Ecological host fitting of Trypanosoma cruzi TcI in Bolivia: mosaic population structure, hybridization and a role for humans in Andean parasite dispersal.
An improved understanding of how a parasite species exploits its genetic repertoire to colonize novel hosts and environmental niches is crucial to establish the epidemiological risk associated with emergent pathogenic genotypes. Trypanosoma cruzi, a genetically heterogeneous, multi-host zoonosis, provides an ideal system to examine the sylvatic diversification of parasitic protozoa. In Bolivia, T. cruzi I, the oldest and most widespread genetic lineage, is pervasive across a range of ecological clines. High-resolution nuclear (26 loci) and mitochondrial (10 loci) genotyping of 199 contemporaneous sylvatic TcI clones was undertaken to provide insights into the biogeographical basis of T. cruzi evolution. Three distinct sylvatic parasite transmission cycles were identified: one highland population among terrestrial rodent and triatomine species, composed of genetically homogenous strains (Ar = 2.95; PA/L = 0.61; DAS = 0.151), and two highly diverse, parasite assemblages circulating among predominantly arboreal mammals and vectors in the lowlands (Ar = 3.40 and 3.93; PA/L = 1.12 and 0.60; DAS = 0.425 and 0.311, respectively). Very limited gene flow between neighbouring terrestrial highland and arboreal lowland areas (distance ~220 km; FST = 0.42 and 0.35) but strong connectivity between ecologically similar but geographically disparate terrestrial highland ecotopes (distance >465 km; FST = 0.016-0.084) strongly supports ecological host fitting as the predominant mechanism of parasite diversification. Dissimilar heterozygosity estimates (excess in highlands, deficit in lowlands) and mitochondrial introgression among lowland strains may indicate fundamental differences in mating strategies between populations. Finally, accelerated parasite dissemination between densely populated, highland areas, compared to uninhabited lowland foci, likely reflects passive, long-range anthroponotic dispersal. The impact of humans on the risk of epizootic Chagas disease transmission in Bolivia is discussed.


Macrocycle-wrapped polyethylenimine for gene delivery with reduced cytotoxicity.
Due to its outstanding capability to facilitate DNA condensation, transportation and endosomal escape, polyethylenimine (PEI) has been frequently studied for gene delivery. However, its molecular weight (M.W.) dependent transfection efficiency and cytotoxicity has severely limited its clinical application. To resolve this dilemma, a supramolecular strategy was developed for the first time, in which PEI with large M.W. (branched, 25 kDa) that has a satisfactory transfection efficiency, yet high non-specific cytotoxicity for gene delivery was wrapped with macrocyclic cucurbit[7]uril (CB[7]). The successful wrapping of the PEI by the macrocyclic CB[7] was proved by 1H NMR spectroscopy and supported by isothermal titration calorimetry (ITC). The plasmid DNA (pDNA) condensability of PEI was not affected by the supramolecular coating as evidenced from the agarose gel electrophoresis assay. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results demonstrated that the particle size, zeta potential, and morphology of the self-assemblies of PEI/pDNA and PEI/CB[7]/pDNA were comparable. As a consequence of the supramolecular wrapping, the cytotoxicity of PEI was significantly constrained as demonstrated by MTT assay, apoptosis assay, and a hemolysis study. In particular, both the cellular uptake and the gene transfection efficiency results suggest that the supramolecular wrapping of PEI by CB[7] exhibits negligible effects on PEI, thus functioning as an effective non-viral gene delivery vector. This novel supramolecular-wrapping strategy provides new insights for facile alleviation of the non-specific toxicity of PEI and potentially other polycationic gene vectors without compromising their transfection efficiency.


Achieving all-age helmet use compliance for snow sports: strategic use of education, legislation and enforcement.
Nova Scotia is the first jurisdiction in the world to mandate ski and snowboard helmet use for all ages at ski hills in the province. This study represents a longitudinal examination of the effects of social marketing, educational campaigns and the introduction of helmet legislation on all-age snow sport helmet use in Nova Scotia. A baseline observational study was conducted to establish the threshold of ski and snowboarding helmet use. Based on focus groups and interviews, a social marketing campaign was designed and implemented to address factors influencing helmet use. A prelegislation observational study assessed the effects of social marketing and educational promotion on helmet use. After all-age snow sport helmet legislation was enacted and enforced, a postlegislation observational study was conducted to determine helmet use prevalence. Baseline data revealed that 74% of skiers and snowboarders were using helmets, of which 80% were females and 70% were males. Helmet use was high in children (96%), but decreased with increasing age. Following educational and social marketing campaigns, overall helmet use increased to 90%. After helmet legislation was enacted, 100% compliance was observed at ski hills in Nova Scotia. Results from this study demonstrate that a multifaceted approach, including education, legislation and enforcement, was effective in achieving full helmet compliance among all ages of skiers and snowboarders.


Similar effects of all WNK3 variants on SLC12 cotransporters.
With-no-lysine kinase 3 (WNK3) is a member of a subfamily of serine/threonine kinases that modulate the activity of the electroneutral cation-coupled chloride cotransporters. WNK3 activates NKCC1/2 and NCC and inhibits the KCCs. Four splice variants are generated from the WNK3 gene. Our previous studies focused on the WNK3-18a variant. However, it has been suggested that other variants could have different effects on the cotransporters. Thus, the present study was designed to define the effects of all WNK3 variants on members of the SLC12 family. By RT-PCR from a fetal brain library, exons 18b and 22 were separately amplified and subcloned into the original WNK3-18a or catalytically inactive WNK3-D294A to obtain all four potential combinations with and without catalytic activity (18a, 18a+22, 18b, and 18b+22). The basal activity of the cotransporters and the effects of WNK3 isoforms were assessed in Xenopus laevis oocytes coinjected with each of the WNK3 variant cRNAs. In isotonic conditions, the basal activity of NCC and NKCC1/2 were increased by coinjection with any of the WNK3. The positive effects occurred even in hypotonic conditions, in which the basal activity of NKCC1 is completely prevented. Consistent with these observations, when expressed in hypotonicity, all KCCs were active, but in the presence of any of the WNK3 variants, KCC activity was completely reduced. That is, NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. We conclude that the effects of all WNK3 variants toward SLC12 proteins are similar.


Effects of mobilization with movement on pain and range of motion in patients with unilateral shoulder impingement syndrome: a randomized controlled trial.
The purpose of this study was to compare the immediate effects of mobilization with movement (MWM) to a sham technique in patients with shoulder impingement syndrome. A randomized controlled trial was performed. Forty-two patients (mean ± SD age, 55 ± 9 years; 81% female) satisfied eligibility criteria, agreed to participate, and were randomized into an MWM group (n = 21) or sham manual contact (n = 21). The primary outcome measures including pain intensity, pain during active range of motion, and maximal active range of motion were assessed by a clinician blinded to group allocation. Outcomes were captured at baseline and after 2 weeks of MWM treatment or sham intervention. The primary analysis was the group × time interaction. The 2×2 analysis of variance revealed a significant group × time interaction for pain intensity during shoulder flexion (F = 7.054; P = .011), pain-free shoulder flexion (F = 32.853; P < .001), maximum shoulder flexion (F = 18.791; P < .01), and shoulder external rotation (F = 7.950; P < .01) in favor of the MWM group. No other significant differences were found. Patients with shoulder impingement syndrome who received 4 sessions of MWM exhibited significantly better outcomes for pain during shoulder flexion, pain-free range of shoulder flexion, maximal shoulder flexion, and maximal external rotation than those patients who were in the sham group.


Telemedicine and primary care obesity management in rural areas - innovative approach for older adults?
The growing prevalence of obesity is paralleling a rise in the older adult population creating an increased risk of functional impairment, nursing home placement and early mortality. The Centers for Medicare and Medicaid recognized the importance of treating obesity and instituted a benefit in primary care settings to encourage intensive behavioral therapy in beneficiaries by primary care clinicians. This benefit covers frequent, brief, clinic visits designed to address older adult obesity. We describe the challenges in the implementation and delivery into real-world settings. The challenges in rural settings that have the fastest growing elderly population, high obesity rates, but also workforce shortages and lack of specialized services are emphasized. The use of Telemedicine has successfully been implemented in other specialties and could be a useful modality in delivering much needed intensive behavioral therapy, particularly in distant, under-resourced environments. This review outlines some of the challenges with the current benefit and proposed solutions in overcoming rural primary care barriers to implementation, including changes in staffing models. Recommendations to extend the benefit's coverage to be more inclusive of non-physician team members is needed but also for improvement in reimbursement for telemedicine services for older adults with obesity.


Early goal-directed therapy, corticosteroid, and recombinant human activated protein C for the treatment of severe sepsis and septic shock in the emergency department.
To describe our experience with early goal-directed therapy (EGDT), corticosteroid administration, and recombinant human activated protein C (rhAPC) administration in patients with severe sepsis or septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) II score > or =25 in the emergency department (ED). This was a retrospective case series of a prospectively maintained ED sepsis registry. Data are presented as median (25th, 75th percentile). The setting was an academic tertiary ED with approximately 60,000 annual patient visits. Patients with severe sepsis or septic shock and an APACHE II score > or =25 entered in an ED sepsis registry over a four-month period were included. Patients who received rhAPC in the intensive care unit were excluded. Central venous catheterization for central venous pressure and central venous oxygen saturation monitoring, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, inotropes, corticosteroids, and rhAPC were initiated by the emergency physicians and continued in the intensive care unit by intensivists. Twenty-four patients were enrolled. Patient characteristics were as follows: age, 79.5 (68.0, 83.5) years; APACHE II score, 31.5 (29.8, 36.0); ED length of stay, 6.5 (4.0, 10.5) hours; predicted mortality, 76.7% (71.9, 86.4); and in-hospital mortality, 45.8%. All patients received broad-spectrum antibiotics, 54.2% completed EGDT, 33.3% received corticosteroids, and 33.3% received rhAPC. Time of antibiotic administration was 1.5 (1.0, 2.0) hours, time of central venous pressure/central venous oxygen saturation monitoring was 1.0 (0.5, 2.5) hour, and time of rhAPC administration was 9.5 (6.8, 10.5) hours after patients met criteria for severe sepsis or septic shock. In-hospital mortality of patients who received rhAPC in addition to other therapies was 25.0%. EGDT, corticosteroid administration, and rhAPC administration are feasible in the ED setting. While these evidence-based therapies individually have been shown to improve outcomes for patients with severe sepsis or septic shock, further studies are needed to examine their combined effectiveness during the early stages of this disease.


