Mood reactivity and affective dynamics in mood and anxiety disorders.
The application of ecological momentary assessment (EMA) in community settings provides a powerful opportunity to obtain measures of emotional reactivity to daily life events, as well as emotional dynamics in real time. This investigation examines the association between emotional reactivity to daily events and emotional experience in mood and anxiety disorders in a large community-based sample. Two-hundred and 87 participants with a lifetime history of bipolar I disorder (BPI; n = 33), bipolar II disorder (BPII; n = 37), major depression (MDD; n = 116), anxiety disorders without a mood disorder (ANX; n = 36), and controls without a lifetime history of mood, anxiety, or substance use disorder (n = 65) completed a 2-week EMA evaluation period concerning mood states and daily events. Following positive events, individuals with BPI reported greater decreases in both sad and anxious mood than did controls, and individuals with MDD experienced greater decreases in anxious mood. Following negative events, the BPII, MDD, and ANX (but not BPI) groups experienced greater increases in anxious mood, with no group differences in sad mood. Greater variability and instability were observed for sad mood in the BPII and MDD groups, and greater variability and instability was observed for anxious mood in all of the mood/anxiety groups. However, no group differences were observed for the inertia of sad or anxious moods. The findings demonstrate differences in emotional reactivity to daily events as well as the general affective dynamics of emotional states among individuals with mood or anxiety disorders, with potential specificity for BPI disorder relative to other disorders. Emotional variability and instability may constitute a nonspecific characteristic of both mood and anxiety disorders. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Constitutive salicylic acid defences do not compromise seed yield, drought tolerance and water productivity in the Arabidopsis accession C24.
Plants that constitutively express otherwise inducible disease resistance traits often suffer a depressed seed yield in the absence of a challenge by pathogens. This has led to the view that inducible disease resistance is indispensable, ensuring that minimal resources are diverted from growth, reproduction and abiotic stress tolerance. The Arabidopsis genotype C24 has enhanced basal resistance, which was shown to be caused by permanent expression of normally inducible salicylic acid (SA)-regulated defences. However, the seed yield of C24 was greatly enhanced in comparison to disease-resistant mutants that display identical expression of SA defences. Under both water-replete and -limited conditions, C24 showed no difference and increased seed yield, respectively, in comparison with pathogen-susceptible genotypes. C24 was the most drought-tolerant genotype and showed elevated water productivity, defined as seed yield per plant per millilitre water consumed, and achieved this by displaying adjustments to both its development and transpiration efficiency (TE). Therefore, constitutive high levels of disease resistance in C24 do not affect drought tolerance, seed yield and seed viability. This study demonstrates that it will be possible to combine traits that elevate basal disease resistance and improve water productivity in crop species, and such traits need not be mutually exclusive.


Cytotoxicity of RNases is increased by cationization and counteracted by K(Ca) channels.
K(Ca) channels are involved in control of cell proliferation and differentiation. Here we have revealed their role in overcoming the RNase-induced cytotoxicity. Toxic effects of Streptomyces aureofaciens RNases Sa, Sa2, Sa3, and of RNase Sa charge reversal mutants on the human embryonic kidney cell lines differing only by the presence of K(Ca) channels were characterized. In contrast to other RNases, a basic variant of RNase Sa and RNase Sa3 exhibit significant cytotoxic activity of the same order of magnitude as onconase. Our data indicate the absence of a correlation between catalytic activity and stability of RNases and cytotoxicity. On the other hand, cationization enhances toxic effect of an RNase indicating the major role of a positive charge. Essentially lower sensitivity to cytotoxic microbial RNases of cells expressing K(Ca) channels was found. These results suggest that cells without the K(Ca) channel activity cannot counteract toxic effect of RNases.


Cardiovascular and respiratory effects of lumbosacral epidural bupivacaine in isoflurane-anesthetized dogs: The effects of two volumes of 0.25% solution.
The purpose of this study was to compare cardiovascular and respiratory effects of two volumes of bupivacaine 0.25% (0.2 mL kg-1-treatment BUP02-and 0.4 mL kg-1 -treatment BUP04) administered epidurally at the lumbosacral intervertebral space in dogs anesthetized with isoflurane. This experimental prospective randomized crossover design trial used six mixed breed adult dogs, four neutered males and two spayed females. Each dog was anesthetized on three different occasions: the first for isoflurane minimum alveolar concentration (MAC) measurement, and the following two assigned treatments (BUP02 or BUP04). On the two treatment days, anesthesia was induced and maintained with isoflurane at 1.3 MAC during the experiments. Cardiovascular and respiratory measurements were recorded before (T0) and 5, 15, 30, 60 and 90 minutes after the epidural administration of bupivacaine. Comparisons between and within groups were performed by a mixed-model ANOVA and Friedman's test when appropriate followed by Bonferroni post-hoc test or Dunnet's test to compare time points within each treatment with T0 (p < 0.05). Mean arterial pressure decreased significantly from 15 to 90 minutes after the administration of BUP02 and from 5 to 60 minutes in BUP04, with lower values in BUP04 than in BUP02 lasting up to 30 minutes after bupivacaine administration. No significant changes in cardiac output and systemic vascular resistance were observed in either treatment. Hypoventilation was only detected in BUP04. Hemoglobin concentration and arterial oxygen content decreased after both treatment of bupivacaine with no significant decrease in oxygen delivery. Two dogs in BUP04 developed Horner's syndrome. The epidural administration of 0.4 mL.kg-1 of bupivacaine to dogs in sternal recumbency anesthetized with isoflurane 1.3 MAC caused more cardiovascular and respiratory depression than 0.2 mL.kg-1.


Co-transduction of cDNAs for c-kit and steel factor into single CD34+ cord blood cells further enhances the growth of erythroid and multipotential progenitors.
Previous studies have demonstrated that the c-kit encoded tyrosine kinase receptor and its ligand, steel factor (SLF), are critical for normal blood cell development. We have reported that transduction of the c-kit gene into single hematopoietic progenitor cells (HPC), CD34(+++) cells, from cord blood (CB) enhances erythroid colony formation via a SLF-dependent mechanism. We therefore decided to evaluate the impact on cell proliferation of co-transducing c-kit and SLF cDNAs into these cells. CD34(+++) cells were sorted as a population or as 1 cell/well for cells expressing the highest levels of CD34 and different levels of c-kit. Cells were then prestimulated with granulocyte macrophage (GM)-colony stimulating factor (CSF), interleukin (IL)-3, IL-6, erythropoietin (Epo) in the presence and absence of various concentrations of SLF. Cells were then transduced with SLF and/or c-kit cDNAs, and then assayed for colony formation with the same cytokine combination. At a single cell level, co-transduction with c-kit and SLF genes significantly enhanced colony formation compared with individual gene transduction, especially by erythroid and multipotential progenitors that responded to stimulation by added cytokines. Little or no growth was seen with the c-kit- and/or SLF-transduced cells without addition of cytokines. The degree of enhancement effected by co-transduction inversely correlated with the degree of expression of c-kit protein before transduction. Optimal enhancing effects were noted in CD34(+++) kit(Lo/-) cells co-transduced with both c-kit and SLF cDNAs. Reverse transcriptase-polymerase chain (RT-PCR) analysis of SLF mRNA expression in CD34(+++) cells and enzyme-linked immunoadsorbent assay (ELISA) measurement of secreted SLF protein demonstrated that the transduced SLF cDNA was expressed and soluble SLF was released in medium cultured with SLF gene transduced MACS-separated CD34(+) cells in the presence, but not in the absence, of IL-3, GM-CSF, IL-6, and Epo. These results demonstrate the enhancement of the proliferation of growth factor responsive HPC that express transduced c-kit and SLF genes.


Lived experience of the intensive care unit for patients who experienced delirium.
Delirium is a common occurrence for patients in the intensive care unit and can have a profound and lasting impact on them. Few studies describe the experience of intensive care patients who have had delirium. To understand the lived experience of intensive care for critically ill patients who experienced delirium. The study participants consisted of 7 men and 3 women, 46 to 70 years old, who had delirium according to the Confusion Assessment Method for the Intensive Care Unit. The van Manen method of hermeneutic phenomenology was used, and data collection entailed audio recorded semistructured interviews. Four themes were detected: "I can't remember," "Wanting to make a connection," "Trying to get it straight," and "Fear and safety concerns." Nurses working in intensive care units need to assess patients for delirium, assess the mental status of patients who have delirium, and help patients and patients' families learn about and deal with the psychological effects of the intensive care unit experience.


Kinetics of T helper subsets and associated cytokines correlate well with the clinical activity of graft-versus-host disease.
CD4(+)interferon (IFN)-γ(+) T cell (Th1) and CD4(+)interleukin (IL)-4(+) T cell (Th2) polarizations are crucial in the pathogenesis of graft-versus-host disease (GVHD). However, this hypothesis is largely based on animal experiments of Parent-into-F1 GVHD model. The causal relationship between kinetics of Th1, Th2 and associated cytokines and the clinical activity of GVHD in a real world situation remains unknown. Peripheral blood was collected every week prospectively from Day 0 to Day 210 (patients without GVHD) or Day 300 (patients with chronic GVHD) after allogeneic peripheral blood stem cell transplantation in consecutive 27 patients. The frequencies of Th1 and Th2 within CD4(+) T cells were determined by flow cytometry and pplasma IFN-γ, IL-12, IL-4, and IL-10 were determined by ELISA. Kinetics of Th1, Th2 frequency, and the plasma IL-10 and IFN-γ more commonly coincided with, rather than predicted, the activity of GVHD. These markers are significantly higher when acute or chronic GVHD developed. The kinetics of IL-10 is especially correlated well with the activity of GVHD during clinical course of immunosuppressive treatment. For patients with hepatic GVHD, there is a positive correlation between plasma IL-10 levels and the severity of hepatic injury. The frequency of Th2 is also significant higher in acute GVHD and tends to be higher in chronic GVHD. Interestingly, there is a very good positive correlation between the frequency of Th1 and Th2 (r = 0.951, p<0.001). The plasma level of IL-4 and IL-12 are not associated with the activity of GVHD. The frequency of Th1, Th2 within CD4(+) T cells and plasma IL-10 and IFN-γ are good biomarkers of GVHD. Plasma IL-10 can also be used to monitor the therapeutic responsiveness. Furthermore, both Th1 and Th2 likely contribute to the pathogenesis of GVHD.


