoxia rely on delivery of oxygen-consuming agents and external stimulation, which can impede the optimal application of HAPs. Herein, a novel self-activating nanovesicle, TH-302@BR-Chitosan NPs, is constructed by assembling bilirubin-chitosan conjugate (named as BR-Chitosan) with a HAP, TH-302. It is interesting to find that the BR-Chitosan shows the inherent oxygen-depleting performance, especially in the presence of over expressed H2O2 in tumor area, during which the BR-Chitosan can facily transform into biliverdin-chitosan (BV-Chitosan) and subsequently result in the disassembly of nanovesicles to release and activate the prodrug. Thus, this in situ strengthening hypoxia level of tumor can greatly promote the chemotherapy efficacy of HAPs. Moreover, as the oxidation derivatives of BR-Chitosan, BV-Chitosan exhibits intense absorbance at the range from long wavelength of visible region to near-infrared region, which can be acted as an effective photothermal agent for photothermal therapy (PTT). This biodegradable and self-activating nanovesicle with concise formulation demonstrates greatly enhanced synergistic therapeutic outcome in the activatable chemo-thermo combined therapy, showing much promising in future clinical transformation.


Urinary Tubular Injury Biomarkers Are Associated With ESRD and Death in the REGARDS Study.
Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and urinary kidney injury molecule-1 (uKIM-1) are established markers of subclinical acute kidney injury. In persons with reduced estimated glomerular filtration rate (eGFR) and albuminuria who are at high risk for end-stage renal disease (ESRD) and death, the associations of these urinary markers with incident ESRD or death is an area of active investigation. Among 1472 black and white participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study with eGFR ≤60 ml/min per 1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] cystatin, 2012) and albumin-to-creatinine ratio (ACR) ≥30 mg/g, we evaluated the associations of baseline uNGAL and uKIM-1 with progression to ESRD and all-cause death. Cox models were sequentially adjusted for urinary creatinine, traditional risk factors, C-reactive protein, ACR, and eGFR. There were 257 ESRD events and 819 deaths over a median follow-up of 5.7 and 6.5 years, respectively. In demographic adjusted models, higher levels of uNGAL were associated with increased risk of ESRD and death, but these associations were attenuated in fully adjusted models including baseline eGFR for both ESRD (hazard ratio [HR] = 1.06 per doubling, 95% confidence interval [CI] 0.98-1.14) and death (HR = 1.04, 95% CI = 1.00-1.08). Higher levels of uKIM-1 were associated with increased risk of ESRD and death in demographic-adjusted models, and although attenuated in fully adjusted models, remained statistically significant for both ESRD (HR = 1.24 per doubling, 95% CI = 1.08-1.42) and death (HR = 1.10, 95% CI =1.03-1.19). In this cohort of high-risk patients with baseline eGFR ≤60 ml/min per 1.73 m2 and albuminuria, renal tubular injury is associated with higher mortality and progression to ESRD. Further studies are necessary to investigate the mechanism underlying this increased risk.


Neonatal screening for alpha-1-antitrypsin deficiency.
The results of a neonatal screening programme for alpha-1-antitrypsin deficiency are presented. Cord blood samples with an alpha-1-antitrypsin concentration below 1.628 mg/ml, as measured by an enzyme-linked immunosorbent assay method, were phenotyped by isoelectric focusing in polyacrylamide gels. Abnormal phenotypes were found in 51% of this group as compared with 11.3% in a control group (P much less than 0.0001). Twenty subjects detected by the initial quantitative alpha-1-antitrypsin determination had a highly pathogenic phenotype (PiZZ, PiSS, PiSZ). In the control group only moderately affected individuals were found (PiMS, PiMZ).


