Sanders classification of fractures of the os calcis. An analysis of inter- and intra-observer variability.
Our study was undertaken to assess the inter- and intra-observer variability of the classification system of Sanders for calcaneal fractures. Five consultant orthopaedic surgeons with different subspecialty interests classified CT scans of 28 calcaneal fractures using this classification system. After six months, they reclassified the scans. Kappa statistics were used to analyse the two groups. The interobserver variability of the classification system was 0.32 (95% confidence interval (CI) 0.26 to 0.38). The subclasses were then combined and assessment of agreement between the general classes as a whole gave a kappa value of 0.33 (95% CI 0.25 to 0.41). The mean kappa value for intra-observer variability of the classification system was 0.42 (95% CI 0.22 to 0.62). When the subclasses were combined, it was 0.45 (95% CI 0.21 to 0.65). Our results show that, despite its popularity, the classification system of Sanders has only fair agreement among users.


Transport of adenine, hypoxanthine and uracil into Escherichia coli.
Uptake of adenine, hypoxanthine and uracil by an uncA strain of Escherichia coli is inhibited by uncouplers or when phosphate in the medium is replaced by less than 1 mM-arsenate, indicating a need for both a protonmotive force and phosphorylated metabolites. The rate of uptake of adenine or hypoxanthine was not markedly affected by a genetic deficiency of purine nucleoside phosphorylase. In two mutants with undetected adenine phosphoribosyltransferase, the rate of adenine uptake was about 30% of that in their parent strain, and evidence was obtained to confirm that adenine had then been utilized via purine nucleoside phosphorylase. In a strain deficient in both enzymes adenine uptake was about 1% of that shown by wild-type strains. Uptake of hypoxanthine was similarly limited in a strain lacking purine nucleoside phosphorylase, hypoxanthine phosphoribosyltransferase and guanine phosphoribosyltransferase. Deficiency of uracil phosphoribosyltransferase severely limits uracil uptake, but the defect can be circumvented by addition of inosine, which presumably provides ribose 1-phosphate for reversal of uridine phosphorylase. The results indicate that there are porter systems for adenine, hypoxanthine and uracil dependent on a protonmotive force and facilitated by intracellular metabolism of the free bases.


A role for thymic stromal lymphopoietin in CD4(+) T cell development.
Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor alpha chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor gamma chain, gamma(c). We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, gamma(c)/TSLPR double KO mice had a greater lymphoid defect than gamma(c) KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in gamma(c) KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into gamma(c) KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti-IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4(+) single positive thymocytes and peripheral T cells in vitro. Additionally, CD4(+) T cells from TSLPR KO mice expanded less efficiently than WT CD4(+) T cells in irradiated hosts, and TSLP preferentially expanded CD4(+) T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4(+) T cells.


Problem and pathological gambling among college athletes.
Problematic gambling is common in college students, and in particular, athletes. The frequency of problem and pathological gambling was determined among 636 college athletes at three Midwest universities using the South Oaks Gambling Screen (SOGS). The Gambling Attitude Scale (GAS) was used to assess college athletes' attitudes toward gambling in general and toward four modes of gambling (casinos, betting on horse races, lottery and the Internet). A profile of college athletes' gambling attitudes and behavior was developed through the data obtained from each of these instruments. Nearly 15% of respondents had a SOGS score >or=3, indicating problem or pathological gambling. Those at risk for a gambling problem gambled frequently, had family and/or friends with perceived gambling problems, were nonwhite, older, started gambling at a younger age, preferred games of skill, and held positive attitudes toward gambling in general and Internet gambling, in particular. Gambling problems are widespread among college athletes who constitute a vulnerable group. Specific interventions are needed to target this group.


Noble metal alloy complex nanostructures: controllable synthesis and their electrochemical property.
Noble metal nanocrystals have been extensively utilized as promising catalysts for chemical transformations and energy conversion. One of their significant applications lies in electrode materials in fuel cells (FCs) due to their superior electrocatalytic performance towards the reactions both on anode and cathode. Nowadays, tremendous efforts have been devoted to improve the catalytic performance and minimize the usage of precious metals. Constructing multicomponent noble metal nanocrystals with complex structures provides the opportunity to reach this goal due to their highly tunable compositions and morphologies, leading to the modification of the related electrochemical properties. In this review, we first highlight the recent advances in the controllable synthesis of noble metal alloy complex nanostructures including nanoframes/nanocages, branched structures, concave/convex structures, core-shell structures and ultrathin structures. Then the effects of the well-defined nanocrystals on the modified and improved electrochemical properties are outlined. Finally, we make a conclusion with the points on the challenges and perspectives of the controllable synthesis of noble metal alloy complex nanostructures and their electrocatalytic performance.


Large thermal hysteresis for iron(II) spin crossover complexes with N-(pyrid-4-yl)isonicotinamide.
A new series of iron(II) 1D coordination polymers with the general formula [FeL1(pina)]·xsolvent with L1 being a tetradentate N2O2(2-) coordinating Schiff-base-like ligand [([3,3']-[1,2-phenylenebis(iminomethylidyne)]bis(2,4-pentanedionato)(2-)-N,N',O(2),O(2)'], and pina being a bridging axial ligand N-(pyrid-4-yl)isonicotinamide, are discussed. The X-ray crystal structure of [FeL1(pina)]·2MeOH was solved for the low-spin state. The compound crystallizes in the monoclinic space group P21/c, and the analysis of the crystal packing reveals the formation of a hydrogen bond network where additional methanol molecules are included. Different magnetic properties are observed for the seven samples analyzed, depending on the nature of the included solvent molecules. The widest hysteresis loop is observed for a fine crystalline sample of composition [FeL1(pina)]·xH2O/MeOH. The 88 K wide thermal hysteresis loop (T1/2↑ = 328 K and T1/2↓ = 240 K) is centered around room temperature and can be repeated without of a loss of the spin transition properties. For the single crystals of [FeL1(pina)]·2MeOH, a 51 K wide hysteresis loop is observed (T1/2↑ = 296 K and T1/2↓ = 245 K) that is also stable for several cycles. For a powder sample of [FeL1(pina)]·0.5H2O·0.5MeOH a cooperative spin transition with a 46 K wide hysteresis loop around room temperature is observed (T1/2↑ = 321 K and T1/2↓ = 275 K). This compound was further investigated using Mössbauer spectroscopy and DSC. Both methods reveal that, in the cooling mode, the spin transition is accompanied by a phase transition while in the heating mode a loss of the included methanol is observed that leads to a loss of the spin transition properties. These results show that the pina ligand was used successfully in a crystal-engineering-like approach to generate 1D coordination polymers and improve their spin crossover properties.


Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.
Current prognostic tools in myelofibrosis (MF) fail to identify patients at the highest risk of death and are limited by their applicability only to the time of diagnosis. We aimed to define an accelerated phase (AP) in MF by characterizing disease features that can identify patients with median overall survival of <or= 12 months at any time in the disease course. Baseline characteristics of 370 consecutive patients with MF from a single center were analyzed to identify features associated with a median overall survival of <or= 12 months. These putative AP features were then validated by following the course of chronic-phase patients (no AP features at baseline) until the development of one or more AP features and determining their subsequent survival. The following three characteristics were associated with poor survival at baseline and were selected as putative AP features: blasts in blood or bone marrow >or= 10%, platelets less than 50 x 10(9)/L, and chromosome 17 aberrations (median overall survival, 10, 12, and 5 months, respectively). In the validation phase, chronic-phase patients who developed AP features during follow-up were found to have short subsequent survival times (median overall survival, 12, 15, and 6 months, respectively). AP was a necessary step in the progression to blast phase, with leukemic transformation being exceedingly rare (3% risk at 10 years) in patients who remained persistently in chronic phase. Blood or bone marrow blasts >or= 10%, platelets less than 50 x 10(9)/L, and chromosome 17 aberrations defined AP in patients with MF. Patients in AP should be candidates for intensive therapeutic interventions.


The relationship between quality of life and clinical efficacy from a randomized trial comparing olanzapine and ziprasidone.
To examine treatment-specific changes in health-related quality of life (QOL) among patients with schizophrenia and to assess the association between clinical and QOL improvement. This post hoc analysis used the findings of a 28-week, randomized, multicenter trial of patients with schizophrenia (DSM-IV) treated with olanzapine (10-20 mg/day) or ziprasidone (80-160 mg/day). Data were collected from August 2001 to December 2002. Efficacy was measured using the Positive and Negative Syndrome Scale (PANSS). Quality of life was assessed with the generic health self-administered Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36) and the disease-specific expert-administered Heinrichs-Carpenter Quality of Life Scale (QLS). Mixed-effects-repeated-measures and last-observation-carried-forward approaches were used to assess the effects of treatment on QOL and the association of clinical outcomes to QOL outcomes. Olanzapine- and ziprasidone-treated patients demonstrated similar improvement from baseline to endpoint on the SF-36 and QLS. All correlations between changes in PANSS scores and the SF-36 were significant (p < .001), ranging from -0.159 to -0.400. All correlations between changes in PANSS scores and the QLS were significant (p < .0001), ranging from -0.286 to -0.603. The correlations between the 2 QOL measures were generally significant but small to moderate in magnitude. The results of this study indicate that, in patients with schizophrenia, olanzapine and ziprasidone treatment are associated with significant QOL and clinical improvements. Further, the significant correlation between change scores on the PANSS and QOL measures suggests that treatment-related clinical improvements are associated with improved health-related and disease-specific QOL. ClinicalStudyResults.org identifier 2347.


