Implications for management and conservation of the population genetic structure of the wedge clam Donax trunculus across two biogeographic boundaries.
In a resource management perspective, the understanding of the relative influence of the physical factors on species connectivity remains a major challenge and is also of great ecological and conservation biology interest. Despite the overfishing threat on the wedge clam Donax trunculus in Europe, relatively little information is known about its population genetic structure and connectivity and their consequences on conservation policies. We employed 16 microsatellite loci to characterise the genetic diversity and population structure of D. trunculus. A total of 514 samples from seven different localities along the Atlantic-Mediterranean transition, from the Atlantic (Gulf of Cádiz) to the north-western Mediterranean were genotyped. The analysis of the population genetic structure displayed a clear distinction along the Atlantic-Mediterranean transition with different clusters in the Atlantic Ocean, the Alboran Sea and the northwestern Mediterranean. Consequently, we recommend that these three areas should be considered as different management units. We showed that all populations seem to be at high long-term risk of extinction with the exception of the protected Doñana National Park population which still seems to have evolutionary potential. Therefore, our results emphasized the necessity of protection of this economic resource and the validity of molecular tools to evaluate the population dynamics.


Repeated Critical Illness and Unplanned Readmissions Within 1 Year to PICUs.
To determine the occurrence rate of unplanned readmissions to PICUs within 1 year and examine risk factors associated with repeated readmission. Retrospective cohort analysis. Seventy-six North American PICUs that participated in the Virtual Pediatric Systems, LLC (VPS, LLC, Los Angeles, CA). Ninety-three thousand three hundred seventy-nine PICU patients discharged between 2009 and 2010. None. Index admissions and unplanned readmissions were characterized and their outcomes compared. Time-to-event analyses were performed to examine factors associated with readmission within 1 year. Eleven percent (10,233) of patients had 15,625 unplanned readmissions within 1 year to the same PICU; 3.4% had two or more readmissions. Readmissions had significantly higher PICU mortality and longer PICU length of stay, compared with index admissions (4.0% vs 2.5% and 2.5 vs 1.6 d; all p < 0.001). Median time to readmission was 30 days for all readmissions, 3.5 days for readmissions during the same hospitalization, and 66 days for different hospitalizations. Having more complex chronic conditions was associated with earlier readmission (adjusted hazard ratio, 2.9 for one complex chronic condition; hazard ratio, 4.8 for two complex chronic conditions; hazard ratio, 9.6 for three or more complex chronic conditions; all p < 0.001 compared no complex chronic condition). Most specific complex chronic condition conferred a greater risk of readmission, and some had considerably higher risk than others. Unplanned readmissions occurred in a sizable minority of PICU patients. Patients with complex chronic conditions and particular conditions were at much higher risk for readmission.


Protection of islet grafts through transforming growth factor-β-induced tolerogenic dendritic cells.
In type 1 diabetes, the insulin-producing β-cells are destroyed by the immune system. One way of restoring glucose control is to transplant β-cells from a donor. Although this procedure may restore endogenous insulin production, immunosuppressive treatment is needed to prevent the recipient from rejecting the donor-derived islets. We investigated the possibilities of transient expression of the immunosuppressive cytokine transforming growth factor (TGF)-β within islets to achieve long-term graft tolerance. We found that brief expression of TGF-β prevented rejection of syngeneic islets, that there was reduction of dendritic cell (DC) activation in the graft, and that there was reduced reactivation of T cells in the graft-draining lymph nodes. In vitro exposure of bone marrow-derived DCs to TGF-β reduced expression of costimulatory molecules CD80 and CD86, as well as production of proinflammatory cytokines such as interleukin-12 p70 in DCs, but did not alter levels of major histocompatibility complex classes I and II. Furthermore, the capacity of TGF-β-treated bone marrow-derived DCs to activate both CD4(+) and CD8(+) T cells was reduced. Adding TGF-β-conditioned tolerogenic DCs to the grafted islets led to long-term survival of the graft, demonstrating that TGF-β-induced tolerogenic DCs can provide an effective means to restore immune tolerance in an already established autoimmune disease.


The safety of deFinity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses.
The purpose of this retrospective analysis was to define the incidence of severe adverse events after exposure to ultrasound contrast agents. Data between January 1, 2001, and September 30, 2007, were collected using invited responses to an on-line web-based questionnaire from 1 general and 12 cardiac ultrasound laboratories. During a period of 4.5 +/- 2.4 years, a total of 66,164 doses of Definity (Lantheus Medical Imaging, North Billerica, MA) and 12,219 doses of Optison (GE Healthcare, Buckinghamshire, UK) were administered, reflecting contrast use in 5% of transthoracic and 28% of stress echocardiographic procedures. More than 10,000 doses were given to critically ill patients in intensive care unit settings or to patients with acute chest pain of suspected cardiac origin. The median age of patients who received an ultrasound contrast agent was 60 years, 49% were male, and the mean body mass index was 32 +/- 1.4 g/m(-2). Severe reactions that were considered "probably" related to an ultrasound contrast agent developed in 8 patients (0.01%), all of whom were outpatients, and 4 (0.006%) of these were consistent with anaphylactoid reactions. There were no deaths reported. All patients recovered with treatment. No serious events were seen in inpatients. This multicenter, retrospective analysis includes the largest number of doses of ultrasound contrast agents ever published and a large number of patients evaluated in a wide variety of settings, including the critically ill. It shows that these agents have a good safety profile in both cardiac and abdominal ultrasound applications. The incidence of severe adverse reactions to ultrasound contrast agents is no greater, and may be lower, than that reported for contrast agents commonly used in other cardiac imaging tests.


Protein elemental sparing and codon usage bias are correlated among bacteria.
Highly expressed proteins can exhibit relatively small material costs, in terms of the quantities of carbon (C), nitrogen (N) or sulphur (S) atoms they contain. This 'elemental sparing' probably reflects selection to reduce the quantities of potentially growth-limiting elements in abundant proteins, but the evolutionary mechanisms for adaptive elemental sparing are still poorly understood. Here, we predict that the extent of 'elemental sparing' in highly expressed proteins will vary among organisms, according to the effectiveness of selection in determining the fate of mutations. We test this hypothesis in bacteria by asking whether 'elemental sparing' is correlated with codon usage bias. Bacteria exhibit extraordinary variation in their life histories and demography and consequently in the effectiveness of selection in determining whether preferred codons are used in highly expressed genes. We find that C sparing and S sparing, but not N sparing, are significantly correlated with adaptive codon usage bias among 148 genera of bacteria, suggesting that selection for elemental sparing and codon bias are promoted by similar bacterial traits. Our study helps identify principles that determine how nutrient scarcity can shape the elemental composition of proteins.


Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium.
Neovascularization induced by vascular endothelial growth factor (VEGF) represents an appealing approach for treating ischemic heart disease. However, VEGF therapy has been associated with transient therapeutic effects and potential risk for hemangioma growth. Adult mesenchymal stem cells (MSCs) derived from bone marrow are a promising source for tissue regeneration and repair. In order to achieve a safe and persistent angiogenic effect, we have explored the potential of autologous MSCs transplantation to enhance angiogenesis and cardiac function of ischemic hearts. One week after myocardial infarction induced by occlusion of left anterior descending artery, autologous MSCs expanded in vitro was administrated intramyocardially into the infarct area of the same donor rats. By 2 months, MSCs implantation significantly elevated VEGF expression levels, accompanied by increased vascular density and regional blood flow in the infarct zone. The neovascularization resulted in a decreased apoptosis of hypertrophied myocytes and markedly improved the left ventricular contractility (ejection fraction: 79.9+/-7.6% vs. 37.2+/-6.9% in control animals). Therefore, mechanisms underlying MSCs improvement of cardiac functions may involve neovascularization induced by differentiation of MSCs to endothelial cells and para-secretion of growth factors, in addition to the apoptosis reduction and previously reported cardiomyocytes regeneration. Two months after cell transplantation, there are significant improvement of left ventricular function. Hence, autologous MSCs transplantation may represent a promising therapeutic strategy free of ethical concerns and immune rejection, for neovascularization in ischemic heart diseases.


[Factors associated with influenza vaccination among elderly persons in Southeastern Brazil].
Even though influenza vaccination is free and widely available in Brazil since 1999, coverage is still inadequate in several of the country's municipalities. The aim of the present study was to estimate vaccine coverage and to identify factors related to vaccination against influenza in the elderly population. A household survey was carried out using a systematic random sample (N=365) of the urban population older than 60 years from the city of Botucatu, Southeastern Brazil. A logistic regression model using vaccination in 2002 as the dependent variable was used. The following covariables were tested: sex, age, socioeconomic variables (per capita income, number of persons per dormitory, schooling, marital status, occupation, time living in the city), history of morbidity and hospital admission, smoking, respiratory symptoms in last 15 days, and community activities (voluntary work, neighborhood and church activities). Vaccine coverage was 63.2% (95% CI: 58.3-68.2). We found a lower proportion of vaccination among the 60-64 years age group. Variables associated with vaccination in the final model were age (OR=1.09 per year; 95% CI: 1.06-1.13); arterial hypertension (OR=1.92; 95% CI: 1.18-3.13); and participation in community activities (OR=1.63; 95% CI: 1.01-2.65). With the exception of hypertension, vaccination among subjects with chronic diseases did not reach adequate levels, as expected for this high-risk group. Participation in social and community activities was associated with vaccination status. Socioeconomic conditions, habits, and age did not restrict access to vaccination campaigns. On the other hand, specific campaigns aimed at the 60-64 years age group may increase vaccination coverage.