Evaluation of the effects of montelukast, mometasone furoate, and combined therapyon adenoid size: a randomized, prospective, clinical trial with objective data
Background/aim: The incidence of adenoid hypertrophy is 2%-3% in children. Adenoidectomy is a commonly performed procedure in children that may cause complications such as early or late bleeding (4%-5%), recurrence of adenoid tissue (10%-20%), and postoperative respiratory problems (27%). Therefore, medical therapy alternatives to adenoidectomy are important and must be tried before surgery. In this study, we investigated the efficacy of mometasone furoate, montelukast, and a combination of these drugs in pediatric patients with adenoid hypertrophy who were scheduled for reduction with medical therapy after not being recommended for surgery.Materials and methods: The study included 120 children with adenoid hypertrophy aged between 4 and 10 years. The patients were randomized into 4 separate groups, with 30 in each group. Group 1 received 100 μg of mometasone furoate per day, group 2 received 4/5 mg (for age) montelukast per day, and group 3 received mometasone furoate + montelukast. Medical therapy continued for 3 months in the treatment groups. Group 4, which comprised patients with mild symptoms, received no treatment and was the control group. The pre- and posttreatment adenoid tissue ratios in lateral neck radiographs were recorded in the four groups. Results: When radiologic measurements of adenoid-to-air passage were calculated, an improvement of 21.76% was observed in group 1 after treatment. The rate of improvement was 22.51% in group 2. There was a 21.79% reduction in adenoid size in group 3 after 3 months? treatment and 12.46% in the control group. There were statistically significant differences between pre- and posttreatment values in every single group administered corticosteroids, montelukast, and combined therapy (P < 0.05).Conclusion: According to our results, both montelukast and mometasone furoate therapies were similarly successful in treating adenoid hypertrophy. Combined therapy has no superiority over single-therapy treatment.


Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling.
Evidence is accumulating regarding the importance of circadian core oscillators, several associated factors, and melatonin signaling in the maintenance of health. Dysfunction of endogenous clocks, melatonin receptor polymorphisms, age- and disease-associated declines of melatonin likely contribute to numerous diseases including cancer, metabolic syndrome, diabetes type 2, hypertension, and several mood and cognitive disorders. Consequences of gene silencing, overexpression, gene polymorphisms, and deviant expression levels in diseases are summarized. The circadian system is a complex network of central and peripheral oscillators, some of them being relatively independent of the pacemaker, the suprachiasmatic nucleus. Actions of melatonin on peripheral oscillators are poorly understood. Various lines of evidence indicate that these clocks are also influenced or phase-reset by melatonin. This includes phase differences of core oscillator gene expression under impaired melatonin signaling, effects of melatonin and melatonin receptor knockouts on oscillator mRNAs or proteins. Cross-connections between melatonin signaling pathways and oscillator proteins, including associated factors, are discussed in this review. The high complexity of the multioscillator system comprises alternate or parallel oscillators based on orthologs and paralogs of the core components and a high number of associated factors with varying tissue-specific importance, which offers numerous possibilities for interactions with melatonin. It is an aim of this review to stimulate research on melatonin signaling in peripheral tissues. This should not be restricted to primary signal molecules but rather include various secondarily connected pathways and discriminate between direct effects of the pineal indoleamine at the target organ and others mediated by modulation of oscillators.


Effect of aging on bone formation induced by recombinant human bone morphogenetic protein-2 combined with fibrous collagen membranes at subperiosteal sites.
This study was designed to examine the effect of aging on bone formation induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) combined with a fibrous collagen membrane (FCM). Implantation was done subperiosteally in bilateral palatal grooves in 34 male Wistar rats divided into three age groups: a 10-week-old group (10w group), a 30-week-old group (30w group) and a 70-week-old group (70w group). RhBMP-2-combined FCMs were implanted on the left palatal grooves as BMP-implanted sites (BMP site), while rhBMP-2 was not implanted on the right palatal grooves as control sites. The rats were sacrificed 6 weeks after implantation, and histometric evaluations were performed. New bone formation was observed in every site of each age group and the new bone was almost completely continuous with the original bone. The new bone volume (NBV) of the BMP site was significantly higher than that of the control site in each age group. The NBV of both the control and BMP sites were highest in the 10w group and lowest in the 70w group. The disparity of NBV between the control and BMP sites, which indicated the response to implanted BMP excluding the effect of skeletal growth and surgical stimulation, did not significantly differ among the age groups. These results indicate that rhBMP-2-combined FCM has the ability to induce new bone formation continuous with original bone even in senescent rats. Furthermore, it appeared that, in the case of palatal subperiosteal implantation, the responsiveness to implanted BMP was independent of age, although the total volume of newly formed bone declined with aging.


Yacon (Smallanthus sonchifolius) as a Food Supplement: Health-Promoting Benefits of Fructooligosaccharides.
Yacon (Smallanthus sonchifolius), a perennial plant of the family Asteraceae native to the Andean regions of South America, is an abundant source of fructooligosaccharides (FOS). This comprehensive review of the literature addressed the role of yacon supplementation in promoting health and reducing the risk of chronic diseases. According to several preclinical and clinical trials, FOS intake favors the growth of health-promoting bacteria while reducing pathogenic bacteria populations. Moreover, the endproducts of FOS fermentation by the intestinal microbiota, short chain fatty acids (SCFA), act as substrates or signaling molecules in the regulation of the immune response, glucose homeostasis and lipid metabolism. As a result, glycemic levels, body weight and colon cancer risk can be reduced. Based on these findings, most studies reviewed concluded that due to their functional properties, yacon roots may be effectively used as a dietary supplement to prevent and treat chronic diseases.


Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials.
Critical Limb Ischemia (CLI) is the most advanced stage of peripheral arterial disease and is usually treated with bypass surgery or endovascular revascularization. However, a considerable proportion of CLI patients are not eligible to these treatment strategies and amputation is often the only option left. In the past decade, research has focused on bone marrow (BM)-derived cell-based strategies that aim at neovascularization to improve limb perfusion. Individual studies did not convincingly prove efficacy of BM-derived cell therapy in CLI patients thus far. Perform a meta-analysis of all randomized controlled trials (RCTs) available that studied BM-derived cell therapy compared to standard care with or without placebo in CLI patients and provide summary efficacy data on this approach. A systematic search in the electronic databases of Medline, Embase, and the Cochrane Controlled Trials Register was performed. All studies were critically appraised and data were extracted and meta-analyzed using a random-effects model. Major amputation and amputation-free survival were considered as the primary endpoints. A total of 12 RCTs jointly including 510 CLI patients were identified and analyzed. The meta-analysis showed beneficial effects of BM-derived cell therapy on both subjective and surrogate objective endpoints, that is, pain score, pain-free walking distance, ankle-brachial index, and transcutaneous oxygen measurements (all P < 0.00001). Overall, the RCTs showed reduced amputation rates in the therapeutic arms of the included trials with a relative risk (RR) on major amputation of 0.58 [95% confidence interval (CI), 0.40-0.84; P = 0.004]. However, when only the placebo-controlled RCTs were considered, the beneficial effect on major amputation rates was considerably reduced and nonsignificant (RR = 0.78; 95% CI, 0.40-1.51; P = 0.46). Amputation-free survival did not significantly differ between the BM treated and the control group (RR = 1.16; 95% CI, 0.92-1.48; P = 0.22). This meta-analysis underlines the promising potential of BM-derived cell therapy in CLI patients. Importantly, the results of placebo-controlled and non-placebo-controlled RCTs seem to diverge, which stresses the necessity to use placebo in the control arms of these trials. Future well-designed larger placebo-controlled RCTs are needed and should include long-term follow-up data to assess durability of treatment effects.


Golden Bristlegrass-Like Hierarchical Graphene Nanofibers Entangled with N-Doped CNTs Containing CoSe2 Nanocrystals at Each Node as Anodes for High-Rate Sodium-Ion Batteries.
Golden bristlegrass-like unique nanostructures comprising reduced graphene oxide (rGO) matrixed nanofibers entangled with bamboo-like N-doped carbon nanotubes (CNTs) containing CoSe2 nanocrystals at each node (denoted as N-CNT/rGO/CoSe2 NF) are designed as anodes for high-rate sodium-ion batteries (SIBs). Bamboo-like N-doped CNTs (N-CNTs) are successfully generated on the rGO matrixed nanofiber surface, between rGO sheets and mesopores, and interconnected chemically with homogeneously distributed rGO sheets. The defects in the N-CNTs formed by a simple etching process allow the complete phase conversion of Co into CoSe2 through the efficient penetration of H2 Se gas inside the CNT walls. The N-CNTs bridge the vertical defects for electron transfer in the rGO sheet layers and increase the distance between the rGO sheets during cycles. The discharge capacity of N-CNT/rGO/CoSe2 NF after the 10 000th cycle at an extremely high current density of 10 A g-1 is 264 mA h g-1 , and the capacity retention measured at the 100th cycle is 89%. N-CNT/rGO/CoSe2 NF has final discharge capacities of 395, 363, 328, 304, 283, 263, 246, 223, 197, 171, and 151 mA h g-1 at current densities of 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 A g-1 , respectively.


Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study.
We sought to assess a novel, noninvasive, portable vagal nerve stimulator (nVNS) for acute treatment of migraine. Participants with migraine with or without aura were eligible for an open-label, single-arm, multiple-attack study. Up to four migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a six-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain. Of 30 enrolled patients (25 females, five males, median age 39), two treated no attacks, and one treated aura only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching (n = 1), raspy voice (n = 1) and redness at the device site (n = 1). No unanticipated, serious or severe adverse events were reported. The pain-free rate at two hours was four of 19 (21%) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22%). nVNS may be an effective and well-tolerated acute treatment for migraine in certain patients.


