Regulation of virulence-associated plasmid genes in enteroinvasive Escherichia coli.
The transposon TnphoA was used for construction of gene fusions and for studies of gene regulation in an enteroinvasive strain of Escherichia coli. Several plasmid-encoded virulence genes (e.g., the ipaB and virG operons) of such enteroinvasive strains are subject to coordinated thermoregulation involving both operon-specific (the VirB and VirF activators) and global regulators. The nucleoid-associated E. coli protein H-NS was shown to be a negative regulator as judged by studies using H-NS gene deletion mutations and by increasing the level of H-NS protein in the cells. An increased gene dosage of H-NS led to enhanced repression of the ipa and virG operons, particularly at low (30 degrees C) growth temperature. The cyclic AMP receptor protein complex, which is another global transcriptional regulator in E. coli, was not required for the regulation of ipa and virG expression. The virG operon was expressed in an activator-independent manner in cells lacking H-NS protein. We suggest that the role of the VirF activator is to counteract the silencing effect of H-NS.


Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers.
The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon.


Improvement of quality of life with nocturnal oxygen therapy in heart failure patients with central sleep apnea.
Previously, we reported the benefit of 12 weeks of home oxygen therapy (HOT) in patients with central sleep apnea (CSA) and heart failure (HF). In the present study, we attempted to confirm the sustained efficacy of HOT in the long term treatment. In the present study, 51 patients with CSA and HF (New York Heart Association (NYHA) functional classes II-III) were assigned to receive either nocturnal oxygen (HOT group n=26) or usual breathing (control group n=25) for 52 weeks. In the HOT group, greater reduction in apnea and hypopnea and greater increase in nocturnal oxygen saturation were observed. These changes were associated with greater improvement in the Specific Activity Scale (0.82 +/-1.17 vs -0.11 +/-0.73 Mets, P=0.009) in NYHA functional class (P=0.007) and in ejection fraction (5.45 +/-11.94 vs 1.28 +/-9.77%). There were no significant differences in the cardiac event rates; however, the later divergence favored the HOT group. The 52-week HOT was well tolerated and the benefit observed in the 12-week trial was sustained over a prolonged period of time. HOT was considered to be a valuable non-pharmacological therapeutic addition for HF patients with CSA.


Youth problem behaviors 8 years after implementing the communities that care prevention system: a community-randomized trial.
Community-based efforts to prevent adolescent problem behaviors are essential to promote public health and achieve collective impact community wide. OBJECTIVE To test whether the Communities That Care (CTC) prevention system reduced levels of risk and adolescent problem behaviors community wide 8 years after implementation of CTC. A community-randomized trial was performed in 24 small towns in 7 states, matched within state, assigned randomly to a control or intervention group in 2003. All fifth-grade students attending public schools in study communities in 2003-2004 who received consent from their parents to participate (76.4% of the eligible population) were included. A panel of 4407 fifth graders was surveyed through 12th grade, with 92.5% of the sample participating at the last follow-up. A coalition of community stakeholders received training and technical assistance to install CTC, used epidemiologic data to identify elevated risk factors and depressed protective factors for adolescent problem behaviors in the community, and implemented tested and effective programs for youths aged 10 to 14 years as well as their families and schools to address their community's elevated risks. MAIN OUTCOMES AND MEASURES Levels of targeted risk; sustained abstinence, and cumulative incidence by grade 12; and current prevalence of tobacco, alcohol, and other drug use, delinquency, and violence in 12th grade. By spring of 12th grade, students in CTC communities were more likely than students in control communities to have abstained from any drug use (adjusted risk ratio [ARR] = 1.32; 95% CI, 1.06-1.63), drinking alcohol (ARR = 1.31; 95% CI, 1.09-1.58), smoking cigarettes (ARR = 1.13; 95% CI, 1.01-1.27), and engaging in delinquency (ARR = 1.18; 95% CI, 1.03-1.36). They were also less likely to ever have committed a violent act (ARR = 0.86; 95% CI, 0.76-0.98). There were no significant differences by intervention group in targeted risks, the prevalence of past-month or past-year substance use, or past-year delinquency or violence. Using the CTC system continued to prevent the initiation of adolescent problem behaviors through 12th grade, 8 years after implementation of CTC and 3 years after study-provided resources ended, but did not produce reductions in current levels of risk or current prevalence of problem behavior in 12th grade. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01088542.