A randomized controlled trial of the effect of fish oil supplementation in late pregnancy and early lactation on the n-3 fatty acid content in human breast milk.
The aim of this research was to investigate the effect of fish oil supplementation, in the third trimester of pregnancy and early lactation period of healthy pregnant Danish women. Forty-four pregnant women were randomly allocated to fish oil supplementation (1.3 g EPA and 0.9 g DHA per day) from week 30 of gestation (FO-group) or to a control regimen (olive oil or no oil; controls). The FO-group was randomly subdivided into women stopping fish oil supplementation at delivery IFO(pregn)], and women continuing supplementation for an additional 30 d [FO(pregn/lact)]. Thirty-six women agreed to collect milk samples at days 4, 16, and 30 postpartum. The FA composition of the milk samples was determined by GLC. At days 4, 16, and 30 in lactation, FO(pregn/lact) women (n = 12) had, respectively 2.3 (P = 0.001), 4.1 (P = 0.001), and 3.3 (P = 0.001) times higher mean contents of LCPUFA(n-3) in their breast milk compared with controls (n = 13), and 1.7 (P = 0.005), 2.8 (P = 0.001), and 2.8 (P = 0.001) times higher LCPUFA(n-3) contents, respectively, at these days compared with FO(pregn) women (n = 11). The latter group did not differ significantly from controls with regard to LCPUFA(n-3) content in the breast milk. Similar results were obtained when analyzing separately for effects on the milk content of DHA. Dietary supplementation with 2.7 g LCPUFA(n-3) per day from week 30 of gestation and onward more than tripled the LCPUFA(n-3) content in early breast milk; supplementation limited to pregnancy only was much less effective.


A virus-encoded potassium ion channel is a structural protein in the chlorovirus Paramecium bursaria chlorella virus 1 virion.
Most chloroviruses encode small K(+) channels, which are functional in electrophysiological assays. The experimental finding that initial steps in viral infection exhibit the same sensitivity to channel inhibitors as the viral K(+) channels has led to the hypothesis that the channels are structural proteins located in the internal membrane of the virus particles. This hypothesis was questioned recently because proteomic studies failed to detect the channel protein in virions of the prototype chlorovirus Paramecium bursaria chlorella virus 1 (PBCV-1). Here, we used a mAb raised against the functional K(+) channel from chlorovirus MA-1D to search for the viral K(+) channel in the virus particle. The results showed that the antibody was specific and bound to the tetrameric channel on the extracellular side. The antibody reacted in a virus-specific manner with protein extracts from chloroviruses that encoded channels similar to that from MA-1D. There was no cross-reactivity with chloroviruses that encoded more diverse channels or with a chlorovirus that lacked a K(+) channel gene. Together with electron microscopic imaging, which revealed labelling of individual virus particles with the channel antibody, these results establish that the viral particles contain an active K(+) channel, presumably located in the lipid membrane that surrounds the DNA in the mature virions.


Chromatin Immunoprecipitation for Analyzing Transcription Factor Binding and Histone Modifications in Drosophila.
Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) is an invaluable technique to assess transcription factor binding and histone modifications in a genome-wide manner, an essential step towards understanding the mechanisms that govern embryonic development. Here, we provide a detailed protocol for all steps involved in generating a ChIP-seq library, starting from embryo collection, fixation, chromatin preparation, immunoprecipitation, and finally library preparation. The protocol is optimized for Drosophila embryos, but can be easily adapted for any model organism. The resulting library is suitable for sequencing on an Illumina HiSeq or MiSeq platform.


Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia.
Vascular endothelial growth factor (VEGF) is produced by most tumour types and stimulates the growth of new blood vessels in the tumour. The expansion of a solid tumour ultimately leads to the development of hypoxic regions, which increases VEGF production and further angiogenesis. In this study, we examined the role of VEGF in the survival of breast tumour cells under hypoxia. Murine 4T1 and human MDA-MB-231 tumour cells were cultured under normoxic and hypoxic growth conditions in the presence or absence of VEGF neutralising antibodies. Apoptosis was assessed in addition to changes in expression of the anti- and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The effect of hypoxia on the novel VEGF receptor, NP1 (neuropilin-1) and the role of the PI3K (phosphatidylinositol-3-kinase) signalling pathway in response to VEGF were examined. VEGF blockade resulted in direct tumour cell apoptosis of both tumour cell lines under normoxia and hypoxia. While blocking VEGF resulted in a downregulation of hypoxia-induced Bcl-2 expression, there was a significant increase in the pro-apoptotic protein Bad relative to cells cultured under hypoxia alone. Both hypoxia and VEGF phosphorylated Akt. Neutralising antibodies to VEGF abrogated this effect, implicating the PI3K pathway in VEGF-mediated cell survival of mammary adenocarcinoma cells. This study demonstrates that VEGF acts as a survival factor not only for endothelial cells as previously thought, but also for some breast tumour cells, protecting them from apoptosis, particularly under hypoxic stress. The data presented provide an additional rationale for combining anti-VEGF strategies with conventional anti-cancer therapies such as chemotherapy and radiotherapy.


Region-specific involvement of actin rearrangement-related synaptic structure alterations in conditioned taste aversion memory.
Actin rearrangement plays an essential role in learning and memory; however, the spatial and temporal regulation of actin dynamics in different phases of associative memory has not been fully understood. Here, using the conditioned taste aversion (CTA) paradigm, we investigated the region-specific involvement of actin rearrangement-related synaptic structure alterations in different memory processes. We found that CTA training could induce increased postsynaptic density (PSD) length in insular cortex (IC), but not in basolateral amygdala (BLA) and prelimbic cortex (PrL) during short-term memory (STM) formation, whereas it led to increased PSD length and synapse density in both IC and PrL during long-term memory (LTM) formation. Inhibition of actin rearrangement in the IC, but not in the BLA and PrL, impaired memory acquisition. Furthermore, actin dynamics in the IC or PrL is necessary for memory consolidation. On the contrary, inhibition of actin dynamics in the IC, BLA, or PrL had no effect on CTA memory retrieval. Our results suggest temporal and regional-specific regulation of actin rearrangement-related synaptic structure in different phases of CTA memory.


TUNEL assay and SCSA determine different aspects of sperm DNA damage.
For the determination of sperm DNA damage, different assays are used. However, no further distinction is made and the literature generally speaks about DNA damage. Thus, this study aimed at comparing the sperm chromatin structure assay (SCSA) and the TUNEL assay. In 79 patients, sperm DNA damage was determined flow cytometrically using the SCSA and the TUNEL assay. Moreover, normal sperm morphology was evaluated according to strict criteria. A statistical comparison of the two methods was performed using standard correlations, Bland and Altman plots, Passing-Bablok regressions and concordance correlation. Results show a significant difference between P- and G-pattern morphology only for the mean channel fluorescence of the SCSA. Spearman's rank correlations between the different parameters of both assays, SCSA and TUNEL, revealed significant associations between the parameters of the assays. However, when applying Bland and Altman plots, Passing-Bablok regression and concordance correlation results showed that these methods are not comparable. These different techniques determine different aspects of sperm DNA damage, i.e. 'real' DNA damage for the TUNEL assay and 'potential' DNA damage in terms of susceptibility to DNA denaturation for the SCSA. Thus, one should clearly distinguish between the different assays, not only practically and methodologically but also linguistically.


Vascular cell responsiveness to Toll-like receptor ligands in carotid atheroma.
Atherosclerosis is potentiated by stimulation of Toll-like receptors (TLRs), which serve to detect pathogen associated molecular patterns (PAMPs). However little is known of which PAMPs may be present in atheroma, or capable of stimulating inflammatory signalling in vascular cells. DNA extracted from human carotid atheroma samples was amplified and sequenced using broad-range 16S gene specific primers to establish historical exposure to bacterial PAMPs. Responsiveness of primary human arterial and venous endothelial and smooth muscle cells to PAMPs specific for each of the TLRs was assessed by measurement of interleukin-8 secretion and E-selectin expression. Extracts of atheromatous tissue stimulated little or no signalling in TLR-transfected HEK-293 cells. However, sequencing of bacterial DNA amplified from carotid atheroma revealed the presence of DNA from 17 different bacterial genera, suggesting historical exposure to bacterial lipopeptide, lipopolysaccharide and flagellin. All cells examined were responsive to the ligands of TLR3 and TLR4, poly inosine:cytosine and lipopolysaccharide. Arterial cells were responsive to a wider range of PAMPs than venous cells, being additionally responsive to bacterial flagellin and unmethylated cytosine-phosphate-guanosine DNA motifs, the ligands of TLR5 and TLR9, respectively. Cells were generally unresponsive towards the ligands of human TLR7 and TLR8, loxoribine and single stranded RNA. Only coronary artery endothelial cells expressed TLR2 mRNA and responded to the TLR2 ligand Pam(3)CSK(4). Vascular cells are responsive to a relatively diverse range of TLR ligands and may be exposed, at least transiently, to ligands of TLR2, TLR4, TLR5 and TLR9 during the development of carotid atheroma.


Dynamic changes in genome-wide histone H3 lysine 4 methylation patterns in response to dehydration stress in Arabidopsis thaliana.
The molecular mechanisms of genome reprogramming during transcriptional responses to stress are associated with specific chromatin modifications. Available data, however, describe histone modifications only at individual plant genes induced by stress. We have no knowledge of chromatin modifications taking place at genes whose transcription has been down-regulated or on the genome-wide chromatin modification patterns that occur during the plant's response to dehydration stress. Using chromatin immunoprecipitation and deep sequencing (ChIP-Seq) we established the whole-genome distribution patterns of histone H3 lysine 4 mono-, di-, and tri-methylation (H3K4me1, H3K4me2, and H3K4me3, respectively) in Arabidopsis thaliana during watered and dehydration stress conditions. In contrast to the relatively even distribution of H3 throughout the genome, the H3K4me1, H3K4me2, and H3K4me3 marks are predominantly located on genes. About 90% of annotated genes carry one or more of the H3K4 methylation marks. The H3K4me1 and H3K4me2 marks are more widely distributed (80% and 84%, respectively) than the H3K4me3 marks (62%), but the H3K4me2 and H3K4me1 levels changed only modestly during dehydration stress. By contrast, the H3K4me3 abundance changed robustly when transcripts levels from responding genes increased or decreased. In contrast to the prominent H3K4me3 peaks present at the 5'-ends of most transcribed genes, genes inducible by dehydration and ABA displayed atypically broader H3K4me3 distribution profiles that were present before and after the stress. A higher number (90%) of annotated Arabidopsis genes carry one or more types of H3K4me marks than previously reported. During the response to dehydration stress the changes in H3K4me1, H3K4me2, and H3K4me3 patterns show different dynamics and specific patterns at up-regulated, down-regulated, and unaffected genes. The different behavior of each methylation mark during the response process illustrates that they have distinct roles in the transcriptional response of implicated genes. The broad H3K4me3 distribution profiles on nucleosomes of stress-induced genes uncovered a specific chromatin pattern associated with many of the genes involved in the dehydration stress response.