Effect of immunosuppression on outcome measures in a model of rat limbal transplantation.
To examine the effect of immunosuppression with intramuscularly injected cyclosporine and topical corticosteroid on limbal allograft survival in a new model in the inbred rat. Orthotopic limbal tissue harvested from male Fischer 344 (isografts) or male Wistar-Firth donors (allografts) was sutured into superior and inferior lamellar excision sites in female recipient Fischer 344 rats. Grafts were examined clinically for at least 55 days. Superficial epithelial cells were sampled weekly, and the DNA extracted and probed for the male-specific gene Sry by polymerase chain reaction. Recipients were killed at established intervals for immunohistochemistry. Graft-recipient animals were randomly assigned to receive either intramuscular cyclosporine plus topical prednisolone phosphate or vehicle for 4 weeks from the time of transplantation. Isografts survived for a median of more than 55 days. Allografts underwent clinical rejection at a median of 6 to 7 days after grafting. Acutely rejecting allografts showed a dense mononuclear infiltrate consisting of activated CD4(+) and CD8(+) T cells with some macrophages. Genomic Sry was usually detectable in cells sampled from the ocular surface for more than 55 days in isografts, but not beyond 7 days in allografts. Immunosuppression prolonged allograft survival significantly, as assessed clinically, but did not prolong donor cell survival on the ocular surface, as assessed by detection of genomic Sry. A robust model of limbal transplantation was developed in the rat. Isografts survived for the long term, whereas allografts underwent rapid rejection. Although clinical allograft survival was prolonged to a modest extent by immunosuppression, donor cell survival on the ocular surface was not improved.


Evidence for a particle produced in association with weak bosons and decaying to a bottom-antibottom quark pair in higgs boson searches at the tevatron.
We combine searches by the CDF and D0 Collaborations for the associated production of a Higgs boson with a W or Z boson and subsequent decay of the Higgs boson to a bottom-antibottom quark pair. The data, originating from Fermilab Tevatron pp collisions at √s = 1.96 TeV, correspond to integrated luminosities of up to 9.7 fb(-1). The searches are conducted for a Higgs boson with mass in the range 100-150 GeV/c(2). We observe an excess of events in the data compared with the background predictions, which is most significant in the mass range between 120 and 135 GeV/c(2). The largest local significance is 3.3 standard deviations, corresponding to a global significance of 3.1 standard deviations. We interpret this as evidence for the presence of a new particle consistent with the standard model Higgs boson, which is produced in association with a weak vector boson and decays to a bottom-antibottom quark pair.


PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression.
PTEN loss, one of the most frequent mutations in prostate cancer (PC), is presumed to drive disease progression through AKT activation. However, two transgenic PC models with Akt activation plus Rb loss exhibited different metastasis development: Pten/RbPE:-/- mice produced systemic metastatic adenocarcinomas with high AKT2 activation, whereas RbPE:-/- mice deficient for the Src-scaffolding protein, Akap12, induced high-grade prostatic intraepithelial neoplasias and indolent lymph node disseminations, correlating with upregulated phosphotyrosyl PI3K-p85α. Using PC cells isogenic for PTEN, we show that PTEN-deficiency correlated with dependence on both p110β and AKT2 for in vitro and in vivo parameters of metastatic growth or motility, and with downregulation of SMAD4, a known PC metastasis suppressor. In contrast, PTEN expression, which dampened these oncogenic behaviors, correlated with greater dependence on p110α plus AKT1. Our data suggest that metastatic PC aggressiveness is controlled by specific PI3K/AKT isoform combinations influenced by divergent Src activation or PTEN-loss pathways.


Physical activity energy expenditure and glucose control in pregnant women with type 1 diabetes: is 30 minutes of daily exercise enough?
To describe activity patterns in pregnant women with type 1 diabetes and evaluate the impact of increased structured physical activity on glucose control. Physical activity energy expenditure (PAEE) and glucose levels (continuous glucose monitoring) were measured in 10 pregnant women with type 1 diabetes (age 33.2 years, gestation 20 weeks, BMI 27.9 kg/m(2), diabetes duration 16.6 years, HbA1c 6.5% [48 mmol/mol], insulin pump duration 2.4 years) during a day at home (free-living) and during a 24-h visit incorporating controlled diet and structured physical activity with light intensity activity (three 20-min self-paced walks) and moderate intensity activity (two 50-min sessions of brisk treadmill walking). PAEE was evaluated through individually calibrated combined heart rate and movement sensing. Free-living PAEE was comparable to that under controlled study conditions (3.8 and 5.1 kcal/kg/day, P = 0.241), with women achieving near to the recommended 30 min of moderate physical activity (median 27 min [interquartile range 14-68]). During the free-living period, more time was spent in light activity (10.3 vs. 7.2 h, P = 0.005), with less sedentary time (13.0 vs. 14.9 h, P = 0.047) and less moderate activity (27 vs. 121 min, P = 0.022). The free-living 24-h mean glucose levels by continuous glucose monitoring were significantly higher (7.7 vs. 6.0 mmol/L, P = 0.028). The effect of controlled diet and exercise persisted overnight, with significantly less time spent hyperglycemic (19 vs. 0%, P = 0.028) and less glucose variability (glucose SD 1.3 vs. 0.7 mmol/L, P = 0.022). A controlled diet and structured physical activity program may assist women with type 1 diabetes in achieving optimal glucose control during pregnancy.


Comprehensive analysis of pseudogenes in prokaryotes: widespread gene decay and failure of putative horizontally transferred genes.
Pseudogenes often manifest themselves as disabled copies of known genes. In prokaryotes, it was generally believed (with a few well-known exceptions) that they were rare. We have carried out a comprehensive analysis of the occurrence of pseudogenes in a diverse selection of 64 prokaryote genomes. Overall, we find a total of around 7,000 candidate pseudogenes. Moreover, in all the genomes surveyed, pseudogenes occur in at least 1 to 5% of all gene-like sequences, with some genomes having considerably higher occurrence. Although many large populations of pseudogenes arise from large, diverse protein families (for example, the ABC transporters), notable numbers of pseudogenes are associated with specific families that do not occur that widely. These include the cytochrome P450 and PPE families (PF00067 and PF00823) and others that have a direct role in DNA transposition. We find suggestive evidence that a large fraction of prokaryote pseudogenes arose from failed horizontal transfer events. In particular, we find that pseudogenes are more than twice as likely as genes to have anomalous codon usage associated with horizontal transfer. Moreover, we found a significant difference in the number of horizontally transferred pseudogenes in pathogenic and non-pathogenic strains of Escherichia coli.


Influence of rural environment on diagnosis, treatment, and prognosis of colorectal cancer.
Several studies have shown that residential location (urban or rural) influences the incidence of colorectal cancer. The aim was to investigate the influence of rural environment on colorectal cancer history and survival in a well defined population. Patients with colorectal cancer diagnosed in the department of Calvados (France) were classified by place of residence (urban/rural) and information on clinical symptoms, tumour extension, treatment, and survival was collected. The study was population based, in the department of Calvados in France. During 1978-1984, 1445 colorectal cancers were collected by the Digestive Tract Cancer Registry of Calvados, 1047 with an urban place of residence (544 males and 503 females) and 284 with a rural place of residence (134 males and 150 females). In both sexes, rural patients with colorectal cancers were treated less frequently in a specialised health care centre (40.0%) than patients from an urban population (53.4%). The difference was mainly but not entirely explained by distance from the specialised health care centre. In females in the rural population, cancers were diagnosed more frequently at the stage of severe clinical symptoms (22.1%) and metastases (18.8%) than they were in the urban population (15.5% and 12.3%). In addition among females a rural environment appeared to confer a worse prognosis (relative risk = 1.3). Our findings suggest an inequality between rural and urban populations, especially for women. The loneliness of rural women leads to a delay in diagnosis and worse survival. In health education campaigns on colorectal cancer, efforts must be made to provide medical information to rural women in order to reduce the delay in diagnosis and improve survival.


Nonessential role of beta3 and beta5 integrin subunits for efficient clearance of cellular debris after light-induced photoreceptor degeneration.
During light-induced photoreceptor degeneration, large amounts of cellular debris are formed that must be cleared from the subretinal space. The integrins alphavbeta5 and alphavbeta3 are involved in the normal physiological process of phagocytosis in the retina. This study was conducted to investigate the question of whether the lack of beta5 and/or beta3 integrin subunits might influence the course of retinal degeneration and/or clearance of photoreceptor debris induced by acute exposure to light. Wild-type, beta5(-/-) and beta3(-/-) single-knockout, and beta3(-/-)/beta5(-/-) Ccl2(-/-)/beta5(-/-) double-knockout mice were exposed to 13,000 lux of white light for 2 hours to induce severe photoreceptor degeneration. Real-time PCR and Western blot analysis were used to analyze gene and protein expression, light- and electron microscopy to judge retinal morphology, and immunofluorescence to study retinal distribution of proteins. Individual or combined deletion of beta3 and beta5 integrin subunits did not affect the pattern of photoreceptor cell loss or the clearance of photoreceptor debris in mice compared with that in wild-type mice. Invading macrophages may contribute to efficient phagocytosis. However, ablation of the MCP-1 gene did not prevent macrophage recruitment. Several chemokines in addition to MCP-1 were induced after light-induced damage that may have compensated for the deletion of MCP-1. Acute clearance of a large amount of cellular debris from the subretinal space involves invading macrophages and does not depend on beta3 and beta5 integrins.


The relative ineffectiveness of criminal network disruption.
Researchers, policymakers and law enforcement agencies across the globe struggle to find effective strategies to control criminal networks. The effectiveness of disruption strategies is known to depend on both network topology and network resilience. However, as these criminal networks operate in secrecy, data-driven knowledge concerning the effectiveness of different criminal network disruption strategies is very limited. By combining computational modeling and social network analysis with unique criminal network intelligence data from the Dutch Police, we discovered, in contrast to common belief, that criminal networks might even become 'stronger', after targeted attacks. On the other hand increased efficiency within criminal networks decreases its internal security, thus offering opportunities for law enforcement agencies to target these networks more deliberately. Our results emphasize the importance of criminal network interventions at an early stage, before the network gets a chance to (re-)organize to maximum resilience. In the end disruption strategies force criminal networks to become more exposed, which causes successful network disruption to become a long-term effort.


