Melatonin modulates autophagy and inflammation protecting human placental trophoblast from hypoxia/reoxygenation.
Melatonin has been proposed as a possible treatment for the deleterious effects of hypoxia/reoxygenation (H/R), such as autophagy, inflammation, and apoptosis. Pathological pregnancies, such as preeclampsia, are associated with placental H/R, and decreased placental melatonin synthesis as well as lower melatonin levels in the placenta and maternal plasma. However, the effects of exogenous melatonin on inflammation and autophagy induced by pregnancy complications associated with H/R await investigation. This study aimed to determine as to whether melatonin protects human primary villous trophoblasts against H/R-induced autophagy, inflammation, and apoptosis. Human primary villous cytotrophoblasts were isolated and immunopurified from normal term placentas. These cells were then exposed or not to 1 mmol/L melatonin for 72 hour in normoxia (8% O2 ), thereby inducing differentiation into syncytiotrophoblast that was then exposed to H/R (0.5% O2 , for 4 hour) or normoxia. H/R decreased endogenous melatonin synthesis (by 68%) and interleukin (IL)-10 levels (by 72%), coupled to increased tumor necrosis factor (TNF) (by 114%), IL-6 (by 55%), and NFκB (by 399%), compared to normoxia. Melatonin treatment reversed the H/R effect, restoring IL-10, TNF, and IL-6 levels to those of the normoxia condition. Melatonin, as well as NFκB inhibition, enhanced autophagy activation, consequently increasing syncytiotrophoblast survival in H/R conditions. This study suggests that H/R, which is present in pregnancy complications, inhibits endogenous melatonin production, thereby contributing to reduced syncytiotrophoblast viability. Results indicate that exogenous melatonin treatment may afford protection against H/R-induced damage, thereby enhancing placental cell survival, and contributing to improved fetal outcomes.


Diagnostic capacity, and predictive values of rapid diagnostic tests for accurate diagnosis of Plasmodium falciparum in febrile children in Asante-Akim, Ghana.
This study seeks to compare the performance of HRP2 (First Response) and pLDH/HRP2 (Combo) RDTs for falciparum malaria against microscopy and PCR in acutely ill febrile children at presentation and follow-up. This is an interventional study that recruited children < 5 years who reported to health facilities with a history of fever within the past 72 h or a documented axillary temperature of 37.5 °C. Using a longitudinal approach, recruitment and follow-up of participants was done between January and May 2012. Based on results of HRP2-RDT screening, the children were grouped into one of the following three categories: (1) tested positive for malaria using RDT and received anti-malarial treatment (group 1, n = 85); (2) tested negative for malaria using RDT and were given anti-malarial treatment by the admitting physician (group 2, n = 74); or, (3) tested negative for malaria using RDT and did not receive any anti-malarial treatment (group 3, n = 101). Independent microscopy, PCR and Combo-RDT tests were done for each sample on day 0 and all follow-up days. Mean age of the study participants was 22 months and females accounted for nearly 50%. At the time of diagnosis, the mean body temperature was 37.9 °C (range 35-40.1 °C). Microscopic parasite density ranged between 300 and 99,500 parasites/µL. With microscopy as gold standard, the sensitivity of HRP2 and Combo-RDTs were 95.1 and 96.3%, respectively. The sensitivities, specificities and predictive values for RDTs were relatively higher in microscopy-defined malaria cases than in PCR positive-defined cases. On day 0, participants who initially tested negative for HRP2 were positive by microscopy (n = 2), Combo (n = 1) and PCR (n = 17). On days 1 and 2, five of the children in this group (initially HRP2-negative) tested positive by PCR alone. On day 28, four patients who were originally HRP2-negative tested positive for microscopy (n = 2), Combo (n = 2) and PCR (n = 4). The HRP2/pLDH RDTs showed comparable diagnostic accuracy in children presenting with an acute febrile illness to health facilities in a hard-to-reach rural area in Ghana. Nevertheless, discordant results recorded on day 0 and follow-up visits using the recommended RDTs means improved malaria diagnostic capability in malaria-endemic regions is necessary.


Predicting the functional effect of amino acid substitutions and indels.
As next-generation sequencing projects generate massive genome-wide sequence variation data, bioinformatics tools are being developed to provide computational predictions on the functional effects of sequence variations and narrow down the search of casual variants for disease phenotypes. Different classes of sequence variations at the nucleotide level are involved in human diseases, including substitutions, insertions, deletions, frameshifts, and non-sense mutations. Frameshifts and non-sense mutations are likely to cause a negative effect on protein function. Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to insertions or deletions. Here, we introduce a versatile alignment-based score as a new metric to predict the damaging effects of variations not limited to single amino acid substitutions but also in-frame insertions, deletions, and multiple amino acid substitutions. This alignment-based score measures the change in sequence similarity of a query sequence to a protein sequence homolog before and after the introduction of an amino acid variation to the query sequence. Our results showed that the scoring scheme performs well in separating disease-associated variants (n = 21,662) from common polymorphisms (n = 37,022) for UniProt human protein variations, and also in separating deleterious variants (n = 15,179) from neutral variants (n = 17,891) for UniProt non-human protein variations. In our approach, the area under the receiver operating characteristic curve (AUC) for the human and non-human protein variation datasets is ∼0.85. We also observed that the alignment-based score correlates with the deleteriousness of a sequence variation. In summary, we have developed a new algorithm, PROVEAN (Protein Variation Effect Analyzer), which provides a generalized approach to predict the functional effects of protein sequence variations including single or multiple amino acid substitutions, and in-frame insertions and deletions. The PROVEAN tool is available online at http://provean.jcvi.org.


Exploring the precursor ion exclusion feature of liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry for improving protein identification in shotgun proteome analysis.
In shotgun proteome analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS), not all coeluting peptides at a given retention time are subjected to MS/MS due to the limitation of spectral acquisition speed of a mass spectrometer. In this work, precursor ion exclusion (PIE) in an electrospray ionization (ESI) quadrupole time-of-flight (QTOF) mass spectrometer was explored as a means of mitigating the undersampling problem. This strategy is based on running replicates of the sample where the precursor ions detected in the initial run(s) are excluded for MS/MS in the subsequent run. Four PIE methods as well as running replicates without PIE were investigated and compared for their effectiveness in identifying peptides and proteins. In the analysis of an MCF-7 breast cancer cell lysate digest by three replicate 2 h gradient LC-ESI runs, the first PIE method used a list of precursor ions detected in the initial run(s) for exclusion and identified a total of 572 proteins from the three runs combined with an average of 3.59 peptides matched to a protein. The second PIE method involved in the generation of a list of m/ z values of precursor ions along with their retention time information from the initial run(s), followed by entering these ions with retention times into the ion exclusion program of the QTOF control software for exclusion at a predefined retention time window (i.e., +/-150 s). In comparison to the first PIE method, this method reduced the possibility of excluding different peptide ions of the same m/ z (within a mass tolerance window) eluted at different retention windows. A total of 657 proteins were identified with an average of 3.75 peptides matched to a protein. The third PIE method studied relied on the exclusion of the precursor ions of peptides identified through database search of the MS/MS spectra generated in the initial run(s). This selective PIE method identified a total of 681 proteins with an average of 3.68 peptides matched to a protein. The final PIE method investigated involves the expansion of the selective PIE list by including nonidentifiable peptide ions found in the database search. This complete PIE method identified a total of 726 proteins with an average of 3.66 peptides per protein. In the case of three replicate runs without PIE, a total of 460 proteins were identified with an average of 3.51 peptides matched to a protein. Thus, the use of an optimal PIE strategy significantly increased the number of proteins identified from replicate runs (i.e., 726 vs 460 or a 58% increase). It is further demonstrated that this PIE strategy also improves protein identification efficiency in the analysis of a yeast whole cell lysate digesta less complex proteome digest. A total of 533 proteins identified from five replicate runs with complete PIE, compared to 353 proteins identified from the five replicate runs without PIE, representing a 51% increase in the number of proteins identified.


[Clinical application of alternative splicing form of c-myc suppressor FUSE-binding protein-interacting repressor for cancer detection and treatment].
Development of useful biomarkers is pivotal for prediction of micro-metastasis, recurrence probability and/or prognosis of the patients. Recent studies have revealed that cancer-specific alternative splicing can be valuable for cancer cell detection. Among them, FUSE-binding protein-interacting repressor, FIR, has been reported to repress c-myc transcription and its exon2-spliced variant, FIRDelta(exon)2, is unable to repress c-myc by competing with authentic FIR in vivo and in vitro. Moreover FIRDelta(exon)2 was frequently discovered in human primary colorectal cancers, but not in the adjacent normal tissues, indicating its cancer-related expression. Thus, the expression level of FIRDelta(exon)2 mRNA in the colorectal cancer tissues as tumor marker candidates is examined. Further, to determine the interacting proteins, FIR-flag or FIRDelta(exon)2-flag stably expressing HeLa cells have been established by G418 selection and nuclear proteins were co immunoprecipitated with flag-conjugated magnetic beads. Those co-immunoprecipitated proteins with FIR or FIRDelta(exon)2 are candidates of tumor makers. In addition, substances that interfers FIR mRNA splicing should be anti-cancer drugs. Together, FIR splicing variant, FIRDelta(exon)2 mRNA or proteins and its interacting proteins are applicable for novel screening tumor markers in colorectal cancer detection.