Alternative polyadenylation reprogramming of MORC2 induced by NUDT21 loss promotes KIRC carcinogenesis.
Alternative polyadenylation (APA), a posttranscriptional mechanism of gene expression via determination of 3'UTR length, has an emerging role in carcinogenesis. Although abundant APA reprogramming is found in kidney renal clear cell carcinoma (KIRC), which is one of the major malignancies, whether APA functions in KIRC remains unknown. Herein, we found that chromatin modifier MORC2 gained oncogenic potential in KIRC among the genes with APA reprogramming, and moreover, its oncogenic potential was enhanced by 3'UTR shortening through stabilization of MORC2 mRNA. MORC2 was found to function in KIRC by downregulating tumor suppressor DAPK1 via DNA methylation. Mechanistically, MORC2 recruited DNMT3A to facilitate hypermethylation of the DAPK1 promoter, which was strengthened by 3'UTR shortening of MORC2. Furthermore, loss of APA regulator NUDT21, which was induced by DNMT3B-mediated promoter methylation, was identified as responsible for 3'UTR shortening of MORC2 in KIRC. Additionally, NUDT21 was confirmed to act as a tumor suppressor mainly depending on downregulation of MORC2. Finally, we designed an antisense oligonucleotide (ASO) to enhance NUDT21 expression and validated its antitumor effect in vivo and in vitro. This study uncovers the DNMT3B/NUDT21/APA/MORC2/DAPK1 regulatory axis in KIRC, disclosing the role of APA in KIRC and the crosstalk between DNA methylation and APA.


Postoperative mental status in elderly hip surgery patients.
To determine if elderly patients undergoing hip surgery became delirious postoperatively and, if so, whether age and/or time of day were related to delirium. Repeated measures. A convenience sample of 70 hip surgery patients 60 years of age and older at a large Midwestern teaching hospital were studied. Patients were excluded who were unconscious, unable to hear, see, and/or verbally communicate in English. Patients were also excluded who had a known history of dementia, Alzheimer's dementia, addiction to alcohol and/or sedative hypnotics, functional psychosis, or any other psychiatric diagnosis. Of the 70 patients, 37 were female and 33 were male. Mean age of the patients was 72.9 years (S.D. = 8.13). Patients were placed into one of three groups: Group 1--age 60 to 69 years (n = 25); Group 2--age 70 to 79 years (n = 25); or Group 3--80 years and older (n = 20). The most common procedure for all groups was total hip replacement (n = 48). Data were collected primarily by both objective and subjective assessment of the patients. Both the Folstein's Mini Mental Status Exam (MMSE) and the NEECHAM Confusion Tool were used to collect data. Chart reviews provided additional data. Patients were assessed preoperatively to obtain baseline assessment and screen out patients with preexisting confusion. Assessments were then done once in the morning and once in the evening for 5 days following surgery. Delirium, sundowning, sundown syndrome. The MMSE and NEECHAM were found to be highly correlated: Morning NEECHAM vs morning MMSE (Correlation Coefficient = .6515; p = .000), evening NEECHAM vs evening MMSE (Correlation Coefficient = .8301; p = .000). A test of repeated measures was used to examine the data. The Within factor was time, the Between factor was age, and the interaction effect was age by time of day. Dependent variables were total NEECHAM scores and total MMSE scores, in addition to total scores of these tests' subsections. An alpha level of .05 was used for all statistical tests. Age had a significant main effect on the NEECHAM (F = 7.44; p = .001) and MMSE (F = 6.04; p = .004). Time did not have a significant effect on either the MMSE (F = .00; p = .953) or the NEECHAM (F = .43; p = .513). There was no statistically significant interaction between age and time of day (NEECHAM, F = .97, p = .384 and MMSE (F = .19, p = .826). No subjects were assessed as demented per the MMSE. Only 12 episodes of acute confusion were noted using the NEECHAM. Patients in this population rarely, if ever, became confused. The older the individual, the more likely he/she was to have confusion. Time of day was neither significant in development of delirium nor on mental status assessment scores in this population. Current research literature notes that 10% to 50% of elderly postoperative patients experience delirium. Patients who have had femoral neck fractures can experience delirium three times more than patients having nonorthopaedic surgery. This study found that delirium in hip surgery patients is rare. A study of the more subtle components of delirium such as attention and memory might reveal less obvious changes in mental status following surgery. Type of orthopaedic surgery also might impact incidence of delirium. A comparative study between elderly total knee and total hip replacement patients would be interesting. Studying patients who have emergency hip surgery related to fracture in comparison to patients having elective hip surgery for degenerative conditions might identify other etiologies for delirium following hip surgery. Fatigue rather than time of day might be studied to observe whether it has a significant impact on mental status or delirium scores.


Capital and income breeding: the role of food supply.
An aspect of life history that has seen increasing attention in recent years is that of strategies for financing the costs of offspring production. These strategies are often described by a continuum ranging from capital breeding, in which costs are met purely from endogenous reserves, to income breeding, in which costs are met purely from concurrent intake. A variety of factors that might drive strategies toward a given point on the capital-income continuum has been reviewed, and assessed using analytical models. However, aspects of food supply, including seasonality and unpredictability, have often been cited as important drivers of capital and income breeding, but are difficult to assess using analytical models. Consequently, we used dynamic programming to assess the role of the food supply in shaping offspring provisioning strategies. Our model is parameterized for a pinniped (one taxon remarkable for the range of offspring-provisioning strategies that it illustrates). We show that increased food availability, increased seasonality, and, to a lesser extent, increased unpredictability can all favor the emergence of capital breeding. In terms of the conversion of energy into offspring growth, the shorter periods of care associated with capital breeding are considerably more energetically efficient than income breeding, because shorter periods of care are associated with a higher ratio of energy put into offspring growth to energy spent on parent and offspring maintenance metabolism. Moreover, no clear costs are currently associated with capital accumulation in pinnipeds. This contrasts with general assumptions about endotherms, which suggest that income breeding will usually be preferred. Our model emphasizes the role of seasonally high abundances of food in enabling mothers to pursue an energetically efficient capital-breeding strategy. We discuss the importance of offspring development for dictating strategies for financing offspring production.


Oxidation of aldose reductase inhibitors ALO-4114 and ALO-3152 catalyzed by liver microsomes.
Rat and Cynomolgus monkey liver microsomes catalyze the oxidation of 2.7-difluoro-4.5-dimethoxyspiro (9H-fluorene-9,4'-imidazolidine)-2',5'-dione (ALO-4114) to its monomethoxymetabolite (ALO-4417). Formation of this product by O-demethylation of ALO-4114 is catalyzed by NADPH and oxygen-dependent microsomal enzymes with the properties of P-450 monooxygenases. The reaction is blocked by inhibitors selective for these enzymes and activity increases about 2-fold in rats pretreated with phenobarbital or methylcholanthrene. The increase in the O-demethylation of ALO-4114 was, however, considerably less than the increase in benzphetamine N-demethylation or nitrophenetole O-deethylation activities in liver microsomes from rats pretreated with either phenobarbital or methylcholanthrene. Rats pretreated with 20 or 40 mg/kg of ALO-4114 for 3-4 days failed to change significantly the rate of ALO-4114 O-demethylase activity of liver microsomes. O-Demethylation of the achiral ALO-4114 yields the chiral ALO-4417. The enantiomers separated on a Daicel Chiracel AS column by HPLC indicated that O-demethylation of ALO-4114 by microsomes from untreated rats was only slightly stereoselective. However, rats pretreated with methylcholanthrene not only enhanced activity, but also increased the formation of one enantiomer. Further oxidative metabolism of the enantiomers was slow and barely detectable in vitro. Studies conducted with Cynomolgus monkey liver microsomes from one male and one female per experimental group were generally consistent with those from the rat, but some differences were noted. Whether the differences are real or only reflect individual variations caused by the small sample size is not known at present.


Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy.
Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies.


Comparative transcriptomic analysis of multiple cardiovascular fates from embryonic stem cells predicts novel regulators in human cardiogenesis.
Dissecting the gene expression programs which control the early stage cardiovascular development is essential for understanding the molecular mechanisms of human heart development and heart disease. Here, we performed transcriptome sequencing (RNA-seq) of highly purified human Embryonic Stem Cells (hESCs), hESC-derived Multipotential Cardiovascular Progenitors (MCPs) and MCP-specified three cardiovascular lineages. A novel algorithm, named as Gene Expression Pattern Analyzer (GEPA), was developed to obtain a refined lineage-specificity map of all sequenced genes, which reveals dynamic changes of transcriptional factor networks underlying early human cardiovascular development. Moreover, our GEPA predictions captured ~90% of top-ranked regulatory cardiac genes that were previously predicted based on chromatin signature changes in hESCs, and further defined their cardiovascular lineage-specificities, indicating that our multi-fate comparison analysis could predict novel regulatory genes. Furthermore, GEPA analysis revealed the MCP-specific expressions of genes in ephrin signaling pathway, positive role of which in cardiomyocyte differentiation was further validated experimentally. By using RNA-seq plus GEPA workflow, we also identified stage-specific RNA splicing switch and lineage-enriched long non-coding RNAs during human cardiovascular differentiation. Overall, our study utilized multi-cell-fate transcriptomic comparison analysis to establish a lineage-specific gene expression map for predicting and validating novel regulatory mechanisms underlying early human cardiovascular development.