Timing is everything: the regulation of type III secretion.
Type Three Secretion Systems (T3SSs) are essential virulence determinants of many Gram-negative bacteria. The T3SS is an injection device that can transfer bacterial virulence proteins directly into host cells. The apparatus is made up of a basal body that spans both bacterial membranes and an extracellular needle that possesses a channel that is thought to act as a conduit for protein secretion. Contact with a host-cell membrane triggers the insertion of a pore into the target membrane, and effectors are translocated through this pore into the host cell. To assemble a functional T3SS, specific substrates must be targeted to the apparatus in the correct order. Recently, there have been many developments in our structural and functional understanding of the proteins involved in the regulation of secretion. Here we review the current understanding of protein components of the system thought to be involved in switching between different stages of secretion.


Natural autoantibodies to TCR public idiotopes: potential roles in immunomodulation.
Autoantibodies directed against variable domain epitopes of the alpha/beta T cell receptor (TCR) occur in sera of man, mouse and other vertebrates. Here, we focus upon autoantibodies expressed in human rheumatoid arthritis (RA) and systemic erythematosus (SLE) with parallel studies involving collagen induced arthritis (CIA) in mice transgenic for human HLA-DR conferring resistance or susceptibility to autoimmune disease. We report specificity characterization of polyclonal and monoclonal IgM and IgG autoantibodies from SLE and for IgM monoclonal autoantibodies of RA patients. The data suggests that autoantibodies directed against "public" idiotopes present in the first complementarity determining region (CDR1) and the third framework (FR3) of the Vbeta gene products are generated in response to over-production of autodestructive T cells bearing particular Vbeta gene products and function to modulate (downregulate) the expression of these T cells. Since antibodies of these specificities are present in polyclonal IgG immunoglobulin (IVIG) preparations used for therapeutic purposes, the immunomodulatory effects of antibodies directed against TCR variable domains may account, at least in part, for the efficacy of IVIG preparations in therapy of autoimmune diseases and in the prevention of graft versus host reactions.


Applying Artificial Intelligence to Address the Knowledge Gaps in Cancer Care.
Rapid advances in science challenge the timely adoption of evidence-based care in community settings. To bridge the gap between what is possible and what is practiced, we researched approaches to developing an artificial intelligence (AI) application that can provide real-time patient-specific decision support. The Oncology Expert Advisor (OEA) was designed to simulate peer-to-peer consultation with three core functions: patient history summarization, treatment options recommendation, and management advisory. Machine-learning algorithms were trained to construct a dynamic summary of patients cancer history and to suggest approved therapy or investigative trial options. All patient data used were retrospectively accrued. Ground truth was established for approximately 1,000 unique patients. The full Medline database of more than 23 million published abstracts was used as the literature corpus. OEA's accuracies of searching disparate sources within electronic medical records to extract complex clinical concepts from unstructured text documents varied, with F1 scores of 90%-96% for non-time-dependent concepts (e.g., diagnosis) and F1 scores of 63%-65% for time-dependent concepts (e.g., therapy history timeline). Based on constructed patient profiles, OEA suggests approved therapy options linked to supporting evidence (99.9% recall; 88% precision), and screens for eligible clinical trials on ClinicalTrials.gov (97.9% recall; 96.9% precision). Our results demonstrated technical feasibility of an AI-powered application to construct longitudinal patient profiles in context and to suggest evidence-based treatment and trial options. Our experience highlighted the necessity of collaboration across clinical and AI domains, and the requirement of clinical expertise throughout the process, from design to training to testing. Artificial intelligence (AI)-powered digital advisors such as the Oncology Expert Advisor have the potential to augment the capacity and update the knowledge base of practicing oncologists. By constructing dynamic patient profiles from disparate data sources and organizing and vetting vast literature for relevance to a specific patient, such AI applications could empower oncologists to consider all therapy options based on the latest scientific evidence for their patients, and help them spend less time on information "hunting and gathering" and more time with the patients. However, realization of this will require not only AI technology maturation but also active participation and leadership by clincial experts.


Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion.
Oxytocin (OT) is a prominent regulator of many aspects of mammalian social behavior and stored in large dense-cored vesicles (LDCVs) in hypothalamic neurons. It is released in response to activity-dependent Ca2+ influx, but is also dependent on Ca2+ release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca2+-dependent mechanisms of its secretion remain to be identified. Here we show that lysosomes surround dendritic LDCVs, and that the direct activation of endolysosomal two-pore channels (TPCs) provides the critical Ca2+ signals to prime OT release by increasing the releasable LDCV pool without directly stimulating exocytosis. We observed a dramatic reduction in plasma OT levels in TPC knockout mice, and impaired secretion of OT from the hypothalamus demonstrating the importance of priming of neuropeptide vesicles for activity-dependent release. Furthermore, we show that activation of type 1 metabotropic glutamate receptors sustains somatodendritic OT release by recruiting TPCs. The priming effect could be mimicked by a direct application of nicotinic acid adenine dinucleotide phosphate, the endogenous messenger regulating TPCs, or a selective TPC2 agonist, TPC2-A1-N, or blocked by the antagonist Ned-19. Mice lacking TPCs exhibit impaired maternal and social behavior, which is restored by direct OT administration. This study demonstrates an unexpected role for lysosomes and TPCs in controlling neuropeptide secretion, and in regulating social behavior.


Dispatcher-assisted telephone CPR: a qualitative study exploring how dispatchers perceive their experiences.
To investigate how emergency medical dispatchers (EMDs) perceive their experience of identifying suspected cardiac arrests (CA), and offer and provide instructions in cardiopulmonary resuscitation via telephone (t-CPR). A qualitative method using the phenomenographic design where 10 EMDs were approached for semi-structured interviews. Perception in identifying CA, perception in offering t-CPR and perception in providing t-CPR. In this analysis, 12 categories and 31 subcategories emerged. The categories for perception in identifying CA were; to trust the witness's account, to be open-minded and to be organised. The categories for perception in offering t-CPR were: to feel prepared to connect with the witness on a mental level by being organised, flexible and supportive, to obtain a basis for assessments and to be observant for diverse obstacles in a situation. Finally, the categories for perception in providing t-CPR were: to feel engaged, to be supportive of the witness, to feel secure by recognising response-feedback from the witness, to observe external conditions with regard to the locality and technical complications, to be composed and adjust to the needs of the situation, to feel competent or to feel despair. By listening in an open-minded way, a vast amount of information can be collected. Using criteria-based dispatch (CBD) and their own resources, the possibilities and difficulties of the situation are analysed. The EMDs believe that they are being an empathic support, relieving the witness of the burden of responsibility, and connecting with them mentally to enable them to act at the scene. There are EMDs who feel competent and experienced in managing these cases, and other EMDs who feel insecure and despair. The choice between providing t-CPR and answering incoming calls is prioritised differently among EMDs. There is also a broad subjective assessment among EMDs of offering t-CPR, especially to persons over 70 years old whom they consider incapable of performing CPR. The competence of the EMDs in t-CPR is dependent on re-training and a feedback on patient outcome. Witnesses who are negative towards acting constitute a common problem. There are witnesses with physical impediments or psychologically not susceptible to suggestions. The EMD is also dependent on the knowledge and trustworthiness of the witness. Convincing answers from witnesses prompt a more secure feeling in the EMDs, just as lack of knowledge in the witness has a negative effect on the efforts.


Outcomes with retrievable inferior vena cava filters: a multicenter study.
To retrospectively review the outcomes after placement and retrieval of retrievable inferior vena cava (IVC) filters at two academic medical centers. All patients who underwent retrievable filter placement between May 2001 and December 2005 were included. Hospital records at both institutions were reviewed, and relevant data were collected concerning the placement and retrieval of all removable filters. A total of 197 patients underwent placement of a retrievable IVC filter. Of those, 143 patients (72.5%) had Günther Tulip filters (GTFs) placed, and 54 patients (27.5%) had Recovery filters placed. A total of 94 patients underwent attempted filter retrieval, accounting for just less than half of all retrievable filters placed during the study period (47.7%). Retrievals were successful in 80 patients (85.1%). Half the retrieval failures (n = 7) were the result of thrombus within the filter, and technical difficulties (eg, filter embedded in IVC wall, tilted filter) were the cause of retrieval failure in the other half. There was no significant difference in retrieval failure rates between the GTF and Recovery filter (16.4% vs 9.5%, respectively). GTFs were removed after a median implantation time of 11 days (range, 1-139 d), whereas Recovery filters were removed after a median implantation time of 28 days (range, 6-117 d). Placement and retrieval of nonpermanent IVC filters can be performed safely with a high technical success rate. In patients at high risk for venous thromboembolism and contraindication to anticoagulation, retrievable filters may be used aggressively to prevent the potentially devastating outcome of pulmonary embolism.


Supernovae: an example of complexity in the physics of compressible fluids.
Because the collapse of massive stars occurs in a few seconds, while the stars evolve on billions of years, the supernovae are typical complex phenomena in fluid mechanics with multiple time scales. We describe them in the light of catastrophe theory, assuming that successive equilibria between pressure and gravity present a saddle-center bifurcation. In the early stage we show that the loss of equilibrium may be described by a generic equation of the Painlevé I form. This is confirmed by two approaches, first by the full numerical solutions of the Euler-Poisson equations for a particular pressure-density relation, secondly by a derivation of the normal form of the solutions close to the saddle-center. In the final stage of the collapse, just before the divergence of the central density, we show that the existence of a self-similar collapsing solution compatible with the numerical observations imposes that the gravity forces are stronger than the pressure ones. This situation differs drastically in its principle from the one generally admitted where pressure and gravity forces are assumed to be of the same order. Moreover it leads to different scaling laws for the density and the velocity of the collapsing material. The new self-similar solution (based on the hypothesis of dominant gravity forces) which matches the smooth solution of the outer core solution, agrees globally well with our numerical results, except a delay in the very central part of the star, as discussed. Whereas some differences with the earlier self-similar solutions are minor, others are very important. For example, we find that the velocity field becomes singular at the collapse time, diverging at the center, and decreasing slowly outside the core, whereas previous works described a finite velocity field in the core which tends to a supersonic constant value at large distances. This discrepancy should be important for explaining the emission of remnants in the post-collapse regime. Finally we describe the post-collapse dynamics, when mass begins to accumulate in the center, also within the hypothesis that gravity forces are dominant.