Mutated K-ras gene analysis in a randomized trial of preoperative chemotherapy plus surgery versus surgery in stage IIIA non-small cell lung cancer.
The observation that the proteins encoded by ras genes play a central role in the signalling pathways used by cells to respond to growth factors and the fact that mutated ras proteins are constantly promoting cell division have led to a PCR-based hunt for additional clinical information. In the present study, K-ras analysis draws the following conclusions: (1) K-ras point mutation frequency was higher in the surgery group (10 of 24 patients) than in the chemotherapy-surgery group (3 of 20 patients). (2) Mutated K-ras was predominantly observed at codon 12 but five mutations appeared at codon 61. (3) Mutations were identified in the squamous cell carcinoma histological NSCLC subtype except in four cases corresponding to adenocarcinoma. (4) A multifarious pattern of substitutions, especially at codon 12, were noted with aspartic K 12 substitutions more prone to develop bone metastases. (5) Although a genotypic K-ras classification of NSCLC may not yet be formulated, our accumulated data (unpublished) suggest a trend toward it. (6) Patients with mutated K-ras tumors in the surgery group had no different survival than those with normal K-ras. However our pooled data as well as other authors' results assert that mutated K-ras constitute an additional prognostic datum that deserves to be included together with TNM classification. In the design of new preoperative (neoadjuvant) chemotherapy trials, stratification of tumors by K-ras status deserves to be further investigated in order to correlate with response, relapse and survival. Mutated K-ras genotype merits further research. Finally, the paradigm of uneven histological distribution and mutated K-ras spectra among researchers should serve as a stimulus to search for further contributions in this field.


Evidence for stabilizing selection and slow divergent evolution of male genitalia in a millipede (Antichiropus variabilis).
It is generally accepted that postcopulatory sexual selection drives rapid divergence of genital morphology among isolated populations. The mode of selection operating upon genitalia can be explored by comparing patterns of population divergence in genetic and genitalic traits. We collected Antichiropus variabilis millipedes from eight localities across the species range. Levels of among-population genetic divergence, at microsatellite loci, and the mitochondrial COI gene were very high. Following geometric morphometric analyses, genital morphology was also found to be highly divergent among the populations surveyed, whereas head morphology had not diverged as markedly. However, pairwise comparisons of F(ST) and P(ST) showed that among-population divergence in both genital and head shape was significantly lower than that experienced by neutral genetic markers. Our results suggest that the genitalia of A. variabilis are currently experiencing a period of stabilizing selection, the mode of selection expected for genitalia that function in species recognition via a "lock-and-key" mechanism. Our results demonstrate that although genital morphology can clearly diverge among genetically isolated populations, divergence is not necessarily as rapid as commonly argued, and continuous directional sexual selection may not always underpin the evolutionary divergence of male genitalia.


Phylodynamic analysis of HIV-1 subtypes B, C and CRF 02_AG in Senegal.
Surveillance of HIV epidemics in key populations and in developing countries is often challenging due to sparse, incomplete, or low-quality data. Analysis of HIV sequence data can provide an alternative source of information about epidemic history, population structure, and transmission patterns. To understand HIV-1 dynamics and transmission patterns in Senegal, we carried out model-based phylodynamic analyses using the structured-coalescent approach using HIV-1 sequence data from three different subgroups: reproductive aged males and females from the adult Senegalese population and men who have sex with other men (MSM). We fitted these phylodynamic analyses to time-scaled phylogenetic trees individually for subtypes C and CRF 02_AG, and for the combined data for subtypes B, C and CRF 02_AG. In general, the combined analysis showed a decreasing proportion of effective number of infections among all reproductive aged adults relative to MSM. However, we observed a nearly time-invariant distribution for subtype CRF 02_AG and an increasing trend for subtype C on the proportion of effective number of infections. The population attributable fraction also differed between analyses: subtype CRF 02_AG showed little contribution from MSM, while for subtype C and combined analyses this contribution was much higher. Despite observed differences, results suggested that the combination of high assortativity among MSM and the unmet HIV prevention and treatment needs represent a significant component of the HIV epidemic in Senegal.