Development of in-group favoritism in children's third-party punishment of selfishness.
When enforcing norms for cooperative behavior, human adults sometimes exhibit in-group bias. For example, third-party observers punish selfish behaviors committed by out-group members more harshly than similar behaviors committed by in-group members. Although evidence suggests that children begin to systematically punish selfish behavior around the age of 6 y, the development of in-group bias in their punishment remains unknown. Do children start off enforcing fairness norms impartially, or is norm enforcement biased from its emergence? How does bias change over development? Here, we created novel social groups in the laboratory and gave 6- and 8-year-olds the opportunity to engage in costly third-party punishment of selfish sharing behavior. We found that by age 6, punishment was already biased: Selfish resource allocations received more punishment when they were proposed by out-group members and when they disadvantaged in-group members. We also found that although costly punishment increased between ages 6 and 8, bias in punishment partially decreased. Although 8-y-olds also punished selfish out-group members more harshly, they were equally likely to punish on behalf of disadvantaged in-group and out-group members, perhaps reflecting efforts to enforce norms impartially. Taken together, our results suggest that norm enforcement is biased from its emergence, but that this bias can be partially overcome through developmental change.


Voltage-Gated Lipid Ion Channels.
Synthetic lipid membranes can display channel-like ion conduction events even in the absence of proteins. We show here that these events are voltage-gated with a quadratic voltage dependence as expected from electrostatic theory of capacitors. To this end, we recorded channel traces and current histograms in patch-experiments on lipid membranes. We derived a theoretical current-voltage relationship for pores in lipid membranes that describes the experimental data very well when assuming an asymmetric membrane. We determined the equilibrium constant between closed and open state and the open probability as a function of voltage. The voltage-dependence of the lipid pores is found comparable to that of protein channels. Lifetime distributions of open and closed events indicate that the channel open distribution does not follow exponential statistics but rather power law behavior for long open times.


Long-term outcomes after percutaneous coronary intervention of left main coronary artery for treatment of cardiac allograft vasculopathy after orthotopic heart transplantation.
The present study evaluated the safety and efficacy of percutaneous coronary intervention (PCI) of the unprotected left main coronary artery (ULMCA) for the treatment of cardiac allograft vasculopathy (CAV) in consecutive unselected patients with orthotopic heart transplantation (OHT). PCI in patients with OHT and develop CAV has been associated with greater restenosis rates compared to PCI in patients with native coronary artery disease. A paucity of short- and long-term data is available from patients with OHT who have undergone PCI for ULMCA disease. The present retrospective, multicenter, international registry included 21 patients with OHT and CAV who underwent ULMCA PCI from 1997 to 2009. Angiographic success was achieved in all patients. Drug-eluting stents were used in 14 of the 21 patients. No major adverse cardiac events or repeat OHT occurred within the first 30 days. At a mean follow-up of 4.9 ± 3.2 years, 3 patients (14%) had died, myocardial infarction had occurred in 1 patient (5%), and target lesion revascularization had been required in 4 patients (19%). Follow-up angiography was performed in 16 patients (76%), and restenosis was observed in 4 (19%). No stent thrombosis of the ULMCA was observed. One patient (5%) underwent coronary artery bypass grafting, and 5 patients (24%) underwent repeat OHT. In conclusion, the results of our study have shown ULMCA PCI to be safe and reasonably effective in patients with OHT and represents a viable treatment strategy for CAV in these patients.


Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial.
Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models. The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD). The pharmacokinetic parameters of UC1010 when given as a subcutaneous injection were measured in healthy women prior to the study in women with PMDD. This was an explorative randomized, double-blind, placebo-controlled study. Swedish multicentre study with 10 centers. Participants were 26 healthy women in a pharmacokinetic phase I study part, and 126 women with PMDD in a phase II study part. Diagnosis followed the criteria for PMDD in DSM-5 using Daily Record of Severity of Problems (DRSP) and Endicott's algorithm. Subjects were randomized to treatment with UC1010 (10 or 16mg) subcutaneously every second day during the luteal phase or placebo during one menstrual cycle. The primary outcome measure was the sum of all 21 items in DRSP (Total DRSP score). Secondary outcomes were Negative mood score i.e. the ratings of the 4 key symptoms in PMDD (anger/irritability, depression, anxiety and lability) and impairment (impact on daily life). 26 healthy women completed the pharmacokinetic phase I study and the dosing in the following trial was adjusted according to the results. 106 of the 126 women completed the phase II study. Within this group, a significant treatment effect with UC1010 compared to placebo was obtained for the Total DRSP score (p=0.041) and borderline significance (p=0.051) for the sum of Negative mood score. Nineteen participants however showed symptoms during the follicular phase that might be signs of an underlying other conditions, and 27 participants had not received the medication as intended during the symptomatic phase. Hence, to secure that the significant result described above was not due to chance, a post hoc sub-group analysis was performed, including only women with pure PMDD who completed the trial as intended (n=60). In this group UC1010 reduced Total DRSP scores by 75% compared with 47% following placebo; the effect size 0.7 (p=0.006), and for sum of Negative mood score (p=0.003) and impairment (p=0.010) with the effect size 0.6. No severe adverse events were reported during the treatment and safety parameters (vital signs and blood chemistry) remained normal during the study. This explorative study indicates promising results for UC1010 as a potential treatment for PMDD. The effect size was comparable to that of SSRIs and drospirenone containing oral contraceptives. UC1010 was well tolerated and deemed safe.


LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control.
We found that a neuron-specific isoform of LSD1, LSD1n, which results from an alternative splicing event, acquires a new substrate specificity, targeting histone H4 Lys20 methylation, both in vitro and in vivo. Selective genetic ablation of LSD1n led to deficits in spatial learning and memory, revealing the functional importance of LSD1n in neuronal activity-regulated transcription that is necessary for long-term memory formation. LSD1n occupied neuronal gene enhancers, promoters and transcribed coding regions, and was required for transcription initiation and elongation steps in response to neuronal activity, indicating the crucial role of H4K20 methylation in coordinating gene transcription with neuronal function. Our results indicate that this alternative splicing of LSD1 in neurons, which was associated with altered substrate specificity, serves as a mechanism acquired by neurons to achieve more precise control of gene expression in the complex processes underlying learning and memory.


The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020).
The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.


Loss of Atrx affects trophoblast development and the pattern of X-inactivation in extraembryonic tissues.
ATRX is an X-encoded member of the SNF2 family of ATPase/helicase proteins thought to regulate gene expression by modifying chromatin at target loci. Mutations in ATRX provided the first example of a human genetic disease associated with defects in such proteins. To better understand the role of ATRX in development and the associated abnormalities in the ATR-X (alpha thalassemia mental retardation, X-linked) syndrome, we conditionally inactivated the homolog in mice, Atrx, at the 8- to 16-cell stage of development. The protein, Atrx, was ubiquitously expressed, and male embryos null for Atrx implanted and gastrulated normally but did not survive beyond 9.5 days postcoitus due to a defect in formation of the extraembryonic trophoblast, one of the first terminally differentiated lineages in the developing embryo. Carrier female mice that inherit a maternal null allele should be affected, since the paternal X chromosome is normally inactivated in extraembryonic tissues. Surprisingly, however, some carrier females established a normal placenta and appeared to escape the usual pattern of imprinted X-inactivation in these tissues. Together these findings demonstrate an unexpected, specific, and essential role for Atrx in the development of the murine trophoblast and present an example of escape from imprinted X chromosome inactivation.


Current state of musculoskeletal ultrasound in paediatric rheumatology: results of an international survey.
The aim of this study was to investigate the current use of musculoskeletal US (MSUS) and the most relevant areas of interest for this imaging modality in paediatric rheumatology. A questionnaire was developed by the paediatric subgroup of the OMERACT US task force and e-mailed to the members of the main international paediatric rheumatology networks and societies. Responses were entered in an electronic database. Results were analysed quantitatively or summarized qualitatively in the case of open questions. The overall response rate was 36% (262/719). The use of MSUS varied among members of the various networks/societies. MSUS was considered of high relevance for improvement of diagnostic skills, for the guidance of joint injections and for the assessment of specific joints, namely the hip, ankle, midfoot and wrist. It was considered useful for early detection of synovitis and in determining disease activity and disease remission. Although at present MSUS is not widely used by paediatric rheumatologists, there is considerable interest in this imaging technology among members of the international networks. The results of this survey suggest that the next objective in the research agenda should be the standardization of the assessment of joints in healthy children. This will then help differentiate pathological (i.e. synovitic) joints from normal joints. The initial target joints should be the hip, ankle, midfoot and wrist. MSUS training focused on the assessment of paediatric patients might be very important in implementing the use of this technique in clinical practice and research.


Pilot Randomized Controlled Trial of the GO Game Intervention on Cognitive Function.
This study investigated the effects of an intervention using the game "GO" on cognitive function in nursing home residents and evaluated the acquisition of GO according to each stage of dementia. Participants were randomly assigned to either the GO intervention group or a control group, and the intervention was performed once weekly for 15 weeks. Cognitive tests were conducted before and after intervention, and 17 participants were included in the final analysis. Analysis of covariance demonstrated that in the intervention group, the digit span total score significantly improved and the digit span backward score was maintained, whereas these scores decreased in the control group. All participants, including those who had moderate dementia, acquired the rules of the game, and participants with mild cognitive impairment and mild dementia could play the game successfully. This study indicates that GO might improve the cognitive function of residents living in nursing homes.