The current status of treatment for colorectal cancer in China: A systematic review.
Colorectal cancer (CRC) is one of the most common cancers all over the world, but its epidemiology is obviously different in various regions. The treatment of CRC also has varying characteristics due to differences in economy, geography, disease onset, chemotherapy, and other factors, although international guidelines are used to guide the treatment of CRC in China. This paper summarizes the current status of CRC treatment, including surgical therapy, neoadjuvant radiotherapy and chemotherapy, postoperative chemotherapy, targeted therapy, maintenance therapy, and immunotherapy, according to the clinical situation in China, so as to provide better therapy and improve clinical practice for patients with CRC. This research shows that the treatment of colorectal cancer continues to progress, and the patient's efficacy and quality of life have improved.


Effect of CO2 cholangiography on post-ERCP cholangitis in patients with unresectable malignant hilar obstruction - a prospective, randomized controlled study.
Air cholangiogram has been used in patients with malignant hilar obstruction to reduce cholangitis after endoscopic retrograde cholangiopancreatography (ERCP). However, it still remains unclear whether CO2 could be used as an alternative for air cholangiography in such patients. To investigate the effect of CO2 cholangiogram on post-ERCP complications. Prospective, randomized controlled study. Tertiary care referral center. 36 patients with Bismuth type II, III or IV were randomized into CO2 group or iodine contrast group (control group). Cholangiography was performed by injection of either CO2 or iodine contrast through a sphincterotome. One or two metal stents were placed. Post-ERCP complications, length of hospital stay after ERCP, 1-month and 1-year mortality. There was no significant difference in age, gender, symptoms, liver function tests, type of tumor origin and Bismuth type between patients in CO2 and contrast groups (p > 0.05). Compared with one-stent placement, more volume of CO2 and longer operation time were observed when performing two-stent placement (both p < 0.05). The rate of cholangitis in CO2 group was significantly lower than that in control group (5.6% vs. 33.3%, p = 0.04). After ERCP, mean hospital stay time was shorter in CO2 group compared with control (p < 0.05). The difference of 1-month and 1-year mortality between two groups was not significant (both p > 0.05). CO2 cholangiogram could be a safe method to visualize intrahepatic bile duct with low incidence of post-ERCP cholangitis, which could be considered for the patients with malignant hilar obstruction.


Absence of non-specific effects of RNA interference triggered by long double-stranded RNA in mouse oocytes.
RNA interference (RNAi) is a conserved eukaryotic mechanism by which double-stranded RNA (dsRNA) triggers the sequence-specific degradation of homologous mRNAs. Recent concerns have arisen in mammalian systems about off-target effects of RNAi, as well as an interferon response. Most mammalian cells respond to long dsRNAs by inducing an antiviral response mediated by interferon that leads to general inhibition of protein synthesis and nonspecific degradation of mRNAs. Moreover, recent reports demonstrate that under certain conditions, short interfering RNAs (siRNAs, 21-25 bp) may activate the interferon system. Mouse oocytes and preimplantation embryos apparently lack this response, as potent and specific inhibition of gene expression triggered by long dsRNA is observed in these cells. In the present study, we analyzed the global pattern of gene expression by microarray analysis in transgenic mouse oocytes expressing long dsRNA and find no evidence of off-targeting. We also report that genes involved in the interferon response pathway are not expressed in mouse oocytes, even after exposure for an extended period of time to long dsRNA.


Induced-charge membrane capacitive deionization enables high-efficient desalination with polarized porous electrodes.
Exposure of a conducting porous material to an electric field in electrolytes induces an electric dipole, which results in capacitive charging of cations and anions at opposite poles. In this letter, we investigate a novel desalination method using this induced-charge capacitive deionization (ICCDI). To do this, we devise a microscale ICCDI platform that can visualize in situ ion concentrations, pH shifts, and fluid flows, and study ion transport dynamics and desalination performances compared to conventional CDI with unipolar / bipolar connections. Similar ion concentration and fluid flow characteristics were observed in Ohmic, limiting, and over-limiting regimes, but variations in desalination performance trends were noted based on the number of stacks. In a single cell, ICCDI generates a higher electric field at the opposite poles of porous electrodes than simple conducted electrodes in CDIs with unipolar/bipolar connections, leading to superior salt removal and/or lower ionic current at a given applied voltage. This marks a clear contrast from CDI with bipolar connection, which lacks any advantage over CDI with unipolar connection in a single cell. These metrics of ICCDI however deteriorated as the stack number increased, likely due to short-circuiting between the dipoles. As a result, ICCDI in current form shows higher desalination efficient than conventional CDIs with low stack numbers (< 6), so we offer the scale-up module by repeating 4-stack ICCDI units. Our study enhances comprehension of ion transport dynamics and desalination performance in ICCDI, and the results could aid in the development of ICCDI for energy/cost-efficient desalination.