The role of social and community service in medical education: the next 100 years.
Abraham Flexner's focus on science in medical school curricula was not intended to exclude or marginalize the importance of service in training American physicians. The erosion of service in academic medicine in the century after his report was the result of forces as wide ranging as research priorities, health care financing, and industry's influence. The authors review the historical context of these changes and make the case that reintroducing service into medical school curricula has never been more important. They describe the impact that neglecting service has had on society, patients, the medical profession, medical students, and medical education. After defining what is meant by social, public, or community service, they go on to detail signature programs at University of Texas Medical Branch, University of New Mexico Health Sciences Center, and Mount Sinai School of Medicine, focusing on the two major categories of health care delivery and education. These examples, in geographically and demographically disparate schools of medicine, demonstrate that it is possible to successfully reintegrate service into the missions of academic medical centers and medical schools.


Frontal and Temporal Structural Connectivity Is Associated with Social Communication Impairment Following Traumatic Brain Injury.
Although it has been well documented that traumatic brain injury (TBI) can result in communication impairment, little work to date has examined the relationship between social communication skills and structural brain integrity in patients with TBI. The aim of the current study was to investigate the association between self- and other-perceived communication problems and white matter integrity in patients with mild to severe TBI. Forty-four individuals (TBI=24) and people with whom they frequently communicate, as well as demographically matched normal healthy comparisons (NC) and their frequent communication partners, were administered, respectively, the La-Trobe Communication Questionnaire Self form (LCQ-SELF) and Other form (LCQ-OTHER). In addition, diffusion tensor imaging data were collected, and fractional anisotropy (FA) measures were extracted for each lobe in both hemispheres. Within the TBI group, but not within the NC group, participants who were perceived by their close others as having more communication problems had lower FA in the left frontal and temporal lobes (p<.01), but not in other brain regions. Frontotemporal white matter microstructural integrity is associated with social communication abilities in adults with TBI. This finding contributes to our understanding of the mechanisms leading to communication impairment following TBI and can inform the development of new neuromodulation therapies as well as diagnostic tools. (JINS, 2016, 22, 705-716).


Activation of the GPR30 receptor promotes lordosis in female mice.
Estrogens are important effectors of reproduction and are critical for upregulating female reproductive behavior or lordosis in females. In addition to the importance of transcriptional regulation of genes by 17β-estradiol-bound estrogen receptors (ER), extranuclear signal transduction cascades such as protein kinase A (PKA) are also important in regulating female sexual receptivity. GPR30 (G-protein coupled receptor 30), also known as GPER1, a putative membrane ER (mER), is a G protein-coupled receptor that binds 17β-estradiol with an affinity that is similar to that possessed by the classical nuclear ER and activates both PKA and extracellular-regulated kinase signaling pathways. The high expression of GPR30 in the ventromedial hypothalamus, a region important for lordosis behavior as well as kinase cascades activated by this receptor, led us to hypothesize that GPR30 may regulate lordosis behavior in female rodents. In this study, we investigated the ability of G-1, a selective agonist of GPR30, to regulate lordosis in the female mouse by administering this agent prior to progesterone in an estradiol-progesterone priming paradigm prior to testing with stud males. As expected, 17β-estradiol benzoate (EB), but not sesame oil, increased lordosis behavior in female mice. G-1 also increased lordosis behavior in female mice and decreased the number of rejective responses towards male mice, similar to the effect of EB. The selective GPR30 antagonist G-15 blocked these effects. This study demonstrates that activation of the mER GPR30 stimulates social behavior in a rodent model in a manner similar to EB.