Lower urinary tract symptoms and benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is an important cause of lower urinary tract symptoms (LUTS). However, many other causes, including smooth muscle dysfunction and neurological factors may contribute to these symptoms, and accurate diagnosis is imperative before invasive treatments are chosen. Careful recording of symptoms, giving emphasis on how they interfere with the patient's quality of life, as well as the use of properly selected tests, constitutes the mainstay of making a correct diagnosis. Men with mild or moderate symptoms not experiencing complications are ideal candidates for medical treatment. For the rest with persistent symptoms or complications such as infection, bleeding, chronic retention or renal impairment further investigation and more invasive forms of treatment need to be considered. We review the patho-physiology of the disease, and current approaches and management of this common problem.


Does combined clinical and ultrasound assessment allow selection of individuals with rheumatoid arthritis for sustained reduction of anti-tumor necrosis factor therapy?
To investigate whether a strategy combining clinical and ultrasound (US) assessment can select individuals with rheumatoid arthritis (RA) for sustained dose reduction of anti-tumor necrosis factor (anti-TNF) therapies. As part of a real-world approach, patients with RA receiving anti-TNF therapies were reviewed in a dedicated biologic therapy clinic. Patients not taking oral corticosteroids with both Disease Activity Score in 28 joints (DAS28) remission (≤2.6) and absent synovitis on power Doppler US (PDUS 0) for >6 months were invited to reduce their anti-TNF therapy dose by one-third. Between January 2012 and February 2014, a total of 70 patients underwent anti-TNF dose reduction. Combined DAS28 and PDUS remission was maintained by 96% of patients at 3 months followup, 63% at 6 months, 37% at 9 months, and 34% at 18 months followup. However, 88% of patients maintained at least low disease activity (LDA) with DAS28 <3.2 and PDUS ≤1 at 6 months. The addition of PDUS identified 8 patients (25% of those that flared) in DAS28 remission, with subclinically active disease. Those who maintained dose reduction were more likely to be rheumatoid factor (RF) negative (46% versus 17%; P = 0.03) and have lower DAS28 scores at biologic therapy initiation (5.58 versus 5.96; P = 0.038). Combined clinical and US assessment identifies individuals in remission who may be suitable for anti-TNF dose reduction and enhances safe monitoring for subclinical disease flares. Despite longstanding severe RA, a subset of our cohort sustained prolonged DAS28 and PDUS remission. LDA at biologic therapy initiation and RF status appeared predictive of sustained remission.


Paediatric palliative care: a systematic review.
To review literature relating to evidence, context and facilitation to describe knowledge translation in paediatric palliative care. Paediatric palliative care requires competences including both paediatric specialists as well as services that are developed for this purpose, and there is a need to facilitate paediatric palliative care knowledge translation. Promoting Action on Research Implementation in the Health Services (PARiHS) is a framework for knowledge translation, which highlights the relationships between evidence, context and facilitation. PARiHS framework has been revised and updated in a new version called i-PARiHS. The electronic databases AgeLine, CINAHL, The Cochrane Library, PsycINFO, PubMed and Scopus were searched. Papers included were limited to English and Swedish publications and restricted to publications dated between 1993 and August 2019. All types of observational and experimental studies using any research design were included. Thirty-eight articles were included and there was a common vision about how and when palliative care should be offered to children. The i-PARiHS was used as a lens to describe the knowledge translation in paediatric palliative care. Symptom relief was the most commonly described evidence-based strategy, and the hospital environment was the most commonly described context. Different types of education were the most commonly used strategies to facilitate knowledge translation. The results mainly focused on increasing knowledge of palliative care in paediatric care. To sum up, the results report strategies to achieve knowledge translation of paediatric palliative care, and these can be interpreted as a guideline for how this process can be facilitated. CRD42018100663.


Robust High-dimensional Volatility Matrix Estimation for High-Frequency Factor Model.
High-frequency financial data allow us to estimate large volatility matrices with relatively short time horizon. Many novel statistical methods have been introduced to address large volatility matrix estimation problems from a high-dimensional Itô process with microstructural noise contamination. Their asymptotic theories require sub-Gaussian or some finite high-order moments assumptions for observed log-returns. These assumptions are at odd with the heavy tail phenomenon that is pandemic in financial stock returns and new procedures are needed to mitigate the influence of heavy tails. In this paper, we introduce the Huber loss function with a diverging threshold to develop a robust realized volatility estimation. We show that it has the sub-Gaussian concentration around the volatility with only finite fourth moments of observed log-returns. With the proposed robust estimator as input, we further regularize it by using the principal orthogonal component thresholding (POET) procedure to estimate the large volatility matrix that admits an approximate factor structure. We establish the asymptotic theories for such low-rank plus sparse matrices. The simulation study is conducted to check the finite sample performance of the proposed estimation methods.


Cryptic evolution: does environmental deterioration have a genetic basis?
Cryptic evolution has been defined as adaptive evolutionary change being masked by concurrent environmental change. Empirical studies of cryptic evolution have usually invoked a changing climate and/or increasing population density as the form of detrimental environmental change experienced by a population undergoing cryptic evolution. However, Fisher (1958) emphasized that evolutionary change in itself is likely to be an important component of "environmental deterioration," a point restated by Cooke et al. (1990) in the context of intraspecific competition. In this form, environmental deterioration arises because a winning lineage has to compete against more winners in successive generations as the population evolves. This "evolutionary environmental deterioration" has different implications for the selection and evolution of traits influenced by resource competition than general environmental change. We reformulate Cooke's model as a quantitative genetic model to show that it is identical in form to more recent developments proposed by quantitative geneticists. This provides a statistical framework for discriminating between the alternative hypotheses of environmental change and environmental deterioration caused by evolutionary change. We also demonstrate that in systems where no phenotypic change has occurred, there are many reasonable biological processes that will generate patterns in predicted breeding values that are consistent with what has been interpreted as cryptic evolution, and care needs to be taken when interpreting these patterns. These processes include mutation, sib competition, and invisible fractions.


Effect of heavy atoms on photochemically induced dynamic nuclear polarization in liquids.
Given its short hyperpolarization time (∼10-6 s) and mostly non-perturbative nature, photo-chemically induced dynamic nuclear polarization (photo-CIDNP) is a powerful tool for sensitivity enhancement in nuclear magnetic resonance. In this study, we explore the extent of 1H-detected 13C nuclear hyperpolarization that can be gained via photo-CIDNP in the presence of small-molecule additives containing a heavy atom. The underlying rationale for this methodology is the well-known external-heavy-atom (EHA) effect, which leads to significant enhancements in the intersystem-crossing rate of selected photosensitizer dyes from photoexcited singlet to triplet. We exploited the EHA effect upon addition of moderate amounts of halogen-atom-containing cosolutes. The resulting increase in the transient triplet-state population of the photo-CIDNP sensitizer fluorescein resulted in a significant increase in the nuclear hyperpolarization achievable via photo-CIDNP in liquids. We also explored the internal-heavy-atom (IHA) effect, which is mediated by halogen atoms covalently incorporated into the photosensitizer dye. Widely different outcomes were achieved in the case of EHA and IHA, with EHA being largely preferable in terms of net hyperpolarization.


Use of medical services by methylphenidate-treated children in the general population.
To examine selected medical services for children treated for attention-deficit/hyperactivity disorder (ADHD) in a general population setting with universal health insurance. Retrospective analysis of administrative prescription and health services databases spanning from 1990 to 1996. British Columbia, Canada. Children (<19 years of age) who had received the psychostimulant methylphenidate (MPH; Ritalin) on a chronic basis (chronic-MPH group), who had received MPH on any other basis (nonchronic-MPH group), and who were in a no-MPH comparison group. The number of individuals who received any of the following services based on claims submitted by qualified practitioners: 1) emergency care, 2) critical care, 3) injury-related diagnostic and treatment services, 4) complementary and alternative medical (CAM) care, and 5) other diagnostic and treatment services (audiometry and allergy testing). Prevalence of services users was higher among MPH-treated than nontreated children for all types of services (except critical care services in the chronic-MPH group) after adjusting for effects of age, sex, socioeconomic status, and geographic setting, with odds ratios ranging from 1.49 to 3.17. There were no differences between the 2 MPH-treated groups. Children treated with MPH for ADHD or presumed ADHD are more frequent users of a wide range of medical services than are other children. Findings support and extend existing evidence of increased use of medical services by this population of children. Findings have implications for service planning, including injury prevention, with these children. High utilization of audiometric, allergy, and CAM services warrants further scrutiny.