Effect of patient choice and hospital competition on service configuration and technology adoption within cancer surgery: a national, population-based study.
There is a scarcity of evidence about the role of patient choice and hospital competition policies on surgical cancer services. Previous evidence has shown that patients are prepared to bypass their nearest cancer centre to receive surgery at more distant centres that better meet their needs. In this national, population-based study we investigated the effect of patient mobility and hospital competition on service configuration and technology adoption in the National Health Service (NHS) in England, using prostate cancer surgery as a model. We mapped all patients in England who underwent radical prostatectomy between Jan 1, 2010, and Dec 31, 2014, according to place of residence and treatment location. For each radical prostatectomy centre we analysed the effect of hospital competition (measured by use of a spatial competition index [SCI], with a score of 0 indicating weakest competition and 1 indicating strongest competition) and the effect of being an established robotic radical prostatectomy centre at the start of 2010 on net gains or losses of patients (difference between number of patients treated in a centre and number expected based on their residence), and the likelihood of closing their radical prostatectomy service. Between Jan 1, 2010, and Dec 31, 2014, 19 256 patients underwent radical prostatectomy at an NHS provider in England. Of the 65 radical prostatectomy centres open at the start of the study period, 23 (35%) had a statistically significant net gain of patients during 2010-14. Ten (40%) of these 23 were established robotic centres. 37 (57%) of the 65 centres had a significant net loss of patients, of which two (5%) were established robotic centres and ten (27%) closed their radical prostatectomy service during the study period. Radical prostatectomy centres that closed were more likely to be located in areas with stronger competition (highest SCI quartile [0·87-0·92]; p=0·0081) than in areas with weaker competition. No robotic surgery centre closed irrespective of the size of net losses of patients. The number of centres performing robotic surgery increased from 12 (18%) of the 65 centres at the beginning of 2010 to 39 (71%) of 55 centres open at the end of 2014. Competitive factors, in addition to policies advocating centralisation and the requirement to do minimum numbers of surgical procedures, have contributed to large-scale investment in equipment for robotic surgery without evidence of superior outcomes and contributed to the closure of cancer surgery units. If quality performance and outcome indicators are not available to guide patient choice, these policies could threaten health services' ability to deliver equitable and affordable cancer care. National Institute for Health Research.


Wearable accelerometers for measuring and monitoring the motor behaviour of infants with brain damage during CareToy-Revised training.
Nowadays, wearable sensors are widely used to quantify physical and motor activity during daily life, and they also represent innovative solutions for healthcare. In the clinical framework, the assessment of motor behaviour is entrusted to clinical scales, but they are dependent on operator experience. Thanks to their intrinsic objectivity, sensor data are extremely useful to provide support to clinicians. Moreover, wearable sensors are user-friendly and compliant to be used in an ecological environment (i.e., at home). This paper aims to propose an innovative approach useful to predict clinical assessment scores of infants' motor activity. Starting from data acquired by accelerometers placed on infants' wrists and trunk during playtime, we exploit the method of functional data analysis to implement new models combining quantitative data and clinical scales. In particular, acceleration data, transformed into activity indexes and combined with baseline clinical data, represent the input dataset for functional linear models. Despite the small number of data samples available, results show correlation between clinical outcome and quantitative predictors, indicating that functional linear models could be able to predict the clinical evaluation. Future works will focus on a more refined and robust application of the proposed method, based on the acquisition of more data for validating the presented models. ClincalTrials.gov; NCT03211533. Registered: July, 7th 2017. ClincalTrials.gov; NCT03234959. Registered: August, 1st 2017.