Feasibility and acceptability of regular weighing, setting weight gain limits and providing feedback by community midwives to prevent excess weight gain during pregnancy: randomised controlled trial and qualitative study.
Regular weighing in pregnant women is not currently recommended in many countries but has been suggested to prevent excessive gestational weight gain. This study aimed to establish the feasibility and acceptability of incorporating regular weighing, setting maximum weight gain targets and feedback by community midwives. Low risk pregnant women cared for by eight community midwives were randomised to usual care or usual care plus the intervention at 10-14 weeks of pregnancy. The intervention involved community midwives weighing and plotting weight on a weight gain chart, setting weight gain limit targets, giving brief feedback at each antenatal appointment and encouraging women to weigh themselves weekly between antenatal appointments. Women and midwives were interviewed about their views of the intervention. The focus of the study was on process evaluation. Community midwives referred 123 women and 115 were scheduled for their dating scan within the study period. Of these, 84/115 were approached at their dating scan and 76/84 (90.5 %) randomised. Data showed a modest difference favouring the intervention group in the percentage of women gaining excessive gestational weight (23.5 % versus 29.4 %). The intervention group consistently reported smaller increases in depression and anxiety scores throughout pregnancy compared with usual care. Most women commented the intervention was useful in encouraging them to think about their weight and believed it should be part of routine antenatal care. Community midwives felt the intervention could be implemented within routine care without adding substantially to consultation length, thus not perceived as adding substantially to their workload. The intervention was feasible and acceptable to pregnant women and community midwives and was readily implemented in routine care. ISRCTN81605162.


Next-Generation Sequencing and Comparative Analysis of Sequential Outbreaks Caused by Multidrug-Resistant Acinetobacter baumannii at a Large Academic Burn Center.
Next-generation sequencing (NGS) analysis has emerged as a promising molecular epidemiological method for investigating health care-associated outbreaks. Here, we used NGS to investigate a 3-year outbreak of multidrug-resistant Acinetobacter baumannii (MDRAB) at a large academic burn center. A reference genome from the index case was generated using de novo assembly of PacBio reads. Forty-six MDRAB isolates were analyzed by pulsed-field gel electrophoresis (PFGE) and sequenced using an Illumina platform. After mapping to the index case reference genome, four samples were excluded due to low coverage, leaving 42 samples for further analysis. Multilocus sequence types (MLST) and the presence of acquired resistance genes were also determined from the sequencing data. A transmission network was inferred from genomic and epidemiological data using a Bayesian framework. Based on single-nucleotide variant (SNV) differences, this MDRAB outbreak represented three sequential outbreaks caused by distinct clones. The first and second outbreaks were caused by sequence type 2 (ST2), while the third outbreak was caused by ST79. For the second outbreak, the MLST and PFGE results were discordant. However, NGS-based SNV typing detected a recombination event and consequently enabled a more accurate phylogenetic analysis. The distribution of resistance genes varied among the three outbreaks. The first- and second-outbreak strains possessed a blaOXA-23-like group, while the third-outbreak strains harbored a blaOXA-40-like group. NGS-based analysis demonstrated the superior resolution of outbreak transmission networks for MDRAB and provided insight into the mechanisms of strain diversification between sequential outbreaks through recombination.


Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding.
Trauma-induced coagulopathy (TIC) is a disorder of the blood clotting process that occurs soon after trauma injury. A diagnosis of TIC on admission is associated with increased mortality rates, increased burdens of transfusion, greater risks of complications and longer stays in critical care. Current diagnostic testing follows local hospital processes and normally involves conventional coagulation tests including prothrombin time ratio/international normalized ratio (PTr/INR), activated partial prothrombin time and full blood count. In some centres, thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are standard tests, but in the UK they are more commonly used in research settings. The objective was to determine the diagnostic accuracy of thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for TIC in adult trauma patients with bleeding, using a reference standard of prothrombin time ratio and/or the international normalized ratio. We ran the search on 4 March 2013. Searches ran from 1970 to current. We searched The Cochrane Library, MEDLINE (OvidSP), EMBASE Classic and EMBASE, eleven other databases, the web, and clinical trials registers. The Cochrane Injuries Group's specialised register was not searched for this review as it does not contain diagnostic test accuracy studies. We also screened reference lists, conducted forward citation searches and contacted authors. We included all cross-sectional studies investigating the diagnostic test accuracy of TEG and ROTEM in patients with clinically suspected TIC, as well as case-control studies. Participants were adult trauma patients in both military and civilian settings. TIC was defined as a PTr/INR reading of 1.2 or greater, or 1.5 or greater. We piloted and performed all review stages in duplicate, including quality assessment using the QUADAS-2 tool, adhering to guidance in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. We analysed sensitivity and specificity of included studies narratively as there were insufficient studies to perform a meta-analysis. Three studies were included in the final analysis. All three studies used ROTEM as the test of global haemostatic function, and none of the studies used TEG. Tissue factor-activated assay EXTEM clot amplitude (CA) was the focus of the accuracy measurements in blood samples taken near to the point of admission. These CAs were not taken at a uniform time after the start of the coagulopathic trace; the time varied from five minutes, to ten minutes and fifteen minutes. The three included studies were conducted in the UK, France and Afghanistan in both civilian and military trauma settings. In two studies, median Injury Severity Scores were 12, inter-quartile range (IQR) 4 to 24; and 22, IQR 12 to 34; and in one study the median New Injury Severity Score was 34, IQR 17 to 43.There were insufficient included studies examining each of the three ROTEM CAs at 5, 10 and 15 minutes to make meta-analysis and investigation of heterogeneity valid. The results of the included studies are thus reported narratively and illustrated by a forest plot and results plotted on the receiver operating characteristic (ROC) plane.For CA5 the accuracy results were sensitivity 70% (95% CI 47% to 87%) and specificity 86% (95% CI 82% to 90%) for one study, and sensitivity 96% (95% CI 88% to 100%) and specificity 58% (95% CI 44% to 72%) for the other.For CA10 the accuracy results were sensitivity 100% (95% CI 94% to 100%) and specificity 70% (95% CI 56% to 82%).For CA15 the accuracy results were sensitivity 88% (95% CI 69% to 97%) and specificity 100% (95% CI 94% to 100%).No uninterpretable ROTEM study results were mentioned in any of the included studies.Risk of bias and concerns around applicability of findings was low across all studies for the patient and flow and timing domains. However, risk of bias and concerns around applicability of findings for the index test domain was either high or unclear, and the risk of bias for the reference standard domain was high. This raised concerns around the interpretation of the sensitivity and specificity results of the included studies, which may be misleading. We found no evidence on the accuracy of TEG and very little evidence on the accuracy of ROTEM. The value of accuracy estimates are considerably undermined by the small number of included studies, and concerns about risk of bias relating to the index test and the reference standard. We are unable to offer advice on the use of global measures of haemostatic function for trauma based on the evidence on test accuracy identified in this systematic review. This evidence strongly suggests that at present these tests should only be used for research. We consider more thoroughly what this research could be in the Discussion section.


Physician-diagnosed asthma and drug utilization in the European Community Respiratory Health Survey.
The aim of this analysis was to estimate the geographical variation in the prevalence of physician-diagnosed asthma and treatment practice for asthma in young adults. The results are based on an ecological analysis of 34 centres in 14 countries, in which a total of 17,029 randomly selected subjects (52% females, age 20-48 yrs) underwent a structured interview and spirometry as part of the European Community Respiratory Health Survey. The sample was enriched with 2,903 symptomatic subjects when investigating treatment in subjects with physician-diagnosed asthma. The prevalence of physician-diagnosed asthma was highest in New Zealand and Australia (11-13%) and lowest in Erfurt, Germany (1.2%) and Spain (1.5-3.0%). The reported use of antiasthma medication in the last 12 months was also highest in New Zealand and Australia (12-16%) and correlated closely with the prevalence of diagnosed asthma (r=0.89, p<0.001). Herbal remedies against breathing problems had been used by 13% of subjects in Hamburg but the reported use of alternative remedies for breathing problems was low in most other centres. The use of inhaled anti-inflammatory drugs in subjects with physician-diagnosed asthma ranged from 49% in the UK to 17% in Italy and correlated with the prevalence of doctors' consultations within the last 12 months (r=0.66, p<0.05). The prevalence of anti-inflammatory treatment was positively related to the prevalence of nocturnal asthma symptoms (p<0.05). We conclude that there is a wide geographical variation in the prevalence of physician-diagnosed asthma and use of antiasthma medication. The geographical variation in the use of anti-inflammatory drugs among individuals with diagnosed asthma may be related to variations in asthma severity, as well as differences in treatment practices between countries.


Accuracy of Substrate Selection by Enzymes Is Controlled by Kinetic Discrimination.
Enzymes have the remarkable ability to select the correct substrate from the pool of chemically similar molecules. The accuracy of such a selection is determined by differences in the free-energy profiles for the right and wrong reaction pathways. Here, we investigate which features of the free-energy landscape govern the variation and minimization of selectivity error. It is generally believed that minimal error is affected by both kinetic (activation barrier heights) and thermodynamic (binding stability) factors. In contrast, using first-passage theoretical analysis, we show that the steady-state selectivity error is determined only by the differences in transition-state energies between the pathways and is independent of the energies of the stable complexes. The results are illustrated for two common catalytic mechanisms: (i) the Michaelis-Menten scheme and (ii) an error-correcting kinetic proofreading scheme with tRNA selection and DNA replication as guiding biological examples. Our theoretical analysis therefore suggests that the selectivity mechanisms are always kinetically controlled.


The shape of neural dependence.
The product-moment correlation coefficient is often viewed as a natural measure of dependence. However, this equivalence applies only in the context of elliptical distributions, most commonly the multivariate gaussian, where linear correlation indeed sufficiently describes the underlying dependence structure. Should the true probability distributions deviate from those with elliptical contours, linear correlation may convey misleading information on the actual underlying dependencies. It is often the case that probability distributions other than the gaussian distribution are necessary to properly capture the stochastic nature of single neurons, which as a consequence greatly complicates the construction of a flexible model of covariance. We show how arbitrary probability densities can be coupled to allow greater flexibility in the construction of multivariate neural population models.