Selected Mildly Obese Donors Can Be Used Safely in Simultaneous Pancreas and Kidney Transplantation.
Donor obesity, defined as donor body mass index (D-BMI) of 30 kg/m or greater, has been associated with increased risk of technical failure and poor pancreas allograft outcomes. Many transplant centers establish a threshold of D-BMI of 30 kg/m to decline donor offers for pancreas transplantation. However, no previous studies differentiate the impact of mild (D-BMI, 30-35 kg/m) versus severe obesity (D-BMI, ≥35 kg/m) on pancreas allograft outcomes. We examined Organ Procurement Transplant Network database records for 9916 simultaneous pancreas-kidney transplants (SPKT) performed between 2000 and 2013. We categorized donor body mass index (D-BMI) into 4 groups: 20 to 25 (n = 5724), 25 to 30 (n = 3303), 30 to 35 (n = 751), and 35 to 50 kg/m (n= 138). Associations of D-BMI with pancreas and kidney allograft failure were assessed by multivariate Cox regression adjusted for recipient, donor, and transplant factors. Compared with D-BMI 20 to 25 kg/m, only D-BMI 35 to 50 kg/m was associated with significantly higher pancreas allograft [adjusted hazard ratio [aHR], 1.37; 95% confidence interval (CI], 1.04-1.79] and kidney allograft (aHR, 1.36; CI, 1.02-1.82) failure over the study period (13 years). Donor BMI 30 to 35 kg/m did not impact pancreas allograft (aHR, 0.99; CI, 0.86-1.37) or kidney allograft (aHR, 0.98; CI, 0.84-1.15) failure. Similar patterns were noted at 3 months, and 1, 5, and 10 years posttransplant. These data support that pancreata from mildly obese donors (BMI, 30-35 kg/m) can be safely used for transplantation, with comparable short-term and long-term outcomes as organs from lean donors. Consideration of pancreata from obese donors may decrease the pancreas discard rate.


Rapid total synthesis of DARPin pE59 and barnase.
We report the convergent total synthesis of two proteins: DARPin pE59 and Bacillus amyloliquefaciens RNase (Barnase). Leveraging our recently developed fast-flow peptide-synthesis platform, we rapidly explored numerous conditions for the assembly of long polypeptides, and were able to mitigate common side reactions, including deletion and aspartimide products. We report general strategies for improving the synthetic quality of difficult peptide sequences with our system. High-quality protein fragments produced under optimal synthetic conditions were subjected to convergent native chemical ligation, which afforded native full-length proteins after a final desulfurization step. Both DARPin and Barnase were folded and found to be as active as their recombinant analogues.


A likelihood method for estimating present-day human contamination in ancient male samples using low-depth X-chromosome data.
The presence of present-day human contaminating DNA fragments is one of the challenges defining ancient DNA (aDNA) research. This is especially relevant to the ancient human DNA field where it is difficult to distinguish endogenous molecules from human contaminants due to their genetic similarity. Recently, with the advent of high-throughput sequencing and new aDNA protocols, hundreds of ancient human genomes have become available. Contamination in those genomes has been measured with computational methods often developed specifically for these empirical studies. Consequently, some of these methods have not been implemented and tested for general use while few are aimed at low-depth nuclear data, a common feature in aDNA datasets. We develop a new X-chromosome-based maximum likelihood method for estimating present-day human contamination in low-depth sequencing data from male individuals. We implement our method for general use, assess its performance under conditions typical of ancient human DNA research, and compare it to previous nuclear data-based methods through extensive simulations. For low-depth data, we show that existing methods can produce unusable estimates or substantially underestimate contamination. In contrast, our method provides accurate estimates for a depth of coverage as low as 0.5× on the X-chromosome when contamination is below 25%. Moreover, our method still yields meaningful estimates in very challenging situations, i.e. when the contaminant and the target come from closely related populations or with increased error rates. With a running time below 5 min, our method is applicable to large scale aDNA genomic studies. The method is implemented in C++ and R and is available in github.com/sapfo/contaminationX and popgen.dk/angsd.


Location-specific quantification of protein-bound metal ions by X-ray anomalous dispersion: Q-XAD.
Here, a method is described which exploits X-ray anomalous dispersion (XAD) to quantify mixtures of metal ions in the binding sites of proteins and can be applied to metalloprotein crystals of average quality. This method has successfully been used to study site-specific metal binding in a protein from the R2-like ligand-binding oxidase family which assembles a heterodinuclear Mn/Fe cofactor. While previously only the relative contents of Fe and Mn in each metal-binding site have been assessed, here it is shown that the method can be extended to quantify the relative occupancies of at least three different transition metals, enabling complex competition experiments. The number of different metal ions that can be quantified is only limited by the number of high-quality anomalous data sets that can be obtained from one crystal, as one data set has to be collected for each transition-metal ion that is present (or is suspected to be present) in the protein, ideally at the absorption edge of each metal. A detailed description of the method, Q-XAD, is provided.


Effect of microalgae as iron supplements on iron-deficiency anemia in rats.
Microalgae are potential iron supplements for improving iron deficiency through an unknown mechanism. To analyze the increase in non-heme iron absorption caused by microalgae, six different microalgal feeds were prepared from Spirulina, Chlorella and Synechococcus sp. PCC 7002 as the main source of dietary iron (25 mg kg-1; denoted as H-Sp, H-Ch, and H-Sy, respectively) or as a partial source of dietary iron (5 mg kg-1; denoted as L-Sp, L-Ch, and L-Sy, respectively) to suppress iron-deficiency anemia in rats. The hemoglobin regeneration efficiencies in anemic rats were in the order ferric citrate (34.7 ± 1.8%) < H-Ch (49.9 ± 4.1%) ≈ H-Sy (50.6 ± 5.3%) ≈ L-Sp (46.9 ± 6.2%) ≈ L-Ch (43.1 ± 6.9%) ≈ L-Sy (43.5 ± 2.4%) ≈ FeSO4 (47.2 ± 4.9%) < H-Sp (54.8 ± 5.5%). The percentage content of intestinal nanosized iron in the H-Sp, H-Ch, and H-Sy treatment groups was significantly higher than that in the L-Sp, L-Ch, and L-Sy groups, and was significantly higher in the microalgal diet groups than in the ferric citrate group, providing strong evidence for nanosized iron supplementation from microalgae. Overall, microalgae, especially Spirulina, are functional iron nutritive fortifiers that can supply intestinal nanosized iron.


Collimation and surface counting in haematology.
The effect on the results obtained in surface counting investigations of using a dual detector counting system and multihole collimators has been investigated. The use of the additional detector results in smoother curves for the uptake of the radionuclide and the use of multihole collimators increases the discrimination of the counting system against the effects of radioactivity outside the region of interest. In a clinical trial to compare multihole collimation with conventional single hole collimation it was found that increased excess counts were obtained over the spleen with the multihole collimators in eight of ten cases.


Nutrition Supplements to Stimulate Lipolysis: A Review in Relation to Endurance Exercise Capacity.
Athletes make great efforts to increase their endurance capacity in many ways. Using nutrition supplements for stimulating lipolysis is one such strategy to improve endurance performance. These supplements contain certain ingredients that affect fat metabolism; furthermore, in combination with endurance training, they tend to have additive effects. A large body of scientific evidence shows that nutrition supplements increase fat metabolism; however, the usefulness of lipolytic supplements as ergogenic functional foods remains controversial. The present review will describe the effectiveness of lipolytic supplements in fat metabolism and as an ergogenic aid for increasing endurance exercise capacity. There are a number of lipolytic supplements available on the market, but this review focuses on natural ingredients such as caffeine, green tea extract, L-carnitine, Garcinia cambogia (hydroxycitric acid), capsaicin, ginseng, taurine, silk peptides and octacosanol, all of which have shown scientific evidence of enhancing fat metabolism associated with improving endurance performance. We excluded some other supplements owing to lack of data on fat metabolism or endurance capacity. Based on the data in this review, we suggest that a caffeine and green tea extract improves endurance performance and enhances fat oxidation. Regarding other supplements, the data on their practical implications needs to be gathered, especially for athletes.


Pharmacological interventions for pain relief during orthodontic treatment.
Pain is a common side effect of orthodontic treatment. It increases in proportion to the amount of force applied to the teeth, and the type of orthodontic appliance used can affect the intensity of the pain. Pain during orthodontic treatment has been shown to be the most common reason for people wanting to discontinue treatment, and has been ranked as the worst aspect of treatment. Although pharmacological methods of pain relief have been investigated, there remains some uncertainty among orthodontists about which painkillers are most suitable and whether pre-emptive analgesia is beneficial. We conducted this Cochrane Review to assess and summarize the international evidence relating to the effectiveness of analgesics for preventing this unwanted side effect associated with orthodontic treatment. The objectives of this review are to determine:- the effectiveness of drug interventions for pain relief during orthodontic treatment; and- whether there is a difference in the analgesic effect provided by different types, forms and doses of analgesia taken during orthodontic treatment. Cochrane Oral Health's Information Specialist searched the following databases: the Cochrane Oral Health Trials Register (to 19 June 2017), the Cochrane Central Register of Controlled Trials (CENTRAL;the Cochrane Library 2016, Issue 7), MEDLINE Ovid (1946 to 19 June 2017), Embase Ovid (1980 to 19 June 2017) and CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 19 June 2017). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched on the 19 June 2017 for ongoing studies. We placed no restrictions on language or date of publication when searching the electronic databases. We included randomized controlled trials (RCTs) relating to pain control during orthodontic treatment. Pain could be measured on a visual analogue scale (VAS), numerical rating scale (NRS) or categorical scale. Two review authors independently screened the search results, agreed the studies to be included and extracted information from the included studies regarding methods, participants, interventions, outcomes, harms and results. We planned to resolve any discrepancies or disagreements through discussion. We used the Cochrane 'Risk of bias' tool to assess the risk of bias in the studies. We identified 32 relevant RCTs, which included 3110 participants aged 9 to 34 years, 2348 of whom we were able to include in our analyses. Seventeen of the studies had more than two arms. We were able to use data from 12 trials in meta-analyses that compared analgesics versus control (no treatment or a placebo); nine that compared non-steroidal anti-inflammatories (NSAIDs) versus paracetamol; and two that compared pre-emptive versus post-treatment ibuprofen for pain control following orthodontic treatment. One study provided data for the comparison of NSAIDs versus local anaesthetic.We found moderate-quality evidence that analgesics effectively reduced pain following orthodontic treatment when compared to no treatment or a placebo at 2 hours (mean difference (MD) -11.66 mm on a 0 to 100 mm VAS, 95% confidence interval (CI) -16.15 to -7.17; 10 studies, 685 participants), 6 hours (MD -24.27 mm on a VAS, 95% CI -31.44 to -17.11; 9 studies, 535 participants) and 24 hours (MD -21.19 mm on a VAS, 95% CI -28.31 to -14.06; 12 studies, 1012 participants).We did not find any evidence of a difference in efficacy between NSAID and paracetamol at 2, 6 or 24 hours (at 24 hours: MD -0.51, 95% CI -8.93 to 7.92; 9 studies, 734 participants; low-quality evidence).Very low-quality evidence suggested pre-emptive ibuprofen gave better pain relief at 2 hours than ibuprofen taken post treatment (MD -11.30, 95% CI -16.27 to -6.33; one study, 41 participants), however, the difference was no longer significant at 6 or 24 hours.A single study of 48 participants compared topical NSAIDs versus local anaesthetic and showed no evidence of a difference in the effectiveness of the interventions (very low-quality evidence).Use of rescue analgesia was poorly reported. The very low-quality evidence did not show evidence of a difference between participants taking ibuprofen and participants taking paracetamol (relative risk (RR) 1.5, 95% CI 0.6 to 3.6). Nor did we find evidence of a difference between groups in likelihood of requiring rescue analgesia when ibuprofen was taken pre-emptively compared to after treatment (RR 0.8, 95% CI 0.3 to 1.9).Adverse effects were identified in one study, with one participant developing a rash that required treatment with antihistamines. This was provisionally diagnosed as a hypersensitivity to paracetamol. Analgesics are more effective at reducing pain following orthodontic treatment than placebo or no treatment. Low-quality evidence did not show a difference in effectiveness between systemic NSAIDs compared with paracetamol, or topical NSAIDs compared with local anaesthetic. More high-quality research is needed to investigate these comparisons, and to evaluate pre-emptive versus post-treatment administration of analgesics.