Prevalence of C-shaped root canals in Iranian population: a systematic review.
Because of the great challenges in the diagnosis and treatment of "C" configuration and lack of any systematic information about its occurrence, the purpose of the present study is to determine the prevalence of C shaped root canals in Iranian population. An exhaustive search was undertaken to identify published and unpublished researches related to the C-shaped canals by using key words. The search of the MEDLINE database included all publications from 1966 to May 2012.Then selected articles were obtained and reviewed. Data evaluated and summarized in the data sheet included methodology, population, number of teeth per study (power), number of root canals, type of root canal configuration, and c-shaped canals. Six studies were included with total of 1062 teeth, all in mandibular second molars. The total incidence of C-shaped canals in Iranian population was obtained 6.96%. The incidence of C-shaped canals in Iranian population is 6.96%, which seems much less than Asian populations but nearer to Middle East countries.


Do you have a good all-around view? Evaluation of a decision-making skills diagnostic tool using 360° videos and head-mounted displays in elite youth soccer.
Elite youth players' decision-making skills are considered important predictors of adult performance in soccer. The presentation of 360° videos in head-mounted displays offers new potential for the diagnostic of these skills in talent development programs. This study evaluated a new diagnostic tool using soccer-specific 360° videos for assessing decision-making skills in youth academy (YA) players. The evaluation consisted of players' subjective feedback as well as the analysis of diagnostic and prognostic validity. It was hypothesized that high-level YA players achieve better diagnostic results than regional-level players, and U19 outperform U17 players. Moreover, YA players' diagnostic results should be positively associated with future adult performance level. During the 2018/19 season, N = 48 youth players participated in the diagnostic procedures (split-half reliability r = .78). Participants were shown 54 videos which terminated when the central midfielder received a teammate's pass. Participants were then asked how to best continue playing. The subjective evaluation explored YA players' experiences with the diagnostic tool via quantitative ratings (e.g., "How exciting was the task?", "How involved did you feel in the game situation?") and additional interviews. Diagnostic validity was examined in a balanced cross-sectional 2 × 2-design (performance level x age group) and prognostic validity in a 3-year prospective design. Sensitivity and case-by-case analyses completed the evaluation. The YA players provided positive quantitative ratings regarding their experienced immersion into the environment. Players' qualitative feedback indicated general acceptance of the diagnostic tool as well as it offered recommendations for improvements. Confirming the diagnostic validity, ANOVA revealed significant main effects for performance level (p < .001, η2 = .29) and age group (p < .01, η2 = .14). Contributing to the prognostic validity, the diagnostic results discriminated between YA players achieving a higher and a lower adult performance level ("League 1-4" vs. "League 5 or below") in adulthood (p < .05; d = 0.80). A ROC curve and the AUC showed that the correct assignment to the adult performance levels is possible with a 71% probability. YA players with a high decision-making accuracy had a six times higher chance of playing in "League 1-4". The results demonstrated empirical evidence for the new diagnostic tool in terms of YA players' acceptance and validity coefficients exceeding effect sizes of former studies. The technology provides opportunities to test soccer-specific situations demanding an all-around view that were not testable in former experimental settings. Further technological advancements will enable the realization of improvements recommended by the players. Nonetheless, case-by-case analyses suggest caution in using such a diagnostic as a selection tool in talent development programs.


Fragility Fractures of the Pelvis: Current Practices and Future Directions.
To summarise the current evidence and clinical practices for patients with fragility fractures of the pelvis (FFP). FFPs are an increasingly prevalent and recognised problem in the elderly population. Recent evidence indicates they have a significant impact on function, morbidity and mortality. While traditional management of FFPs was predominantly non-surgical, surgical options have been increasingly used, with a range of surgical methods available. To date, limited consensus exists on the optimal strategy for suitable patient selection, and clinical trials in this population have proved problematic. The management of FFPs requires a multi-faceted approach to enhance patient care, including adequate pain control, minimisation of complications and optimisation of medical management. Early return to mobilisation should be a key treatment goal to maintain functional independence. The selection of patients who will maximally benefit from surgical treatment, and the most appropriate surgical strategy to employ, remains contentious.