Autoregulatory functioning of a Drosophila gene product that establish es and maintains the sexually determined state.
Sxl appears to head a regulatory gene hierarchy that controls Drosophila sexual dimorphism in response to the X chromosome/autosome balance. Only XXAA cells normally have Sxl(+) activity. It maintains both the female morphogenetic sequence and a level of X-linked dosage-compensated gene expression compatible with diplo-X cell survival. In the absence of this activity, male sexual development and dosage-compensated gene hyperactivation ensure. Loss-of-function Sxl mutations generally have female-specific lethal effects caused by upsets in dosage compensation. New female-viable Sxl mutant alleles and combinations which lack Sxl's female sex determination function, yet still provide sufficient dosage compensation function for diplo-X survival, are described here. Consequently, such mutants cause genotypic females to develop as phenotypic males. Some of these sex-transforming Sxl mutants do not require the maternally produced da(+) activity that is normally essential for the functioning of zygotic Sxl alleles. In this paper, products of these unusual alleles are shown to act in trans to induce the expression of zygotic Sxl(+) alleles that would otherwise be unable to function due to a lack of maternal da(+) activity. This result indicates a third function for Sxl(+) product: a positive autoregulatory role. Controls for the autoregulation experiments demonstrated the sex-trans-forming epigenetic effect of the da mutation for the first time in diploids. In these experiments the female-specific zygotic lethal effects that normally would have accompanied loss of maternal da(+) activity were suppressed by mutations known to block dosage-compensation gene hyperactivation-the autosomal, male-specific lethals. Three types of abnormal sexual phenotypes were produced in the experiments described here, each with important implications for the mechanism of sex determination: (1) a true intersex phenotype produced by one particular Sxl allele shows that Sxl(+) must be involved in the cellular response to the X/A balance rather than in its establishment; (2) a maternally induced, female-sterile phenotype indicates that either the process of autoregulation or the mutants used to demonstrate it are tissue specific and (3) a mosaic intersexual phenotype whose character implies that the Sxl(+ ) activity level is set early in development, both by the da( +)-mediated X/A balance signal and by autoregulation, and is maintained subsequently in a cell autonomous fashion, independent of the initiating X/A balance signal. Thus, this study supports the view that sex determination is truly determinative in the standard developmental sense, and that Sxl is the carrier of the sexually determined state.


Fibrinolysis use among patients requiring interhospital transfer for ST-segment elevation myocardial infarction care: a report from the US National Cardiovascular Data Registry.
Guidelines for patients with ST-segment elevation myocardial infarction (STEMI) recommend timely reperfusion with primary percutaneous coronary intervention (pPCI) or fibrinolysis. Among patients with STEMI who require interhospital transfer, it is unclear how reperfusion strategy selection and outcomes vary with interhospital drive times. To assess the association of estimated interhospital drive times with reperfusion strategy selection among transferred patients with STEMI in the United States. We identified 22,481 patients eligible for pPCI or fibrinolysis who were transferred from 1771 STEMI referring centers to 366 STEMI receiving centers in the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines database between July 1, 2008, and March 31, 2012. In-hospital mortality and major bleeding. The median estimated interhospital drive time was 57 minutes (interquartile range [IQR], 36-88 minutes). When the estimated drive time exceeded 30 minutes, only 42.6% of transfer patients treated with pPCI achieved the first door-to-balloon time within 120 minutes. Only 52.7% of eligible patients with a drive time exceeding 60 minutes received fibrinolysis. Among 15,437 patients with estimated drive times of 30 to 120 minutes who were eligible for fibrinolysis or pPCI, 5296 (34.3%) received pretransfer fibrinolysis, with a median door-to-needle time of 34 minutes (IQR, 23-53 minutes). After fibrinolysis, the median time to transfer to the STEMI receiving center was 49 minutes (IQR, 34-69 minutes), and 97.1% underwent follow-up angiography. Patients treated with fibrinolysis vs pPCI had no significant mortality difference (3.7% vs 3.9%; adjusted odds ratio, 1.13; 95% CI, 0.94-1.36) but had higher bleeding risk (10.7% vs 9.5%; adjusted odds ratio, 1.17; 95% CI, 1.02-1.33). In the United States, neither fibrinolysis nor pPCI is being optimally used to achieve guideline-recommended reperfusion targets. For patients who are unlikely to receive timely pPCI, pretransfer fibrinolysis, followed by early transfer for angiography, may be a reperfusion option when potential benefits of timely reperfusion outweigh bleeding risk.


Pharmacological aspects of Nerium indicum Mill: A comprehensive review.
Phytomedicine is the oldest medical practice known to man. Since the dawn of mankind, various plant resources are used to cure different diseases and also for a long and healthy life. The ancient knowledge of plant based medicine has transferred from generations to generations and accumulated as ethnopharmacological knowledge among different ethnic groups. India is the spanning bed of traditional phytomedicinal system where Ayurveda was born out of the knowledge of traditional medicine. In various other countries of South-Eastern Asia, South America, and in Arabian countries, still today, a great number of people rely primarily on phytomedicines to cure diseases. In the complementary and alternative medicinal systems, Nerium indicum is one such plant which is famed for its therapeutic efficiency in different diseases globally. In the present time, when the pharmaceutical companies are concentrating more toward the plant based traditional medicines to avoid the side-effects and resistance against synthetic drugs, N. indicum has proved its efficiency in different disease models. Therefore, this review comprehensively covers the medicinal and pharmacological activities of different parts of the plant N. indicum.


Quantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies.
Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.


RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia.
Despite vast improvements in our understanding of cancer genetics, a large percentage of cancer cases present without knowledge of the causative genetic events. Tyrosine kinases are frequently implicated in the pathogenesis of numerous types of cancer, but identification and validation of tyrosine kinase targets in cancer can be a time-consuming process. We report the establishment of an efficient, functional screening assay using RNAi technology to directly assess and compare the effect of individually targeting each member of the tyrosine kinase family. We demonstrate that siRNA screening can identify tyrosine kinase targets containing activating mutations in Janus kinase (JAK) 3 (A572V) in CMK cells and c-KIT (V560G) in HMC1.1 cells. In addition, this assay identifies targets that do not contain mutations, such as JAK1 and the focal adhesion kinases (FAK), that are crucial to the survival of the cancer cells. This technique, with additional development, might eventually offer the potential to match specific therapies with individual patients based on a functional assay.


Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features.
The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P < 0.001). Most NOTCH1-wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92-133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90-30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53-399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001-1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31-276.15; P = 0.031). TP53 disruptive mutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein.


Patterns of use and outcomes for radiation therapy in the Quality Initiative in Rectal Cancer (QIRC) trial.
The Quality Initiative in Rectal Cancer (QIRC) trial targeted surgeon intraoperative technique and not radiation therapy (RT) use. We performed a post hoc analysis of RT use among patients in the QIRC trial, not by arm of trial but rather for the entire group. We wished to identify associations between local recurrence risk and use of preoperative, postoperative or no RT. We compared demographic, tumour and process of care measures among patients receiving preoperative, postoperative or no RT. A multivariable Cox regression model assessed local recurrence risk. The QIRC trial enrolled 1015 patients at 16 hospitals between 2002 and 2004. Radiation therapy use did not differ between trial arms, and median follow-up was 3.6 years. For the preoperative, postoperative and no RT groups, respectively, the percentage of patients was 12.8%, 19.3% and 67.9%; the percentage of stage II/III tumours was 57.0%, 88.7% and 48.1%; and the local recurrence rate was 5.3%, 10.2% and 5.5% (p = 0.05). After controlling for patient and tumour characteristics, including tumour stage, the hazard ratio (HR) for local recurrence was increased in the postoperative RT versus the no RT group (HR 1.64, 95% confidence interval 1.04-2.58, p = 0.027). Use of preoperative RT was low; most patients with stage II/III disease did not receive RT and, as expected, the postoperative RT group had the highest risk of local recurrence. Our results suggest opportunities to improve rectal cancer RT use in Ontario.


A Network-Based Model of Oncogenic Collaboration for Prediction of Drug Sensitivity.
Tumorigenesis is a multi-step process, involving the acquisition of multiple oncogenic mutations that transform cells, resulting in systemic dysregulation that enables proliferation, invasion, and other cancer hallmarks. The goal of precision medicine is to identify therapeutically-actionable mutations from large-scale omic datasets. However, the multiplicity of oncogenes required for transformation, known as oncogenic collaboration, makes assigning effective treatments difficult. Motivated by this observation, we propose a new type of oncogenic collaboration where mutations in genes that interact with an oncogene may contribute to the oncogene's deleterious potential, a new genomic feature that we term "surrogate oncogenes." Surrogate oncogenes are representatives of these mutated subnetworks that interact with oncogenes. By mapping mutations to a protein-protein interaction network, we determine the significance of the observed distribution using permutation-based methods. For a panel of 38 breast cancer cell lines, we identified a significant number of surrogate oncogenes in known oncogenes such as BRCA1 and ESR1, lending credence to this approach. In addition, using Random Forest Classifiers, we show that these significant surrogate oncogenes predict drug sensitivity for 74 drugs in the breast cancer cell lines with a mean error rate of 30.9%. Additionally, we show that surrogate oncogenes are predictive of survival in patients. The surrogate oncogene framework incorporates unique or rare mutations from a single sample, and therefore has the potential to integrate patient-unique mutations into drug sensitivity predictions, suggesting a new direction in precision medicine and drug development. Additionally, we show the prevalence of significant surrogate oncogenes in multiple cancers from The Cancer Genome Atlas, suggesting that surrogate oncogenes may be a useful genomic feature for guiding pancancer analyses and assigning therapies across many tissue types.