Tobacco harm reduction: how rational public policy could transform a pandemic.
Nicotine, at the dosage levels smokers seek, is a relatively innocuous drug commonly delivered by a highly harmful device, cigarette smoke. An intensifying pandemic of disease caused or exacerbated by smoking demands more effective policy responses than the current one: demanding that nicotine users abstain. A pragmatic response to the smoking problem is blocked by moralistic campaigns masquerading as public health, by divisions within the community of opponents to present policy, and by the public-health professions antipathy to any tobacco-control endeavours other than smoking cessation. Yet, numerous alternative systems for nicotine delivery exist, many of them far safer than smoking. A pragmatic, public-health approach to tobacco control would recognize a continuum of risk and encourage nicotine users to move themselves down the risk spectrum by choosing safer alternatives to smoking--without demanding abstinence.


Streptococcus pneumoniae Infection Promotes Histone H3 Dephosphorylation by Modulating Host PP1 Phosphatase.
Pathogenic bacteria can alter host gene expression through post-translational modifications of histones. We show that a natural colonizer, Streptococcus pneumoniae, induces specific histone modifications, including robust dephosphorylation of histone H3 on serine 10 (H3S10), during infection of respiratory epithelial cells. The bacterial pore-forming toxin pneumolysin (PLY), along with the pyruvate oxidase SpxB responsible for H2O2 production, play important roles in the induction of this modification. The combined effects of PLY and H2O2 trigger host signaling that culminates in H3S10 dephosphorylation, which is mediated by the host cell phosphatase PP1. Strikingly, S. pneumoniae infection induces dephosphorylation and subsequent activation of PP1 catalytic activity. Colonization of PP1 catalytically deficient cells results in impaired intracellular S. pneumoniae survival and infection. Interestingly, PP1 activation and H3S10 dephosphorylation are not restricted to S. pneumoniae and appear to be general epigenomic mechanisms favoring intracellular survival of pathogenic bacteria.


Does clinical management improve outcomes following self-harm? Results from the multicentre study of self-harm in England.
Evidence to guide clinical management of self-harm is sparse, trials have recruited selected samples, and psychological treatments that are suggested in guidelines may not be available in routine practice. To examine how the management that patients receive in hospital relates to subsequent outcome. We identified episodes of self-harm presenting to three UK centres (Derby, Manchester, Oxford) over a 10 year period (2000 to 2009). We used established data collection systems to investigate the relationship between four aspects of management (psychosocial assessment, medical admission, psychiatric admission, referral for specialist mental health follow up) and repetition of self-harm within 12 months, adjusted for differences in baseline demographic and clinical characteristics. 35,938 individuals presented with self-harm during the study period. In two of the three centres, receiving a psychosocial assessment was associated with a 40% lower risk of repetition, Hazard Ratios (95% CIs): Centre A 0.99 (0.90-1.09); Centre B 0.59 (0.48-0.74); Centre C 0.59 (0.52-0.68). There was little indication that the apparent protective effects were mediated through referral and follow up arrangements. The association between psychosocial assessment and a reduced risk of repetition appeared to be least evident in those from the most deprived areas. These findings add to the growing body of evidence that thorough assessment is central to the management of self-harm, but further work is needed to elucidate the possible mechanisms and explore the effects in different clinical subgroups.


High mutation rate and mutational bias at (TAA)n microsatellite loci in chickpea (Cicer arietinum L.).
Microsatellites, very short tandemly repeated DNA sequences, are being extensively used in evolutionary genetics and molecular breeding of crop plants, because of their high degree of allelic variability, which is presumably caused by a high rate of mutation that changes microsatellite array length. In humans and various animals, mutation rates vary greatly and fall within the range of 10(-3) to 10(-6). In plants, the mutation rate at microsatellite loci seems to be higher than in animals, but no experimental estimates are available yet. Here, we report high spontaneous mutation rates (micro) and mutational bias at fifteen perfect (TAA)n microsatellite loci in inbred populations of chickpea. We show a significantly higher mutation rate, averaged across all loci, in the long-lived variety Ghab 2 (mu = 1.0 x 10(-2); detected in 16,050 allele-generations) compared to the variety Syrian Local (mu = 3.9 x 10(-3); detected in 15,600 allele-generations), which has a short life-span, with the majority of mutants (96.9%) in both varieties differing by < or = 1 repeat unit. Compared to animals, higher mutation rates in chickpea are likely to be due to the presence of long (TAA)n microsatellite repeat arrays and the larger number of DNA replications that meristematic initials of the plants undergo before reaching the reproductive phase. Thus, the long-lived variety undergoes more DNA replications, resulting in an accumulation of more mutations than in the variety with the shorter life-span.


Study of the molecular mechanism of decreased liver synthesis of albumin in inflammation.
Hypoalbuminemia in inflammatory disorders is not an infrequent finding. However, little is known about albumin synthesis in these patients. In the present study we have measured the albumin synthesis in four patients with inflammatory diseases using the [14C]carbonate technique. Because inflammation causes a decreased albumin synthesis and this decreased synthesis could not be related to a reduced amino acid supply, we have also examined the possible molecular mechanisms of reduced albumin synthesis during inflammation using in vivo and in vitro experiments in rats. In rats with turpentine-induced inflammation, serum albumin concentration and liver albumin mRNa level were markedly decreased. These changes could not be reproduced by administration of fibrinogen-, or fibrin-degradation products, or several hormones, such as corticosteroids, growth hormone, and adrenaline. However, monocytic products, especially interleukin 1, postulated to be important mediators of the inflammatory response, reduced albumin synthesis and liver albumin messenger RNA content but not total protein synthesis in rats in vivo and in primary cultures of rat hepatocytes. These findings suggest that monocytic products play an important role in reduced albumin synthesis during inflammation.


Tracking footprints of artificial selection in the dog genome.
The size, shape, and behavior of the modern domesticated dog has been sculpted by artificial selection for at least 14,000 years. The genetic substrates of selective breeding, however, remain largely unknown. Here, we describe a genome-wide scan for selection in 275 dogs from 10 phenotypically diverse breeds that were genotyped for over 21,000 autosomal SNPs. We identified 155 genomic regions that possess strong signatures of recent selection and contain candidate genes for phenotypes that vary most conspicuously among breeds, including size, coat color and texture, behavior, skeletal morphology, and physiology. In addition, we demonstrate a significant association between HAS2 and skin wrinkling in the Shar-Pei, and provide evidence that regulatory evolution has played a prominent role in the phenotypic diversification of modern dog breeds. Our results provide a first-generation map of selection in the dog, illustrate how such maps can rapidly inform the genetic basis of canine phenotypic variation, and provide a framework for delineating the mechanistic basis of how artificial selection promotes rapid and pronounced phenotypic evolution.


Delayed splenic rupture: an unusual cause of the acute surgical abdomen.
The diagnosis of delayed rupture of the spleen may be difficult to make because of the presumed triviality of the precipitating injury, an unpredictable time lag between the injury and the development of symptoms, and the possibility of atypical signs and symptoms remote from the bleeding spleen. The clinician may confuse the signs and symptoms with those of acute appendicitis or with some other cause. The authors present two case histories to illustrate the diagnostic difficulties caused by delayed rupture of the spleen. Whenever the acute surgical abdomen is present with concomitant anemia, the diagnosis of delayed rupture of the spleen should be considered.


History of clinical transplantation.
The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations in surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipients had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts.


A filter-flow perspective of haematogenous metastasis offers a non-genetic paradigm for personalised cancer therapy.
Research into mechanisms of haematogenous metastasis has largely become genetic in focus, attempting to understand the molecular basis of 'seed-soil' relationships. Preceding this biological mechanism is the physical process of dissemination of circulating tumour cells (CTCs) in the circulation. Patterns of metastatic spread have been previously quantified using the metastatic efficiency index, a measure quantifying metastatic incidence for a given primary-target organ pair and the relative blood flow between them. We extend this concept to take into account the reduction in CTCs which occurs in organ capillary beds connected by a realistic vascular network topology. Application to a dataset of metastatic incidence reveals that metastatic patterns depend strongly on assumptions about the existence and location of micrometastatic disease which governs CTC dynamics on the network, something which has heretofore not been considered - an oversight which precludes our ability to predict metastatic patterns in individual patients.


Reactions of HOCO radicals through hydrogen-atom hopping utilizing clathrate hydrates as an observational matrix.
The carboxyl (HOCO) radical, which is an important species in atmospheric chemistry and combustion, is an intermediate in the reaction: CO + OH → CO2 + H and serves as a hydrogen donor to the reaction partners. The cis-HOCO radical, one of the ground-state HOCO radicals, is supposed to be decomposed into CO2 and the hydrogen atom by a tunneling effect. In order to prove the hypothesis, we performed electron spin resonance (ESR) measurements to investigate the decay mechanisms of the ground-state HOCO and DOCO radicals in gamma-ray-irradiated CO2 hydrates, which may hold the radicals stably. The ground-state HOCO and DOCO radicals decayed according to a second-order decay model and transformed into formic acid and CO2. The ratio of the decay rate constants of HOCO and DOCO radicals shows a good agreement with that in the kinetic isotope effect for the hydrogen and deuterium abstraction reactions. These results indicate that they react with another HOCO radical in the adjacent hydrate cage without the tunneling effect. This implies that the ground-state HOCO radicals are not decomposed by the tunneling effect but are decayed through reactions with some atoms, molecules, and/or radicals even in the gas phase. In addition, the hydrogen-atom hopping through the temporary hydrogen bonds between the HOCO radical and CO2 results in a seeming diffusion of the HOCO radicals in the CO2 hydrate; this would be an important concept for the studies of the radical diffusions and the supply of hydrogen atoms in gas, liquid, and solid phases.