Genetic Control of Plasticity in Root Morphology and Anatomy of Rice in Response to Water Deficit.
Elucidating the genetic control of rooting behavior under water-deficit stress is essential to breed climate-robust rice (Oryza sativa) cultivars. Using a diverse panel of 274 indica genotypes grown under control and water-deficit conditions during vegetative growth, we phenotyped 35 traits, mostly related to root morphology and anatomy, involving 45,000 root-scanning images and nearly 25,000 cross sections from the root-shoot junction. The phenotypic plasticity of these traits was quantified as the relative change in trait value under water-deficit compared with control conditions. We then carried out a genome-wide association analysis on these traits and their plasticity, using 45,608 high-quality single-nucleotide polymorphisms. One hundred four significant loci were detected for these traits under control conditions, 106 were detected under water-deficit stress, and 76 were detected for trait plasticity. We predicted 296 (control), 284 (water-deficit stress), and 233 (plasticity) a priori candidate genes within linkage disequilibrium blocks for these loci. We identified key a priori candidate genes regulating root growth and development and relevant alleles that, upon validation, can help improve rice adaptation to water-deficit stress.


Plasticity of skeletal muscle mitochondria in response to contractile activity.
Regularly performed exercise in the form of endurance training produces a well-established adaptation in skeletal muscle termed mitochondrial biogenesis. The physiological benefit of this is an enhanced performance of muscle when subject to endurance exercise. This is not only of great advantage for athletic endeavours, but it also clearly improves the quality of life of previously sedentary individuals and those involved in injury rehabilitation. Here we review the molecular basis for mitochondrial biogenesis in muscle, from the initial signals arising in contracting muscle, to the transcription factors involved in mitochondrial and nuclear DNA transcription, as well as the post-translational import mechanisms required for the synthesis of the organelle. We discuss specific protein components associated with reactive oxygen species production, and suggest some questions which remain unanswered with respect to the role of exercise-induced mitochondrial biogenesis in ageing, apoptosis and disease.


Effectiveness of Internet-based cognitive behaviour therapy for depression in routine psychiatric care.
Efficacy of guided Internet-based cognitive behaviour therapy (ICBT) for depression has been demonstrated in several randomised controlled trials. Knowledge on the effectiveness of the treatment, i.e. how it works when delivered within routine care, is however scarce. The aim of this study was to investigate the effectiveness of ICBT for depression. We conducted a cohort study investigating all patients (N=1203) who had received guided ICBT for depression between 2007 and 2013 in a routine care setting at an outpatient psychiatric clinic providing Internet-based treatment. The primary outcome measure was the Montgomery Åsberg Depression Rating Scale-Self rated (MADRS-S). Patients made large improvements from pre-treatment assessments to post-treatment on the primary outcome (effect size d on the MADRS-S=1.27, 99% CI, 1.14-1.39). Participants were significantly improved in terms of suicidal ideation and sleep difficulties. Improvements were sustained at 6-month follow-up. Attrition was rather large at 6-month follow-up. However, additional data was collected through telephone interviews with dropouts and advanced statistical models indicated that missing data did not bias the findings. ICBT for depression can be highly effective when delivered within the context of routine psychiatric care. This study suggests that the effect sizes are at least as high when the treatment is delivered in routine psychiatric care by qualified staff as when delivered in a controlled trial setting.


Tenofovir for prevention of mother to child transmission of hepatitis B in migrant women in a resource-limited setting on the Thailand-Myanmar border: a commentary on challenges of implementation.
The aim of this manuscript is to highlight challenges in the implementation of maternal tenofovir disoproxil fumarate (tenofovir) for prevention of mother to child transmission (PMTCT) of hepatitis B virus (HBV) in resource limited setting. Current preventive strategies in resource-limited settings fail mainly due to prohibitive costs of hepatitis B immunoglobulin (HBIG) and a high proportion of homebirths, meaning both HBIG and hepatitis B birth dose vaccine are not given. A new strategy for PMTCT without the necessity of HBIG, could be daily tenofovir commenced early in gestation. Implementation challenges to early tenofovir for PMTCT can provide insight to elimination strategies of HBV as the burden of disease is high in resource-limited settings. Challenges encountered during implementation of a study of tenofovir for PMTCT before 20 weeks gestation in rural and resource-limited areas on the Thailand-Myanmar border were identified informally from trial study logbooks and formally from comments from patients and staff at monthly visits. ClinicalTrials.gov Identifier: NCT02995005. During implementation 171 pregnant women were hepatitis B surface antigen (HBsAg) positive by point of-care test over 19 months (May-2018 until Dec-2019). In this resource-limited setting where historically no clinic has provided tenofovir for PMTCT of HBV, information provided by staff resulted in a high uptake of study screening (95.5% (84/88) when offered to pregnant women. False positive point-of-care rapid tests hinder a test and treat policy for HBV and development of improved rapid tests that include HBeAg and/or HBV DNA would increase efficiency. Integrated care of HBV to antenatal care, transport assistance and local agreements to facilitate access, could increase healthcare at this critical stage of the life course. As safe storage of medication in households in resource-limited setting may not be ideal, interactive counseling about this must be a routine part of care. Despite challenges, results from the study to date suggest tenofovir can be offered to HBV-infected women in resource-limited settings before 20 weeks gestation with a high uptake of screening, high drug accountability and follow-up, with provision of transportation support. This commentary has highlighted practical implementation issues with suggestions for strategies that support the objective of PMTCT and the World Health Organization goal of HBV elimination by 2030.


Variation in clinical preventive services.
Preventive services are not delivered at optimal rates in primary care settings, and the literature suggests that a systems approach is key to improvement. Studying variation among clinics could help us to understand the extent of system use in practice. The proportion of patients who are up-to-date for preventive services in 44 primary care practices in the Midwest. PREVENTIVE SERVICES EXAMINED: Papanicolaou (Pap) smear, cholesterol testing, mammography, clinical breast examination, blood pressure measurement, influenza and pneumococcal vaccinations, and advice on tobacco use. 6830 patients surveyed after their clinic visit (response rate, 85%). The proportion of patients up-to-date for preventive services varied widely among clinics. For example, up-to-date rates for Pap smear testing ranged from 70% to 93% and 45% to 88% for cholesterol screening. There was little correlation between a clinic's performance on one preventive service (relative to the other 43 clinics) and its performance on others. When correlations between pairs of up-to-date rates within clinics were examined, only 4 of 28 service pairs were positive and statistically significant and only 1 had a correlation coefficient that exceeded 0.5 (for mammography and clinical breast examination). There is wide variation in the rates at which various preventive services are performed, both between and within clinics. This variation, which is probably due to a lack of organized prevention systems that cover multiple services, provides a clear target for improvement efforts.


Association of race and socioeconomic status with automatic external defibrillator training prevalence in the United States.
Automated external defibrillators (AEDs) improve survival from out-of-hospital cardiac arrest (OHCA), however bystander use remains low. Limited AED training may contribute to infrequent use of these devices, yet no studies have assessed AED training nationally. Given previously documented racial disparities among Latinos in CPR provision and OHCA outcomes, we hypothesized that racial and socioeconomic differences exist in AED training, with Whites having increased training compared to Latinos and higher socioeconomic status being associated with increased training. We administered a random digit dial survey to a nationally-representative adult sample. Using survey-weighted logistic regression adjusted for location, we assessed race and socioeconomic status of individuals trained in AEDs compared to never-trained individuals. From 09/2015-11/2015, 9022 individuals completed the survey. Of those, 68% had never been AED trained. Self-identified Whites and Blacks were more likely to have AED training compared to Latinos (OR: 1.90, 95% CI: 1.43-2.53 and OR: 1.73, 95% CI: 1.39-2.15, respectively). Higher educational attainment was associated with an increased likelihood of training, with an OR of 4.36 (95% CI: 2.57-7.40) for graduate school compared to less than high school education. Increased household income was not associated with an increase in AED training (p = .08). The minority of respondents reported AED training. Whites and Blacks were more likely to be trained than Latinos. Higher educational attainment was associated with an increased likelihood of training. These findings highlight an important opportunity to improve training disparities and layperson response to OHCA.


Prolonged intake of fermented soybean (natto) diets containing vitamin K2 (menaquinone-7) prevents bone loss in ovariectomized rats.
The effect of the prolonged intake of dietary vitamin K2 (menaquinone-7, MK-7) on bone loss in ovariectomized (OVX) rats was investigated. OVX rats were freely given experimental diets containing the fermented soybean (natto; including 9.4 micrograms MK-7/100 g diet) without or with supplemental MK-7 (containing 14.1 or 18.8 micrograms of MK-7 as total per 100 g diet) for 150 days. Feeding produced a significant elevation of MK-7 concentration in the serum of OVX rats. In this case, the femoral MK-4 content was significantly increased, but MK-7 was not detected in the femoral tissues, indicating degradation of MK-7. Serum gamma-carboxylated osteocalcin concentration was significantly decreased by OVX. This decrease was significantly prevented by the feeding of the natto diets with supplemental MK-7 (18.8 micrograms/100 g diets). OVX caused a significant decrease in femoral dry weight, femoral calcium content, and mineral density. These decreases were significantly prevented by feeding with diets containing natto with MK-7 (total, 18.8 micrograms/100 g diets). This study demonstrates that the prolonged intake of natto dietary including MK-7 has a preventive effect on bone loss induced by OVX. Dietary MK-7 may be useful in the prevention of osteoporosis.