Postoperative complications in head and neck cancer.
Head and neck cancer (HNC) encompasses several malignancies arising from different structures in the head and neck. The management of HNC is complex and requires multidisciplinary involvement with a range of treatment options that may lead to complications that have negative effects on patient outcomes. This article presents the role of surgery as primary treatment for HNC and describes postoperative complications, factors related to the development of complications, their clinical implications, and management. Comprehensive pre- and postoperative care is crucial in decreasing the incidence of complications and their impact on patient outcomes. Nurse need to be vigilant to prevent, monitor, and care for patients at risk for postoperative complications to decrease their morbidity, enhance their quality of life, and extend survival.


The legacy of a community mobilisation project to reduce alcohol related harm.
The Community Mobilisation for the Prevention of Alcohol Related Injury (COMPARI) project was established to investigate how alcohol related harm could be reduced within the Geraldton community through community action. Twenty-two major component activities were carried out over three years. On completion of the demonstration phase the project was taken over by the community and evolved into the region's main alcohol and drug service provider. This research seeks to identify the legacy of COMPARI from interviews with 23 key informants and from serial measures of alcohol consumption and harm. Key informants indicated that the original community prevention focus of the project has been diluted and there is more emphasis on individual prevention through education and training. A culture of intersectoral collaboration on alcohol issues has endured and this contributes to better use of resources and higher levels of treatment referral. There was also strong acknowledgement that the local committee was crucial in sustaining the project. Since the inception of COMPARI, local alcohol consumption has decreased and a proxy measure of alcohol harm, weekend, night, hospital accident and emergency occasions of service, also indicates better outcomes in Geraldton. The original project initiated cultural and structural change in the way alcohol problems are dealt with in Geraldton and this has produced on-going benefit for the community.


Copper pollution exacerbates the effects of ocean acidification and warming on kelp microscopic early life stages.
Ocean warming (OW), ocean acidification (OA) and their interaction with local drivers, e.g., copper pollution, may negatively affect macroalgae and their microscopic life stages. We evaluated meiospore development of the kelps Macrocystis pyrifera and Undaria pinnatifida exposed to a factorial combination of current and 2100-predicted temperature (12 and 16 °C, respectively), pH (8.16 and 7.65, respectively), and two copper levels (no-added-copper and species-specific germination Cu-EC50). Meiospore germination for both species declined by 5-18% under OA and ambient temperature/OA conditions, irrespective of copper exposure. Germling growth rate declined by >40%·day-1, and gametophyte development was inhibited under Cu-EC50 exposure, compared to the no-added-copper treatment, irrespective of pH and temperature. Following the removal of copper and 9-day recovery under respective pH and temperature treatments, germling growth rates increased by 8-18%·day-1. The exception was U. pinnatifida under OW/OA, where growth rate remained at 10%·day-1 before and after copper exposure. Copper-binding ligand concentrations were higher in copper-exposed cultures of both species, suggesting that ligands may act as a defence mechanism of kelp early life stages against copper toxicity. Our study demonstrated that copper pollution is more important than global climate drivers in controlling meiospore development in kelps as it disrupts the completion of their life cycle.


Bimolecular electron transfers that follow a Sandros-Boltzmann dependence on free energy.
Rate constants (k) for exergonic and endergonic electron-transfer reactions of equilibrating radical cations (A(•+) + B ⇌ A + B(•+)) in acetonitrile could be fit well by a simple Sandros-Boltzmann (SB) function of the reaction free energy (ΔG) having a plateau with a limiting rate constant k(lim) in the exergonic region, followed, near the thermoneutral point, by a steep drop in log k vs ΔG with a slope of 1/RT. Similar behavior was observed for another charge shift reaction, the electron-transfer quenching of excited pyrylium cations (P(+)*) by neutral donors (P(+)* + D → P(•) + D(•+)). In this case, SB dependence was observed when the logarithm of the quenching constant (log k(q)) was plotted vs ΔG + s, where the shift term, s, equals +0.08 eV and ΔG is the free energy change for the net reaction (E(redox) - E(excit)). The shift term is attributed to partial desolvation of the radical cation in the product encounter pair (P(•)/D(•+)), which raises its free energy relative to the free species. Remarkably, electron-transfer quenching of neutral reactants (A* + D → A(•-) + D(•+)) using excited cyanoaromatic acceptors and aromatic hydrocarbon donors was also found to follow an SB dependence of log k(q) on ΔG, with a positive s, +0.06 eV. This positive shift contrasts with the long-accepted prediction of a negative value, -0.06 eV, for the free energy of an A(•-)/D(•+) encounter pair relative to the free radical ions. That prediction incorporated only a Coulombic stabilization of the A(•-)/D(•+) encounter pair relative to the free radical ions. In contrast, the results presented here show that the positive value of s indicates a decrease in solvent stabilization of the A(•-)/D(•+) encounter pair, which outweighs Coulombic stabilization in acetonitrile. These quenching reactions are proposed to proceed via rapidly interconverting encounter pairs with an exciplex as intermediate, A*/D ⇌ exciplex ⇌ A(•-)/D(•+). Weak exciplex fluorescence was observed in each case. For several reactions in the endergonic region, rate constants for the reversible formation and decay of the exciplexes were determined using time-correlated single-photon counting. The quenching constants derived from the transient kinetics agreed well with those from the conventional Stern-Volmer plots. For excited-state electron-transfer processes, caution is required in correlating quenching constants vs reaction free energies when ΔG exceeds ∼+0.1 eV. Beyond this point, additional exciplex deactivation pathways-fluorescence, intersystem crossing, and nonradiative decay-are likely to dominate, resulting in a change in mechanism.


Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months.
Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, β-galactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems. If left without treatment, Krabbe disease results in progressive neurodegeneration with reduced quality of life and early death. The purpose of this prospective study was to describe the natural progression of early onset Krabbe disease in a large cohort of patients. Patients with early onset Krabbe disease were prospectively evaluated between 1999 and 2018. Data sources included diagnostic testing, parent questionnaires, standardized multidisciplinary neurodevelopmental assessments, and neuroradiological and neurophysiological tests. We evaluated 88 children with onset between 0 and 5 months. Median age of symptom onset was 4 months; median time to diagnosis after onset was 3 months. The most common initial symptoms were irritability, feeding difficulties, appendicular spasticity, and developmental delay. Other prevalent symptoms included axial hypotonia, abnormal deep tendon reflexes, constipation, abnormal pupillary response, scoliosis, loss of head control, and dysautonomia. Results of nerve conduction studies showed that 100% of patients developed peripheral neuropathy by 6 months of age. Median galactocerebrosidase enzyme activity was 0.05 nmol/h/mg protein. The median survival was 2 years. This is the largest prospective natural history study of Krabbe disease. It provides a comprehensive description of the disease during the first 2 years of life. With recent inclusion of state mandated newborn screening programs and promising therapeutic interventions, enhancing our understanding of disease progression in early onset Krabbe disease will be critical for developing treatments, designing clinical trials, and evaluating outcomes.


Investigation of Racial Disparities in Early Supportive Medication Use and End-of-Life Care Among Medicare Beneficiaries With Stage IV Breast Cancer.
Early supportive care may improve quality of life and end-of-life care among patients with cancer. We assessed racial disparities in early use of medications for common cancer symptoms (depression, anxiety, insomnia) and whether these potential disparities modify end-of-life care. We used 2007 to 2012 SEER-Medicare data to evaluate use of supportive medications (opioid pain medications and nonopioid psychotropics, including antidepressants/anxiolytics and sleep aids) in the 90 days postdiagnosis among black and white women with stage IV breast cancer who died between 2007 and 2012. We used modified Poisson regression to assess the relationship between race and supportive treatment use and end-of-life care (hospice, intensive care unit, more than one emergency department visit or hospitalization 30 days before death, in-hospital death). The study included 752 white and 131 black women. We observed disparities in nonopioid psychotropic use between black and white women (adjusted risk ratio [aRR], 0.51; 95% CI, 0.35 to 0.74) but not in opioid pain medication use. There were also disparities in hospice use (aRR, 0.86; 95% CI, 0.74 to 0.99), intensive care unit admission or more than one emergency department visit or hospitalization 30 days before death (aRR, 1.28; 95% CI, 1.01 to 1.63), and risk of dying in the hospital (aRR, 1.59; 95% CI, 1.22 to 2.09). Supportive medication use did not attenuate end-of-life care disparities. We observed racial disparities in early supportive medication use among patients with stage IV breast cancer. Although they did not clearly attenuate end-of-life care disparities, medication use disparities may be of concern if they point to disparities in adequacy of symptom management given the potential implications for quality of life.


Cardiac output determination by use of lithium dilution during exercise in horses.
To compare cardiac output (CO) obtained by the lithium dilution method (LiDCO) with CO calculated from the Fick principle (FickCO), in horses maximally exercising on a high-speed treadmill. 13 Thoroughbreds. In part 1 of the study, 5 horses performed a warm-up (walk, trot, and canter) and exercise test (walk, trot, canter, and gallop [90% to 100% maximum oxygen consumption [{VO(2)max}]) with measurements of LiDCO and FickCO obtained simultaneously after 60 seconds at each exercise level, for a total of 7 measurements. In part 2 of the study, 8 horses performed a warm-up (walk, trot, and canter) followed by an exercise test (walk and gallop [90% to 100% [VO(2)max], repeated twice). Measurements of LiDCO and FickCO were obtained 60 seconds into the first walk and each gallop of the exercise tests, for a total of 3 measurements. Cardiac output increased significantly with increasing speeds by use of both methods. In part 1, lithium dilution significantly overestimated CO, compared with the Fick principle, during the exercise test (as both injection number and exercise intensity increased). Mean +/- SD bias was 246 +/- 264 mL of blood/min/kg in part 1 and 67 +/- 100mL of blood/kg/min in part 2. Three injections of lithium (part 2) did not result in the same degree of overestimation of LiDCO that was observed with 7 injections (part 1). Lithium dilution may be an acceptable substitute for the Fick principle as a means to measure CO in maximally exercising client-owned horses.