The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans.
Remote ischemic preconditioning (IPC) reduces tissue injury caused by ischemia-reperfusion (IR) in distant organs. We tested the hypothesis that remote IPC (rIPC) modifies inflammatory gene transcription in humans. Using a microarray method, we demonstrated that a simple model of brief forearm ischemia suppresses proinflammatory gene expression in circulating leukocytes. Genes encoding key proteins involved in cytokine synthesis, leukocyte chemotaxis, adhesion and migration, exocytosis, innate immunity signaling pathways, and apoptosis were all suppressed within 15 min (early phase IPC) and more so after 24 h (second window IPC). Changes in leukocyte CD11b expression measured by flow cytometry mirrored this pattern, with there being a significant (P = 0.01) reduction at 24 h. The results of this study show that the rIPC stimulus modifies leukocyte inflammatory gene expression. This effect may contribute to the protective effect of IPC against IR injury and may have broader implications in other inflammatory processes. This is the first study of human gene expression following rIPC stimulus. rIPC stimulus suppressed proinflammatory gene transcription in human leukocytes.


Religion, spirituality, and health outcomes in cancer: A case for a meta-analytic investigation.
A growing body of research shows that a majority of patients with cancer report having religious and spiritual (R/S) beliefs, engaging in R/S behaviors, or deriving comfort from R/S experiences. These studies have been reviewed but not subjected to rigorous critical analysis. A meta-analytic approach is needed to provide a more definitive understanding of the relationships between R/S (affective, behavioral, and cognitive dimensions) and physical, mental, and social health in all phases of cancer including diagnosis, treatment, survivorship, and palliative care. A meta-analysis can quantify the degree of association between R/S dimensions and patient-reported health outcomes and the conditions under which these associations are strengthened or attenuated. Results can, in turn, help focus future work in this area by highlighting key variables for inclusion in studies of R/S and cancer and identifying particular subgroups for whom dimensions of R/S are particularly important to their health.


The patient is in: patient involvement strategies for diagnostic error mitigation.
Although healthcare quality and patient safety have longstanding international attention, the target of reducing diagnostic errors has only recently gained prominence, even though numerous patients, families and professional caregivers have suffered from diagnostic mishaps for a long time. Similarly, patients have always been involved in their own care to some extent, but only recently have patients sought more opportunities for engagement and participation in healthcare improvements. This paper brings these two promising trends together, analysing strategies for patient involvement in reducing diagnostic errors in an individual's own care, in improving the healthcare delivery system's diagnostic safety, and in contributing to research and policy development on diagnosis-related issues.


Granulocyte and monocyte adsorption apheresis as an effective treatment for Reiter disease.
Reiter disease (RD) is characterized by a triad of sterile arthritis, urethritis and conjunctivitis. The conditions occur concomitantly or sequentially, and are associated with mucocutaneous features such as circinate balanitis and stomatitis. Arthritis usually occurs in attacks followed by recovery, but it sometimes progresses to permanent damage of the affected joints. Because the symptoms of this disorder are attributable to activated neutrophils, we assessed the efficacy of granulocyte and monocyte adsorption apheresis (GCAP) in a 73-year-old man with RD who had skin rashes on his penis, scrotum and right hand, with severe arthralgia. The patient's skin rash and joint pain responded dramatically to five sessions of GCAP delivered at intervals of 5 days. We present a detailed description of the patient and discuss the mechanisms of GCAP, and suggest that GCAP may be useful for treating RD.


Policy interoperability in stem cell research: demystifying harmonization.
Scientific developments in the field of stem cell research continue to emerge at incredible speed and so too has the contentious debate surrounding their broad implications. Though economic, socio-ethical and legal concerns remain, at both national and international forums; we are witnessing a departure from an "embryo-centric" approach, to one that is focused on the globalization of research and to the ensuing need for policy interoperability. The common response to the challenges associated with the meaning, scope, and ethical significance of variance in national policies, is a call for the creation of uniform legal and ethical standards. However, this call towards policy convergence on the fundamental ethical and governance principles underpinning policies choices has led to confusion and to the mystification of the notion of harmonization. In this article we aim demystify the notion of policy harmonization in the context of stem cell research. We will do so by surveying the diverse elements to be harmonized. We will then present the problems of policy interoperability in the context of the globalization of SC research, in order to propose that the goal of harmonization in this field lies in the identification of prospective strategies to foster seamless cross-jurisdictional collaboration. Finally, policy interoperability will be analyzed through the lens of a range of policy approaches addressing the cross-jurisdictional transfer of hESC lines with the aim of demonstrating that the apparent ethical-political-legal divide in some contexts largely vanishes once we grasp the notion of harmonization and identify points of convergence.