Developmental changes in human dural innervation.
There is limited published work on the abundant innervation of the human dura mater, its role and responses to injury in humans. The dura not only provides mechanical support for the brain but may also have other functions, including control of the outflow of venous blood from the brain via the dural sinuses. The trigeminal nerve supplies sensory fibres to the dura as well as the leptomeninges, intracranial blood vessels, face, nose and mouth. Its relatively large size in embryonic life suggests an importance in development; the earliest fetal reflexes, mediated by the trigeminal, are seen by 8 weeks. Trigeminal functions vital to the fetus include the coordination of sucking and swallowing and the protective oxygen-conserving reflexes. Like other parts of the nervous system, the trigeminal undergoes pruning and remodelling throughout development. We have investigated changes in the innervation of the human dura with age in 27 individuals aged between 31 weeks of gestation and 60 years of postnatal life. Using immunocytochemistry with antibodies to neurofilament, we have found significant changes in the density of dural innervation with age The density of innervation increased between 31 and 40 weeks of gestation, peaking at term and decreasing in the subsequent 3 months, remaining low until the sixth decade. Our observations are consistent with animal studies but are, to our knowledge, the first to show age-related changes in the density of innervation in the human dura. They provide new insights into the functions of the human dura during development.


Vinegar Treatment Prevents the Development of Murine Experimental Colitis via Inhibition of Inflammation and Apoptosis.
This study investigated the preventive effects of vinegar and acetic acid (the active component of vinegar) on ulcerative colitis (UC) in mice. Vinegar (5% v/v) or acetic acid (0.3% w/v) treatment significantly reduced the disease activity index and histopathological scores, attenuated body weight loss, and shortened the colon length in a murine experimental colitis model induced by dextran sulfate sodium (DSS). Further mechanistic analysis showed that vinegar inhibited inflammation through suppressing Th1 and Th17 responses, the NLRP3 inflammasome, and MAPK signaling activation. Vinegar also inhibited endoplasmic reticulum (ER) stress-mediated apoptosis in the colitis mouse model. Surprisingly, pretreatment with vinegar for 28 days before DSS induction increased levels of the commensal lactic acid-producing or acetic acid-producing bacteria, including Lactobacillus, Bifidobacteria, and Enterococcus faecalis, whereas decreased Escherichia coli levels were found in the feces of mice. These results suggest that vinegar supplementation might provide a new dietary strategy for the prevention of UC.


Psychosocial impact of the summer 2007 floods in England.
The summer of 2007 was the wettest in the UK since records began in 1914 and resulted in severe flooding in several regions. We carried out a health impact assessment using population-based surveys to assess the prevalence of and risk factors for the psychosocial consequences of this flooding in the United Kingdom. Surveys were conducted in two regions using postal, online, telephone questionnaires and face-to-face interviews. Exposure variables included the presence of flood water in the home, evacuation and disruption to essential services (incident management variables), perceived impact of the floods on finances, house values and perceived health concerns. Validated tools were used to assess psychosocial outcome (mental health symptoms): psychological distress (GHQ-12), anxiety (GAD-7), depression (PHQ-9) and probable post-traumatic stress disorder (PTSD checklist-shortform). Multivariable logistic regression was used to describe the association between water level in the home, psychological exposure variables and incident management variables, and each mental health symptom, adjusted for age, sex, presence of an existing medical condition, employment status, area and data collection method. The prevalence of all mental health symptoms was two to five-fold higher among individuals affected by flood water in the home. People who perceived negative impact on finances were more likely to report psychological distress (OR 2.5, 1.8-3.4), probable anxiety (OR 1.8, 1.3-2.7) probable depression (OR 2.0, 1.3-2.9) and probable PTSD (OR 3.2, 2.0-5.2). Disruption to essential services increased adverse psychological outcomes by two to three-fold. Evacuation was associated with some increase in psychological distress but not significantly for the other three measures. The psychosocial and mental health impact of flooding is a growing public health concern and improved strategies for minimising disruption to essential services and financial worries need to be built in to emergency preparedness and response systems. Public Health Agencies should address the underlying predictors of adverse psychosocial and mental health when providing information and advice to people who are or are likely to be affected by flooding.


An exploration of knowledge, attitudes and behaviours of young multiethnic Muslim-majority society in Malaysia in relation to reproductive and premarital sexual practices.
The increasing trend of premarital sexual experience and unintended pregnancies in Malaysia warrants sustained and serious attention. The sensitivities of sex-related issues in a Muslim-majority country create various types of barriers to sexual and reproductive health information, support and practices. This study aims to gain understanding of knowledge, attitudes and behaviours of young women in Malaysia concerning reproductive, contraception and premarital sexual practices. A cross-sectional study was performed, using an anonymous self-administered questionnaire carried out among 1695 female university students in a public university in Malaysia. Respondents had low scores for knowledge of reproduction and pregnancy (median=4, of maximum score 10), contraceptive uses (median=6, of maximum score 16) and contraceptive availability (median=3, of maximum score 13). The majority of women surveyed do not have liberal values in relation to premarital sexual behaviour (median=37, of maximum 40); higher scores on this scale corresponded to opposing premarital sex. The multivariate analyses showed that ethnic group was the strongest correlate of knowledge and attitude scores; being of Malay Muslim ethnicity was associated significantly with lower knowledge scores and premarital sex permissiveness. Other significant correlates were year of study, maternal occupational groups, level of religious faith, dating status and urban-rural localities. Level of premarital sex permissiveness was inversely correlated with reproduction and pregnancy knowledge score, and contraceptive knowledge scores. Reproductive health knowledge and attitudes were intricately linked to religious values and cultural norms differences surrounding sexual issues.


Differences in metastatic patterns in relation to time between primary surgery and first relapse from breast cancer suggest synchronized growth of dormant micrometastases.
A significant variation in the metastatic pattern among breast cancer patients exists. Clinical observations suggest that these differences are related to time to recurrence (TTR), thus suggesting a common systemic growth signal at the time of surgery. Our goal was to identify a marker for synchronized growth of micrometastases. To quantify the metastatic pattern at first relapse, 180 patients with metastatic breast cancer were studied. Standard deviation (SD) of lesions size and lesion number was calculated and served as a marker for variation. Patients with low SD (multiple/similar sized lesions) were assumed to have synchronized growth, whereas patients with high SD were assumed to have unsynchronized growth. Patients were grouped according to TTR; early (< 3 years-) or late (> 3 years- after surgery). In patients not receiving systemic adjuvant treatment, median SD was significantly lower in the early group (2.5 mm) compared with 6.4 mm in the late group (p = 0.005). In node negative patients, median SD was significantly lower in the early group (3.0 mm) when compared with the late group (5.7 mm, p = 0.02). An additional drop in SD was observed immediately after end of adjuvant endocrine therapy. Our results identify SD as a marker of synchronized metastatic growth in breast cancer. A metastatic phenotype characterized by multiple similar sized metastases, suggesting synchronized onset of growth of micrometastases was predominantly found in patients recurring early after surgery and was counteracted by adjuvant treatment. Systemic growth signals caused by surgery might be antagonized during the time window following surgery.


3D-quantitative structure-activity relationship and antiviral effects of curcumin derivatives as potent inhibitors of influenza H1N1 neuraminidase.
Curcumin derivatives have been shown to inhibit replication of human influenza A viruses (IAVs). However, it is not clear whether curcumin and its derivatives can inhibit neuraminidase (NA) of influenza virus. In this study, a meaningful 3D quantitative structure-activity relationship model (comparative molecular field analysis R2 = 0.997, q2 = 0.527, s = 0.064, F = 282.663) was built to understand the chemical-biological interactions between their activities and neuraminidase. Molecular docking was used to predict binding models between curcumin derivatives and neuraminidase. Real-time polymerase chain reactions showed that the five active curcumin derivatives might have direct effects on viral particle infectivity in H1N1-infected lung epithelial (MDCK) cells. Neuraminidase activation assay showed that five active curcumin derivatives decreased H1N1-induced neuraminidase activation in MDCK cells. Indirect immunofluorescence assay indicated that two active curcumin derivatives (tetramethylcurcumin and curcumin) down-regulated the nucleoprotein expression. Curcumin inhibited IAV in vivo. The therapeutic mechanism of curcumin in the treatment of influenza viral pneumonia is related to improving the immune function of infected mice and regulating secretion of tumor necrosis-α, interleukin-6, and interferon-γ. These results indicate that curcumin derivatives inhibit IAV by blocking neuraminidase in the cellular model and curcumin also has anti-IAV activity in the animal model.


Crust-mantle mechanical coupling in Eastern Mediterranean and eastern Turkey.
Present-day crust-mantle coupling in the Eastern Mediterranean and eastern Turkey is studied using the Global Positioning System (GPS) and seismic anisotropy data. The general trend of the shear wave fast-splitting directions in NE Turkey and Lesser Caucaus align well with the geodetic velocities in an absolute plate motion frame of reference pointing to an effective coupling in this part of the region of weak surface deformation. Farther south, underneath the Bitlis Suture, however, there are significant Pn delays with E-W anisotropy axes indicating significant lateral escape. Meanwhile, the GPS reveals very little surface deformation. This mismatch possibly suggests a decoupling along the suture. In the Aegean, the shear wave anisotropy and the Pn anisotropy directions agree with the extensional component of the right-lateral shear strains except under the Crete Basin and other parts of the southern Aegean Sea. This extensional direction matches perfectly also with the southward pulling force vectors across the Hellenic trench; however, the maximum right-lateral shear directions obtained from the GPS data in the Aegean do not match either of these anisotropies. Seismic anisotropy from Rayleigh waves sampled at 15 s, corresponding to the lower crust, match the maximum right-lateral maximum shear directions from the GPS indicating decoupling between the crust and the mantle. This decoupling most likely results from the lateral variations of the gravitational potential energies and the slab-pull forces.