Malignant Mesothelioma Diagnosis.
Malignant mesothelioma is a relatively rare pleural tumor that may mimic benign mesothelial lesions and various other tumors including carcinomas and sarcomas. This makes the diagnosis challenging for the pathologist. To provide a brief but useful update on the immunohistochemical, cytogenetic, and molecular markers that are currently available for the diagnosis of malignant mesothelioma. Reference materials including peer-reviewed publications, text books, and consensus opinion reports among pathologists. It is important to correlate histologic findings on adequate biopsy samples with clinical and radiologic features. Useful diagnostic mesothelial markers include calretinin, WT-1, cytokeratin 5/6, and D2-40 (podoplanin). It is recommended that at least 2 mesothelial and 2 carcinoma markers with greater than 80% sensitivity and specificity be used for the diagnosis of mesothelioma when all clinical, radiologic, and histologic features are concordant. p16 deletion is reported in up to 70% of primary epithelioid and 90% to 100% of sarcomatoid pleural mesotheliomas. Presence of this homozygous gene deletion is so far the best indicator of mesothelioma. To date, this deletion has not been reported in any benign mesothelial lesion. The impact of various histologic patterns on the clinical and prognostic aspects of mesothelioma is addressed. The pleomorphic pattern, when present in more than 10% of tumor, translates into a highly aggressive behavior and is associated with poor survival. Recent studies have shown that the high-grade subgroup of deciduoid mesothelioma with pleomorphic histologic pattern also has a more aggressive clinical course. Nuclear grade (combination of nuclear atypia and mitotic count) may also prove to be an independent prognostic factor.


GeoSentinel: the global emerging infections sentinel network of the International Society of Travel Medicine.
GeoSentinel is a network of 22 member travel/tropical medicine clinics (14 in the United States and 8 in other countries) initiated in 1995 by the International Society of Travel Medicine (ISTM). GeoSentinel is based on the concept that these clinics are ideally situated to effectively detect geographic and temporal trends in morbidity among travelers. The core surveillance tool is a single-page faxable form submitted to a central data site for each post-travel patient, including immigrants, refugees, and foreign visitors. Diagnoses are entered either as specific etiologies or as syndromes and are then linked to geographic locations, reference dates, and clinical presentations. In addition, electronic communication with the larger body of worldwide ISTM member clinics is periodically done to obtain broader data collection in response to specific inquiries. The scope of GeoSentinel has broadened from the initial vision of a provider-based sentinel network tracking emerging infections at their point of entry into developed countries. Its present goals are (1) to monitor global trends in disease occurrence among travelers; (2) to ascertain risk factors and morbidity in groups of travelers categorized by travel purpose and type of traveler; (3) to respond to urgent public health queries; (4) to develop educational priorities for travelers' health; and (5) to effect a rapid response by electronically disseminating alerts to surveillance sites, to all ISTM members in 55 countries, and to public health authorities. In addition, a major byproduct of the network, and now one of its strongest assets, has been the growth of partnerships between ISTM, Centers for Disease Control and Prevention and health-care providers around the world, as well as other medical societies, government, and private organizations. The demographic data, travel patterns, and clinical presentations for the first 2813 patient records analyzed from the GeoSentinel sites are summarized in this paper.


Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors.
Cholecystokinin (CCK)-A and CCK-B/gastrin receptors were evaluated with in vitro receptor autoradiography in 406 human tumors of various origins using a sulfated 125I-labeled CCK decapeptide analogue 125I-(D-Tyr-Gly, Nle28,3l)-CCK 26-33 and 125I-labeled Leu15-gastrin as radioligands. CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%). They were found occasionally in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas. They were either not expressed or rarely expressed in colorectal cancers, differentiated thyroid cancers, non-small cell lung cancers, meningiomas, neuroblastomas, schwannomas, glioblastomas, lymphomas, renal cell cancers, prostate carcinomas, and the remaining neuroendocrine tumors (i.e., pituitary adenomas, pheochromocytomas, paragangliomas, and parathyroid adenomas). CCK-A receptors were expressed rarely in tumors except in gastroenteropancreatic tumors (38%), meningiomas (30%), and some neuroblastomas (19%). The identified CCK-A and CCK-B receptors were specific and of high affinity in the subnanomolar range. The rank order of potency of various CCK analogues was: sulfated CCK-8 = L-364,718 >> nonsulfated CCK-8 = L-365,260 > or = gastrin for CCK-A receptors and sulfated CCK-8 > gastrin = nonsulfated CCK-8 > L-365,260 > L-364,718 for CCK-B receptors. CCK-B receptors could also be selectively and specifically labeled with a newly designed nonsulfated 125I-(D-Tyr-Gly, Nle28,31)-CCK 26-33. Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors. Gastrin and CCK mRNAs were lacking in medullary thyroid cancers. Thus, these results may have pathogenic, diagnostic, differential diagnostic, and therapeutic implications.


A population-based study of fish allergy in the Philippines, Singapore and Thailand.
Fish allergy is the third most common food allergy after milk and egg in parts of Europe, but there is little data about prevalence in South East Asia where it is an important part of regular diets. We aimed to obtain an estimate of the population prevalence of fish allergy among older children in the Philippines, Singapore and Thailand. The population prevalence of fish allergy in 14- to 16-year-old children in the 3 countries was evaluated using a structured written questionnaire which was distributed to students of randomly selected secondary schools. An extended questionnaire to determine convincing fish allergy on the basis of typical clinical manifestations within 2 h of ingestion was administered to those with positive responses. From a cohort of 25,842 students, responses were 81.1% in the Philippines (n = 11,434), 67.9% in Singapore (n = 6,498) and 80.2% (n = 2,034) in Thailand. Using criteria for convincing food allergy, fish allergy was much higher in the Philippines [2.29%, 95% confidence interval (CI) 2.02-2.56] than in Singapore (0.26%, 95% CI 0.14-0.79) and Thailand (0.29%, 95% CI 0.06-0.52). Weighted multiple logistic regression analyses showed that compared to the Philippines, prevalence rates were lower in Singapore [odds ratio (OR) 0.40, 95% CI 0.27-0.60, p < 0.0001] and Thailand (OR 0.13, 95% CI 0.05-0.33, p < 0.0001). Females were more likely to have fish allergy compared to males for all children combined (OR 1.32, 95% CI 1.11-1.58, p = 0.002). Most allergies appeared mild, as only 28% of cases sought medical consultation at the time of the reaction and 31.2% of cases reported continued exposure despite allergic symptoms. Fish allergy in late childhood is more common in the Philippines compared to Singapore and Thailand. Differences in food processing, dietary habits and other cultural practices might be important risk factors for the development of fish allergy in these populations.


Roles of adsorption sites in electron transfer from CdS quantum dots to molecular catalyst cobaloxime studied by time-resolved spectroscopy.
Electron transfer from CdS quantum dots (QDs) to cobaloxime (Co(dmgH)2pyCl) is demonstrated by transient absorption spectroscopy (TAS), and further confirmed using photoluminescence (PL) techniques. The analysis of the PL quenching results offers a novel way to understand the roles of the surface adsorption sites of CdS QDs in the performance of charge transfer in the CdS QDs-cobaloxime hybrid system. Two types of quenching dynamics reveal that there are two different adsorption modes of cobaloxime on the CdS QD surface. When cobaloxime substitutes the surface capping ligands of CdS QDs under low cobaloxime concentrations, the transfer is nearly unfavorable for both the free and trapped electrons. When cobaloxime occupies the surface defect sites of the CdS QDs under high cobaloxime concentrations, the transfer of both the free and trapped electrons is very effective, with an extremely high quenching rate constant of ∼10(12) M(-1) s(-1). Therefore, controlling the molecular adsorption sites and adjusting the surface defect properties of semiconductor QDs provide a strategy to improve the electron transfer efficiency of the QDs-cobaloxime photocatalytic system.