Effect of acute and chronic salt loading on erythrocyte 22Na efflux in males with essential hypertension.
1. Present results confirm our previous work which showed that a sodium intake over 3 mmol day-1 kg-1 decreased the total erythrocyte efflux rate constant in untreated males with essential hypertension. 2. The infusion of saline (2.25 mmol of Na+/kg) over 30 min decreased the efflux rate constant. 3. The change after chronic sodium loading and the intravenous infusion of saline is in the ouabain-sensitive component (ouabain-sensitive Na+, K+ aTPase pump activity) of total efflux. 4. The reduction in efflux by an acute sodium load occurred only when chronic sodium intake was low. 5. Posture did not affect the efflux rate constant whether sodium intake was high or low. 6. The reduction in efflux after chronic ingestion and acute administration of sodium occurred only when erythrocytes were incubated in plasma. It did not occur in artificial medium, which suggested that a plasma factor mediated the effect of added sodium on cell sodium efflux. 7. The effect of sodium on cell sodium transport by a plasma factor with ouabain-like properties (which may be a natriuretic hormone) constitutes a regulatory system. This system, the sodium--ouabain-sensitive cell sodium-transport pathway system, has important implications for the understanding of blood pressure control and sodium homeostasis.


Small-plasmid-mediated antibiotic resistance is enhanced by increases in plasmid copy number and bacterial fitness.
Plasmids play a key role in the horizontal spread of antibiotic resistance determinants among bacterial pathogens. When an antibiotic resistance plasmid arrives in a new bacterial host, it produces a fitness cost, causing a competitive disadvantage for the plasmid-bearing bacterium in the absence of antibiotics. On the other hand, in the presence of antibiotics, the plasmid promotes the survival of the clone. The adaptations experienced by plasmid and bacterium in the presence of antibiotics during the first generations of coexistence will be crucial for the progress of the infection and the maintenance of plasmid-mediated resistance once the treatment is over. Here we developed a model system using the human pathogen Haemophilus influenzae carrying the small plasmid pB1000 conferring resistance to β-lactam antibiotics to investigate host and plasmid adaptations in the course of a simulated ampicillin therapy. Our results proved that plasmid-bearing clones compensated for the fitness disadvantage during the first 100 generations of plasmid-host adaptation. In addition, ampicillin treatment was associated with an increase in pB1000 copy number. The augmentation in both bacterial fitness and plasmid copy number gave rise to H. influenzae populations with higher ampicillin resistance levels. In conclusion, we show here that the modulations in bacterial fitness and plasmid copy number help a plasmid-bearing bacterium to adapt during antibiotic therapy, promoting both the survival of the host and the spread of the plasmid.


Erythropoietin modulates the neural control of hypoxic ventilation.
Numerous factors involved in general homeostasis are able to modulate ventilation. Classically, this comprises several kind of molecules, including neurotransmitters and steroids that are necessary for fine tuning ventilation under different conditions such as sleep, exercise, and acclimatization to high altitude. Recently, however, we have found that erythropoietin (Epo), the main regulator of red blood cell production, influences both central (brainstem) and peripheral (carotid bodies) respiratory centers when the organism is exposed to hypoxic conditions. Here, we summarize the effect of Epo on the respiratory control in mammals and highlight the potential implication of Epo in the ventilatory acclimatization to high altitude, as well as in the several respiratory sickness and syndromes occurring at low and high altitude.


Increasing Access to State Psychiatric Hospital Beds: Exploring Supply-Side Solutions.
The objective of this study was to identify supply-side interventions to reduce state psychiatric hospital admission delays. Healthcare Enterprise Accounts Receivable Tracking System (HEARTS) data were collected for all patients admitted between July 1, 2010, and July 31, 2012, to one of North Carolina's three state-operated psychiatric hospitals (N=3,156). Additional information on hospital use was collected at nine meetings with hospital administrators and other local stakeholders. A discrete-event simulation model was built to simulate the flow of adult nonforensic patients through the hospital. Hypothetical scenarios were used to evaluate the effects of varying levels of increased capacity on annual number of admissions and average patient wait time prior to admission. In the base case, the model closely approximated actual state hospital utilization, with an average of 1,251±65 annual admissions and a preadmission wait time of 3.3±.1 days across 50 simulations. Results from simulated expansion scenarios highlighted substantial capacity shortfalls in the current system. For example, opening an additional 24-bed unit was projected to decrease average wait time by only 6%. Capacity would need to be increased by 165% (356 beds) to reduce average wait time below 24 hours. Without more robust community-based hospital and residential capacity, major increases in state psychiatric hospital inpatient capacity are necessary to ensure timely admission of people in crisis.


Conversion of autoimmune hypothyroidism to hyperthyroidism.
Graves' disease and Hashimoto's thyroiditis are the two autoimmune spectrum of thyroid disease. Cases of conversion from hyperthyroidism to hypothyroidism have been reported but conversion from hypothyroidism to hyperthyroidism is very rare. Although such cases have been reported rarely in the past we are now seeing such conversions from hypothyroidism to hyperthyroidism more frequently in clinical practice. We are reporting three cases of middle aged Asian females who presented with classical symptoms of hypothyroidism and the investigations showed elevated thyroid stimulating hormone with positive thyroid antibodies. Diagnosis of autoimmune hypothyroidism was made and thyroxine replacement therapy was initiated. Patients became asymptomatic with normalization of thyroid stimulating hormone level. After few years they developed symptoms of hyperthyroidism with suppressed thyroid stimulating hormone level. Over replacement of thyroxine was considered and the dose of thyroxine was decreased, but they remain symptomatic. After gradual decrease in the dose of thyroxine it was stopped finally. Even after few months of stopping thyroxine, the symptoms of hyperthyroidism did not improve and the biochemical and imaging modalities confirmed that the patients have developed hyperthyroidism. Anti-thyroid treatment was then started and the patients became symptom free. High index of suspicion should be there for possible conversion of hypothyroidism to hyperthyroidism if a patient with primary hypothyroidism develops persistent symptoms of hyperthyroidism. Otherwise it can be missed easily considering it as an over replacement with thyroid hormone.


Acute paracetamol poisoning.
Of 41 cases of acute paracetamol poisoning one died of gastrointestinal haemorrhage and acute massive necrosis of the liver, three became jaundiced, and 13 others had biochemical evidence of hepatocellular damage. Liver damage is a toxic effect which is present in most patients who ingest more than 15 g. of paracetamol. One patient with liver damage survived renal failure due to acute tubular necrosis. It is suggested that the renal lesion was also the result of paracetamol overdosage.Profound hypoglycaemia and metabolic acidosis may also complicate severe poisoning. Plasma levels of para-aminophenol fall rapidly, and procedures currently used to enhance the elimination of the drug cannot be expected to prevent development of hepatic damage.


Coherent Doppler lidar signal spectrum with wind turbulence.
The average signal spectrum (periodogram) for coherent Doppler lidar is calculated for a turbulent wind field. Simple approximations are compared with the exact calculation. The effects of random errors in the zero velocity reference, the effects of averaging spectral estimates by use of multiple lidar pulses, and the effects of the range dependence of the lidar signal power over the range gate are included. For high spatial resolution measurements the lidar signal power is concentrated around one spectral estimate (spectral bin), and correct interpretation of the contribution from turbulence is difficult because of the effects of spectral leakage. For range gates that are larger than the lidar pulse volume, the signal power is contained in many spectral bins and the effects of turbulence can be determined accurately for constant signal power over the range gate and for the far-field range dependence of the signal power.


Report: Atmospheric pollutants discharged from municipal solid waste incineration and gasification-melting facilities in Japan.
This article reports on the discharge of particulate matter, acid gases, nitrogen oxides, and dioxins from 107 municipal solid waste incineration and gasification-melting facilities in Japan between the years 2001 and 2003; the pollution control methods and the operational data are summarized. The knowledge on amounts of slaked lime used and the emission of acid gases is reported, the emission concentrations did not exceed the limit values in all facilities. In Japan, the regulation of dioxin emissions by the revised Waste Management and Public Cleansing Law (Ministry of the Environment, Government of Japan 2007) has been enforced since December 1997. Bag filters have been installed in all facilities constructed after this time, and catalytic reactors have been installed in 66% of these facilities. The regulated values for combustion temperature, the cooling temperature of gases discharged from furnaces and the concentration of carbon monoxide in the gases discharged from stacks were satisfactory in almost all facilities. In facilities constructed since December 1997, the dioxin concentrations in the discharged gases were considerably lower than in those constructed before this time. All facilities met the emission limit values for particulate matter, acid gases, nitrogen oxides and dioxins.


Spa therapy of upper respiratory tract inflammations.
The upper airway respiratory diseases (i.e. common cold, allergic rhinitis, nonallergic/vasomotor rhinitis, acute and chronic rhinosinusitis and nasal polyposis) in which nasal congestion is a common symptom are often undertreated due to the frequent inadequate efficacy and safety concern with current therapies. In scientific literature, few studies seem to support the hypothesis that nasal inhalatory treatment with thermal water promotes the improvement of nasal symptoms, even if the mechanisms by which the improvement from SPA therapy can be expected remain debated. A prospective comparative study with a pre-post design has been performed consecutively enrolling 33 (males 70 %) patients of both genders older than 12 years of age, affected by chronic sinonasal inflammation. All patients underwent a 14-days course of radioactive water warm vapour inhalations followed by nasal aerosol of the same thermal water 10 min each once/day at Merano Therme. At the beginning and end of the study, in all the subjects, nasal function evaluation by active anterior rhinomanometry, mucociliary transport time (MCTt) determination and nasal cytology were performed. After the inhalatory treatment, the mucociliary function was improved and the pathologic mucociliary transport times recorded at the beginning of the study being significantly reduced to physiologic ones. Besides, before treatment, the cytologic picture showed an inflammatory cell infiltration (eosinophils, neutrophils with/without bacteria, mast cells) in 37 % of patients; after therapy in 66 % of these patients, the rhinocytogram was normal. Our results suggest, according to the literature data, that SPA therapy with radioactive water could represent an alternative choice in chronic inflammatory diseases of the upper airways, nonresponsive to pharmacological therapy.