Implementation and Evaluation of Evidence-Based Psychotherapeutic Practices for Youth in a Mental Health Organization.
The current initiative and program evaluation study is a demonstration of the research to practice process in youth-focused psychotherapy. We collaborated within a community-university partnership to create practice and research infrastructure in order to develop, implement, and evaluate two new models of service founded on evidence-based psychotherapeutic practice parameters. The two new service models incorporated validated interventions to address behavior problems in elementary age children, and depression in adolescents, which were delivered in separate but similarly run intensive outpatient programs within a mental health setting. We utilized a rigorous training, technical assistance, fidelity monitoring, and outcome measurement strategy to promote the integrity and quality of services provided. The resultant programs were delivered with acceptable to high fidelity and effects on youth and parenting measures collected during program and from pre to post showed a decrease in targeted problems in youth and positive benefits for families. This initiative and program evaluation adds to the accumulating research-to-practice literature in children's mental health.


Neuronal density, size and shape in the human anterior cingulate cortex: a comparison of Nissl and NeuN staining.
There are an increasing number of quantitative morphometric studies of the human cerebral cortex, especially as part of comparative investigations of major psychiatric disorders. In this context, the present study had two aims. First, to provide quantitative data regarding key neuronal morphometric parameters in the anterior cingulate cortex. Second, to compare the results of conventional Nissl staining with those observed after immunostaining with NeuN, an antibody becoming widely used as a selective neuronal marker. We stained adjacent sections of area 24b from 16 adult brains with cresyl violet or NeuN. We measured the density of pyramidal and non-pyramidal neurons, and the size and shape of pyramidal neurons, in laminae II, III, Va, Vb and VI, using two-dimensional counting methods. Strong correlations between the two modes of staining were seen for all variables. However, NeuN gave slightly higher estimates of neuronal density and size, and a more circular perikaryal shape. Brain pH was correlated with neuronal size, measured with both methods, and with neuronal shape. Age and post-mortem interval showed no correlations with any parameter. These data confirm the value of NeuN as a tool for quantitative neuronal morphometric studies in routinely processed human brain tissue. Absolute values are highly correlated between NeuN and cresyl violet stains, but cannot be interchanged. NeuN may be particularly useful when it is important to distinguish small neurons from glia, such as in cytoarchitectural studies of the cerebral cortex in depression and schizophrenia.


Use of complementary and alternative medical therapies among children with special health care needs in southern Arizona.
The objective of this study was to assess the frequency and type of complementary and alternative medicine (CAM) therapies used by families of children with special health care needs in southern Arizona, as well as the correlates of their use. Families of 376 children who were receiving services in a regional facility that serves children with special health care needs and were residing in southern Arizona were surveyed regarding CAM use. Sixty-four percent of these families reported using CAM for their child. The most common CAM therapies were spiritual healing/prayer/blessings. Of the conditions that were evaluated as correctable, the use rate was 24% as compared with a 76% use rate for children with a nonrepairable condition. Use of CAM for the child was strongly related to the use of CAM in the past by the family member who responded to the survey. The reasons that parents most frequently chose for using CAM were advice from a medical practitioner and advice from a family member. Use of CAM for children with special health care needs is common. Its frequency and type are significantly associated with the child's condition and prognosis.


Lycopene Enriched Tomato Extract Inhibits Hypoxia, Angiogenesis, and Metastatic Markers in early Stage N-Nitrosodiethylamine Induced Hepatocellular Carcinoma.
Targeting altered pathways during initial stage of hepatocellular carcinoma (HCC) development is viewed as an effective and promising strategy to control this disease. Present study investigated the potential effect of lycopene-enriched tomato extract (LycT) on hypoxia-induced factor (HIF)-1α, HOX, VEGF, CD31, matrix metalloproteinase (MMP)-2, MMP-9, and alpha fetoprotein (AFP)expression during initial stages of N-nitrosodiethylamine (NDEA) induced HCC. Female Balb/c mice (8-10 wk) were assigned to 4 groups: control, NDEA (200 mg NDEA i.p./kg body weight, cumulative), LycT (5 mg lycopene orally/kg body weight; 3 times a week), and LycT + NDEA. LycT treatment began 2 wk before NDEA administration and continued until the end of the 10 wk study. The onset of HCC by NDEA was associated with significant alteration in serum biochemical markers [alanine transaminases (ALT), aspartate transaminases (AST), and alkaline phosphatases (ALP), lactate dehydrogenase (LDH), urea, A/G ratio, and bilirubin] and in liver histopathology. LycT treatment significantly reduced the levels of these markers. LycT treatment to NDEA mice also led to significant reduction in protein levels of AFP, HIF-1α, VEGF, CD31, MMP-2, and MMP-9 in comparison with NDEA group alone. These parameters are important biomarkers of hypoxia, angiogenesis, and metastasis, which reflect the advanced disease stage. The study provides evidence that prophylactic dietary supplementation with LycT may counteract HCC progression and/or protect against disease onset.


Diffusion and Binding of Mismatch Repair Protein, MSH2, in Breast Cancer Cells at Different Stages of Neoplastic Transformation.
The interior of cells is a highly complex medium, containing numerous organelles, a matrix of different fibers and a viscous, aqueous fluid of proteins and small molecules. The interior of cells is also a highly dynamic medium, in which many components move, either by active transport or passive diffusion. The mobility and localization of proteins inside cells can provide important insights into protein function and also general cellular properties, such as viscosity. Neoplastic transformation affects numerous cellular properties, and our goal was to investigate the diffusional and binding behavior of the important mismatch repair (MMR) protein MSH2 in live human cells at various stages of neoplastic transformation. Toward this end, noncancerous, immortal, tumorigenic, and metastatic mammary epithelial cells were transfected with EGFP and EGFP-tagged MSH2. MSH2 forms two MMR proteins (MutSα and MutSβ) and we assume MSH2 is in the complex MutSα, though our results are similar in either case. Unlike the MutS complexes that bind to nuclear DNA, EGFP diffuses freely. EGFP and MutSα-EGFP diffusion coefficients were determined in the cytoplasm and nucleus of each cell type using fluorescence recovery after photobleaching. Diffusion coefficients were 14-24 μm2/s for EGFP and 3-7 μm2/s for MutSα-EGFP. EGFP diffusion increased in going from noncancerous to immortal cells, indicating a decrease in viscosity, with smaller changes in subsequent stages. MutSα produces an effective diffusion coefficient that, coupled with the free EGFP diffusion measurements, can be used to extract a pure diffusion coefficient and a pseudo-equilibrium constant K*. The MutSα nuclear K* increased sixfold in the first stage of cancer and then decreased in the more advanced stages. The ratio of nuclear to cytoplasmic K*for MutSα increased almost two orders of magnitude in going from noncancerous to immortal cells, suggesting that this quantity may be a sensitive metric for recognizing the onset of cancer.


Air pollution and heart rate variability: effect modification by chronic lead exposure.
Outdoor air pollution and lead exposure can disturb cardiac autonomic function, but the effects of both these exposures together have not been studied. We examined whether higher cumulative lead exposures, as measured by bone lead, modified cross-sectional associations between air pollution and heart rate variability among 384 elderly men from the Normative Aging Study. We used linear regression, controlling for clinical, demographic, and environmental covariates. We found graded, significant reductions in both high-frequency and low-frequency powers of heart rate variability in relation to ozone and sulfate across the quartiles of tibia lead. Interquartile range increases in ozone and sulfate were associated respectively, with 38% decrease (95% confidence interval = -54.6% to -14.9%) and 22% decrease (-40.4% to 1.6%) in high frequency, and 38% decrease (-51.9% to -20.4%) and 12% decrease (-28.6% to 9.3%) in low frequency, in the highest quartile of tibia lead after controlling for potential confounders. We observed similar but weaker effect modification by tibia lead adjusted for education and cumulative traffic (residuals of the regression of tibia lead on education and cumulative traffic). Patella lead modified only the ozone effect on heart rate variability. People with long-term exposure to higher levels of lead may be more sensitive to cardiac autonomic dysfunction on high air pollution days. Efforts to understand how environmental exposures affect the health of an aging population should consider both current levels of pollution and history of lead exposure as susceptibility factors.


Failure of multiplex meningitis/encephalitis (ME) NAT during cryptococcal meningitis in solid organ recipients.
Cryptococcal meningitis is a severe cause of central nervous system infections among immunocompromised solid organ transplant (SOT) patients. While new diagnostic methods as multiplex meningitis/encephalitis (ME) NAT (nucleic acid test) are increasingly used as a first-line tool in hospital practice, data in HIV-negative patients including SOT remain scarce. We report here false-negative results of multiplex NAT among SOT patients with proven cryptococcal meningitis.


Incidence, outcome and predictors of bleomycin pulmonary toxicity in a university hospital in Oman.
To determine the incidence and predictors of bleomycin pulmonary toxicity in a university hospital in Oman. This retrospective chart review consisted of 46 patients treated with bleomycin-containing regimes at Sultan Qaboos University Hospital in Oman between January 2007 and December 2010. Data regarding patient age, chemotherapy protocol, cumulative bleomycin dose, smoking history, renal function and concurrent use of granulocyte colony stimulating factor (GCSF) were collected from the hospital's electronic database. Analyses were performed using univariate statistical techniques. Of the 46 patients, 22% (n = 10) experienced bleomycin pulmonary toxicity. There was an overall mortality of 4.3% (n = 2; N = 46), with significantly more deaths in the bleomycin pulmonary toxicity group compared to the cohort that did not have bleomycin pulmonary toxicity (20% versus 0%; p = 0.043). The bleomycin pulmonary toxicity group was significantly older compared to the cohort that did not have bleomycin pulmonary toxicity (48 versus 34 years; p = 0.017). Furthermore, adriamycin, bleomycin, vinblastine, dacarbazine, as front-line chemotherapy, was found to have a trend towards increased risk of bleomycin pulmonary toxicity (90% versus 56%; p = 0.067; power = 31%). There did not seem to be significant differences in bleomycin dose (143 versus 149 units; p = 0.727), smoking status (10% versus 14%; p = 1.000) and systolic blood pressure (133 versus 131 mmHg; p = 0.746) between the two study groups. This study confirms a relatively high incidence of bleomycin pulmonary toxicity in a tertiary hospital in Oman. Older patients were significantly more likely to suffer bleomycin pulmonary toxicity compared to younger patients.