Meta-analysis of risk factors for racehorse catastrophic musculoskeletal injury in flat racing.
Studies of racehorse injury or fatality in various countries have identified common, and in some cases conflicting, risk factors. We conducted a systematic search of the relevant literature published from 1990 to 2017. Peer-reviewed articles were included if they reported the incidence of fatal or catastrophic musculoskeletal injury (CMI) in Thoroughbred flat races (n=21) or risk factors for CMI (n=65). Pooled effect sizes were estimated using the random-effects DerSimonian-Laird model. The pooled incidence of CMI was 1.17 (95% confidence interval 0.90, 1.44) per 1000 race starts. Almost 300 factors have been investigated in epidemiological studies for potential associations with CMI. Factors found to have consistent evidence of increasing risk of CMI are: (1) Horse-level factors such as older horse age and age at first start, male sex, and higher race class or lower claiming price; (2) Race-level factors such as firmer track conditions on turf and wetter conditions on dirt, longer race distance, and a greater number of starters; and (3) Management-related factors including more time since previous start, greater number of starts, longer career length, issues identified at pre-race examination, previous injury, and recent administration of medication or injections. Studies investigating recent cumulative distance of high-speed exercise were conflicting and suggestive of at least two mechanisms of injury related to the accumulation of bone damage: (1) In well adapted bone following a period of intense training; and (2) In poorly adapted bone at relatively low levels of training intensity. Future studies should evaluate success of interventions and mechanisms for injury.


Rapid detection of genetic mutations associated with haemochromatosis.
The purpose of this study was to establish a rapid method suitable for large-scale population screening, including blood donors, for the detection of two genetic mutations at codons 63 and 282 on the HFE gene that are associated with haemochromatosis. A method using the polymerase chain reaction with sequence-specific primers (PCR-SSP) was designed and tested using a panel of 185 individuals previously typed for HFE mutations by PCR-RFLP. The PCR-SSP method detected the two mutations showing complete agreement with the genotypes obtained by PCR-RFLP. Three HFE alleles, termed HFE-1, -2, and -3, were identified. This PCR-SSP method allows efficient HFE genotyping for large numbers of individuals.


Assessment of teratogenic effects of lidocaine in rat embryos cultured in vitro.
Lidocaine has been reported to cause neural tube closure defects in vitro in mice at clinically relevant concentrations. However, no studies have been conducted to further investigate this potentially hazardous effect of lidocaine. This study was aimed to reassess teratogenic effects of lidocaine in vitro in rats. Sprague-Dawley rat embryos were explanted at 8:00 AM on gestational day 9 and were cultured in medium containing various concentrations of lidocaine. (Embryos in the control group were cultured without lidocaine). After 50 h of culture, they were evaluated for growth size and morphology, including the neural tube closure. In the presence of 250 microM of lidocaine, embryos showed a increased incidence of situs inversus compared with control group but were otherwise normal. At 375 microM, embryos showed slight growth retardation but no significant morphologic abnormalities. At 500 microM, all viable embryos showed severe morphologic abnormalities. However, morphologic abnormalities were so-called nonspecific types and neural tube closure defects were not observed. Results from the current study indicate that lidocaine causes teratogenic effects in vitro in rats only at concentrations much higher than clinically relevant concentrations. Furthermore, lidocaine did not cause neural tube closure defects at any concentrations evaluated.