Genes involved in the synthesis of the exopolysaccharide methanolan by the obligate methylotroph Methylobacillus sp strain 12S.
Methylobacillus sp. strain 12S produces an exopolysaccharide (EPS), methanolan, composed of glucose, mannose and galactose. Twenty-four ORFs flanking a Tn5 insertion site in an EPS-deficient mutant were identified, and 21 genes (epsCBAKLDEFGHIJMNOPQRSTU) were predicted to participate in methanolan synthesis on the basis of the features of the primary sequence. Gene disruption analyses revealed that epsABCEFGIJNOP and epsR are required for methanolan synthesis, whereas epsKD and epsH are not essential. EpsFG and EpsE showed homology with Wzc (chain length regulator) and Wza (export protein) of group 1 capsule-producing Escherichia coli, suggesting that methanolan was synthesized via a Wzy-like biosynthesis system. This possibility was supported by the fact that the putative hydropathy profiles of EpsH and EpsM were similar to those of Wzx and Wzy, which are also involved in the flipping of the repeating unit in the cytoplasmic membrane and the polymerization of the capsule in the Wzy-dependent system. EpsBJNOP and EpsR are probably glycosyltransferases involved in the synthesis of the repeating unit onto the lipid carrier. In particular, EpsB appeared to catalyse the initial transfer of the glucose moiety. On the basis of their predicted location in the cells, it is proposed that EpsI and EpsL are involved in methanolan export to the cell surface. E. coli strains expressing EpsQ, EpsS and EpsT showed enhanced activities of GDP-mannose pyrophosphorylase, UDP-galactose 4-epimerase and UDP-glucose pyrophosphorylase, respectively, revealing that they were responsible for the production of the activated compositional sugars of methanolan. EpsU contains a conserved a lytic transglycosylase motif, indicating that it could participate in the degradation of polysaccharides. EpsA and EpsK, which have conserved DNA-binding and cAMP-binding motifs, respectively, were deduced to be transcriptional regulators. In particular, EpsA seems to positively regulate the transcription of methanolan synthesis genes, since the constitutive expression of epsA in strain 12S increased the EPS production. Interestingly, EpsD showed homology with peptidyl prolyl cis-trans isomerases that catalyse the folding of proteins following translocation across the cytoplasmic membrane.


Both the "What" and "Why" of Youth Sports Participation Matter; a Conditional Process Analysis.
This study builds on previous research combining achievement goal orientation from Achievement Goal Theory and motivational regulation from Self-Determination Theory. The aim was to assess the combination of the "what" and "why" of youth sport activity, and how it relates to the need for competence and self-esteem. Achievement goal orientation, specifically task and ego, was employed to represent the "what", whilst intrinsic and external regulation reflected the "why". Based on a sample of 496 youth sports participants, structural equation modeling with a bootstrapping procedure was used to examine whether the indirect relationship between achievement goal orientation and self-esteem was conditional to motivational regulation. The results show partial support for the conditional process models. Specifically, task orientation was indirectly linked with self-esteem through competence need, and the relationship was stronger with higher levels of intrinsic regulation for sport. Furthermore, ego orientation was negatively associated with self-esteem through a positive relationship with competence frustration. However, this relationship emerged only for those higher in intrinsic regulation. External regulation did not emerge as a moderator, but presented a positive relationship with competence frustration. Findings are discussed in light of both Achievement Goal Theory and Self-Determination Theory, and underline the importance of considering both the "what" and "why" when attempting to understand motivation in youth sport.


Fluorogenic polydiacetylene supramolecules: immobilization, micropatterning, and application to label-free chemosensors.
This Account describes a new strategy for the preparation of label-free sensor systems based on the fluorogenic properties of the conjugated polymer, polydiacetylene (PDA). PDA has been extensively investigated as a sensor matrix, owing to a brilliant blue-to-red color transition that takes place in response to environmental perturbations. It has been known for some time that "blue-phase" PDAs are nonfluorescent while their "red-phase" counterparts fluoresce. For the most part, however, the significance of the different fluorogenic properties of PDAs has been ignored in the context of sensor applications. In the course of developing PDA-based sensors, we discovered that PDA vesicles can be readily immobilized on solid substrates. This is an attractive property of PDAs since it leads to the combined advantages of the vesicle sensors (which have three-dimensional interactions between sensor and target molecules) and film sensors (which are applicable to a two-dimensional array or chip format). Stable blue-phase immobilized PDAs can be prepared by employing one of three strategies involving the formation of covalent adducts, biotin-avidin complexes, or complexes formed through nonspecific physical adsorption. A procedure for generating well-patterned fluorescence images is necessary for the immobilized PDAs to function in chip-based sensor systems. Patterned fluorescence images are readily constructed by employing (1) the photolithographic technique, (2) the micromolding in capillaries (MIMIC) method, or (3) an array spotting system. Heat treatment of the patterned "blue-phase" PDA vesicles transforms the nonfluorescent images into their fluorescent red forms. The observation that finely resolved fluorescence patterns can be generated by heat treatment of microarrayed PDAs is highly significant in that it indicates that fluorescence signals might be produced by specific molecular recognition events. Indeed, red fluorescence emission is observed when immobilized PDAs are subjected to specific molecular recognition events, such as ligand--cyclodextrin or protein-protein interactions. The facile immobilization of PDA vesicles on solid substrates and the affinity-induced fluorescence emission combine to make this system applicable to the fabrication of label-free PDA sensors. Since in theory any molecular recognition event that promotes the blue-to-red color transition of PDAs should result in the generation of fluorescence, it should be possible to reformat a variety of previously described colorimetric PDA sensors into fluorescence-based sensor systems. The fluorescence properties of PDAs, when combined with modern methods for the fabrication of microarrays, should stimulate the development of a number of new label-free chemosensor systems.


Antinuclear antibodies and HLA class II alleles in Jamaican patients with systemic lupus erythematosus.
The relationship between human leukocyte antigens class II (HLA) and antinuclear antibodies was investigated in Jamaican patients with Systemic Lupus Erythematosus (SLE). Samples of blood of 82 patients with SLE and 75 healthy controls were tested for antinuclear antibodies using the fluorescent antinuclear antibody (FANA) test, counterimmunoelectrophoresis (CIEP) and the Crithidia luciliae immunofluorescence test (CL-IFT). A DNA-based HLA typing method was used to determine the frequencies of alleles of HLA-DRB1, DRB3, DRB4 and DRB5 in patients and healthy controls. The FANA test was positive in all of the sera from patients with SLE. Anti-dsDNA antibodies were present in 49% (40/82), anti-Sm/RNP 44% (36/82) and anti-Ro/La 43% (35/82) of the sera from SLE patients. The frequency of HLA-DR4 was significantly lower in SLE patients than in healthy controls (2/82, 2% vs 15/75, 20%; RR = 0.12; p = 0.0004; CP = 0.005) but no other HLA-DRB1 SLE associations were found. A positive HLA-DR3 anti-Ro/La antibody association was found in the patients with SLE (9/21, 43% vs 5/55, 9%; odds ratio (OR) = 7.5; CP = 0.01). In contrast, possession of HLA-DR6 was negatively associated with the absence of anti-dsDNA antibodies (9/32, 28% vs 27/44, 61%; OR = 0.2; CP = 0.05). The HLA-DR6 allele is associated with the absence of antinuclear antibodies and HLA-DR3 with the presence of anti-Ro/La antibodies in Jamaican patients with SLE. However, these results and those of previous studies of Jamaican patients suggest that the HLA-DR3 association with the development of SLE reported in other populations might in fact reflect the association of HLA-DR3 with anti-Ro/La antibodies. Further investigations are needed to determine whether HLA-DRB antinuclear antibody associations define clinical subsets of SLE in Jamaican patients.


Gender differences in modifiable risk factors for hip fracture: 10-year follow-up of a prospective study of 0.5 million Chinese adults.
Little is known about the incidence rates and importance of major modifiable risk factors for hip and major osteoporotic fractures in low- and middle-income countries. We estimated the age- and sex-specific incidence of hip, major osteoporotic, and any fractures and their associated risk factors in Chinese adults. This was a prospective study of 512,715 adults, aged 30-79 years, recruited from 10 diverse areas in China from 2004 to 2008 and followed up for 10 years. Age- and sex-specific incidence rates were estimated, and Cox regression was used to yield adjusted hazard ratios (HRs) and population attributable fractions for risk factors. The incidence rates of hip fracture in Chinese adults were 5.1 (95% confidence interval [CI] 5.0-5.3) per 10,000 person-years; they were higher in women than in men and increased by two- to threefold per 10-year older age. Among men, five risk factors for hip fracture, including low education (HR = 1.23; 95% CI 1.04-1.45), regular smoker (1.22, 1.03-1.45), lower weight (1.59, 1.34-1.88), alcohol drinker (1.18, 1.02-1.36), and prior fracture (1.62, 1.33-1.98), accounted for 44.3% of hip fractures. Among women, lower weight (1.30, 1.15-1.46), low physical activity (1.22, 1.10-1.35), diabetes (1.62, 1.41-1.86), prior fracture (1.54, 1.33-1.77), and self-rated poor health (1.29, 1.13-1.47) accounted for 24.9% of hip fractures. Associations of risk factors with major osteoporotic or any fractures were weaker than those with hip fractures. The age- and sex-specific incidence rates of hip fracture in Chinese adults were comparable with those in Western populations. Five potentially modifiable factors accounted for half of the hip fractures in men and one quarter in women.


Combinatorial, site-specific requirement for heterochromatic silencing factors in the elimination of nucleosome-free regions.
High-resolution nucleosome occupancy maps of heterochromatic regions of wild-type and silencing-defective mutants of the fission yeast Schizosaccharomyces pombe revealed that heterochromatin induces the elimination of nucleosome-free regions (NFRs). NFRs associated with transcription initiation sites as well as those not associated with promoters are affected. We dissected the roles of the histone H3K9 methyltransferase Clr4 and the HP1 proteins Swi6 and Chp2, as well as the two catalytic activities of the SHREC histone deacetylase (HDAC)/ATPase effector complex. Strikingly, different DNA sites have distinct combinatorial requirements for these factors: Five classes of NFRs were identified that are eliminated by silencing factors through a mechanistic hierarchy governed by Clr4. The SHREC HDAC activity plays a major role in the elimination of class I-IV NFRs by antagonizing the action of RSC, a remodeling complex implicated in NFR formation. We propose that heterochromatin formation involves the deployment in several sequence-specific mechanisms to eliminate gaps between nucleosomes, thereby blocking access to the DNA.