Ethnic differences in risk from mercury among Savannah River fishermen.
Fishing plays an important role in people's lives and contaminant levels in fish are a public health concern. Many states have issued consumption advisories; South Carolina and Georgia have issued them for the Savannah River based on mercury and radionuclide levels. This study examined ethnic differences in risk from mercury exposure among people consuming fish from the Savannah River, based on site-specific consumption patterns and analysis of mercury in fish. Among fish, there were significant interspecies differences in mercury levels, and there were ethnic differences in consumption patterns. Two methods of examining risk are presented: (1) Hazard Index (HI), and (2) estimates of how much and how often people of different body mass can consume different species of fish. Blacks consumed more fish and had higher HIs than Whites. Even at the median consumption, the HI for Blacks exceeded 1.0 for bass and bowfin, and, at the 75th percentile of consumption, the HI exceeded 1.0 for almost all species. At the White male median consumption, noHI exceeded 1, but for the 95th percentile consumer, the HI exceeded 1.0 almost regardless of which species were eaten. Although females consumed about two thirds the quantity of males, HIs exceeded 1 for most Black females and for White females at or above the 75th percentile of consumption. Thus, close to half of the Black fishermen were eating enough Savannah River fish to exceed HI = 1. Caution must be used in evaluating an HI because the RfDs were developed to protect the most vulnerable individuals. The percentage of each fish species tested that exceeded the maximum permitted limits of mercury in fish was also examined. Over 80% of bowfin, 38% of bass, and 21% of pickerel sampled exceeded 0.5 ppm. The risk methodology is applicable anywhere that comparable data can be obtained. The risk estimates are representative for fishermen along the Savannah River, and are not necessarily for the general populations.


Coordinate bonding strategy for molecularly imprinted hydrogels: toward pH-responsive doxorubicin delivery.
Molecularly imprinted hydrogel (MIH) as drug delivery system has been studied. It still remains a challenge to construct the stimuli-responsive MIH. Here, we report a coordinate bond strategy for imprinting doxorubicin (Dox) in hydrogel capable of pH-responsive and sustained drug delivery. The imprinting condition such as template-monomer interactions induced by metal ion was carefully investigated by spectroscopic methods. The obtained Dox-MIH was evaluated by absorption and in vitro release experiments. It has been demonstrated that the cupric ion mediated interaction between Dox and 4-vinyl pyridine via coordination and the optimal coordinate ratio of Dox/Cu(2+) was 2:1. The rebinding amount of MIH to Dox was 2.7-fold that of nonimprinted hydrogel and the Dox-loaded MIH showed a pH-responsive release property. Not more than 10% of loaded drug was released from Dox-MIH at pH 7.2 during a time course of 7 days. However, near to 60% of loaded drug was sustainedly released at pH 5.0 during the same period. These results indicated that Dox-MIH with pH-responsive behavior possessed great promising as sustained-release delivery system of anticancer drug.


Primary care hypnotic and anxiolytic prescription: Reviewing prescribing practice over 8 years.
Over the last few years, hypnotic and anxiolytic medications have had their clinical efficacy questioned in the context of concerns regarding dependence, tolerance alongside other adverse effects. It remains unclear how these concerns have impacted clinical prescribing practice. This is a study reviewing community-dispensed prescribing data for patients on the East Practice Medical Center list in Arbroath, Scotland, in 2007, 2011 and 2015. Anxiolytic and hypnotic medications were defined in accordance with the British National Formulary chapter 4.1.1 and chapter 4.1.2. All patients receiving a drug within this class in any of the study years were collated and anonymized using primary care prescribing data. The patients' age, gender, name of the prescribed drug(s), and total number of prescriptions in this class over the year were extracted. The proportion of patients prescribed a benzodiazepine medication decreased between 2007 and 2015: 83.8% (n = 109) in 2007, 70.5% (n = 122) in 2011, and 51.7% (n = 138) in 2015 (P = 0.006). The proportion of these patients prescribed a nonbenzodiazepine drug increased between 2007 and 2015: 30% (n = 39) in 2007, 46.2% (n = 80) in 2011, and 52.4% (n = 140) in 2015 (P = 0.001). There was a significant increase in the number of patients prescribed melatonin (P = 0.020). This study reports a reduction in benzodiazepine prescriptions in primary care alongside increases in nonbenzodiazepine and melatonin prescribing, with an increase in prescribing rates of this drug class overall. Changes in this prescribing practice may reflect the medicalization of insomnia, local changes in prescribing practice and alongside national recommendations.


Invariant NK T cells: potential for immunotherapeutic targeting with glycolipid antigens.
Invariant NK T (iNKT) cells are a subset of T lymphocytes that recognize glycolipid antigens bound with the antigen-presenting molecule CD1d. iNKT cells have potent immunoregulatory activities that can promote or suppress immune responses during different pathological conditions. These immunoregulatory properties can be harnessed for therapeutic purposes with cognate glycolipid antigens, such as the marine sponge-derived glycosphingolipid α-galactosylceramide. Preclinical studies have shown substantial promise for iNKT cell-based treatments of infections, cancer and autoimmune and inflammatory diseases. Translation of these preclinical studies to the clinic, while faced with some obstacles, has already had some initial success. In this article, we review the immunodulatory activities of iNKT cells and the potential for developing iNKT cell-based prophylactic and curative therapies of human disease.


The Dartmouth Database of Children's Faces: acquisition and validation of a new face stimulus set.
Facial identity and expression play critical roles in our social lives. Faces are therefore frequently used as stimuli in a variety of areas of scientific research. Although several extensive and well-controlled databases of adult faces exist, few databases include children's faces. Here we present the Dartmouth Database of Children's Faces, a set of photographs of 40 male and 40 female Caucasian children between 6 and 16 years-of-age. Models posed eight facial expressions and were photographed from five camera angles under two lighting conditions. Models wore black hats and black gowns to minimize extra-facial variables. To validate the images, independent raters identified facial expressions, rated their intensity, and provided an age estimate for each model. The Dartmouth Database of Children's Faces is freely available for research purposes and can be downloaded by contacting the corresponding author by email.


Combining Mass Spectrometric Metabolic Profiling with Genomic Analysis: A Powerful Approach for Discovering Natural Products from Cyanobacteria.
An innovative approach was developed for the discovery of new natural products by combining mass spectrometric metabolic profiling with genomic analysis and resulted in the discovery of the columbamides, a new class of di- and trichlorinated acyl amides with cannabinomimetic activity. Three species of cultured marine cyanobacteria, Moorea producens 3L, Moorea producens JHB, and Moorea bouillonii PNG, were subjected to genome sequencing and analysis for their recognizable biosynthetic pathways, and this information was then compared with their respective metabolomes as detected by MS profiling. By genome analysis, a presumed regulatory domain was identified upstream of several previously described biosynthetic gene clusters in two of these cyanobacteria, M. producens 3L and M. producens JHB. A similar regulatory domain was identified in the M. bouillonii PNG genome, and a corresponding downstream biosynthetic gene cluster was located and carefully analyzed. Subsequently, MS-based molecular networking identified a series of candidate products, and these were isolated and their structures rigorously established. On the basis of their distinctive acyl amide structure, the most prevalent metabolite was evaluated for cannabinomimetic properties and found to be moderate affinity ligands for CB1.


Research on innovation management of science and technology innovation team members based on constructive conflict evolution game.
How to give full play to the positive function of constructive conflicts (task conflicts and process conflicts) in the science and technology innovation team, give appropriate stimulation, mobilize the enthusiasm of employees and improve the team's innovative ability to improve team performance and organizational effectiveness are issues that deserve both team leaders' and scholars' attention. Through selecting multiple medical technology R&D personnel from a specific science and technology innovation team of health organization, the research studies the constructive conflicts among the members of the science and technology innovation team, constructs and analyzes the conflict evolution game model, proposes countermeasures and suggestions for improving the innovation ability of the science and technology innovation team and discusses the innovation management mechanism of the science and technology innovation team. The study shows that task conflicts, process conflicts and innovation game decisions cannot be avoided. The unstable choice of members does not promote innovation. However, on the one hand, constructive conflicts can be controlled to maintain a moderate state of control. On the other hand, it is also necessary to establish a mutually trusting communication environment and convenient communication channels in the science and technology innovation team, combined with modern information management technology, to handle the problems that were difficult to be found or accumulated for a long time under the previous management mechanism and cooperate with the science and technology innovation team to improve the technology innovation team's innovation capability.