Paramedic and physician perspectives on the potential use of remotely supported prehospital ultrasound.
During remotely supported prehospital ultrasound (RSPU), an ultrasound operator performs a scan and sends images to a remote expert for interpretation. This novel technology has been undergoing investigation in the randomised controlled SatCare trial, which seeks to assess the capability of RSPU to improve patient outcomes and standard of prehospital care in the Highlands of Scotland. This study aimed to explore the views of emergency medicine physicians and paramedics prior to starting the trial. An interview schedule was prepared a priori and was based upon normalisation process theory (NPT), which can be used to assess ways in which practitioners work to embed novel technologies in clinical practice. Semi-structured interviews were conducted with four consultant physicians and eight paramedics, who were recruited using purposive sampling until theoretical saturation. Analysis used open and hierarchical axial coding, and NPT as a framework to assist in the management and analysis of codes. The prospect of RSPU evoked significantly different responses from emergency care physicians and paramedics. Paramedics thought of RSPU as a logical progression of prehospital care, which addresses core prehospital challenges such as lack of decision-making support and a limited ability to identify life-threatening occult conditions. Paramedics saw RSPU as part of a trend to increase their skills and responsibilities, and viewed ultrasound as a validated tool within emergency medicine. Paramedics felt that ultrasound was simple to learn and would be practical for use within the prehospital arena. In contrast, physicians expressed a greater spectrum of views; most saw limited value to prehospital diagnosis and were concerned that RSPU would distract both paramedics and physicians from their existing roles (particularly in the context of the increasing demand and workload within Scotland's publicly funded National Health Service). Physicians were also concerned that ultrasound skills were poorly incorporated into training and practice in the British emergency medicine system. Furthermore, they believed that ultrasound was difficult to learn, prone to misinterpretation and easy to become deskilled in. Both sets of participants believed that the relational skills required between the two groups and the practical complexities of RSPU may pose challenges in its implementation. In particular, concerns were raised regarding the time that would be required to conduct the ultrasound scans and difficulties with transmission and communication in the Highlands. Both groups questioned the likelihood of measurable benefits from RSPU for patients. Furthermore, both groups were unsure how the technology would benefit those patients in urban areas close to the emergency department or whether RSPU would be effectively utilised in rural areas where serious emergencies are infrequent. There are substantial differences in emergency physician and paramedic perspectives on RSPU; however, both parties were willing to engage with the research process. Both groups have reservations, especially the emergency physicians who perceive significant barriers to the acquisition of skills, as well as the relational and contextual integration of RSPU. This study demonstrates the importance of conversations with physicians and paramedics throughout the research process, particularly as the role of prehospital care remains controversial.


Dental Trauma Guide: a source of evidence-based treatment guidelines for dental trauma.
Diagnosis and treatment for traumatic dental injuries are very complex owing to the multiple trauma entities represented by six luxation types and nine fracture types affecting both the primary and the permanent dentition. When it is further considered that fracture and luxation injuries are often combined, the result is that more than 100 trauma scenarios exist, when the two dentitions are combined. Each of these trauma scenarios has a specific treatment demand and prospect for healing. With such a complexity in diagnosis and treatment, it is obvious that even experienced practitioners may have problems in selecting proper treatment for some of these trauma types. To remedy this situation, an Internet-based knowledge base consisting of 4000 dental trauma cases with long-term follow up is now available to the public and the professions on the Internet using the address http://www.DentalTraumaGuide.org. It is the aspiration that the use of this Guide may lead the practitioner to offer an evidence-based diagnosis and treatment.


DNA/RNA chimera templates improve the emission intensity and target the accessibility of silver nanocluster-based sensors for human microRNA detection.
In recent years microRNAs (miRNAs) have been established as important biomarkers in a variety of diseases including cancer, diabetes, cardiovascular disease, aging, Alzheimer's disease, asthma, autoimmune disease and liver diseases. As a consequence, a variety of monitoring methods for miRNAs have been developed, including a fast and simple method for miRNA detection by exploitation of the unique photoluminescence of DNA-templated silver nanoclusters (DNA/AgNCs). To increase the versatility of the AgNC-based method, we have adopted DNA/RNA chimera templates for AgNC-based probes, allowing response from several human miRNAs which are hardly detectable with DNA-based probes. Here, we demonstrate in detail the power of DNA/RNA chimera/AgNC probes in detecting two human miRNAs, let-7a and miR-200c. The DNA/RNA chimera-based probes are highly efficient to determine the level of miRNAs in several human cell lines.


Myocardial infarction pain: systematic description and analysis.
The aim of the study was to describe various components of pain in suspected acute myocardial infarction (MI). Ninety-four patients admitted to a Coronary Care Unit (CCU) complaining of chest pain with the preliminary diagnosis suspect MI were included in the study. Thirty-eight subjects were eventually diagnosed as having MI and 56 subjects as non-MI. A comparison of chest pain description was performed between MI and non-MI subjects. The Pain-o-meter (POM) and the Visual Analogue Scale (VAS) were used to assess pain intensity. MI patients reported more intense sensory and affective pain than non-MI patients. MI patients also reported more intense affective pain than sensory pain, whereas non-MI patients reported just the opposite. The number of affective words chosen by MI patients differentiated them more clearly from non-MI patients than any other factor in the pain description. Pain intensity was significantly correlated to the estimated size of the infarct.


Directed connectivity between primary and premotor areas underlying ankle force control in young and older adults.
The control of ankle muscle force is an integral component of walking and postural control. Aging impairs the ability to produce force steadily and accurately, which can compromise functional capacity and quality of life. Here, we hypothesized that reduced force control in older adults would be associated with altered cortico-cortical communication within a network comprising the primary motor area (M1), the premotor cortex (PMC), parietal, and prefrontal regions. We examined electroencephalographic (EEG) responses from fifteen younger (20-26 yr) and fifteen older (65-73 yr) participants during a unilateral dorsiflexion force-tracing task. Dynamic Causal Modelling (DCM) and Parametric Empirical Bayes (PEB) were used to investigate how directed connectivity between contralateral M1, PMC, parietal, and prefrontal regions was related to age group and precision in force production. DCM and PEB analyses revealed that the strength of connections between PMC and M1 were related to ankle force precision and differed by age group. For young adults, bidirectional PMC-M1 coupling was negatively related to task performance: stronger backward M1-PMC and forward PMC-M1 coupling was associated with worse force precision. The older group exhibited deviations from this pattern. For the PMC to M1 coupling, there were no age-group differences in coupling strength; however, within the older group, stronger coupling was associated with better performance. For the M1 to PMC coupling, older adults followed the same pattern as young adults - with stronger coupling accompanied by worse performance - but coupling strength was lower than in the young group. Our results suggest that bidirectional M1-PMC communication is related to precision in ankle force production and that this relationship changes with aging. We argue that the observed differences reflect compensatory reorganization that counteracts age-related sensorimotor declines and contributes to maintaining performance.


Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes.
There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.


Photosensitive post tuning of chalcogenide photonic crystal waveguides.
We present experimental results on post-tuning the dispersion of a two-dimensional photonic crystal waveguide made from Ge(33)As(12)Se(55) chalcogenide glass by exploiting the material photosensitivity to near-bandgap light. The change in the refractive index and volume of the material in response to exposure to 633nm light resulted in a shift of more than 5nm in the resonant coupling wavelength between a tapered optical fiber and the modes of a W1 waveguide. This represents a first proof of principle demonstration of the photosensitive post-tuning of a planar photonic crystal device.


Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development.
3-M primordial dwarfism is an inherited disease characterized by severe pre- and postnatal growth retardation and by mutually exclusive mutations in three genes, CUL7, OBSL1, and CCDC8. The mechanism underlying 3-M dwarfism is not clear. We showed here that CCDC8, derived from a retrotransposon Gag protein in placental mammals, exclusively localized on the plasma membrane and was phosphorylated by CK2 and GSK3. Phosphorylation of CCDC8 resulted in its binding first with OBSL1, and then CUL7, leading to the membrane assembly of the 3-M E3 ubiquitin ligase complex. We identified LL5β, a plasma membrane protein that regulates cell migration, as a substrate of 3-M ligase. Wnt inhibition of CCDC8 phosphorylation or patient-derived mutations in 3-M genes disrupted membrane localization of the 3-M complex and accumulated LL5β. Deletion of Ccdc8 in mice impaired trophoblast migration and placental development, resulting in intrauterine growth restriction and perinatal lethality. These results identified a mechanism regulating cell migration and placental development that underlies the development of 3-M dwarfism.


Mitochondria as generators and targets of nitric oxide.
Mitochondrial biochemistry is complex, expanding from oxidative phosphorylation, lipid catabolism and haem biosynthesis, to apoptosis, calcium homeostasis, and production of reactive oxygen and nitrogen species, including nitric oxide (NO). This molecule is produced by a mitochondrial nitric-oxide synthase (mtNOS). The rates of consumption and production determine the steady-state concentration of NO at subcellular levels, leading to the regulation of several mitochondrial events. Temporospatial processes tightly regulate the production of NO in mitochondria to maximize target effects and minimize deleterious reactions. Temporal regulatory mechanisms of mtNOS include activation by calcium and transcriptional/translational regulation. Calcium-activated mtNOS inhibits mitochondrial respiration. This regulation antagonizes the effects of calcium on matrix calcium-dependent dehydrogenases, preventing the formation of anoxic foci. Temporal regulation of NO production by intracellular calcium signalling requires the understanding of the heterogeneous intracellular calcium response and calcium distribution. NO production in mitochondria is spatially regulated by subcellular localization of mtNOS (e.g. acylation and protein-protein interactions), in addition to transcriptional regulation. Given the short half-life of NO in biological systems, organelle localization of mtNOS is crucial for NO to function as a signal molecule. These temporospatial processes are biologically important to allow NO to act as an effective signal molecule to regulate mitochondrial events.