Prolonged dark adaptation changes connexin expression in the mouse retina.
In the retina, ambient light levels influence the cell coupling provided by gap junction (GJ) channels, to compensate the visual function for various lighting conditions. However, the effects of ambient light levels on expression of connexins (Cx), the proteins that form the GJ channels, are poorly understood. In the present study, we first determined whether gene expression of specific Cx (Cx26, Cx31.1, Cx36, Cx37, Cx40, Cx43, Cx45, Cx50, and Cx57) was affected by prolonged dark adaptation. Cx mRNA relative levels were determined in mouse retinas dark adapted for 3 hr, 1 day, and 7 days by using quantitative real-time PCR. Transcript levels of some Cx were repressed after 3 hr (Cx57), 1 day (Cx45), or 7 days (Cx36 and Cx43) of dark adaptation; others were increased after 1 day (Cx50) or 7 days (Cx31.1 and Cx37); and two of them (Cx26 and Cx40) were not significantly altered. The second aim was to determine whether prolonged dark adaptation affects protein expression of two important Cx in retina: neuronal Cx36 and glial Cx43. We were able to demonstrate that important changes in protein distribution and expression also took place in retina during long-term dark adaptation. Given their localization, the specific alterations in Cx expression may reflect their distinct response to ambient light levels.


Laryngotracheal separation procedure for elderly patients.
A procedure for laryngotracheal separation was performed on 5 elderly patients in poor general condition to prevent habitual aspiration pneumonia. Intractable aspiration was relieved in all the patients with no major postoperative complications. In this intervention, a modification of the procedure previously reported, the anterior part of the tracheal and cricoid cartilage was removed, and the subglottic mucosa was sutured to fashion a blind pouch. This procedure could be adjusted even in cases of severe laryngoptosis or after high tracheostomy. Laryngotracheal separation is likely to be useful as a simple and safe procedure even for older patients. If this comes to be, it will serve as a valuable intervention in today's aging society.


Cost-effectiveness of gemcitabine versus PEGylated liposomal doxorubicin for recurrent or progressive ovarian cancer: comparing chemotherapy with nanotherapy.
This article examines the cost-effectiveness of chemotherapy (gemcitabine) versus nanotherapy (PEGylated liposomal doxorubicin) in the treatment of ovarian cancer. Significant differences in costs were mainly due to the initial drug costs, which were €1285.28 in favor of chemotherapy. These costs were more than offset by hospitalization costs, which were €2670.21 in favor of the nanotherapy. The cost per quality-adjusted life week (QALW) for the nanotherapy was estimated to be €220.92/QALW for the base case and ranged from €170-318/QALW based on model assumptions. The clinical benefit associated with nanotherapy was achieved, yielding not only positive cost-effectiveness results, but also, surprisingly, financial savings. Although more studies are necessary, this first comprehensive analysis supports the further use of nanotherapy for ovarian cancer.


Vesicular erythema migrans: an atypical and easily misdiagnosed form of Lyme disease.
Erythema migrans is the initial sign in the majority of patients infected with Borrelia, the genus of spirochetes that causes Lyme disease. Early identification and treatment decrease the risk of progression to later stages of disease. Although a "bull's eye" appearance owing to lesional clearing is considered classic for erythema migrans, this feature is surprisingly often lacking among patients in the United States. Furthermore, cutaneous Lyme disease can exhibit a wide range of morphologic variability in a minority of patients. Herein, we describe the case of a patient with Lyme disease in which the presence of atypical vesicular features, in conjunction with the initial absence of clearing, resulted in multiple misdiagnoses and delayed treatment. We also review the literature on the epidemiology and management of erythema migrans for cases in which the diagnosis may pose a challenge.


Changes in cellular signaling proteins in extracts from A549, H460, and U2OS cells treated with cisplatin or docetaxel.
Cell extracts from A549, H460, and U2OS human cancer cell lines treated with cisplatin and docetaxel were analyzed by mass spectrometry (MS) proteomic analysis. The extracts were enriched for cellular signaling proteins using a mix of three different immobilized kinase inhibitors (Purvalanol B, Bisindolylmaleimide X, and (R)-3-(4-((1-Phenylethyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzoic acid (SB6-060-05)) on sepharose bead columns. Raw data is deposited in the PRIDE database [1], project number PXD005286. Data presented () shows changes relative to untreated control for each biological replicate for the three cell lines.


Child height and intergenerational transmission of health: Evidence from ethnic Indians in England.
A large literature documents a widespread prevalence of small stature among Indian children as well as adults. We show that a height gap relative to a richer population such as whites in England also exists, although substantially reduced, among adult immigrants of Indian ethnicity in England. This is despite positive height selection into migration, demonstrated by ethnic Indian adults in England being on average 6-7cm taller than in India. However, the difference between natives and ethnic Indians in England disappears among their younger sons and daughters, although it re-appears among adolescents. We estimate that, conditional on age, gender and parental height, ethnic Indian children of age 2-4 in England are 6-8% taller than in India. Such degree of catch up in one generation is remarkable, also because in England children of ethnic Indians have much smaller birthweight than whites, by about 0.4kg on average.


CO variability and its association with household cooking fuels consumption over the Indo-Gangetic Plains.
This study examines the spatio-temporal trends obtained from decade long (Jan 2003-Dec 2014) satellite observational data of Atmospheric Infrared Sounder (AIRS) and Measurements of Pollution in the Troposphere (MOPITT) on carbon monoxide (CO) concentration over the Indo-Gangetic Plains (IGP) region. The time sequence plots of columnar CO levels over the western, central and eastern IGP regions reveal marked seasonal behaviour, with lowest CO levels occurring during the monsoon months and the highest CO levels occurring during the pre-monsoon period. A negative correlation between CO levels and rainfall is observed. CO vertical profiles show relatively high values in the upper troposphere at ∼200 hPa level during the monsoon months, thus suggesting the role of convective transport and advection in addition to washout behind the decreased CO levels during this period. MOPITT and AIRS observations show a decreasing trend of 9.6 × 1015 and 1.5 × 1016 molecules cm-2 yr-1, respectively, in columnar CO levels over the IGP region. The results show the existence of a spatial gradient in CO from the eastern (higher levels) to western IGP region (lower levels). Data from the Census of India on the number of households using various cooking fuels in the IGP region shows the prevalence of biomass-fuel (i.e. firewood, crop residue, cowdung etc.) use over the eastern and central IGP regions and that of liquefied petroleum gas over the western IGP region. CO emission estimates from cooking activity over the three IGP regions are found to be in the order east > central > west, which support the existence of the spatial gradient in CO from eastern to the western IGP region. Our results support the intervention of present Indian government on limiting the use of biomass-fuels in domestic cooking to achieve the benefits in terms of the better air quality, household health and regional/global climate change mitigation.


Optically compensated polarization reciprocity in interferometric fiber-optic gyroscopes.
Polarization reciprocity is studied both theoretically and experimentally in an optically compensated configuration of interferometric fiber optic gyroscope (IFOG). In conventional IFOGs based on the minimal scheme, the output port of the coil coupler cannot be used mainly because of its polarization nonreciprocity (PN), and thus it is usually called the "nonreciprocal port". We show that the PN errors at the nonreciprocal port are effectively eliminated by optical compensation. With this unique property, the optically compensated IFOG can possess two low-PN ports for rotation sensing at the same time. From another perspective, one port IFOGs are possible to be constructed with less structural complexity.


Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids.
The mammalian liver possesses a remarkable regenerative ability. Two modes of damage response have been described: (1) The "oval cell" response emanates from the biliary tree when all hepatocytes are affected by chronic liver disease. (2) A massive, proliferative response of mature hepatocytes occurs upon acute liver damage such as partial hepatectomy (PHx). While the oval cell response has been captured in vitro by growing organoids from cholangiocytes, the hepatocyte proliferative response has not been recapitulated in culture. Here, we describe the establishment of a long-term 3D organoid culture system for mouse and human primary hepatocytes. Organoids can be established from single hepatocytes and grown for multiple months, while retaining key morphological, functional and gene expression features. Transcriptional profiles of the organoids resemble those of proliferating hepatocytes after PHx. Human hepatocyte organoids proliferate extensively after engraftment into mice and thus recapitulate the proliferative damage-response of hepatocytes.


Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders.
DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.


Effects of active video games on body composition: a randomized controlled trial.
Sedentary activities such as video gaming are independently associated with obesity. Active video games, in which players physically interact with images on screen, may help increase physical activity and improve body composition. The aim of this study was to evaluate the effect of active video games over a 6-mo period on weight, body composition, physical activity, and physical fitness. We conducted a 2-arm, parallel, randomized controlled trial in Auckland, New Zealand. A total of 322 overweight and obese children aged 10-14 y, who were current users of sedentary video games, were randomly assigned at a 1:1 ratio to receive either an active video game upgrade package (intervention, n = 160) or to have no change (control group, n = 162). The primary outcome was the change from baseline in body mass index (BMI; in kg/m(2)). Secondary outcomes were changes in percentage body fat, physical activity, cardiorespiratory fitness, video game play, and food snacking. At 24 wk, the treatment effect on BMI (-0.24; 95% CI: -0.44, -0.05; P = 0.02) favored the intervention group. The change (±SE) in BMI from baseline increased in the control group (0.34 ± 0.08) but remained the same in the intervention group (0.09 ± 0.08). There was also evidence of a reduction in body fat in the intervention group (-0.83%; 95% CI: -1.54%, -0.12%; P = 0.02). The change in daily time spent playing active video games at 24 wk increased (10.03 min; 95% CI: 6.26, 13.81 min; P < 0.0001) with the intervention accompanied by a reduction in the change in daily time spent playing nonactive video games (-9.39 min; 95% CI: -19.38, 0.59 min; P = 0.06). An active video game intervention has a small but definite effect on BMI and body composition in overweight and obese children. This trial was registered in the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au/ as ACTRN12607000632493.


Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time.
In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ∼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.


Experimental transmission of bovine spongiform encephalopathy to European red deer (Cervus elaphus elaphus).
Bovine spongiform encephalopathy (BSE), a member of the transmissible spongiform encephalopathies (TSE), primarily affects cattle. Transmission is via concentrate feed rations contaminated with infected meat and bone meal (MBM). In addition to cattle, other food animal species are susceptible to BSE and also pose a potential threat to human health as consumption of infected meat products is the cause of variant Creutzfeldt-Jakob disease in humans, which is invariably fatal. In the UK, farmed and free ranging deer were almost certainly exposed to BSE infected MBM in proprietary feeds prior to legislation banning its inclusion. Therefore, although BSE has never been diagnosed in any deer species, a possible risk to human health remains via ingestion of cervine products. Chronic wasting disease (CWD), also a TSE, naturally infects several cervid species in North America and is spreading rapidly in both captive and free-ranging populations. Here we show that European red deer (Cervus elaphus elaphus) are susceptible to intra-cerebral (i/c) challenge with BSE positive cattle brain pool material resulting in clinical neurological disease and weight loss by 794-1290 days and the clinical signs are indistinguishable to those reported in deer with CWD. Spongiform changes typical of TSE infections were present in brain and accumulation of the disease-associated abnormal prion protein (PrPd) was present in the central and peripheral nervous systems, but not in lymphoid or other tissues. Western immunoblot analysis of brain material showed a similar glycosylation pattern to that of BSE derived from infected cattle and experimentally infected sheep with respect to protease-resistant PrP isoforms. However, the di-, mono- and unglycosylated bands migrated significantly (p < 0.001) further in the samples from the clinically affected deer when compared to BSE infected brains of cattle and sheep. This study shows that deer are susceptible to BSE by intra-cerebral inoculation and display clinical signs and vacuolar pathology that are similar to those of CWD. These findings highlight the importance of preventing the spread to Europe of CWD from North America as this may necessitate even more extensive testing of animal tissues destined for human consumption within the EU. Although the absence of PrPd in lymphoid and other non-neurological tissues potentially limits the risk of transmission to humans, the replication of TSE agents in peripheral tissues following intra-cerebral challenge is often limited. Thus the assessment of risk posed by cervine BSE as a human pathogen or for environmental contamination should await the outcome of ongoing oral challenge experiments.


A Comparison of Prehospital Versus Emergency Department Intubations in Iraq and Afghanistan.
Airway obstruction is the second most common cause of potentially preventable death on the battlefield. We compared survival in the combat setting among patients undergoing prehospital versus emergency department (ED) intubation. Patients were identified from the Department of Defense Trauma Registry (DODTR) from January 2007 to August 2016. We defined the prehospital cohort as subjects undergoing intubation prior to arrival to a forward surgical team (FST) or combat support hospital (CSH), and the ED cohort as subjects undergoing intubation at an FST or CSH. We compared study variables between these cohorts; survival was our primary outcome. There were 4341 intubations documented in the DODTR during the study period: 1117 (25.7%) patients were intubated prehospital and 3224 (74.3%) were intubated in the ED. Patients intubated prehospital had a lower median age (24 versus 25 years, p < .001), composed a higher proportion of host nation forces (36.1% versus 29.1%, p < .001), had a lower proportion of injuries from explosives (57.6% versus 61.0%, p = .030), and had higher median injury severity scores (20 versus 18, p = .045). A lower proportion of the prehospital cohort survived to hospital discharge (76.4% versus 84.3%, p < .001). The prehospital cohort had lower odds of survival to hospital discharge in both univariable (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.51-0.71) and multivariable analyses controlling for confounders (OR 0.70, 95% CI 0.58-0.85). In a subgroup analysis of patients with a head injury, the lower odds of survival persisted in the multivariable analysis (OR 0.49, 95% CI 0.49-0.82). Patients intubated in the prehospital setting had a lower survival than those intubated in the ED. This finding persisted after controlling for measurable confounders.


MLH1-93G > A is a risk factor for MSI colorectal cancer.
The -93G > A (rs1800734) polymorphism within the core promoter region of the MutL homolog 1 (MLH1) gene has recently been proposed as a low penetrance variant for colorectal cancer (CRC). We evaluated the significance of rs1800734 on CRC risk by genotyping 10 409 CRC cases and 6965 controls. The per allele odds ratio (OR) for all CRC-associated MLH1-93G > A was 1.06 (P = 0.037). Using a subset of 3132 cases with known microsatellite instability (MSI) status, the risk was shown to be confined to microsatellite instability-high (MSI-H) CRC; OR = 1.39 (P = 1.45 × 10(-4)). A meta-analysis of our study and four smaller published studies (totalling 801 cases, 10 890 controls) provided for increased evidence of relationship between MLH1-93G > A and MSI-H CRC risk (P = 3.43 × 10(-12)). The impact of MLH1-93G > A on CRC risk was shown to be independent of the 14 low penetrance loci for CRC identified by recent genome-wide association studies. These data provide further evidence that MLH1-93G > A is a low-penetrance variant for CRC and support the proposition that MLH1-93G > A acts as marker for a somatic event defining a specific CRC subtype.


Why functionalist accounts of emotion tend to be tenuous in social and cultural contexts. A commentary.
The present contribution provides some constructive criticism of Keltner's and colleagues proposal for advancing the Social Functionalist Theory of emotion. I first briefly summarise some of the key premises of Social Functionalist Theory and then provide more detailed comments on the four key principles of the theory concerning emotional experience, cognition, expression, and the cultural archiving of emotion. I develop the argument that the link between emotions and the six relational needs (security, commitment, status, trust, fairness, and belongingness) emphasised by Keltner and colleagues are likely to differ across cultural and historical contexts. Moreover, I suggest that practices and representations of emotion are neither consistent nor uniform. Instead, they are frequently tied to strategic attempts at manufacturing relational emotions for political purposes. Third, I argue that whether emotions are functional for the social and cultural world is a matter of perspective.


[Clinical features of Pneumocystis pneumonia in patients with systemic lupus erythematosus].
Systemic lupus erythematosus (SLE) is often associated with various opportunistic infections, particularly during treatment with corticosteroids or immunosuppressants. We studied the clinical characteristics of 15 patients with SLE who underwent diagnostic bronchoalveolar lavage (BAL) and compared 6 patients with confirmed Pneumocystis pneumonia (PcP+), with 9 patients without Pneumocystis pneumonia (PcP-). The serum concentrations of beta-D-glucan and KL-6 were significantly higher in PcP+ than in PcP- patients, whereas serum LDH was similar in both groups. The serum concentrations of complement, a marker of SLE activity, and of IgG did not predict the presence of PcP. In all patients, the overall cell and lymphocyte counts were increased in the BAL fluid, without any significant difference between the PcP+ and PcP- groups. Ground-glass opacities on chest computed tomography, and oxygenation impairment (PaO2/FiO2<200Torr) were more common in PcP+ than PcP- patients. We concluded that, in patients with SLE, serum beta-D-glucan and KL-6 might be useful in the diagnosis of PcP, particularly when severe hypoxemia precludes BAL.


EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial.
Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia. In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22-89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22-28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987. 92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores -2.29 [SD 1.75] vs -1.60 [1.66]; difference of adjusted least square means -0.69 [SE 0.25]; 95% CI -1.19 to -0.20; p=0.0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo. EMA401 (100 mg twice daily) provides superior relief of postherpetic neuralgia compared with placebo at the end of 28 days of treatment. EMA401 was well tolerated by patients. Spinifex Pharmaceuticals.


Timing of neuronal death in trkA, trkB and trkC mutant embryos reveals developmental changes in sensory neuron dependence on Trk signalling.
The sensory neurons of the embryonic mouse trigeminal ganglion are supported in culture by different neurotrophins at successive stages of development. Initially the neurons survive in response to BDNF and NT3 and later switch to becoming NGF-dependent (Buchman, V. I. and Davies, A. M. (1993), Development 118, 989-1001). To determine if this in vitro switch in neurotrophin responsiveness is physiologically relevant, we studied the timing of neuronal death in the trigeminal ganglia of embryos that are homozygous for null mutations in the trkA, trkB and trkC genes, which encode receptor tyrosine kinases for NGF, BDNF and NT3, respectively. In wild-type embryos, the number of pyknotic nuclei increased from E11 to peak between E13 and E14, and decreased gradually at later ages, becoming negligible by birth. Neuronal death in the trigeminal ganglia of trkA-/- embryos also peaked between E13 and E14, but was almost threefold greater than in wild-type embryos at this stage. Whereas there was no significant difference between the number of pyknotic nuclei in trkA-/- and wild-type embryos at E11 and E12, there was a substantial increase in the number of pyknotic nuclei in the trigeminal ganglia of trkB-/- at these earlier stages. Counts of the total number of neurons in E13 trigeminal ganglia revealed a marked decrease in trkB-/- but not trkA-/- or trkC-/- embryos. Consistent with the later onset of excessive neuronal death in trkA-/- embryos, there was a marked decrease in the neuronal complement of the trigeminal ganglia of trkA-/- embryos at E15. These results demonstrate that TrkB signalling is required for the in vivo survival of many trigeminal neurons during the early stages of target field innervation before they become NGF-dependent.