What is the Current Knowledge About the Cardiovascular Risk for Users of Cannabis-Based Products? A Systematic Review.
The purpose of the study was to examine the published evidence on the cardiovascular risk related to the use of cannabis-based products by performing a systematic review of recent literature. The World Health Organization (WHO) emphasizes that cannabis use represents a risky behavior as it may lead to many adverse effects, and in particular, cardiovascular effects. A systematic review of articles published between January 1, 2011 and May 31, 2016 was performed in agreement with the PRISMA statement. Articles presenting data on humans exposed to cannabis-based products and suffering from any cardiovascular condition were eligible for inclusion. The inclusion process was based on a search algorithm and performed in a blinded standardized manner. Overall, 826 articles were found in the literature search, 115 of which remained after performing the inclusion procedure. These were 81 case reports, 29 observational studies, 3 clinical trials, and 2 experimental studies. A total of 116 individuals was the subject of case reports. The mean age was 31 years (95%CI = 29-34), and patients were more frequently men (81.9%) than women (18.1%). They mainly suffered from ischemic strokes or myocardial infarctions. Data provided by the 29 included observational studies evidenced an association between exposure to cannabis-based products and cardiovascular disease. Currently, this evidence is stronger for ischemic strokes than for any other cardiovascular diseases. While the data are limited, there is some suggestion that cannabis use may have negative cardiovascular consequences, particularly at large doses.


Patterns and management of chronic obstructive pulmonary disease in urban and rural China: a community-based survey of 25 000 adults across 10 regions.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, with COPD deaths in China accounting for one-third of all such deaths. However, there is limited available evidence on the management of COPD in China. A random sample of 25 011 participants in the China Kadoorie Biobank, aged 38-87 years, from 10 regions in China was surveyed in 2013-2014. Data were collected using interviewer-administered questionnaires on the diagnosis ('doctor-diagnosed' or 'symptoms-based') and management of COPD (including use of medication and other healthcare resources), awareness of diagnosis and severity of symptoms in COPD cases. Overall, 6.3% of the study population were identified as COPD cases (doctor-diagnosed cases: 4.8% and symptom-based cases: 2.4%). The proportion having COPD was higher in men than in women (7.9% vs 5.3%) and varied by about threefold (3.7%-10.0%) across the 10 regions. Among those with COPD, 54% sought medical advice during the last 12 months, but <10% reported having received treatment for COPD. The rates of hospitalisation for COPD, use of oxygen therapy at home and influenza or pneumococcal vaccinations in the previous year were 15%, 3% and 4%, respectively. Of those with COPD, half had moderate or severe respiratory symptoms, and over 80% had limited understanding of their disease and need for treatment. Despite a high prevalence of COPD in China and its substantial impact on activities of daily living, knowledge about COPD and its management were limited.


Novel Two-Step Process in Cellulose Depolymerization: Hematite-Mediated Photocatalysis by Lytic Polysaccharide Monooxygenase and Fenton Reaction.
To transform cellulose from biomass into fermentable sugars for biofuel production requires efficient enzymatic degradation of cellulosic feedstocks. The recently discovered family of oxidative enzymes, lytic polysaccharide monooxygenase (LPMO), has a high potential for industrial biorefinery, but its energy efficiency and scalability still have room for improvement. Hematite (α-Fe2O3) can act as a photocatalyst by providing electrons to LPMO-catalyzed reactions, is low cost, and is found abundantly on the Earth's surface. Here, we designed a composite enzymatic photocatalysis-Fenton reaction system based on nano-α-Fe2O3. The feasibility of using α-Fe2O3 nanoparticles as a composite catalyst to facilitate LPMO-catalyzed cellulose oxidative degradation in water was tested. Furthermore, a light-induced Fenton reaction was integrated to increase the liquefaction yield of cellulose. The innovative approach finalized the cellulose degradation process with a total liquefaction yield of 93%. Nevertheless, the complex chemical reactions and products involved in this system require further investigation.


Modelling seasonal effects of temperature and precipitation on honey bee winter mortality in a temperate climate.
Insect pollinators are essential to global food production. For this reason, it is alarming that honey bee (Apis mellifera) populations across the world have recently seen increased rates of mortality. These changes in colony mortality are often ascribed to one or more factors including parasites, diseases, pesticides, nutrition, habitat dynamics, weather and/or climate. However, the effect of climate on colony mortality has never been demonstrated. Therefore, in this study, we focus on longer-term weather conditions and/or climate's influence on honey bee winter mortality rates across Austria. Statistical correlations between monthly climate variables and winter mortality rates were investigated. Our results indicate that warmer and drier weather conditions in the preceding year were accompanied by increased winter mortality. We subsequently built a statistical model to predict colony mortality using temperature and precipitation data as predictors. Our model reduces the mean absolute error between predicted and observed colony mortalities by 9% and is statistically significant at the 99.9% confidence level. This is the first study to show clear evidence of a link between climate variability and honey bee winter mortality.


Development of an instrument to measure adherence to strength training in postmenopausal breast cancer survivors.
To develop a theory-based instrument for assessing barriers and motivators to strength- or weight-training exercise (SWTE) in postmenopausal breast cancer survivors with measurable bone loss after treatment. Exploratory, descriptive, and methodologic. Academic oncology clinics in the midwestern United States, homes, and a fitness center. 85 women, predominantly Caucasian (99%), breast cancer survivors, aged 35-75 years, six months after treatment, who were enrolled in a larger study were randomized to receive SWTE; 65 completed the instrument. Development of a 47-item Likert-type instrument using interviews, contributions from experts, published research, and Self-Efficacy Theory. Barriers and motivators of adherence to SWTE. Four subscales emerged that accounted for 26%-59% of the variance. Factor subscales for barriers were "not prioritizing time for self" and "overcoming other barriers to adherence." Subscales for motivators included "education and feedback" and "social support." The final instrument contained 47 items dispersed across four subscales. Additional psychometric testing of the instrument with a larger population is indicated. Nurses and healthcare professionals may use the instrument to readily identify barriers and motivators to SWTE adherence to improve program design and implementation efforts aimed at facilitating enhanced exercise adherence in breast cancer survivors with measurable bone loss after treatment.


Generation of anti-idiotypic reagents in the EGFRvIII tumor-associated antigen system.
The use of anti-idiotype (anti-id) vaccines for immunotherapy of human cancers is attractive, as immunization with true anti-id reagents (Ab2 beta) has been shown to induce both cellular and humoral immunity, frequently when the original antigen does not, or when a state of anergy to the self-expressed tumor-associated antigen exists. The aim of this study was to investigate the potential of an anti-id vaccine approach to the glioma-associated antigen epidermal growth factor receptor variant III (EGFRvIII) for human clinical trials. By using conventional methodology, seven rat mAbs specific for the binding site of the murine anti-EGFRvIII-specific mAb Y10, as defined by the ability to inhibit the binding of mAb Y10 to EGFRvIII expressed on cells or as purified protein, were generated, and a subset (3/7) was found to be true Ab2 beta, as defined by the ability to induce the formation of antibody directed against EGFRvIII in two species (mouse and rabbit) when used as immunogen. The ability of these three Ab2 beta to elicit a protective anti-tumor response when used as a vaccine in the syngeneic, subcutaneous C57Bl/6-B16mseEGFRvIII tumor model was investigated. Following vaccination with one Ab2 beta mAb (2C7), 6/20 mice failed to develop tumor upon challenge, and 3/20 mice with outgrowing tumors exhibited dramatic regression of incipient tumors. Vaccination with a second mAb (5G8) resulted in one tumor-free survivor and one tumor regressor; vaccination with the third Ab2 beta mAb (7D3) did not confer protection, but did significantly increase the latency period until tumor outgrowth in all vaccinated recipients. The ability of Ab2 beta mAb 2C7 to induce an anti-EGFRvIII response in non-human primates was investigated by using the saponin adjuvant approved for human clinical trial, QS-21. Three of three macaques produced anti-EGFRvIII titers, as detected on EGFRvIII-expressing cells by both ELISA and fluorescence-activated cytometric analysis, following six immunizations with Ab2 beta mAb 2C7 and QS-21. The results obtained confirm that an anti-id response in the EGFRvIII antigen system can be induced in rodents, rabbits, and non-human primates, and it may prove a useful adjunct to immunotherapeutic approaches to EGFRvIII-positive gliomas, breast carcinomas, and non-small-cell lung tumors.