Predictability of road traffic and congestion in urban areas.
Mitigating traffic congestion on urban roads, with paramount importance in urban development and reduction of energy consumption and air pollution, depends on our ability to foresee road usage and traffic conditions pertaining to the collective behavior of drivers, raising a significant question: to what degree is road traffic predictable in urban areas? Here we rely on the precise records of daily vehicle mobility based on GPS positioning device installed in taxis to uncover the potential daily predictability of urban traffic patterns. Using the mapping from the degree of congestion on roads into a time series of symbols and measuring its entropy, we find a relatively high daily predictability of traffic conditions despite the absence of any priori knowledge of drivers' origins and destinations and quite different travel patterns between weekdays and weekends. Moreover, we find a counterintuitive dependence of the predictability on travel speed: the road segment associated with intermediate average travel speed is most difficult to be predicted. We also explore the possibility of recovering the traffic condition of an inaccessible segment from its adjacent segments with respect to limited observability. The highly predictable traffic patterns in spite of the heterogeneity of drivers' behaviors and the variability of their origins and destinations enables development of accurate predictive models for eventually devising practical strategies to mitigate urban road congestion.


[Recommendations for the use of ambulatory blood pressure monitoring. Consensus document of the Chilean Hypertension Society].
Continuous ambulatory blood pressure monitoring is a diagnostic technique devised as a consequence of the great variations in blood pressure measurements. It allows multiple daily measurements, nocturnal monitoring, avoids the stress of blood pressure measurements, gives a picture of pressure behavior during 24 hours and reduces observer related errors. The equipment used must be accurate and validated using international protocols. Accepted indications for continuous ambulatory blood pressure monitoring are white coat hypertension, episodic hypertension, resistance to medications and assessment of symptoms or autonomic dysfunction. Other indications with less clear cut usefulness, are high risk cardiac, renal or pregnant patients and an accurate blood pressure control. We describe equipment calibration, elements that must be considered in the reports, result interpretation and conclusions. Normal blood pressure ranges for children and pregnant women are also reported.


A robust deconvolution method to disentangle multiple water pools in diffusion MRI.
The diffusion-weighted magnetic resonance imaging (dMRI) signal measured in vivo arises from multiple diffusion domains, including hindered and restricted water pools, free water and blood pseudo-diffusion. Not accounting for the correct number of components can bias metrics obtained from model fitting because of partial volume effects that are present in, for instance, diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI). Approaches that aim to overcome this shortcoming generally make assumptions about the number of considered components, which are not likely to hold for all voxels. The spectral analysis of the dMRI signal has been proposed to relax assumptions on the number of components. However, it currently requires a clinically challenging signal-to-noise ratio (SNR) and accounts only for two diffusion processes defined by hard thresholds. In this work, we developed a method to automatically identify the number of components in the spectral analysis, and enforced its robustness to noise, including outlier rejection and a data-driven regularization term. Furthermore, we showed how this method can be used to take into account partial volume effects in DTI and DKI fitting. The proof of concept and performance of the method were evaluated through numerical simulations and in vivo MRI data acquired at 3 T. With simulations our method reliably decomposed three diffusion components from SNR = 30. Biases in metrics derived from DTI and DKI were considerably reduced when components beyond hindered diffusion were taken into account. With the in vivo data our method determined three macro-compartments, which were consistent with hindered diffusion, free water and pseudo-diffusion. Taking free water and pseudo-diffusion into account in DKI resulted in lower mean diffusivity and higher fractional anisotropy values in both gray and white matter. In conclusion, the proposed method allows one to determine co-existing diffusion compartments without prior assumptions on their number, and to account for undesired signal contaminations within clinically achievable SNR levels.


The story of rRNA expansion segments: Finding functionality amidst diversity.
Expansion segments (ESs) are multinucleotide insertions present across phyla at specific conserved positions in eukaryotic rRNAs. ESs are generally absent in bacterial rRNAs with some exceptions, while the archaeal rRNAs have microexpansions at regions that coincide with those of eukaryotic ESs. Although there is an increasing prominence of ribosomes, especially the ribosomal proteins, in fine-tuning gene expression through translation regulation, the role of rRNA ESs is relatively underexplored. While rRNAs have been established as the major catalytic hub in ribosome function, the presence of ESs widens their scope as a species-specific regulatory hub of protein synthesis. In this comprehensive review, we have elaborately discussed the current understanding of the functional aspects of rRNA ESs of cytoplasmic eukaryotic ribosomes and discuss their past, present, and future. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems Translation > Ribosome Structure/Function Translation > Regulation.


Mortality among persons in care with hepatitis C virus infection: the Chronic Hepatitis Cohort Study (CHeCS), 2006-2010.
The number of deaths in hepatitis C virus (HCV)-infected persons recorded on US death certificates has been increasing, but actual rates and causes of death in these individuals have not been well elucidated. Disease-specific, liver-related, and non-liver-related mortality data for HCV-infected patients in an observational cohort study, the Chronic Hepatitis Cohort Study (CHeCS) at 4 US healthcare systems, were compared with multiple cause of death (MCOD) data in 12 million death certificates in 2006-2010. Premortem diagnoses, liver biopsies, and FIB-4 scores (a noninvasive measure of liver damage) were examined. Of 2 143 369 adult patients seen at CHeCS sites in 2006-2010, 11 703 (0.5%) had diagnosed chronic HCV infection, and 1590 (14%) died. The majority of CHeCS decedents were born from 1945 to 1965 (75%), white (50%), and male (68%); mean age of death was 59 years, 15 years younger than MCOD deaths. The age-adjusted mortality rate for liver disease in CHeCS was 12 times higher than the MCOD rate. Before death, 63% of decedents had medical record evidence of chronic liver disease, 76% had elevated FIB-4 scores, and, among those biopsied, 70% had moderate or worse liver fibrosis. However, only 19% of all CHeCS decedents and only 30% of those with recorded liver disease had HCV listed on their death certificates. HCV infection is greatly underdocumented on death certificates. The 16 622 persons with HCV listed in 2010 may represent only one-fifth of about 80 000 HCV-infected persons dying that year, at least two-thirds of whom (53 000 patients) would have had premortem indications of chronic liver disease.


Hatha yoga for acute, chronic and/or treatment-resistant mood and anxiety disorders: A systematic review and meta-analysis.
The aim of this study was to systematically investigate the effectiveness of hatha yoga in treating acute, chronic and/or treatment-resistant mood and anxiety disorders. Medline, Cochrane Library, Current Controlled Trials, Clinical Trials.gov, NHR Centre for Reviews and Dissemination, PsycINFO and CINAHL were searched through June 2018. Randomized controlled trials with patients with mood and anxiety disorders were included. Main outcomes were continuous measures of severity of mood and anxiety symptoms. Cohen's d was calculated as a measure of effect size. Meta-analyses using a random effects model was applied to estimate direct comparisons between yoga and control conditions for depression and anxiety outcomes. Publication bias was visually inspected using funnel plots. Eighteen studies were found, fourteen in acute patients and four in chronic patients. Most studies were of low quality. For depression outcomes, hatha yoga did not show a significant effect when compared to treatment as usual, an overall effect size of Cohen's d -0.64 (95% CI = -1.41, 0.13) or to all active control groups, Cohen's d -0.13 (95% CI = -0.49, 0.22). A sub-analysis showed that yoga had a significant effect on the reduction of depression compared to psychoeducation control groups, Cohen's d -0.52 (95% CI = -0.96, -0.08) but not to other active control groups, Cohen's d 0.28 (95% CI = -0.07, 0.63) For studies using a follow-up of six months or more, hatha yoga had no effect on the reduction of depression compared to active control groups, Cohen's d -0.14 (95% CI = -0.60, 0.33). Regarding anxiety, hatha yoga had no significant effect when compared to active control groups, Cohen's d -0.09 (95% CI = -0.47, 0.30). The I2 and Q-statistic revealed heterogeneity amongst comparisons. Qualitative analyses suggest some promise of hatha yoga for chronic populations. The ability to draw firm conclusions is limited by the notable heterogeneity and low quality of most of the included studies. With this caveat in mind, the results of the current meta-analysis suggest that hatha yoga does not have effects on acute, chronic and/or treatment-resistant mood and anxiety disorders compared to treatment as usual or active control groups. However, when compared to psychoeducation, hatha yoga showed more reductions in depression. It is clear that more high-quality studies are needed to advance the field.


Plasma stability and pharmacokinetics of radiolabeled deferoxamine-biotin derivatives.
The extraordinary high affinity of biotin for streptavidin may be exploited in a two-step in vivo approach for delivering radiolabeled biotin derivatives suitable for imaging and therapy to lesion-bound streptavidin-conjugated monoclonal antibodies. Compared to the use of directly radiolabeled monoclonal antibodies, the two-step approach is desirable because of the fast renal clearance of radiobiotin, which reduces in vivo background levels and radiation dose. Deferoxamine binds with high-affinity trivalent metals useful for imaging and radiotherapy. Three deferoxaminebiotin derivatives were synthesized, radiolabeled and their stabilities tested in vitro in dog plasma and in vivo in the dog by an avidin binding assay and high-performance liquid chromatography. Defero-desaminolysyl-biotin (DLB) was unstable, with immediate degradation evident. A plasma enzyme, biotinidase, converts biocytin to biotin. DLB closely resembles biocytin, and analysis of the urine and plasma suggested rapid degradation of DLB to biotin and desaminolsyl-deferoxamine. Defero-biotin, a direct conjugate of deferoxamine and biotin, was similarly tested and found to be more stable. Defero-acetyl-cysteinyl-biotin contains a carboxyl group adjacent to the amide bond cleavage site of biotinidase. In vitro at 24 hr in plasma, defero-acetyl-cysteinyl-biotin was 87% stable, compared to 45% and 15% for defero-biotin and DLB, respectively. The pharmacokinetics of the three derivatives were similar, with 80% of the injected doses found in the urine at 6 hr; however, only defero-acetyl-cysteinyl-biotin was present as the intact moiety.