Hormone induced differential transcriptome analysis of Sertoli cells during postnatal maturation of rat testes.
Sertoli cells (Sc) are unique somatic cells of testis that are the target of both FSH and testosterone (T) and regulate spermatogenesis. Although Sc of neonatal rat testes are exposed to high levels of FSH and T, robust differentiation of spermatogonial cells becomes conspicuous only after 11-days of postnatal age. We have demonstrated earlier that a developmental switch in terms of hormonal responsiveness occurs in rat Sc at around 12 days of postnatal age during the rapid transition of spermatogonia A to B. Therefore, such "functional maturation" of Sc, during pubertal development becomes prerequisite for the onset of spermatogenesis. However, a conspicuous difference in robust hormone (both T and FSH) induced gene expression during the different phases of Sc maturation restricts our understanding about molecular events necessary for the spermatogenic onset and maintenance. Here, using microarray technology, we for the first time have compared the differential transcriptional profile of Sc isolated and cultured from immature (5 days old), maturing (12 days old) and mature (60 days old) rat testes. Our data revealed that immature Sc express genes involved in cellular growth, metabolism, chemokines, cell division, MAPK and Wnt pathways, while mature Sc are more specialized expressing genes involved in glucose metabolism, phagocytosis, insulin signaling and cytoskeleton structuring. Taken together, this differential transcriptome data provide an important resource to reveal the molecular network of Sc maturation which is necessary to govern male germ cell differentiation, hence, will improve our current understanding of the etiology of some forms of idiopathic male infertility.


Thyroid growth immunoglobulins in feline hyperthyroidism.
Feline hyperthyroidism bears a strong clinical and pathologic resemblance to toxic nodular goiter in humans. To evaluate whether the observed thyroid growth might be due to circulating thyroid antibodies, as has been postulated in humans, we studied the effect of purified immunoglobulin (Ig) G preparations on a rat thyroid follicular (FRTL-5) cell line. When compared with control, hyperthyroid cat IgG caused significantly increased [3H]-thymidine (Tdr) incorporation into DNA (p less than 0.02) and stimulated cellular proliferation 15-fold. Stimulation of 3H-Tdr incorporation tended to be biphasic and could be inhibited completely by a potent, specific TSH receptor blocking antibody. Hyperthyroid cat IgG also significantly inhibited 125I-bTSH binding to porcine thyroid membranes, an effect that could be reproduced using electrophoretically pure IgG and normal cat thyroid membranes. Unlike its effect on growth, hyperthyroid cat IgG did not stimulate intracellular cAMP, and there was no correlation between thyroid function in vivo and IgG growth-promoting activity in vitro. These data suggest that elevated titers of thyroid growth IgGs, probably acting through the TSH receptor, are present in feline hyperthyroidism and may play a role in goiter formation. Unlike growth, the thyroid hyperfunction observed is not IgG dependent. Further study of feline hyperthyroidism may contribute important insights into human nodular goiter and into the mediation of thyroid growth in general.


Molecular identification of necrophagous muscidae and sarcophagidae fly species collected in Korea by mitochondrial cytochrome C oxidase subunit I nucleotide sequences.
Identification of insect species is an important task in forensic entomology. For more convenient species identification, the nucleotide sequences of cytochrome c oxidase subunit I (COI) gene have been widely utilized. We analyzed full-length COI nucleotide sequences of 10 Muscidae and 6 Sarcophagidae fly species collected in Korea. After DNA extraction from collected flies, PCR amplification and automatic sequencing of the whole COI sequence were performed. Obtained sequences were analyzed for a phylogenetic tree and a distance matrix. Our data showed very low intraspecific sequence distances and species-level monophylies. However, sequence comparison with previously reported sequences revealed a few inconsistencies or paraphylies requiring further investigation. To the best of our knowledge, this study is the first report of COI nucleotide sequences from Hydrotaea occulta, Muscina angustifrons, Muscina pascuorum, Ophyra leucostoma, Sarcophaga haemorrhoidalis, Sarcophaga harpax, and Phaonia aureola.


The CD14+HLA-DRlo/neg Monocyte: An Immunosuppressive Phenotype That Restrains Responses to Cancer Immunotherapy.
Recent successes in cancer immunotherapy have been tempered by sub-optimal clinical responses in the majority of patients. The impaired anti-tumor immune responses observed in these patients are likely a consequence of immune system dysfunction contributed to by a variety of factors that include, but are not limited to, diminished antigen presentation/detection, leukopenia, a coordinated network of immunosuppressive cell surface proteins, cytokines and cellular mediators. Monocytes that have diminished or no HLA-DR expression, called CD14+HLA-DRlo/neg monocytes, have emerged as important mediators of tumor-induced immunosuppression. These cells have been grouped into a larger class of suppressive cells called myeloid derived suppressor cells (MDSCs) and are commonly referred to as monocytic myeloid derived suppressor cells. CD14+HLA-DRlo/neg monocytes were first characterized in patients with sepsis and were shown to regulate the transition from the inflammatory state to immune suppression, ultimately leading to immune paralysis. These immunosuppressive monocytes have also recently been shown to negatively affect responses to PD-1 and CTLA-4 checkpoint inhibition, CAR-T cell therapy, cancer vaccines, and hematopoietic stem cell transplantation. Ultimately, the goal is to understand the role of these cells in the context of immunosuppression not only to facilitate the development of targeted therapies to circumvent their effects, but also to potentially use them as a biomarker for understanding disparate responses to immunotherapeutic regimens. Practical aspects to be explored for development of CD14+HLA-DRlo/neg monocyte detection in patients are the standardization of flow cytometric gating methods to assess HLA-DR expression, an appropriate quantitation method, test sample type, and processing guidances. Once detection methods are established that yield consistently reproducible results, then further progress can be made toward understanding the role of CD14+HLA-DRlo/neg monocytes in the immunosuppressive state.


Symmetry-breaking in the H2@C60 endofullerene revealed by inelastic neutron scattering at low temperature.
The fine structure of the rotational ground state of molecular ortho-hydrogen confined inside the fullerene cage C60 is investigated by inelastic neutron scattering (INS). The INS line corresponding to transitions between the three sub-levels comprising the ortho ground state to the non-degenerate para ground state was studied as a function of temperature down to 60 mK in neutron energy gain. The experiments show that at ambient pressure the three ortho sub-levels are split into a low energy non-degenerate level and a high energy doubly degenerate level separated by 0.135 ± 0.010 meV. This observation is consistent with hydrogen molecules being located at sites with axial symmetry superseding the icosahedral symmetry of isolated rigid C60 cages in the solid phase. To gain insight into the role of inter-cage interactions in determining the symmetry breaking potential, the effects of hydrostatic pressure on the fine structure of the line was also investigated. The analysis of the INS spectra shows that the potential and the energy levels of H2 are sensitive to the orientation of neighbouring cages, consistent with the low-temperature crystalline phase of C60.


Recommendations from the Council of Residency Directors (CORD) Social Media Committee on the Role of Social Media in Residency Education and Strategies on Implementation.
Social media (SM) is a form of electronic communication through which users create online communities and interactive platforms to exchange information, ideas, messages, podcasts, videos, and other user-generated content. Emergency medicine (EM) has embraced the healthcare applications of SM at a rapid pace and continues to explore the potential benefit for education. Free Open Access Meducation has emerged from the ever-expanding collection of SM interactions and now represents a virtual platform for sharing educational media. This guidance document constitutes an expert consensus opinion for best practices in the use of SM in EM residency education. The goals are the following: 1) Recommend adoption of SM as a valuable graduate medical education (GME) tool, 2) Provide advocacy and support for SM as a GME tool, and 3) Recommend best practices of educational deliverables using SM. These guidelines are intended for EM educators and residency programs for the development and use of a program-specific SM presence for residency education, taking into account appropriate SM stewardship that adheres to institution-specific guidelines, content management, Accreditation Council for GME milestone requirements, and integration of SM in EM residency curriculum to enhance the learner's experience. Additionally, potential obstacles to the uptake of SM as an educational modality are discussed with proposed solutions.


Mesenchymal stromal cells lower platelet activation and assist in platelet formation in vitro.
The complex process of platelet formation originates with the hematopoietic stem cell, which differentiates through the myeloid lineage, matures, and releases proplatelets into the BM sinusoids. How formed platelets maintain a low basal activation state in the circulation remains unknown. We identify Lepr+ stromal cells lining the BM sinusoids as important contributors to sustaining low platelet activation. Ablation of murine Lepr+ cells led to a decreased number of platelets in the circulation with an increased activation state. We developed a potentially novel culture system for supporting platelet formation in vitro using a unique population of CD51+PDGFRα+ perivascular cells, derived from human umbilical cord tissue, which display numerous mesenchymal stem cell (MSC) properties. Megakaryocytes cocultured with MSCs had altered LAT and Rap1b gene expression, yielding platelets that are functional with low basal activation levels, a critical consideration for developing a transfusion product. Identification of a regulatory cell that maintains low baseline platelet activation during thrombopoiesis opens up new avenues for improving blood product production ex vivo.