Do commercially available metal salts mediate calixarene formation via hydrogen-bonded dimers?
In this article we report the first example of a Lewis acid promoted, one-pot, Brønsted acid free, high-yielding synthesis of the calixarene macrocycle from the "monomer" p-tert-butylphenol. We report that when a commercially available metal salt (Lewis acid) is incorporated within the calixarene-forming reaction, a certain amount of control over the size of the calixarenes produced can be gained. Although a detailed mechanistic rationale on how the macrocycle is assembled is unclear, what is evident from this work is that the metal cation, the counteranion, and the oxidation state of the salt employed are all important contributors to the outcome of the reaction process. Indeed, evidence to date suggests that a subtle "symbiotic" relationship exists between the metal cation, its oxidation state, and the anion that allows the efficient transformation of the "monomeric" p-tert-butylphenol into linear oligomers and, ultimately, into macrocyclic calixarenes. Athough the metal salt mediated process described herein is efficient and high-yielding, what is also fundamentally important is that a comprehensive mechanistic understanding of how the calixarenes are assembled be accrued. Searching for possible indicators or clues, we propose that oligomeric methylene-linked phenolic entities are initially formed and that these, we tentatively suggest, generate metal and/or anion hydrogen-bonded supramolecular intermediates. It is possible that the preorganization of the linear polyphenolic oligomers allows the formation of hydrogen-bonded structures which, critically, result in the formation of supramolecular assemblies that are subsequently "stitched" together, generating the p-tert-butylcalix[n]arenes (n = 4-9) in excellent yields. Substantiating the possibility that hydrogen-bonded entities are generated (and that these subsequently afford metal-templated assemblies), we make reference to a seldom cited 1962 Nature publication that reported the propensity of polyphenolic linear oligomers to form "well-defined intramolecularly hydrogen-bonded conformations".


Association between the tumor necrosis factor locus and the clinical outcome of Leishmania chagasi infection.
A periurban outbreak of visceral leishmaniasis (VL) caused by the protozoan Leishmania chagasi is ongoing outside Natal, northeast Brazil. Manifestations range from asymptomatic infection to disseminated visceral disease. Literature reports suggest that both genetic and environmental factors influence the outcome of infection. Due to the association of the tumor necrosis factor (TNF) locus with other infectious diseases, we examined whether polymorphic alleles at this locus are associated with the outcome of L. chagasi infection. Neighborhoods with ongoing transmission were identified through patients admitted to local hospitals. Altogether, 1,024 individuals from 183 families were classified with the following disease phenotypes: (i) symptomatic VL, (ii) asymptomatic infection (positive delayed-type hypersensitivity [DTH+]), or (iii) no evidence of infection (DTH-). Genotypes were determined at a microsatellite marker (MSM) upstream of the TNFB gene encoding TNF-beta and at a restriction fragment length polymorphism (RFLP) at position -307 in the promoter of the TNFA gene encoding TNF-alpha. Analyses showed that the distribution of TNFA RFLP alleles (TNF1 and TNF2) and the TNF MSM alleles (TNFa1 to TNFa15) differed between individuals with VL and those with DTH+ phenotypes. TNF1 was transmitted more frequently than expected from heterozygous parents to DTH+ offspring (P = 0.0006), and haplotypes containing TNF2 were associated with symptomatic VL (P = 0.0265, transmission disequilibrium test). Resting serum TNF-alpha levels were higher in TNF1/2 heterozygotes than in TNF1/1 homozygotes (P < 0.05). These data led us to hypothesize that an individual's genotype at the TNF locus may be associated with whether he or she develops asymptomatic or symptomatic disease after L. chagasi infection. The results preliminarily suggest that this may be the case, and follow-up with larger populations is needed for verification.


A molecular view of the role of chirality in charge-driven polypeptide complexation.
Polyelectrolyte molecules of opposite charge are known to form stable complexes in solution. Depending on the system conditions, such complexes can be solid or liquid. The latter are known as complex coacervates, and they appear as a second liquid phase in equilibrium with a polymer-dilute aqueous phase. This work considers the complexation between poly(glutamic acid) and poly(lysine), which is of particular interest because it enables examination of the role of chirality in ionic complexation, without changes to the overall chemical composition. Systematic atomic-level simulations are carried out for chains of poly(glutamic acid) and poly(lysine) with varying combinations of chirality along the backbone. Achiral chains form unstructured complexes. In contrast, homochiral chains lead to formation of stable β-sheets between molecules of opposite charge, and experiments indicate that β-sheet formation is correlated with the formation of solid precipitates. Changes in chirality along the peptide backbone are found to cause "kinks" in the β-sheets. These are energetically unfavorable and result in irregular structures that are more difficult to pack together. Taken together, these results provide new insights that may be of use for the development of simple yet strong bioinspired materials consisting of β-rich domains and amorphous regions.


Utilization of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold in the design of potent inhibitors of serine proteases: SAR studies using carboxylates.
A series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide and isothiazolidin-3-one 1,1 dioxide scaffolds has been synthesized and the inhibitory profile of these compounds toward human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3) was then determined. Most of the compounds were found to be potent, time-dependent inhibitors of elastase, with some of the compounds exhibiting k(inact)/K1 values as high as 4,928,300 M(-1) s(-1). The inhibitory potency of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide platform was found to be influenced by both the pKa and the inherent structure of the leaving group. Proper selection of the primary specificity group (R(I)) was found to lead to selective inhibition of HLE over Cat G, however, those compounds that inhibited HLE also inhibited PR 3, albeit less efficiently. The predictable mode of binding of these compounds suggests that, among closely-related serine proteases, highly selective inhibitors of a particular serine protease can be fashioned by exploiting subtle differences in their S' subsites. This study has also demonstrated that the degradative action of elastase on elastin can be abrogated in the presence of inhibitor 17.


Investigation of the mechanism of retraction of the cell margin and rearward flow of nodules during mitotic cell rounding.
We have studied two types of cell motility directed toward the cell center: retraction of the cell margin and rearward flow of small cytoplasmic nodules during mitotic cell rounding in Potoroo tridactylis kidney (PtK2) cells by time-lapse video microscopy, drug treatments, and photoactivation of fluorescence. Nodules flow rearward on thin, actin-rich fibers (retraction fibers) exposed as the cell margin retracts. Retraction of the cell margin and rearward flow of nodules require intact actin filaments, but are insensitive to an inhibitor of myosin function (butanedione monoxime). Using photoactivation of fluorescence marking, we have determined that actin filaments in the majority of retraction fibers remain stationary while the cell margin retracts and nodules flow rearward. The pointed ends of retraction fiber actin filaments face the cell center. We argue that nodule motility is driven by a novel actin-based force that perhaps also partially contributes to retraction of the cell margin during cell rounding at mitosis.


Growth hormone receptor deficiency (Laron syndrome): clinical and genetic characteristics.
Approximately 60 cases of GHRD (Laron syndrome) were reported before 1990 and half of these were from Israel. We have described 47 additional patients from an inbred population of South Ecuador and have emphasized certain clinical features including: markedly advanced osseous maturation for height age; normal body proportions in childhood but child-like proportions in adults; much greater deviation of stature than head size, giving an appearance of large cranium and small facies; underweight in childhood despite the appearance of obesity and true obesity in adulthood; blue scleras; and limited elbow extension. The Ecuadorean patients differed markedly and most importantly from the other large concentration, in Israel, by being of normal or superior intelligence, suggesting a unique linkage in the Ecuadorean population. The Ecuadorean population also differed in that those patients coming from Loja province had a markedly skewed sex ratio (19 females: 2 males), while those from El Oro province had a normal sex distribution (14 females: 12 males). The phenotypic similarity between the El Oro and Loja patients indicates that this abnormal sex distribution is not a direct result of the GHRD.


Neurofeedback and quantitative electroencephalography.
This study was conducted in an attempt to determine the efficacy of neurofeedback (NFB) in the treatment of patients suffering from vertigo or tinnitus. Results indicated that after NFB, power for delta and theta bands was reduced; however, an increase of power was noted for the alpha bands. Furthermore, normalization was observed for the vestibular evoked potentials (VestEP). After NFB, a normalization of the VestEP was also demonstrated in a patient suffering from a bilateral tinnitus. A follow-up study (12 months after NFB) demonstrated that the VestEP were normal.


Improving the Quality of Primary Care by Optimizing Implementation Research Reporting.
The potential of implementation research in understanding strategies for changing practice is undermined by poor reporting, leaving readers unable to replicate such strategies and unclear whether they apply in the context of their practice. These challenges are particularly pertinent in the complex, diverse world of primary care. The recently published Standards for Reporting Implementation Studies (StaRI) provides a framework for comprehensive reporting of implementation research. A key concept is the consideration and reporting in "dual strands": on the one hand, the implementation strategy and on the other, the evidence-based intervention. Other requirements are full descriptions of context, strategies and interventions (and how the strategies were adopted or adapted), and evaluation methods, which will require flexible interpretation of journal limit constraints or innovative approaches to supplementary information. The choice is between accepting the unsatisfactory status quo or adopting strategies to improve reporting with a view to optimizing the potential of implementation research to advance primary care.


Conditioned augmentation of natural killer cell activity. Independence from nociceptive effects and dependence on interferon-beta.
Injection of mice with 20 micrograms polyinosinic: polycytidylic acid (Poly I:C) after exposure to camphor odor results in a conditioned augmentation of natural killer cell (NK) activity. In this study, we show that the conditioned response is not the result of nociceptive stimulation and that interferon-beta (IFN), but not IFN-alpha can replace Poly I:C as the unconditioned stimulus (US). Two conditioned stimuli (CS) were used with equivalent results. A combination CS consisting of a novel taste (saccharin) and a 125 mg/kg injection of LiCl that induces gastric upset was paired with a Poly I:C or IFN-beta (1 X 10(4) IU) injection. This resulted in an augmentation of NK activity when the conditioned animals were reexposed to the saccharin-LiCl CS. In addition, an identical conditioned response was elicited when a camphor odor CS was paired with either of these US. To test whether the conditioned response might be an artifact not detected by our controls, a mock conditioning experiment was performed, which assessed the differential effect of multiple exposures to the saccharin-LiCl CS without a CS/US pairing. The mock conditioned group was significantly suppressed relative to saline treated controls, whereas the mock nonconditioned group and the mock conditioned group that was not reexposed to the CS after conditioning did not show significant suppression. This indicates that the augmentation observed in the conditioned group after CS/US pairing was not the result of exposure to the CS itself. Small doses of Poly I:C (5 micrograms or 2.5 micrograms) given on days 3 and 5 (or on day 5 only) to boost NK activity had the effect of increasing the magnitude of the conditioned response measured on day 6. In addition, an identical conditioned response was observed when the interval between the CS/US pairing and the later CS exposures was changed, which places the test for the conditioned response either on day 6 (CS given on days 3 and 5) or day 10 (CS given on days 7 and 9). These results show that the observed conditioned enhancement of NK activity in conditioned animals is not caused by any nociceptive properties of the CS itself and is dependent on the IFN-beta produced after Poly I:C injection in the conditioned paradigm.