The influence of preservation injury on rejection in the hepatic transplant recipient.
The records of 215 liver transplant recipients were reviewed and the degree of preservation injury was estimated by the initial aminotransferase levels. This was compared with the incidence of rejection found in the subsequent 30 days. Those with aspartate aminotransferase greater than 2000 U/L were classified as having severe preservation injury while those with ASAT less than 600 U/L were considered to have had minimal preservation injury. There were no significant differences between these groups in recipient age, sex, cold ischemia time, preoperative physical status, panel-reactive antibodies, or cytotoxic crossmatch. The solution used for organ preservation and the donor age were the only factors that were found to be significantly different between the groups. Older donors were more common in the severe preservation injury group. Severe preservation injury was found more frequently in grafts preserved in Eurocollins solution and the group with minimal preservation injury more frequently used Wisconsin solution. There was significantly more rejection seen in the severe preservation injury group (71%) than in the group without preservation injury (33%). Although there was more rejection in the severe preservation injury group, the rejections were not more severe as judged by the need for multiple courses of therapy or the need for OKT3. Recurrent rejection was also not more frequent in either group. Graft survival was worse in the severe preservation injury group, with a significant increase in early graft loss, but no difference in the frequency of chronic rejection. Recovery of graft function was also delayed in the preservation injury group.


Physiological Ecology of Microorganisms in Subglacial Lake Whillans.
Subglacial microbial habitats are widespread in glaciated regions of our planet. Some of these environments have been isolated from the atmosphere and from sunlight for many thousands of years. Consequently, ecosystem processes must rely on energy gained from the oxidation of inorganic substrates or detrital organic matter. Subglacial Lake Whillans (SLW) is one of more than 400 subglacial lakes known to exist under the Antarctic ice sheet; however, little is known about microbial physiology and energetics in these systems. When it was sampled through its 800 m thick ice cover in 2013, the SLW water column was shallow (~2 m deep), oxygenated, and possessed sufficient concentrations of C, N, and P substrates to support microbial growth. Here, we use a combination of physiological assays and models to assess the energetics of microbial life in SLW. In general, SLW microorganisms grew slowly in this energy-limited environment. Heterotrophic cellular carbon turnover times, calculated from 3H-thymidine and 3H-leucine incorporation rates, were long (60 to 500 days) while cellular doubling times averaged 196 days. Inferred growth rates (average ~0.006 d-1) obtained from the same incubations were at least an order of magnitude lower than those measured in Antarctic surface lakes and oligotrophic areas of the ocean. Low growth efficiency (8%) indicated that heterotrophic populations in SLW partition a majority of their carbon demand to cellular maintenance rather than growth. Chemoautotrophic CO2-fixation exceeded heterotrophic organic C-demand by a factor of ~1.5. Aerobic respiratory activity associated with heterotrophic and chemoautotrophic metabolism surpassed the estimated supply of oxygen to SLW, implying that microbial activity could deplete the oxygenated waters, resulting in anoxia. We used thermodynamic calculations to examine the biogeochemical and energetic consequences of environmentally imposed switching between aerobic and anaerobic metabolisms in the SLW water column. Heterotrophic metabolisms utilizing acetate and formate as electron donors yielded less energy than chemolithotrophic metabolisms when calculated in terms of energy density, which supports experimental results that showed chemoautotrophic activity in excess of heterotrophic activity. The microbial communities of subglacial lake ecosystems provide important natural laboratories to study the physiological and biogeochemical behavior of microorganisms inhabiting cold, dark environments.


Mucopolysaccharidoses type I and II: new neuroimaging findings in the cerebellum.
The neuroimaging literature on mucopolysaccharidoses (MPS) is focusing mostly on supratentorial findings. Our study aims to extend the spectrum of neuroimaging findings in patients with MPS focusing on the cerebellum. Twelve patients were included (7 MPS type I and 5 MPS type II). The median age at last MRI was 9.9 years (mean age 10.1 years, range 1.8-28.8 years). All available brain MR images were retrospectively evaluated for infratentorial and supratentorial abnormalities with semiquantitative analysis and qualitative evaluation. Infratentorial findings included enlarged perivascular spaces (PVS) in the cerebellum in 7/12, mega cisterna magna in 3/12 and macrocerebellum in 2/12 patients. Enlarged cerebellar PVS developed later than those in the supratentorial brain and showed mild changes in size over time. The macrocerebellum developed progressively and seems to be caused by a thickening of the cortical cerebellar gray matter. Enlarged PVS in the brain stem were found in 10/12 patients. Supratentorial findings included enlarged PVS in all patients. Ventriculomegaly and white matter signal abnormalities were noted in 8/12, cerebral atrophy in 7/12 patients. Involvement of the posterior fossa structures in MPS I and II is not uncommon. Our study revealed two neuroimaging findings that have not been previously described in MPS: enlarged PVS in the cerebellum and a macrocerebellum. The pathogenesis and clinical significance of these new findings remain unclear and should be assessed in a larger cohort of patients.


Oncologic Procedures Amenable to Fluorescence-guided Surgery.
Although fluorescence imaging is being applied to a wide range of cancers, it remains unclear which disease populations will benefit greatest. Therefore, we review the potential of this technology to improve outcomes in surgical oncology with attention to the various surgical procedures while exploring trial endpoints that may be optimal for each tumor type. For many tumors, primary treatment is surgical resection with negative margins, which corresponds to improved survival and a reduction in subsequent adjuvant therapies. Despite unfavorable effect on patient outcomes, margin positivity rate has not changed significantly over the years. Thus, patients often experience high rates of re-excision, radical resections, and overtreatment. However, fluorescence-guided surgery (FGS) has brought forth new light by allowing detection of subclinical disease not readily visible with the naked eye. We performed a systematic review of clinicatrials.gov using search terms "fluorescence," "image-guided surgery," and "near-infrared imaging" to identify trials utilizing FGS for those received on or before May 2016. fluorescence surgery for tumor debulking, wide local excision, whole-organ resection, and peritoneal metastases. fluorescence in situ hybridization, fluorescence imaging for lymph node mapping, nonmalignant lesions, nonsurgical purposes, or image guidance without fluorescence. Initial search produced 844 entries, which was narrowed down to 68 trials. Review of literature and clinical trials identified 3 primary resection methods for utilizing FGS: (1) debulking, (2) wide local excision, and (3) whole organ excision. The use of FGS as a surgical guide enhancement has the potential to improve survival and quality of life outcomes for patients. And, as the number of clinical trials rise each year, it is apparent that FGS has great potential for a broad range of clinical applications.


Analysis of Thermoelectric Energy Harvesting with Graphene Aerogel-Supported Form-Stable Phase Change Materials.
Graphene aerogel-supported phase change material (PCM) composites sustain the initial solid state without any leakage problem when they are melted. The high portion of pure PCM in the composite can absorb or release a relatively large amount of heat during heating and cooling. In this study, these form-stable PCM composites were used to construct a thermoelectric power generator for collecting electrical energy under the external temperature change. The Seebeck effect and the temperature difference between the two sides of the thermal device were applied for thermoelectric energy harvesting. Two different PCM composites were used to collect the thermoelectric energy harvesting due to the different phase transition field in the heating and cooling processes. The graphene nano-platelet (GNP) filler was embedded to increase the thermal conductivities of PCM composites. Maximum output current was investigated by utilizing these two PCM composites with different GNP filler ratios. The thermoelectric energy harvesting efficiencies during heating and cooling were 62.26% and 39.96%, respectively. In addition, a finite element method (FEM) numerical analysis was conducted to model the output profiles.


Stereoscopic imaging through scattering media.
We develop and experimentally test a method for three-dimensional imaging of hidden objects in a scattering medium. In our scheme, objects hidden between two biological tissues at different depths from the viewing system are recovered, and their three-dimensional locations are computed. Analogous to a fly's two eyes, two microlens arrays are used to observe the hidden objects from different perspectives. At the output of each lens array we construct the objects from several sets of many speckled images with a previously suggested technique that uses a reference point. The differences of the reconstructed images in both arrays with respect to the reference point yield the information regarding the relative depth among the various objects.


ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models.
Dopamine D(2) receptor antagonism contributes to the therapeutic action of antipsychotic drugs (APDs) but also produces undesirable side effects, including extrapyramidal motor deficits, cognitive dulling, and prolactinemia. The introduction of atypical APDs was a significant advancement in the treatment of schizophrenia. Whereas these agents are D(2) receptor antagonists, they are also potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonists, a feature that may explain their improved efficacy and tolerability. Recently, we reported that N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel selective 5-HT(2A) receptor inverse agonist that fails to bind D(2) receptors, is active in several models predictive of antipsychotic activity. Using ACP-103, we tested the hypothesis that combining high levels of 5-HT(2A) inverse agonism with low levels of D(2) antagonism would result in a favorable interaction, such that antipsychotic efficacy could be achieved with reduced D(2) receptor-related adverse effects. Here we show that ACP-103 1) potently inhibited head-twitching produced by the 5-HT(2A/2C) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine, 2) increased the potency of haloperidol against amphetamine-induced hyperactivity, 3) interacted synergistically with haloperidol or risperidone to suppress hyperactivity induced by the N-methyl-d-aspartate receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), and, by contrast, 4) attenuated haloperido-l- or risperidone-induced prolactinemia. ACP-103 also attenuated catalepsy produced by haloperidol or risperidone. However, the doses that were required for this effect were higher than would be expected for a 5-HT(2A) receptor-mediated mechanism. These data indicate that utilizing ACP-103 as an adjunctive therapy to currently used APDs may result in enhanced antipsychotic efficacy while reducing adverse effects including those attributable to D(2) receptor antagonism.