My Patient Taking A Novel Oral Anticoagulant Needs Surgery, Device Implantation, Or Ablation.
Atrial fibrillation (AF) is a highly prevalent chronic condition and a growing number of patients are on chronic anticoagulation therapy with novel oral anticoagulant (NOAC) agents: dabigatran, rivaroxaban, and apixaban. Many of these patients are expected to require invasive procedures. There is no clear consensus regarding the peri-procedural management of patients using NOACs, as to how to minimize both bleeding risk and thromboembolism risk. This review of the current available literature is designed to help formulate peri-procedural anticoagulation strategies for patients with AF taking NOACs who are being considered for catheter ablation, device implant, or other surgery. To help frame the discussion, we offer 3 case vignettes that we will revisit to at the end of the review of the existing literature. Case 1: A 62 year-old female with hypertension, diabetes, and symptomatic paroxysmal AF who is prescribed dabigatran for thromboembolism prevention. She has failed attempts at maintaining sinus rhythm with antiarrhythmic drugs. She is now being considered for catheter ablation of AF. Case 2: A 76 year-old male with hypertension, diabetes, prior stroke, and ischemic cardiomyopathy who has persistent drug-refractory AF. He is maintained on chronic anticoagulation with dabigatran for thromboembolism prevention. He has an implantable cardioverter-defibrillator (ICD) which requires a generator change. Case 3: A 58 year-old male with hypertension and paroxysmal AF who takes rivaroxaban for thromboembolic prophylaxis and is being considered for a knee replacement surgery.


Outcome evaluation of a new model of critical care orientation.
The shortage of critical care nurses and the service expansion of 2 intensive care units provided a unique opportunity to create a new model of critical care orientation. The goal was to design a program that assessed critical thinking, validated competence, and provided learning pathways that accommodated diverse experience. To determine the effect of a new model of critical care orientation on satisfaction, retention, turnover, vacancy, preparedness to manage patient care assignment, length of orientation, and cost of orientation. A prospective, quasi-experimental design with both quantitative and qualitative methods. The new model improved satisfaction scores, retention rates, and recruitment of critical care nurses. Length of orientation was unchanged. Cost was increased, primarily because a full-time education consultant was added. A new model for nurse orientation that was focused on critical thinking and competence validation improved retention and satisfaction and serves as a template for orientation of nurses throughout the medical center.


Factors associated with declining a rapid human immunodeficiency virus test in labor and delivery.
The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend routine rapid HIV testing in labor and delivery (L&D) for women with undocumented HIV status using an opt-out approach. Identifying factors associated with declining a rapid HIV test in L&D will be helpful in developing strategies to improve rapid HIV testing uptake. Data from the Mother-Infant Rapid Intervention at Delivery study were analyzed. Women ≥24 weeks gestation, in labor, with undocumented HIV status were offered rapid HIV testing using informed consent. Women who declined rapid HIV testing (decliners) but agreed to be interviewed were compared to women who accepted testing (acceptors). 102 decliners and 478 acceptors met inclusion criteria for analysis. Decliners of rapid HIV testing were more likely to have had prenatal care (PNC), after adjusting for age, Hispanic ethnicity, high-school education and city of enrollment (adjusted OR 2.4, 95% CI 1.06-5.58). Having had PNC was collinear with prior HIV education and previous offer of an HIV test during the current pregnancy, so these factors were not part of the model. During PNC, standard informed consent may involve discussions that negatively affect later uptake of testing in L&D. Therefore an opt-out approach to testing may improve testing rates. Furthermore, decliners may have felt that testing in L&D was redundant because of previous testing during PNC; however, if previous testing occurred, this was undocumented at L&D. Documentation and timely communication of HIV status is critical to provide appropriate HIV prophylaxis.


The period prevalence and costs of treating nonmelanoma skin cancers in patients over 65 years of age covered by medicare.
Nonmelanoma skin cancer (NMSC) prevalence and treatment costs are rapidly increasing at an unknown rate. To determine actual prevalence and treatment costs for NMSC in patients over 65 years of age covered by Medicare. We used a 5% random sample of Medicare claims available for 1994 and 1995. Demographic characteristics, period prevalence, treatment types and frequencies, treating physician specialty, and allowable treatment charges associated with the diagnosis of NMSC were analyzed and described. More than 789,000 patients over age 65 covered by Medicare had a diagnosis and treatment for NMSC in 1995. Fifty-eight percent were men and 98% were Caucasian. The majority were from the South and West regions of the United States. Dermatologists treated more than 60% of these NMSCs. Treatment costs were approximately $285 million. The largest percentage of treatment expenditures (34%) was for excisions. The number of patients with NMSC is far greater than previous estimates. Dermatologists treat the majority of NMSCs. The mean treatment cost per patient is $329. Total expenditures for NMSC eradication represent 0.7% of the Medicare budget. NMSC is a major public health concern because of its increasing prevalence, costs, and the aging U.S. population.


African-American adolescent girls' initiation of sexual activity: survival analysis.
African-American adolescent females tend to initiate participation in sexual activity at an earlier age than Caucasian adolescent females. Early initial participation in sexual activity is associated with increased risk of HIV infection. However, limited prospective data are available on the rate at which African-American adolescent females delay their initial participation in sexual activity. The purpose is to determine low-income, inner-city, African-American adolescent females' survival or continued nonparticipation in sexual activity over a 20-month period and to determine predictors associated with survival. A longitudinal, quasi-experimental research design with multiple data collection points was used. The convenience sample consisted of 396 African-American females with a mean age of 12.4 years (SD = 1.1 years) and their mothers. The adolescents completed questionnaires assessing perceptions of maternal monitoring, HIV transmission knowledge, self-efficacy to refuse sex, intention to refuse sex, and age. Their mothers completed questionnaires assessing perception of maternal monitoring, safer sex self-efficacy, marital status, and educational level. At baseline, the adolescents reported nonparticipation in sexual activity. Survival analysis was conducted to determine the timing and predictors of sexual activity initiation for these adolescents. Of the 396 adolescents, 28.5% did not survive; they participated in sexual activity within the 20-month period. Predictors of non-survival were the adolescents' age, perception of maternal monitoring, and intention to refuse sex. Findings suggest interventions that increase maternal monitoring and adolescents' intentions to refuse sex could be beneficial in delaying sexual activity.


Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.
Inherited bone marrow failure (IBMF) syndromes are a heterogeneous group of rare hematological disorders characterized by the impairment of hematopoiesis, which harbor specific clinical presentations and pathogenic mechanisms. Some of these syndromes may progress through clonal evolution, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Most prominent are failures of DNA repair such as Fanconi Anemia and much rarer failure of ribosomal apparatus, e.g., Diamond Blackfan Anemia or of telomere elongation such as dyskeratosis congenita. In these congenital disorders, hematopoietic stem cell transplantation (HSCT) is often a consideration. However, HSCT will not correct the underlying disease and possible co-existing extra-medullary (multi)-organ defects, but will improve BMF. Indications as well as transplantation characteristics are most of the time controversial in this setting because of the rarity of reported cases. The present paper proposes a short overview of current practices.


The relationship between sleep quality and depressive symptoms in adolescents.
While poor sleep quality and sleep problems are signs of depression in adolescents, depressive symptoms among this age group further deteriorate sleep quality. The aim of this study was to explore the relationship between sleep quality and depressive symptoms in adolescents of 14 to 20 years of age. This study was conducted with a descriptive and cross-sectional research design. The sample group consisted of 313 adolescents in İstanbul, Turkey. The data were collected using a questionnaire form, the Beck Depression Inventory (BDI), and the Pittsburgh Sleep Quality Index (PSQI). The mean BDI score of the adolescents was 12.99 ± 8.94 (range: 0-53) and 4.8% had severe depressive symptoms. The global PSQI score of the adolescents was 4.69 ± 2.87 (range: 0-16) and 63.6% had good sleep quality, whereas the remaining 36.4% had poor sleep quality. There was a moderate positive correlation between BDI and PSQI scores. The factors affecting the quality of sleep of adolescents were mild and moderate-severe depressive symptom level, smoking, and the presence of sleep problems in a family member. This study shows a relationship between sleep quality and depressive symptom levels of adolescents. The findings of the current research will contribute to the development of school wellbeing programs that will be prepared with the aim of improving sleep quality and reducing depressive symptoms.


Plasma membrane area increases with spread area by exocytosis of a GPI-anchored protein compartment.
The role of plasma membrane (PM) area as a critical factor during cell motility is poorly understood, mainly due to an inability to precisely follow PM area dynamics. To address this fundamental question, we developed static and dynamic assays to follow exocytosis, endocytosis, and PM area changes during fibroblast spreading. Because the PM area cannot increase by stretch, spreading proceeds by the flattening of membrane folds and/or by the addition of new membrane. Using laser tweezers, we found that PM tension progressively decreases during spreading, suggesting the addition of new membrane. Next, we found that exocytosis increases the PM area by 40-60% during spreading. Reducing PM area reduced spread area, and, in a reciprocal manner, reducing spreadable area reduced PM area, indicating the interconnection between these two parameters. We observed that Golgi, lysosomes, and glycosylphosphatidylinositol-anchored protein vesicles are exocytosed during spreading, but endoplasmic reticulum and transferrin receptor-containing vesicles are not. Microtubule depolymerization blocks lysosome and Golgi exocytosis but not the exocytosis of glycosylphosphatidylinositol-anchored protein vesicles or PM area increase. Therefore, we suggest that fibroblasts are able to regulate about half of their original PM area by the addition of membrane via a glycosylphosphatidylinositol-anchored protein compartment.


Multi-layer analysis of multi-frequency brain networks as a new tool to study EEG topological organization.
Oscillatory activity rising from the interaction among neurons is widely observed in the brain at different scales and is thought to encode distinctive properties of the neural processing. Classical investigations of neuroelectrical activity and connectivity usually focus on specific frequency bands, considered as separate aspects of brain functioning. However, this might not paint the whole picture, preventing to see the brain activity as a whole, as the result of an integrated process. This study aims to provide a new framework for the analysis of the functional interaction between brain regions across frequencies and different subjects. We ground our work on the latest advances in graph theory, exploiting multi-layer community detection. In our multi-layer network model, layers keep track of single frequencies, including all the information in a unique graph. Community detection is then applied by means of a multilayer formulation of modularity. As a proof-of-concept of our approach, we provide here an application to multi-frequency functional brain networks derived from resting state EEG collected in a group of healthy subjects. Our results indicate that α-band selectively characterizes an inter-individual common organization of EEG brain networks during open eyes resting state. Future applications of this new approach may include the extraction of subject-specific features able to capture selected properties of the brain processes, related to physiological or pathological conditions.