An adenylyl cyclase, CyaB, acts as an osmosensor in Myxococcus xanthus.
We have previously reported that a receptor-type adenylyl cyclase (CyaA) of Myxococcus xanthus undergoes an osmosensor mainly during spore germination (Y. Kimura et al., J. Bacteriol. 184:3578-3585, 2002). In the present study, we cloned another receptor-type adenylyl cyclase gene (cyaB) and characterized the function of the cyaB-encoded protein. Disruption of cyaB generates a mutant that showed growth retardation at high ionic (NaCl) or high nonionic (sucrose) osmolarity. When vegetative cells were stimulated with 0.15 M NaCl, the increases in intracellular cyclic AMP levels of cyaB mutant cells were lower than those of wild-type cells. Under nonionic osmostress, the cyaB mutant exhibited reduced spore germination; however, the germination rate of the cyaB mutant was significantly higher than that of the cyaA mutant.


Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity.
Major histocompatibility complex class I (MHCI) genes were discovered unexpectedly in healthy CNS neurons in a screen for genes regulated by neural activity. In mice lacking just 2 of the 50+ MHCI genes H2-K(b) and H2-D(b), ocular dominance (OD) plasticity is enhanced. Mice lacking PirB, an MHCI receptor, have a similar phenotype. H2-K(b) and H2-D(b) are expressed not only in visual cortex, but also in lateral geniculate nucleus (LGN), where protein localization correlates strongly with synaptic markers and complement protein C1q. In K(b)D(b-/-) mice, developmental refinement of retinogeniculate projections is impaired, similar to C1q(-/-) mice. These phenotypes in K(b)D(b-/-) mice are strikingly similar to those in beta2 m(-/-)TAP1(-/-) mice, which lack cell surface expression of all MHCIs, implying that H2-K(b) and H2-D(b) can account for observed changes in synapse plasticity. H2-K(b) and H2-D(b) ligands, signaling via neuronal MHCI receptors, may enable activity-dependent remodeling of brain circuits during developmental critical periods.


Maxillary Surgical Ciliated Cyst After Orthognathic Surgery.
Surgical ciliated cysts, also known as implantation cysts or postoperative maxillary cysts, are uncommon cystic formations predominantly arising in the posterior maxillary region after radical maxillary sinus surgery. Herein, we present the case of a 28-year-old male patient who had previously undergone orthognathic surgery and later experienced a minor car accident without major consequences. Approximately four years after surgery, the patient sought dental care due to the presence of a painless swelling in the maxillary region. Upon intraoral examination, the swelling extended from the area around the right canine to the upper left molar, covered by red mucosa. Image studies revealed an extensive well-defined osteolytic lesion causing thinning, erosion, buccal cortical plate perforation, and root resorption. An incisional biopsy was performed, and microscopic examination revealed a cystic lesion lined by ciliated respiratory-type epithelium and capsule variably fibrotic with sparse chronic inflammation. The final diagnosis was surgical ciliated cysts. The treatment approach involved decompression followed by enucleation and curettage, with the addition of bone grafting and the application of Leukocyte-Platelet Rich Fibrin (L-PRF). The patient has been under clinical follow-up for approximately 17 months with no signs of recurrence. A careful morphological evaluation is essential to avoid misdiagnosis and ensure a satisfactory treatment approach. In conclusion, this case highlights the importance of accurate diagnosis and appropriate treatment approaches for surgical ciliated cysts to ensure favorable patient outcomes.


Mono-, di- and trisubstituted derivatives of eflornithine: synthesis for in vivo delivery of DL-alpha-difluoromethylornithine in plasma.
The aim of this study was to synthesize a series of mono-, di- and trisubstituted derivatives of the human African trypanosomiasis drug eflornithine (alpha-difluoromethylornithine, DMFO, CAS 70052-12-9) to determine their partition coefficients, and to assess whether they deliver the parent drug in the plasma. If increased plasma concentrations of eflornithine could be achieved in this way, an oral dosage form would be possible. The derivatives, nine in total, were successfully synthesized by multi-step derivatisation of eflornithine on either its alpha-carboxylic or/and alpha-amino or/and delta-amino groups by either esterification or/and amidation or/and carbamylation, and their structures confirmed by NMR and MS spectroscopy. The majority of derivatives were more lipophilic than eflornithine with log D values in phosphate buffer solution (pH 7.4) ranging from -1.34 to 1.59 (vs. -0.98 for eflornithine). The in vivo absorption after oral administration to Sprague-Dawley rats showed that no derivative delivered eflornithine in the plasma, indicating that the derivatives were either not absorbed from the gastrointestinal tract or not metabolized to the parent drug. Two of the monosubstituted activities were toxic for T. brucei blood stream forms.


Strong divergence in trait means but not in plasticity across hatchery and wild populations of sea-run brown trout Salmo trutta.
There is ample evidence that organisms adapt to their native environment when gene flow is restricted. However, evolution of plastic responses across discrete environments is less well examined. We studied divergence in means and plasticity across wild and hatchery populations of sea-run brown trout (Salmo trutta) in a common garden experiment with two rearing environments (hatchery and a nearly natural experimental stream). Since natural and hatchery environments differ, this arrangement provides an experiment in contemporary adaptation across the two environments. A Q(ST) - F(ST) approach was used to investigate local adaptation in survival and growth over the first summer. We found evidence for divergent selection in survival in 1 year and in body length in both years and rearing environments. In general, the hatchery populations had higher survival and larger body size in both environments. Q(ST) in body size did not differ between the rearing environments, and constitutive divergence in the means was in all cases stronger than divergence in the plastic responses. These results suggest that in this system, constitutive changes in mean trait values are more important for local adaptation than increased plasticity. In addition, ex situ rearing conditions induce changes in trait means that are adaptive in the hatchery, but potentially harmful in the wild, suggesting that hatchery rearing is likely to be a suboptimal management strategy for trout populations facing selection in the stream environment.


Analysis of East Asia genetic substructure using genome-wide SNP arrays.
Accounting for population genetic substructure is important in reducing type 1 errors in genetic studies of complex disease. As efforts to understand complex genetic disease are expanded to different continental populations the understanding of genetic substructure within these continents will be useful in design and execution of association tests. In this study, population differentiation (Fst) and Principal Components Analyses (PCA) are examined using >200 K genotypes from multiple populations of East Asian ancestry. The population groups included those from the Human Genome Diversity Panel [Cambodian, Yi, Daur, Mongolian, Lahu, Dai, Hezhen, Miaozu, Naxi, Oroqen, She, Tu, Tujia, Naxi, Xibo, and Yakut], HapMap [ Han Chinese (CHB) and Japanese (JPT)], and East Asian or East Asian American subjects of Vietnamese, Korean, Filipino and Chinese ancestry. Paired Fst (Wei and Cockerham) showed close relationships between CHB and several large East Asian population groups (CHB/Korean, 0.0019; CHB/JPT, 00651; CHB/Vietnamese, 0.0065) with larger separation with Filipino (CHB/Filipino, 0.014). Low levels of differentiation were also observed between Dai and Vietnamese (0.0045) and between Vietnamese and Cambodian (0.0062). Similarly, small Fst's were observed among different presumed Han Chinese populations originating in different regions of mainland of China and Taiwan (Fst's <0.0025 with CHB). For PCA, the first two PC's showed a pattern of relationships that closely followed the geographic distribution of the different East Asian populations. PCA showed substructure both between different East Asian groups and within the Han Chinese population. These studies have also identified a subset of East Asian substructure ancestry informative markers (EASTASAIMS) that may be useful for future complex genetic disease association studies in reducing type 1 errors and in identifying homogeneous groups that may increase the power of such studies.


Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 7: Antibiotic-impregnated shunt systems versus conventional shunts in children: a systematic review and meta-analysis.
The objective of this systematic review and meta-analysis was to answer the following question: Are antibiotic-impregnated shunts (AISs) superior to standard shunts (SSs) at reducing the risk of shunt infection in pediatric patients with hydrocephalus? Both the US National Library of Medicine PubMed/MEDLINE database and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words relevant to AIS use in children. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected. An evidentiary table was assembled summarizing the studies and the quality of their evidence (Classes I-III). A meta-analysis was conducted using a random-effects model to calculate a cumulative estimate of treatment effect using risk ratio (RR). Heterogeneity was assessed using the chi-square and I(2) statistics. Based on the quality of the literature and the result of the meta-analysis, a recommendation was rendered (Level I, II, or III). Six studies, all Class III, met our inclusion criteria. All but one study focused on a retrospective cohort and all but one were conducted at a single institution. Four of the studies failed to demonstrate a lowered infection rate with the use of an AIS. However, when the data from individual studies were pooled together, the infection rate in the AIS group was 5.5% compared with 8.6% in the SS group. Using a random-effects model, the cumulative RR was 0.51 (95% CI 0.29-0.89, p < 0.001), indicating that a shunt infection was 1.96 times more likely in patients who received an SS. We recommend AIS tubing because of the associated lower risk of shunt infection compared to the use of conventional silicone hardware (quality of evidence: Class III; strength of recommendation: Level III). Antibiotic-impregnated shunt (AIS) tubing may be associated with a lower risk of shunt infection compared with conventional silicone hardware and thus is an option for children who require placement of a shunt. Level III, unclear degree of clinical certainty.