Persistent medication-induced neural adaptations, descending facilitation, and medication overuse headache.
An impediment to the investigation of mechanisms that drive headache is the inability of preclinical models to measure headache. Migraine attacks are associated with the development of cutaneous allodynia in some patients. Such cutaneous allodynia suggests a state of 'central sensitization' of pain transmission pathways and may additionally reflect the engagement of descending facilitation from pain modulatory circuits. For this reason, cutaneous allodynia has been measured in animal models as a surrogate of marker that may be relevant to headache. Overuse of antimigraine medications can promote an increase in the frequency and intensity of headache, a syndrome termed medication overuse headache (MOH). The mechanisms leading to MOH are not known, but may involve the processes of amplification including central sensitization and descending facilitation. This review explores potential mechanistic insights that have emerged from such studies and that could contribute to MOH. Development of MOH has been recently associated with long-lasting adaptive changes that occur within the peripheral and central nervous systems. Preclinical studies have shown that repeated or continuous treatment with antimigraine drugs result in persistent upregulation of neurotransmitters within the orofacial division of the trigeminal ganglia and in development of cutaneous allodynia in response to migraine triggers, even weeks after discontinuation of the antimigraine drug. Additionally, descending facilitation is critical for the expression of cutaneous allodynia and may mask the expression of diffuse noxious inhibitory controls. Medication-induced persistent pronociceptive adaptations might be responsible for lowering the threshold and amplifying the response to migraine triggers leading to increased frequency of headache attacks.


Operating room technician trainees teach medical students - an inter-professional peer teaching approach for infection prevention strategies in the operation room.
Education is a cornerstone strategy to prevent health-associated infections. Trainings benefit from being interactive, simulation-based, team-orientated, and early in professional socialization. We conceived an innovative inter-professional peer-teaching module with operating room technician trainees (ORTT) teaching infection prevention behavior in the operating room (OR) to medical students (MDS). ORTT delivered a 2-h teaching module to small groups of MDS in a simulated OR setting with 4 posts: 'entering OR'; 'surgical hand disinfection'; 'dressing up for surgery and preparing a surgical field', 'debriefing'. MDS and ORTT evaluated module features and teaching quality through 2 specific questionnaires. Structured field notes by education specialist observers were analyzed thematically. On Likert scales from - 2 to + 2, mean overall satisfaction was + 1.91 (±0.3) for MDS and + 1.66 (±0.6 SD) for ORTT while teaching quality was rated + 1.89 (±0.3) by MDS and self-rated with + 1.34 (±0.5) by ORTT. Students and observers highlighted that the training fostered mutual understanding and provided insight into the corresponding profession. Undergraduate inter-professional teaching among ORTT and MDS in infection prevention and control proved feasible with high educational quality. Inducing early mutual understanding between professional groups might improve professional collaboration and patient safety.


Superfertility is more prevalent in obese women with recurrent early pregnancy miscarriage.
To investigate the effects of obesity on superfertility. Retrospective observational study. A tertiary referral implantation clinic. Four hundred and fourteen women attending a tertiary implantation clinic with a history of recurrent miscarriage (RMC), over a 4-year period. Pattern of pregnancy loss and time to pregnancy intervals for each pregnancy were collected by medical staff from women with RMC. The women were categorised into normal, overweight and obese according to their body mass index (BMI). Kaplan-Meier curves were constructed estimating the cumulative probability of a spontaneous pregnancy over time. The pregnancy loss patterns were correlated with BMI and data were compared between the categories using the Kruskal-Wallis test. Pregnancy loss pattern and time to pregnancy intervals. Overall, 23.2, 51.4 and 64.2% of women conceived within first 1, 3 and 6 months, respectively. Obese women had cumulative pregnancy rates of 65.2 and 80% by three and 6 months, respectively, which was more than the cumulative pregnancy rates for women with normal BMI (49.2 and 65.8%). Comparison of survival curves indicated a significant difference in time to conceive for obese when compared with normal and overweight women (*P = 0.01), suggesting a higher prevalence of superfertility in obese women with RMC. Our findings suggest that obese women may have a greater efficacy to achieve pregnancy, but with an increased risk of miscarriage, which may suggest the possible metabolic effects of obesity on endometrium.


Acoustic emission technology can warn of impending iatrogenic femur fracture during femoral canal preparation for uncemented hip replacement. A cadaveric animal bone study.
During uncemented hip arthroplasty the femoral prosthesis can be fitted too tightly into the femoral canal, causing a hoop-stress fracture of the proximal femur. The research undertaken evaluated Acoustic Emission (AE) technology as a potential method of detecting a fracture forming in this manner, in an attempt to assess whether this technology may be used as a means of early warning of impending fracture during surgery. Deer femora were prepared in a manner similar to surgery and uncemented hip arthroplasty broaches were inserted until fracture occurred. AE sensors were mounted on the femoral cortex and also on the broach. Five femora were fractured manually by hammering the broaches in a manner similar to surgery. Four femora were fractured using a hydraulic loading machine to insert the broach. Stepwise increases in the AE signals coincided with stepwise increases in surface strain of the femoral cortex, crack mouth growth and fracture. Both sensors recorded similar signal profiles. The sensor on the femur registered greater magnitude signals than the sensor on the broach, suggesting that there is signal impedance across the bone-broach interface. AE signals from sensors mounted on the femur and on the broach can detect damage processes happening within the femur during insertion of the broach in the time period of approximately 100 s prior to fracture. These damage processes may represent micro cracking, and ultimately fracture. This supports the possibility of the use of AE signals as a means to monitor internal damage within the femur and possibly predict impending fracture. It is clear that AE signals change significantly prior to fracture however in order to attempt to develop a warning system, further understanding of the significance of the signals and limitations of these methods must be gained.


Neuroanatomical correlates of brainstem coma.
The brainstem tegmentum, including the reticular formation, contains distinct nuclei, each of which has a set of chemical, physiological and anatomical features. Damage to the brainstem tegmentum is known to cause coma, the most radical disturbance of consciousness. However, it has remained unclear which nuclei within the tegmentum are crucial for the maintenance of consciousness in humans. Accordingly, we initiated a retrospective study of MRIs obtained from 47 patients with brainstem stroke. The lesion boundaries were charted on patient MRIs and transferred onto a corresponding series of 4.7 T MRIs obtained from a control brainstem specimen that later was cut on a freezing microtome and analysed histologically. In addition, medical charts and available post-mortem materials were used to obtain relevant clinical and anatomical data to verify the MRI readings in each case. We found that in the 38 patients who did not have coma, brainstem damage either was located outside the tegmentum (n = 29) or produced a very small and unilateral compromise of the tegmentum (n = 9). In contrast, in patients who had coma (n = 9), the lesions in the tegmentum were mostly bilateral (n = 7) and were located either in the pons alone (n = 4) or in the upper pons and the midbrain (n = 5). The maximum overlap territory of the lesions coincided with the location of the rostral raphe complex, locus coeruleus, laterodorsal tegmental nucleus, nucleus pontis oralis, parabrachial nucleus and the white matter in between these nuclei. We also found that four coma subjects developed hyperthermia and died in the absence of any infections. In these cases, the maximum lesion overlap was centred in the core of pontine tegmentum. Our findings suggest that lesions confined to the upper pons can cause coma in humans even in the absence of damage to the midbrain. The findings also point to the brainstem nuclei whose lesions are likely to be associated with loss of consciousness and fatal hyperthermia in humans.


Inhibition of Azoxymethane-induced Colorectal Aberrant Crypt Foci in Mice Fed a High-fat Diet by Pleurotus eryngii (Eringi) and Hypsizygus marmoreus (Bunashimeji).
Obesity markedly increases the risk of colorectal cancer. Recently, the preventive effects of edible mushrooms on triglyceride elevation and visceral fat accumulation have been reported. Here, the effects of Pleurotus eryngii (Eringi) and Hypsizygus marmoreus (Bunashimeji) on azoxymethane (AOM)-induced aberrant crypt foci (ACF; precancerous lesions) in the colorectums of mice fed a high-fat diet were examined. Eringi (ER) and Bunashimeji (BU) mushroom powder samples were used. Six-week-old male C57BL/6J mice received an intraperitoneal injection of AOM (10 mg/kg) once a week for two weeks, and were sacrificed and dissected at 6 weeks after the start of the experiment. After the initiation of the experiment, they received a normal diet (ND), high-fat diet (HFD), HFD + ER (1 or 5% of diet), or HFD + BU (1 or 5% of diet). As a result, body and fat weights were significantly lower in the 5% ER and BU groups than in the HFD group. Liver triglyceride levels were also significantly lower in the 5% ER and BU groups. Total liver cholesterol levels were significantly lower in the 5% ER group. The numbers of ACF (especially large ACF) showed strong inhibitory effects in both ER and BU groups. Measurement of the cell proliferation marker Ki-67 labeling index in the colonic mucosa demonstrated more significant suppression in both ER and BU groups than in the HFD group. These results suggest that the simultaneous intake of ER and BU may inhibit colorectal tumorigenesis in HFD-fed mice.


Mutations in yeast replication proteins that increase CAG/CTG expansions also increase repeat fragility.
Expansion of trinucleotide repeats (TNRs) is the causative mutation in several human genetic diseases. Expanded TNR tracts are both unstable (changing in length) and fragile (displaying an increased propensity to break). We have investigated the relationship between fidelity of lagging-strand replication and both stability and fragility of TNRs. We devised a new yeast artificial chromomosme (YAC)-based assay for chromosome breakage to analyze fragility of CAG/CTG tracts in mutants deficient for proteins involved in lagging-strand replication: Fen1/Rad27, an endo/exonuclease involved in Okazaki fragment maturation, the nuclease/helicase Dna2, RNase HI, DNA ligase, polymerase delta, and primase. We found that deletion of RAD27 caused a large increase in breakage of short and long CAG/CTG tracts, and defects in DNA ligase and primase increased breakage of long tracts. We also found a correlation between mutations that increase CAG/CTG tract breakage and those that increase repeat expansion. These results suggest that processes that generate strand breaks, such as faulty Okazaki fragment processing or DNA repair, are an important source of TNR expansions.