Kinematic evidence for superfast locomotory muscle in two species of teneriffiid mites.
Locomotory muscles typically operate over a narrow range of contraction frequencies, characterized by the predominant fiber types and functional roles. The highest documented frequencies in the synchronous sound-producing muscles of insects (550 Hz) and toadfish (200 Hz) far exceed the contraction frequencies observed in weight-bearing locomotory muscles, which have maximum documented frequencies below 15-30 Hz. Laws of scaling, however, predict that smaller arthropods may employ stride frequencies exceeding this range. In this study we measured running speed and stride frequency in two undescribed species of teneriffiid mites from the coastal sage scrub of southern California. Relative speeds of both species [129-133 body lengths (BL)s(-1)] are among the fastest documented for any animal. Measured stride frequencies for both species far exceed those documented for any weight-bearing locomotory muscle, with measured values for one species ranging from 93 Hz at 25 degrees C to 111 Hz at 45 degrees C. Stride frequencies either closely approximate or, for one species, exceed predicted values based on an interspecific scaling of frequency and animal mass. Consequently, while the ultra-high frequencies of these muscles must depend on appropriately scaled kinetics of the calcium transient and contraction-relaxation cycle, these do not appear to limit the operating frequencies during running. The predicted low muscle forces operating at these very high frequencies evidently suffice for locomotion, probably because of the larger relative muscle force generated by smaller animals.


Low-Concentration Norepinephrine Infusion for Major Surgery: A Safety and Feasibility Pilot Randomized Controlled Trial.
Prevention of hypotension during the intra- and postoperative period is an important goal. Peripheral administration of low-concentration norepinephrine may be a safe and effective strategy to reduce the risk of hypotension. We conducted a 2-center, randomized pilot feasibility trial, with a target of 60 adult patients undergoing major noncardiac surgery. We randomized patients to receive a peripheral low-concentration (10 µg/mL) norepinephrine or placebo (saline 0.9%) infusion. The study drug infusion was titrated to achieve a minimum systolic blood pressure target, preselected within 10% of baseline value and within the range limit 100 to 120 mm Hg during surgery and for up to 4 or 24 hours postoperatively. We achieved a high consent rate (84%), successful study drug administration throughout surgery (98% of patients) and absence of unblinding. There were no important study drug-related adverse events. The average intraoperative systolic blood pressure was 120 ± 12.6 mm Hg in the norepinephrine group and 115 ± 14.9 mm Hg in the placebo group. The mean difference between the intraoperative systolic blood pressure achieved less the preselected minimum systolic blood pressure target was 10.0 ± 12.7 mm Hg in the norepinephrine group and 2.9 ± 14.7 mm Hg in the placebo group; difference in means, 7.1 (95% confidence interval, 0.2-14.0) mm Hg. A future large trial evaluating the effectiveness and safety of peripheral administration of low-concentration norepinephrine during the perioperative period is feasible, and likely to achieve a minimum systolic blood pressure threshold.


Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability.
Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.


Effects of almond consumption on the reduction of LDL-cholesterol: a discussion of potential mechanisms and future research directions.
Diet plays a seminal role in the prevention and treatment of cardiovascular disease. Consumption of tree nuts has been shown to reduce low-density lipoprotein cholesterol (LDL-C), a primary target for coronary disease prevention, by 3-19%. Almonds have been found to have a consistent LDL-C-lowering effect in healthy individuals, and in individuals with high cholesterol and diabetes, in both controlled and free-living settings. Almonds are low in saturated fatty acids, rich in unsaturated fatty acids, and contain fiber, phytosterols, and plant protein. Other cardioprotective nutrients unique to almonds include α-tocopherol, arginine, magnesium, copper, manganese, calcium, and potassium. Mechanisms responsible for the LDL-C reduction observed with almond consumption are likely associated with the nutrients almonds provide. Biologically active by nature, these nutrients target primary mechanistic routes of LDL-C reduction, including decreased (re)absorption of cholesterol and bile acid, increased bile acid and cholesterol excretion, and increased LDL-C receptor activity. The nutrients present in almonds may regulate enzymes involved in de novo cholesterol synthesis and bile acid production. Research is needed to understand all mechanisms by which almonds reduce cardiovascular disease risk.


Active hippocampal networks undergo spontaneous synaptic modification.
The brain is self-writable; as the brain voluntarily adapts itself to a changing environment, the neural circuitry rearranges its functional connectivity by referring to its own activity. How the internal activity modifies synaptic weights is largely unknown, however. Here we report that spontaneous activity causes complex reorganization of synaptic connectivity without any external (or artificial) stimuli. Under physiologically relevant ionic conditions, CA3 pyramidal cells in hippocampal slices displayed spontaneous spikes with bistable slow oscillations of membrane potential, alternating between the so-called UP and DOWN states. The generation of slow oscillations did not require fast synaptic transmission, but their patterns were coordinated by local circuit activity. In the course of generating spontaneous activity, individual neurons acquired bidirectional long-lasting synaptic modification. The spontaneous synaptic plasticity depended on a rise in intracellular calcium concentrations of postsynaptic cells, but not on NMDA receptor activity. The direction and amount of the plasticity varied depending on slow oscillation patterns and synapse locations, and thus, they were diverse in a network. Once this global synaptic refinement occurred, the same neurons now displayed different patterns of spontaneous activity, which in turn exhibited different levels of synaptic plasticity. Thus, active networks continuously update their internal states through ongoing synaptic plasticity. With computational simulations, we suggest that with this slow oscillation-induced plasticity, a recurrent network converges on a more specific state, compared to that with spike timing-dependent plasticity alone.


Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in patients with haematological disorders after chemotherapy or stem cell transplantation.
This is the protocol for a review and there is no abstract. The objectives are as follows: To determine whether different platelet transfusion thresholds for administration of prophylactic platelet transfusions (platelet transfusions given to prevent bleeding) affect the efficacy and safety of prophylactic platelet transfusions in preventing bleeding in patients with haematological disorders after chemotherapy with or without stem cell transplantation.


Trace elements accumulation in edible tissues of five sturgeon species from the Caspian Sea.
This study is focused on twenty trace elements (Ag, Ba, Bi, Cd, Co, Cr, Cs, Cu, Ga, In, Mn, Mo, Pb, Rb, Sb, Sn, Sr, Ti, V, Zn) accumulation in muscles of five sturgeon species (Acipenser guldenstaedti, A. persicus, A. nudiventris, A. stellatus and Huso huso) from the southern part of the Caspian Sea. Moreover the relationships between some biological characteristics and the levels of the selected elements as well as inter-elemental relationships were assessed. The samples (10 specimens for each the five species) were collected from two important sturgeon fishery zones located in the Iranian part of the Sea in 2002. Concentrations of the elements were determined using ICP-MS. Only in the case of Cs could significant differences between two selected sampling areas be detected. There were significant differences in levels of Co, Ga, Rb, Sn, Ti, Pb and Bi in muscles of the species. Only in the case of Cd weight related differences among the species were found. The significant length dependent relationships were observed for Ga and Ba. Patterns of elements accumulation were assessed by statistical methods and compared to the other researches. In all the cases, the amounts of toxic trace elements (Cd, Cu, Pb and Zn) were markedly below the international guidelines for human consumption.


Predicting medical and surgical complications of carotid endarterectomy: comparing the risk indexes.
Several generic cardiac risk assessment tools predict perioperative cardiac complications, but their ability to predict a broader range of medical, neurologic, and surgical complications is unknown. A multicenter retrospective observational cohort study of 1998 patients undergoing carotid endarterectomy (CEA). Complications within 30 days of surgery were assessed by medical record review, including death or nonfatal stroke and cardiac, noncardiac medical, minor neurologic, and wound complications. Logistic regression and receiver operating characteristic curve analyses assessed the predictive abilities of the Goldman, Detsky, Revised Cardiac Risk, and American Society of Anesthesiologists indexes and of 2 CEA-specific risk models (the Halm and Tu scores). Death or stroke occurred in 3.2% of patients, cardiac complications in 4.0%, noncardiac medical complications in 3.2%, minor neurologic complications in 6.9%, and wound complications in 6.0%. All risk models (except the Tu score) significantly predicted cardiac complications equally well (P<.05). All 6 risk models were equivalent in predicting noncardiac medical complications. Only the Revised Cardiac Risk Index and the 2 CEA-specific risk models (Halm and Tu scores) predicted death or stroke and minor neurologic and wound complications. The Halm score was superior in predicting death or stroke compared with the Tu score and the Revised Cardiac Risk Index (area under the receiver operating characteristic curve, 0.72 vs 0.62 and 0.61, respectively; P<.05). Patients with cardiac, noncardiac medical, minor neurologic, or wound complications had 3- to 16-fold increased odds of death or stroke. The Halm score CEA-specific risk model and the generic Revised Cardiac Risk Index predicted a broad range of medical, neurologic, and surgical complications following CEA.


Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus.
The CA1 pyramidal neurons in the hippocampus contain a high density of adrenal corticosteroid receptors. By intracellular recording, CA1 neurons in slices from adrenalectomized rats have been found to display a markedly reduced afterhyperpolarization (that is, the hyperpolarizing phase after a brief depolarizing current pulse) when compared with their sham controls. No differences were found for other tested membrane properties. Brief exposure of hippocampal slices from adrenalectomized rats to glucocorticoid agonists, 30 to 90 minutes before recording, greatly enhanced the afterhyperpolarization. In addition, glucocorticoids attenuated the norepinephrine-induced blockade of action potential accommodation in CA1 neurons. The findings indicate that glucocorticoids can reduce transmitter-evoked excitability in the hippocampus, presumably via a receptor-mediated genomic action.