Electrophysiological and functional effects of the KCNQ channel blocker XE991 on murine portal vein smooth muscle cells.
The effect of the KCNQ channel blockers XE991, chromanol 293B and linopirdine, was studied on voltage-dependent K+ currents in smooth muscle cells dissociated freshly from mouse portal vein (mPV) and isometric tension recordings from whole mPV. Voltage clamp experiments showed XE991 inhibited an outward current in a concentration-dependent manner with an IC50 of 5.8 microM. Block was voltage independent. Chromanol 293B and linopirdine also blocked the voltage-dependent K+ current but were less potent than XE991. At least two components--a linear (I(linear)) and an outward relaxation (I(out))--contributed to the XE991-sensitive conductance. XE991-sensitive currents were sustained at all test potentials and XE991 inhibited the enhanced holding current at -60 mV produced by bathing cells in an external solution containing 36 mM KCl. Current clamp experiments in the perforated-patch configuration showed XE991 and linopirdine depolarised the resting membrane potential and augmented the evoked response in a concentration-dependent manner. In functional experiments the spontaneous contractile activity of the mPV was increased significantly by XE991 and linopirdine. The stimulatory effect of XE991 was not affected by the presence of 4-AP, glibenclamide nor paxilline. These data provide evidence for an important role for KCNQ channels in governing cellular excitability in mPV smooth muscle cells.


One Session Treatment for Specific Phobias: An Adaptation for Paediatric Blood-Injection-Injury Phobia in Youth.
Blood-injection-injury (BII) phobia is a chronic and debilitating disorder, which has largely been neglected in the child literature. The present paper briefly reviews the aetiology of specific phobias with particular attention to BII and provides an integrated developmental model of this disorder in youth. Evidence-based treatments for child-specific phobias are discussed, and the development of a modified one session treatment (OST) approach to enhance treatment outcomes for BII phobia in children and adolescents is described. This approach is illustrated in two children with a primary diagnosis of BII phobia. The cases illustrate the unique challenges associated with treating BII in youth and the need for a modified intervention. Modifications included addressing the role of pain (e.g., psychoeducation, more graduated exposure steps) and disgust (e.g., disgust eliciting exposure tasks) in the expression of the phobia and fainting in the maintenance of this phobia. Moreover, it is recommended that parents be more actively involved throughout treatment (e.g., education session prior to OST, contingency management training, guidance regarding planning exposure tasks following treatment) and for families to participate in a structured e-therapy maintenance programme post-treatment.


Association of the arterial access site at angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg).
Bleeding and transfusion after percutaneous coronary intervention (PCI) are known predictors of mortality. Transradial arterial access reduces bleeding and transfusion related to femoral access complications, although its association with mortality is unknown. To determine the association of arterial access site (radial or femoral) with transfusion and mortality in unselected PCIs. By data linkage of three prospectively collated provincial registries, 38,872 procedures in 32,822 patients in British Columbia were analysed. The association between access site, transfusion and outcomes was assessed by logistic regression, propensity score matching and probit regression. 30-Day and 1-year mortality. 1134 (3.5%) patients had at least one blood transfusion. Transfused patients had a significantly increased 30-day and 1-year mortality, adjusted odds ratio (95% CI) 4.01 (3.08 to 5.22) and 3.58 (2.94 to 4.36), respectively. By probit regression the absolute increase in risk of death at 1 year associated with receiving a transfusion was 6.78%. The number needed to treat was 14.74 (prevention of 15 transfusions required to "avoid" one death). Radial access halved the transfusion rate. After adjustment for all variables, radial access was associated with a significant reduction in 30-day and 1-year mortality, odds ratio = 0.71 (95% CI 0.61 to 0.82) and 0.83 (0.71 to 0.98), respectively (all p<0.001). In a registry of all comers to PCI, transradial access was associated with a halving of the transfusion rate and a reduction in 30-day and 1-year mortality.


The current image of single SnO2 nanobelt nanodevice studied by conductive atomic force microscopy.
A single SnO2 nanobelt was assembled on a pair of Au electrodes by electric-field assembly method. The electronic transport property of single SnO2 nanobelt was studied by conductive atomic force microscopy (C-AFM). Back-to-back Schottky barrier-type junctions were created between AFM tip/SnO2 nanobelt/Au electrode which can be concluded from the I-V curve. The current images of single SnO2 nanobelt nanodevices were also studied by C-AFM techniques, which showed stripes patterns on the nanobelt surface. The current images of the nanobelt devices correlate the microscopy with separate transport properties measurement together.