Cholesterylation: a tail of hedgehog.
Cholesterylation is a post-translational attachment of sterol to proteins. This modification has been a characteristic of a single family of hedgehog proteins (Hh). Hh is a well-established morphogenic molecule important in embryonic development. It was also found to be involved in the progression of many cancer types. Herein, we describe the mechanism of biosynthesis of cholesterylated Hh, the role of this unusual modification on protein functions and novel chemical probes, which could be used to specifically target this modification, both in vitro and in vivo.


Automatic optimization of drug cocktails on an integrated microfluidic system.
Drug cocktails have been popular for a variety of therapies of complicated diseases. Nevertheless, it is a tediously challenging task to optimize formulations, especially using traditional methods. Hence, an automatic system capable of precise dispensing multiple drugs is of great need. Herein, a new integrated microfluidic system combined with a two-axis traverse module was developed to dispense and mix a small amount of drug combination precisely and automatically. This on-chip dispensing process could be performed with a precise and accurate manner when compared to the manual operations. The efficacy of both single and multiple drugs could be examined through the developed microfluidic system with extremely low variation of drug formulations. Analysis of cell viabilities for normal and tumor cells was also performed to verify potential drug combinations. It is envisioned that this automatic system, which is flexible to combine with standard cell analysis methods and novel drug formulation algorithm, could provide precise and high-throughput drug cocktail formulations and expedite the drug screening processes.


[Acute lumbar sprain treated with massage combined with acupuncture at different distal acupoints: a randomized controlled trial].
To observe treatment efficacy of acupuncture at different distal acupoints for acute lumbar sprain after massage. One hundred and fifty patients with acute lumbar sprain were randomly divided into a Yaotongdian (Extra) group, a Houxi (SI 3) group, a Weizhong (BL 40) group, a Chengshan (BL 57) group and a Shuigou (GV 26) group, total 5 groups, 30 cases in each one. After the same massage treatment and based on groups divided, different distal acupoints above-mentioned were selected to be acupunctured. Visual analogue scale (VAS) scores, lumbar activity and treatment efficacy of patients in 5 groups were evaluated. With acupuncture at distal acupoints after massage,VAS scores of patients in 5 groups were decreased compared with those after massage treatment (all P<0.05); lumbar activity was all obviously improved (all P<0.01); and cured and markedly effective rates were all increased in comparison with those after massage (all P<0.01). But among 5 groups the differences of VAS scores, lumbar activity and cured and markedly effective rates were not statistically significant(all P>0.05). Based on massage treatment, acupuncture at distal acupoints could further improve the treatment efficacy for acute lumbar sprain, but there is no obvious effective difference among every distal acupoint. As long as choosing acupoints with lower pain threshold and stimulating enough, good efficacy could be acquired for acute lumbar sprain.


Free tissue transfer in patients with renal disease.
Several authors have cited renal disease as a risk factor for free flap failure. The authors performed a retrospective analysis of all patients who underwent free tissue transfer with concomitant renal disease, including acute renal failure, end-stage renal disease, chronic renal insufficiency, and functional kidney transplants, to determine what effect renal disease has on flap survival and overall reconstructive outcome. More than 1053 free flaps were examined. Renal disease was identified in 32 patients who underwent 33 free tissue transfers. Average patient age was 57 years (range, 36 to 80 years). Twelve patients (38 percent) were on chronic dialysis (end-stage renal disease), 18 patients (56 percent) had chronic renal insufficiency, and three patients (9 percent) had the diagnosis of acute renal failure at the time of surgery. Three patients in the chronic renal insufficiency group had a functioning renal transplant. Average follow-up was 16 months. Immediate postoperative complications occurred in 14 patients (42 percent of the 33 flaps). Overall perioperative mortality was 3 percent. Within the first 30 days there were two cases (6 percent) of primary flap failure; an additional four legs were lost as the result of complications related to their bypass grafts. There were no primary flap failures after 30 days; however, within the first year after surgery an additional seven limbs were lost as the result of progressive ischemia or infection, and an additional three patients died. This resulted in a 52 percent incidence of major morbidity or mortality during the first year and a 55 percent reconstructive success rate in survivors at 1 year. No significant difference was seen in postoperative morbidity or mortality when comparing the end-stage renal disease group to the chronic renal insufficiency group; however, patients with renal disease and diabetes tended to have poorer outcomes. Renal disease, especially renal disease associated with diabetes and peripheral vascular disease, can be a strong indicator of possible reconstructive failure. The surgeon and patient should be aware of the medical and surgical complications associated with this procedure at the outset.


The multiple stressor ecological risk assessment for the mercury-contaminated South River and upper Shenandoah River using the Bayesian network-relative risk model.
We have conducted a regional scale risk assessment using the Bayesian Network Relative Risk Model (BN-RRM) to calculate the ecological risks to the South River and upper Shenandoah River study area. Four biological endpoints (smallmouth bass, white sucker, Belted Kingfisher, and Carolina Wren) and 4 abiotic endpoints (Fishing River Use, Swimming River Use, Boating River Use, and Water Quality Standards) were included in this risk assessment, based on stakeholder input. Although mercury (Hg) contamination was the original impetus for the site being remediated, other chemical and physical stressors were evaluated. There were 3 primary conclusions from the BN-RRM results. First, risk varies according to location, type and quality of habitat, and exposure to stressors within the landscape. The patterns of risk can be evaluated with reasonable certitude. Second, overall risk to abiotic endpoints was greater than overall risk to biotic endpoints. By including both biotic and abiotic endpoints, we are able to compare risk to endpoints that represent a wide range of stakeholder values. Third, whereas Hg reduction is the regulatory priority for the South River, Hg is not the only stressor driving risk to the endpoints. Ecological and habitat stressors contribute risk to the endpoints and should be considered when managing this site. This research provides the foundation for evaluating the risks of multiple stressors of the South River to a variety of endpoints. From this foundation, tools for the evaluation of management options and an adaptive management tools have been forged. Integr Environ Assess Manag 2017;13:85-99. © 2016 SETAC.


Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers.
Ayahuasca is a traditional South American psychoactive beverage used in Amazonian shamanism, and in the religious ceremonies of Brazilian-based syncretic religious groups with followers in the US and several European countries. This tea contains measurable amounts of the psychotropic indole N,N-dimethyltryptamine (DMT), and beta-carboline alkaloids with MAO-inhibiting properties. In a previous report we described a profile of stimulant and psychedelic effects for ayahuasca as measured by subjective report self-assessment instruments. In the present study the cerebral bioavailability and time-course of effects of ayahuasca were assessed in humans by means of topographic quantitative-electroencephalography (q-EEG), a noninvasive method measuring drug-induced variations in brain electrical activity. Two doses (one low and one high) of encapsulated freeze-dried ayahuasca, equivalent to 0.6 and 0.85 mg DMT kg(-1) body weight, were administered to 18 healthy volunteers with previous experience in psychedelic drug use in a double-blind crossover placebo-controlled clinical trial. Nineteen-lead recordings were undertaken from baseline to 8 h after administration. Subjective effects were measured by means of the Hallucinogen Rating Scale (HRS). Ayahuasca induced a pattern of psychoactive effects which resulted in significant dose-dependent increases in all subscales of the HRS, and in significant and dose-dependent modifications of brain electrical activity. Absolute power decreased in all frequency bands, most prominently in the theta band. Mean absolute power decreases (95% CI) at a representative lead (P3) 90 min after the high dose were -20.20+/-15.23 microV2 and -2.70+/-2.21 microV2 for total power and theta power, respectively. Relative power decreased in the delta (-1.20+/-1.31% after 120 min at P3) and theta (-3.30+/-2.59% after 120 min at P3) bands, and increased in the beta band, most prominently in the faster beta-3 (1.00+/-0.88% after 90 min at P3) and beta-4 (0.30+/-0.24% after 90 min at P3) subbands. Finally, an increase was also seen for the centroid of the total activity and its deviation. EEG modifications began as early as 15-30 min, reached a peak between 45 and 120 min and decreased thereafter to return to baseline levels at 4-6 h after administration. The central effects of ayahuasca could be objectively measured by means of q-EEG, showing a time pattern which closely paralleled that of previously reported subjective effects. The modifications seen for the individual q-EEG variables were in line with those previously described for other serotonergic psychedelics and share some features with the profile of effects shown by pro-serotonergic and pro-dopaminergic drugs. The q-EEG profile supports the role of 5-HT2 and dopamine D2-receptor agonism in mediating the effects of ayahuasca on the central nervous system.


Asymmetric Total Synthesis of (-)-Arborisidine and (-)-19-epi-Arborisidine Enabled by a Catalytic Enantioselective Pictet-Spengler Reaction.
A five-step total synthesis of arborisidine, a caged pentacyclic monoterpene indole alkaloid, has been accomplished in both racemic and enantioselective manners. The synthesis features the following three key steps: (a) a regioselective Pictet-Spengler reaction of tryptamine with 2,3-pentanedione; (b) a chemo- and stereoselective intramolecular oxidative cyclization; and (c) a complexity-generating aza-Cope/Mannich cascade followed by in situ oxidation and epimerization. A chiral pyrenylpyrrolidino-squaramide catalyzed enantioselective Pictet-Spengler reaction between tryptamine and 2,3-pentanedione is subsequently uncovered, allowing us to develop a five-step asymmetric synthesis of (-)-arborisidine, an enantiomer of the natural substance. Both (±)-19-epi-arborisidine and (-)-19-epi-arborisidine are also synthesized, which undergo epimerization at room temperature in the presence of aqueous 2 N KOH to (±)-arborisidine and (-)-arborisidine, respectively. The 19-epi-isomer is also partially epimerized to arborisidine upon preparative TLC purification (eluent: MeOH/CHCl3 saturated with NH3) and equilibrium studies indicate that arborisidine is thermodynamically more stable than its 19-epimer. In line with Kam's biosynthesis proposal and their purification protocol, we suspect that 19-epi-arborisidine could also be a natural product.