Self-care strategies for the management of bowel symptoms following sphincter-saving surgery for rectal cancer.
The primary aim of this article is to identify the self-care strategies that patients use to manage bowel symptoms experienced following sphincter-saving surgery for rectal cancer. Comparisons will be made with self-care strategies used by patients to manage chronic fecal incontinence and the bowel symptoms associated with other chronic bowel diseases, such as irritable bowel syndrome and inflammatory bowel disease. Published studies and conceptual literature from 2000-2010 were the data sources. Three major themes emerged from the literature reflecting the self-care strategies used by patients to manage bowel symptoms: functional self-care strategies (e.g., taking medication), social activity-related self-care strategies (e.g., planning social events), and alternative self-care strategies (e.g., complementary therapies). An analysis of studies highlighted that, through the process of trial and error, patients learned the strategies that were most effective in the management of their bowel symptoms. Knowledge of such strategies will be beneficial to healthcare professionals when educating patients about effective management of bowel symptoms following sphincter-saving surgery.


Talking about Internal States in Mother-Child Reminiscing Influences Children's Self-Representations: A Cross-Cultural Study.
This study examined the relation of mother-child discussions of internal states during reminiscing to the development of trait and evaluative self-representations in 131 European American and Chinese immigrant 3-year-olds. Mothers and children discussed one positive and one negative event, and children were interviewed for self-descriptions. Euro-American mothers and children made more references to internal states and focused more on causal talk than did Chinese, and Euro-American children were more likely than Chinese children to describe their own traits and evaluative characteristics. Mothers' and children's use of internal state language during reminiscing of the negative event uniquely predicted children's trait and evaluative self-representations, independent of culture. Explanations of internal states and conversing in the negative event context were particularly effective in predicting children's self-representations. Discussions of internal states further mediated cultural influences on children's self-representations. The findings provide new insight into the contribution of parent-child reminiscing to the development of self.


Role of emergent chest radiography in evaluation of hyperacute stroke.
To use data from a large multicenter trial to assess the role and significance of chest radiograph (CXR) in the initial evaluation of acute stroke. Predefined clinical characteristics of patients who had recorded data on CXR examination during the initial evaluation were collected. We compared features of patients who had a CXR done before IV thrombolytics with those who did not. Rates of adverse cardiopulmonary events, intubation, and in-hospital mortality were also compared. Logistic regression analysis was performed to evaluate for the association of CXR performance with door-to-needle time ≥60 minutes. In a cohort of 615 patients, 243 had CXR done before IV thrombolytics. Patients with CXR before treatment had significantly higher admission neurologic deficit, initial respiratory rates, and door-to-needle time than those with CXR after treatment. The rates of cardiopulmonary adverse events in the first 24 hours of admission, endotracheal intubation in the first 7 hours, and in-hospital mortality were not different between the 2 groups. Patients with CXR done before treatment had longer mean door-to-needle times than those without pretreatment radiography (75.8 vs 58.3 minutes, p = 0.0001). Performance of CXR was independently associated with door-to-needle time ≥60 minutes (odds ratio 2.78, 95% confidence interval 1.97-3.92; p = 0.00001). Performance of CXR prior to IV thrombolytics prolongs door-to-needle time in acute ischemic stroke patients. CXR before treatment should be reserved for situations wherein acute cardiopulmonary conditions would otherwise preclude the administration of IV thrombolytics or substantially influence management.


Hepatic metabolism affects the atropselective disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice.
To understand the role of hepatic vs extrahepatic metabolism in the disposition of chiral PCBs, we studied the disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) and its hydroxylated metabolites (HO-PCBs) in mice with defective hepatic metabolism due to the liver-specific deletion of cytochrome P450 oxidoreductase (KO mice). Female KO and congenic wild type (WT) mice were treated with racemic PCB 136, and levels and chiral signatures of PCB 136 and HO-PCBs were determined in tissues and excreta 3 days after PCB administration. PCB 136 tissue levels were higher in KO compared to WT mice. Feces was a major route of PCB metabolite excretion, with 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol being the major metabolite recovered from feces. (+)-PCB 136, the second eluting PCB 136 atropisomers, was enriched in all tissues and excreta. The second eluting atropisomers of the HO-PCBs metabolites were enriched in blood and liver; 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol in blood was an exception and displayed an enrichment of the first eluting atropisomers. Fecal HO-PCB levels and chiral signatures changed with time and differed between KO and WT mice, with larger HO-PCB enantiomeric fractions in WT compared to KO mice. Our results demonstrate that hepatic and, possibly, extrahepatic cytochrome P450 (P450) enzymes play a role in the disposition of PCBs.


Motivational versus metabolic effects of carbohydrates on self-control.
Self-control is critical for achievement and well-being. However, people's capacity for self-control is limited and becomes depleted through use. One prominent explanation for this depletion posits that self-control consumes energy through carbohydrate metabolization, which further suggests that ingesting carbohydrates improves self-control. Some evidence has supported this energy model, but because of its broad implications for efforts to improve self-control, we reevaluated the role of carbohydrates in self-control processes. In four experiments, we found that (a) exerting self-control did not increase carbohydrate metabolization, as assessed with highly precise measurements of blood glucose levels under carefully standardized conditions; (b) rinsing one's mouth with, but not ingesting, carbohydrate solutions immediately bolstered self-control; and (c) carbohydrate rinsing did not increase blood glucose. These findings challenge metabolic explanations for the role of carbohydrates in self-control depletion; we therefore propose an alternative motivational model for these and other previously observed effects of carbohydrates on self-control.


Blood pressure changes in African American patients receiving chiropractic care in a teaching clinic: a preliminary study.
The purpose of this preliminary study was to determine if a course of chiropractic care would change blood pressure measurements in African American patients and to determine if a study was feasible in a chiropractic teaching clinic. Twenty-four African American patients received chiropractic care in a chiropractic teaching clinic over a study period that spanned 23 visits for each patient. Inclusion criteria consisted of patients having a diagnosis of prehypertension (120-139/80-89) or hypertension stage 1 (140-159/90-99). The mean values of 3 baseline blood pressure readings were compared with the mean values of blood pressure readings taken on visits 21, 22, and 23. For the entire sample, reductions for both systolic and diastolic blood pressures were not statistically significant (P > .07). When 4 patients having body mass index values that were considered as outliers were excluded, a statistically significant decrease in diastolic blood pressure was observed (P = .004). By group, a statistically significant reduction occurred in the hypertension stage 1 group for systolic and diastolic blood pressures. This study showed that research of this nature may be feasible in chiropractic teaching clinics. The preliminary findings of this study showed that, for a subgroup of African American patients receiving chiropractic care, blood pressure decreased for (a) hypertension stage 1 patients and (b) the sample when those with excessive body mass index were excluded.


A public health approach to rapid scale-up of antiretroviral treatment in Malawi during 2004-2006.
Approximately 1 million people are infected with HIV in Malawi, where AIDS is the leading cause of death in adults. By December 31, 2007, more than 141,000 patients were initiated on antiretroviral treatment (ART) by use of a public health approach to scale up HIV services. We analyzed national quarterly and longitudinal cohort data from October 2004 to December 2006 to examine trends in characteristics of patients initiating ART, end-of-quarter clinical outcomes, and 6- and 12-month survival probability. During a 27-month period, 72,666 patients were initiated on ART, of whom about two-thirds were women. The percentage of patients initiated on ART who were children and farmers increased from 5.5% to 9.0% and 23% to 32%, respectively (P < 0.001 for trends). Estimated survival probability ranged from 85% to 88% at 6 months and 81% to 84% at 12 months on ART. In Malawi, a public health approach to ART increased treatment access and maintained high 6- and 12-month survival. Resource-limited countries scaling up ART programs may benefit from this approach of simplified clinical decision making, standardized ART regimens, nonphysician care, limited laboratory support, and centralized monitoring and evaluation.


Evening chronotype is associated with metabolic disorders and body composition in middle-aged adults.
Chronotype is a trait determining individual circadian preference in behavioral and biological rhythm relative to external light-dark cycle. However, little is known about the relationship between chronotype and metabolic disorders. The aim of this study was to examine whether late chronotype is related to metabolic abnormalities and body composition in middle-aged adults, independent of sleep duration and lifestyle. A total of 1620 participants aged 47-59 years were recruited from the Korean Genome and Epidemiology Study. Chronotype was assessed by the Morningness-Eveningness Questionnaire. Associations of chronotype with diabetes, metabolic syndrome, sarcopenia, and visceral obesity were analyzed. All participants underwent the oral glucose tolerance test, and body composition was measured with dual energy x-ray absorptiometry. Visceral obesity was designated as visceral fat area, measured by abdominal computed tomography, of >100 cm(2). Chronotype was classified as morning in 29.6% of subjects, evening in 5.9%, neither morning nor evening in 64.5%. Evening type, when compared with morning type, was significantly associated with diabetes (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.01-2.95), metabolic syndrome (OR, 1.74; 95% CI, 1.05-2.87), and sarcopenia (OR, 3.16; 95% CI, 1.36-7.33) after adjusting for confounding factors. Gender differences in the associations were evident. In men, evening type was associated with diabetes (OR, 2.98; 95% CI, 1.39-6.39) and sarcopenia (OR, 3.89; 95% CI, 1.33-11.33). Only metabolic syndrome was associated with evening type in women (OR, 2.22; 95% CI, 1.11-4.43). At the population level, evening chronotype was independently associated with diabetes, metabolic syndrome, and sarcopenia. These results support the importance of circadian rhythms in metabolic regulation.