Cytomegalovirus disease in inflammatory bowel disease: epidemiology and disease characteristics in a large single-centre experience.
Patients with inflammatory bowel disease (IBD) show an increased risk of developing cytomegalovirus (CMV) disease because of immunosuppressive medication and malnutrition. Here, we aimed to investigate the prevalence and clinical characteristics of CMV disease in our cohort of IBD patients. We carried out a retrospective analysis of 1023 IBD patients treated at our IBD clinic at the University Hospital Zurich between 2007 and 2014. CMV disease was defined as a positive immunohistochemistry for CMV and 14 patients were identified. The prevalence of CMV disease in our IBD cohort was 1.37%. Twelve patients had ulcerative colitis and two had Crohn's disease with colonic involvement. All patients who developed CMV disease received immunosuppressive medication or, as in one case, had HIV infection. The most used immunosuppressive medications were steroids and azathioprine. The most common therapeutic strategy was the consecutive use of ganciclovir and valganciclovir. Ten patients recovered and two were treatment refractory; among these, one required colectomy and two had a relapse. CMV disease may influence the clinical course of IBD. There is probably an association between CMV disease and IBD-specific medication. Risk factors, epidemiology and therapeutic strategy need to be further investigated.


A cost consequences analysis of local corticosteroid injection and physiotherapy for the treatment of new episodes of unilateral shoulder pain in primary care.
Local steroid injections and community-based physiotherapy have been shown to be of similar benefit for treating shoulder pain presenting to primary care. This paper presents a cost consequences analysis of a prospective economic evaluation, conducted alongside a randomized clinical trial (RCT) of corticosteroid injections versus physiotherapy for new episodes of unilateral shoulder pain, to determine the economic implications of injection versus physiotherapy. A pragmatic RCT with 207 patients randomized to either physiotherapy (n = 103) or local steroid injection (n = 104) was conducted. The resource inputs required were identified for each treatment arm in terms of capital, staff and consumables. These were measured for the period up to 6 months post-randomization. Outcome measures included shoulder disability, shoulder pain, global assessment of health change and the EQ5D, all at 6 months. A sensitivity analysis was performed around the general practitioner minor surgical fee. Analysis is presented on the 199 patients for which the general practice record review (101 physiotherapy, 98 injection) was available. The total mean costs, per patient, were 71.28 pound sterling for the injection group and 114.60 pound sterling for the physiotherapy group. The difference in average total cost per patient was 43.32 pound sterling (95% bootstrap confidence interval: 16.21 pound sterling, 68.03 pound sterling ). This is a statistically significant difference in cost. Outcome was similar in both groups across all measures following intervention. Smaller mean differences in cost were observed between the treatment groups in the sensitivity analysis, but the difference remained in favour of injection over physiotherapy. This study has shown, given similar clinical outcomes across the treatment groups, that corticosteroid injections were the cost-effective option for patients presenting with new episodes of unilateral shoulder pain in primary care.


Secreted frizzled-related protein-5 is epigenetically downregulated and functions as a tumor suppressor in kidney cancer.
Secreted frizzled-related protein-5 (sFRP-5) has been identified as 1 of the secreted antagonists that bind Wnt protein. However, the functional significance of sFRP-5 in renal cell cancer (RCC) has not been reported. We hypothesized that sFRP-5 may be epigenetically downregulated through DNA methylation and histone modification and function as a tumor suppressor gene in RCC. Using tissue microarray and real-time RT-PCR, we found that sFRP-5 was significantly downregulated in kidney cancer tissues and cell lines, respectively. DNA bisulfite sequencing of the sFRP-5 promoter region in RCC cell lines showed it to be densely methylated, whereas there was few promoter methylation in normal kidney. The sFRP-5 expression was restored and the acetylation of H3 and H4 histones associated with the sFRP-5 promoter region were significantly increased after treatment with demethylation agent (5-Aza-dc) and histone deacetylase inhibitor (TSA). When RCC cells were transfected with the sFRP-5 gene, significant inhibition of anchorage independent colony formation and cell invasion were observed compared to controls. The sFRP-5 transfection also significantly induced apoptosis in RCC cells. In conclusion, this is the first report documenting that the sFRP-5 is downregulated by promoter methylation and histone acetylation and functions as a tumor suppressor gene by inducing apoptosis in RCC cells.


Ag@Nb2O5 plasmonic blocking layer for higher efficiency dye-sensitized solar cells.
Engineering photons on a nanoscale via guidance and localization by metal nanostructures has a profound influence on the performance of devices that try to mimic the process of photosynthesis. The conventional route for the synthesis of plasmonic nanoparticles and their integration into the porous structure of the photoanode either directly or after being capped with a dielectric material not only adds to the complexity but also to the cost of the cell. The present study introduces the concept of a plasmonic blocking layer that concurrently acts as a light harvester and an electron-blocking layer in a dye-sensitized solar cell (DSSC), wherein the plasmonic silver nanoparticles are incorporated into an Nb2O5 blocking layer by a simple one-step process. The cell with the plasmonic blocking layer achieves an efficiency of 9.24% when compared with a cell with a non-plasmonic blocking layer (7.6%), registering an impressive enhancement in the efficiency by 22%. Moreover, the cell with the plasmonic blocking layer shows an improvement in the efficiency by 49% when compared with the cell without a blocking layer (6.19%).


Improving teacher-child relationship quality and teacher-rated behavioral adjustment amongst externalizing preschoolers: effects of a two-component intervention.
The school-based Playing-2-gether is a 12-week intervention with two components aimed at decreasing child externalizing behavior through improving teacher-child interactions. The first component is rooted in attachment theory and aimed at enhancing teacher-child relationship quality, and the second is based on learning theory and aimed at improving teachers' behavior management. In this three-wave randomized study, effects of Playing-2-gether on the teacher-child relationship quality and on teacher-rated child behavioral adjustment were investigated. To this aim, 175 dyads consisting of male preschoolers with relatively high levels of externalizing problem behavior and their teachers were randomly assigned to Playing-2-gether (n = 89) or an education-as-usual control condition (n = 86). Teacher-rated questionnaires were collected at pre-test, after the first intervention component, and at post-test. At post-test, the intervention group showed a larger decrease in teacher-child conflict, child conduct problems, and child hyperactivity/inattention. Supplementary analyses showed that all positive effects were already visible after the first intervention component and that teacher-child conflict, child conduct problems and hyperactivity/inattention did not further reduce during the second component. In addition, an increase in closeness was found following the first component, but subsequently disappeared at post-test.


Plasticity of subventricular zone neuroprogenitors in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease involves cross talk between inflammatory and Wnt/β-catenin signaling pathways: functional consequences for neuroprotection and repair.
In Parkinson's disease (PD), neurogenesis is impaired in the subventricular zone (SVZ) of postmortem human PD brains, in primate nonhuman and rodent models of PD. The vital role of Wingless-type MMTV integration site (Wnt)/β-catenin signaling in the modulation of neurogenesis, neuroprotection, and synaptic plasticity coupled to our recent findings uncovering an active role for inflammation and Wnt/β-catenin signaling in MPTP-induced loss and repair of nigrostriatal dopaminergic (DAergic) neurons prompted us to study the impact of neuroinflammation and the Wnt/β-catenin pathway in the response of SVZ neuroprogenitors (NPCs) in MPTP-treated mice. In vivo experiments, using bromodeoxyuridine and cell-specific markers, and ex vivo time course analyses documented an inverse correlation between the reduced proliferation of NPCs and the generation of new neuroblasts with the phase of maximal exacerbation of microglia reaction, whereas a shift in the microglia proinflammatory phenotype correlated with a progressive NPC recovery. Ex vivo and in vitro experiments using microglia-NPC coculture paradigms pointed to NADPH-oxidase (gpPHOX(91)), a major source of microglial ROS, and reactive nitrogen species as candidate inhibitors of NPC neurogenic potential via the activation of glycogen synthase 3 (pGSK-3β(Tyr216)), leading to loss of β-catenin, a chief downstream transcriptional effector. Accordingly, MPTP/MPP(+) (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) caused β-catenin downregulation and pGSK-3β(Tyr216) overexpression, whereas manipulation of Wnt/β-catenin signaling with RNA interference-mediated GSK-3β knockdown or GSK-3β antagonism reversed MPTP-induced neurogenic impairment ex vivo/in vitro or in vivo. Reciprocally, pharmacological modulation of inflammation prevented β-catenin downregulation and restored neurogenesis, suggesting the possibility to modulate this endogenous system with potential consequences for DAergic neuroprotection and self-repair.


Interplay of approximate planning strategies.
Humans routinely formulate plans in domains so complex that even the most powerful computers are taxed. To do so, they seem to avail themselves of many strategies and heuristics that efficiently simplify, approximate, and hierarchically decompose hard tasks into simpler subtasks. Theoretical and cognitive research has revealed several such strategies; however, little is known about their establishment, interaction, and efficiency. Here, we use model-based behavioral analysis to provide a detailed examination of the performance of human subjects in a moderately deep planning task. We find that subjects exploit the structure of the domain to establish subgoals in a way that achieves a nearly maximal reduction in the cost of computing values of choices, but then combine partial searches with greedy local steps to solve subtasks, and maladaptively prune the decision trees of subtasks in a reflexive manner upon encountering salient losses. Subjects come idiosyncratically to favor particular sequences of actions to achieve subgoals, creating novel complex actions or "options."