The hippocampus as a cognitive graph.
A theory of cognitive mapping is developed that depends only on accepted properties of hippocampal function, namely, long-term potentiation, the place cell phenomenon, and the associative or recurrent connections made among CA3 pyramidal cells. It is proposed that the distance between the firing fields of connected pairs of CA3 place cells is encoded as synaptic resistance (reciprocal synaptic strength). The encoding occurs because pairs of cells with coincident or overlapping fields will tend to fire together in time, thereby causing a decrease in synaptic resistance via long-term potentiation; in contrast, cells with widely separated fields will tend never to fire together, causing no change or perhaps (via long-term depression) an increase in synaptic resistance. A network whose connection pattern mimics that of CA3 and whose connection weights are proportional to synaptic resistance can be formally treated as a weighted, directed graph. In such a graph, a "node" is assigned to each CA3 cell and two nodes are connected by a "directed edge" if and only if the two corresponding cells are connected by a synapse. Weighted, directed graphs can be searched for an optimal path between any pair of nodes with standard algorithms. Here, we are interested in finding the path along which the sum of the synaptic resistances from one cell to another is minimal. Since each cell is a place cell, such a path also corresponds to a path in two-dimensional space. Our basic finding is that minimizing the sum of the synaptic resistances along a path in neural space yields the shortest (optimal) path in unobstructed two-dimensional space, so long as the connectivity of the network is great enough. In addition to being able to find geodesics in unobstructed space, the same network enables solutions to the "detour" and "shortcut" problems, in which it is necessary to find an optimal path around a newly introduced barrier and to take a shorter path through a hole opened up in a preexisting barrier, respectively. We argue that the ability to solve such problems qualifies the proposed hippocampal object as a cognitive map. Graph theory thus provides a sort of existence proof demonstrating that the hippocampus contains the necessary information to function as a map, in the sense postulated by others (O'Keefe, J., and L. Nadel. 1978. The Hippocampus as a Cognitive Map. Clarendon Press, Oxford, UK). It is also possible that the cognitive mapping functions of the hippocampus are carried out by parallel graph searching algorithms implemented as neural processes. This possibility has the great attraction that the hippocampus could then operate in much the same way to find paths in general problem space; it would only be necessary for pyramidal cells to exhibit a strong nonpositional firing correlate.


A mouse brain homolog of the Drosophila Shab K+ channel with conserved delayed-rectifier properties.
We have cloned and expressed a mouse brain K+ channel that is the homolog of the Drosophila Shab K+ channel. Mouse and Drosophila Shab K+ channels (mShab and fShab, respectively) represent an instance of K+ channels and structurally related species that are both functionally and structurally conserved; most kinetic, voltage-sensitive, and pharmacological properties are similar for the 2 channels. The greatest functional difference between the currents is recovery from inactivation, which is several times slower for mShab than for fShab currents. In addition to conserved structure, the mShab polypeptide has an unusually long nonconserved region at the carboxyl end of the protein. Truncation of 293 residues from the carboxyl end produced no noticeable change in voltage-sensitive, kinetic, or pharmacological properties. Thus, the measured functional properties of mShab are determined by the remaining 564 residues, most of which are conserved. The mShab and fShab channels are naturally occurring structural variants having substitutions in conserved portions that appear relatively neutral with respect to all measured properties except for, possibly, the rate of recovery from inactivation. The mShab current closely resembles a native delayed-rectifier-type potassium current, IK, in hippocampal neurons.


Burrowing in marine muds by crack propagation: kinematics and forces.
The polychaete Nereis virens burrows through muddy sediments by exerting dorsoventral forces against the walls of its tongue-depressor-shaped burrow to extend an oblate hemispheroidal crack. Stress is concentrated at the crack tip, which extends when the stress intensity factor (KI) exceeds the critical stress intensity factor (KIc). Relevant forces were measured in gelatin, an analog for elastic muds, by photoelastic stress analysis, and were 0.015+/-0.001 N (mean +/- s.d.; N=5). Measured elastic moduli (E) for gelatin and sediment were used in finite element models to convert the forces in gelatin to those required in muds to maintain the same body shapes observed in gelatin. The force increases directly with increasing sediment stiffness, and is 0.16 N for measured sediment stiffness of E=2.7 x 10(4) Pa. This measurement of forces exerted by burrowers is the first that explicitly considers the mechanical behavior of the sediment. Calculated stress intensity factors fall within the range of critical values for gelatin and exceed those for sediment, showing that crack propagation is a mechanically feasible mechanism of burrowing. The pharynx extends anteriorly as it everts, extending the crack tip only as far as the anterior of the worm, consistent with wedge-driven fracture and drawing obvious parallels between soft-bodied burrowers and more rigid, wedge-shaped burrowers (i.e. clams). Our results raise questions about the reputed high energetic cost of burrowing and emphasize the need for better understanding of sediment mechanics to quantify external energy expenditure during burrowing.


Managing unwanted immunogenicity of biologicals.
All protein drugs (biologicals) have an immunogenic potential and we are armed with multiple guidelines, regulatory documents and white papers to assist us in assessing the level of risk for unwanted immunogenicity of new biologicals. However, for certain biologicals, significant immunogenicity becomes only apparent after their use in patients. Causes of immunogenicity are multifactorial but not yet fully understood. Within the pharmaceutical industry there are only a few opportunities to openly discuss the causes and consequences of immunogenicity with regard to the development of new biologicals. The annual Open Scientific Symposium of the European Immunogenicity Platform (EIP) is one such meeting that brings together scientists and clinicians from academia and industry to build know-how and expertise in the field of immunogenicity. The critical topics discussed at the last EIP meeting (February 2014) will be reviewed here. The current opinion of this expert group is that the assessment of unwanted immunogenicity can be improved by using prediction tools, optimizing the performance of immunogenicity assays and learning from the clinical impact of other biologicals that have already been administered to patients. A multidisciplinary approach is warranted to better understand and minimize drug immunogenicity and its clinical consequences.


Nutrition and physical activity in child care centers: the impact of a wellness policy initiative on environment and policy assessment and observation outcomes, 2011.
The child care environment has emerged as an ideal setting in which to implement policies that promote healthy body weight of children. The purpose of this study was to assess the effect of a wellness policy and training program on the physical activity and nutrition environment in 24 child care centers in Georgia. We used the Environment and Policy Assessment and Observation instrument to identify changes to foods served, staff behaviors, and physical activity opportunities. Observations were performed over 1 day, beginning with breakfast and concluding when the program ended for the day. Observations were conducted from February 2010 through April 2011 for a total of 2 observations in each center. Changes to nutrition and physical activity in centers were assessed on the basis of changes in scores related to the physical activity and nutrition environment documented in the observations. Paired t test analyses were performed to determine significance of changes. Significant improvements to total nutrition (P < .001) and physical activity scores (P < .001) were observed. Results indicate that centers significantly improved the physical activity environments of centers by enhancing active play (P = .02), the sedentary environment (P = .005), the portable environment (P = .002), staff behavior (P = .004), and physical activity training and education (P < .001). Significant improvements were found for the nutrition environment (P < .001), and nutrition training and education (P < .001). Findings from this study suggest that implementing wellness policies and training caregivers in best practices for physical activity and nutrition can promote healthy weight for young children in child care settings.


Changes in renal function following nephroureterectomy may affect the use of perioperative chemotherapy.
Nephroureterectomy alone fails to adequately treat many patients with advanced upper tract urothelial carcinoma (UTUC). Perioperative platinum-based chemotherapy has been proposed but requires adequate renal function. Our aim was to determine whether the ability to deliver platinum-based chemotherapy following nephroureterectomy is affected by postoperative changes in renal function. We retrospectively reviewed data on 388 patients undergoing nephroureterectomy for UTUC between 1991 and 2009. Four institutions were included. All patients underwent nephroureterectomy. All patients had serum creatinine measured before and after surgery. The value closest to 3 mo after surgery was taken as the postoperative value (range: 2-52 wk). Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease study equation. eGFR values before and after surgery were compared using the paired t test. We chose an eGFR of 45 and 60 ml/min per 1.73 m(2) as possible cut-offs for chemotherapy eligibility and compared eligibility before and after surgery using the chi-square test. Our cohort of 388 patients included 233 men (60%) with a median age of 70 yr. Mean eGFR decreased by 24% after surgery. Using a cut-off of 60 ml/min per 1.73 m(2), 49% of patients were eligible for chemotherapy before surgery, but only 19% of patients remained eligible postoperatively. Using a cut-off of 45 ml/min per 1.73 m(2), 80% of patients were eligible preoperatively, but only 55% remained eligible after surgery. This distribution persisted when we limited the analysis to patients with advanced pathologic stage (T3 or higher). Patients older than the median age of 70 yr were more likely to be ineligible for chemotherapy both pre- and postoperatively by either definition, and they were significantly more likely to have an eGFR <45 ml/min per 1.73 m(2) postoperatively, regardless of their starting eGFR. This study is limited by its retrospective nature, and there was some variability in the timing of postoperative serum creatinine measurements. eGFR is significantly diminished after nephroureterectomy, particularly in elderly patients. These changes in renal function likely affect eligibility for adjuvant cisplatin-based therapy. Accordingly, we suggest strong consideration of neoadjuvant regimens.