Incidence of stroke in Taiwan.
Few epidemiological studies concerning the incidence of stroke have been conducted in Taiwan. In an attempt to investigate this common disease, we studied the incidence of stroke in Taiwan in a prospective incidence study. A cohort of 8,562 stroke-free people were followed up for 4 years to observe new stroke occurrence. The methods of sampling the study population have been reported elsewhere. In addition to the help of local doctors, who reported the new stroke cases, we also sent public nurses to visit the study population annually to screen the new cases of stroke. There were 104 (61 men and 43 women) first-ever stroke cases identified by a neurologist in a period between October 1, 1986 and December 31, 1990. The average annual incidence rate of first-ever stroke for people aged 36 years or older in this study was 330 per 100,000. Incidence rate was higher in eastern Taiwan and in rural communities. Percentages of the major types of stroke were as follows: cerebral infarction, 71%; cerebral hemorrhage, 22%; subarachnoid hemorrhage, 1%; and unclassified, 6%. The significant risk factors for stroke were hypertension and intake of food with a high sodium content. The age-specific incidence rates in this study are higher than those reported from the United Kingdom and the United States. The rates are close to those in a report from Japan and a report from a city in mainland China at the same latitude. Cerebral hemorrhages are more common among people in Taiwan than among Occidental people.


Periodic Compounds: Syntheses at High Pressures and Temperatures.
A new class of compounds, called "periodic compounds," identified by the selection rule G = Sigmad(i)e(i)/Sigmad(i), where G assumes the integral values 1, 2, 3, . . . corresponding to the periodic table groups I, II, III, . . ., is discussed. The number of bonding electrons contributed by an atom of kind i is designated e(i), and d(i) gives the number, per formula weight, of atoms of this kind. Both e(i) and d(i) assume integral values. Periodic compounds consist of symmetrical and unsymmetrical types. The recent synthesis of the unsymmetrical periodic compound B(2)O, an isoelectronic analog of carbon, suggests that many more unsymmetrical types may be amenable to synthesis, particularly by high-pressure and high-temperature techniques.


Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning.
Ischemia-reperfusion (I/R) liver injury occurs when blood flow is restored after prolonged ischemia. A short interruption of blood flow (ischemic preconditioning [IP]) induces tolerance to subsequent prolonged ischemia through ill-defined mechanisms. Cardiotrophin (CT)-1, a cytokine of the interleukin-6 family, exerts hepatoprotective effects and activates key survival pathways like JAK/STAT3. Here we show that administration of CT-1 to rats or mice protects against I/R liver injury and that CT-1-deficient mice are exceedingly sensitive to this type of damage. IP markedly reduced transaminase levels and abrogated caspase-3 and c-Jun-NH2-terminal kinase activation after I/R in normal mice but not in CT-1-null mice. Moreover, the protective effect afforded by IP was reduced by previous administration of neutralizing anti-CT-1 antibody. Prominent STAT3 phosphorylation in liver tissue was observed after IP plus I/R in normal mice but not in CT-1-null mice. Oxidative stress, a process involved in IP-induced hepatoprotection, was found to stimulate CT-1 release from isolated hepatocytes. Interestingly, brief ischemia followed by short reperfusion caused mild serum transaminase elevation and strong STAT3 activation in normal and IL-6-deficient mice, but failed to activate STAT3 and provoked marked hypertransaminasemia in CT-1-null animals. In conclusion, CT-1 is an essential endogenous defense of the liver against I/R and is a key mediator of the protective effect induced by IP.


Qualitative data analysis for health services research: developing taxonomy, themes, and theory.
To provide practical strategies for conducting and evaluating analyses of qualitative data applicable for health services researchers. DATA SOURCES AND DESIGN: We draw on extant qualitative methodological literature to describe practical approaches to qualitative data analysis. Approaches to data analysis vary by discipline and analytic tradition; however, we focus on qualitative data analysis that has as a goal the generation of taxonomy, themes, and theory germane to health services research. We describe an approach to qualitative data analysis that applies the principles of inductive reasoning while also employing predetermined code types to guide data analysis and interpretation. These code types (conceptual, relationship, perspective, participant characteristics, and setting codes) define a structure that is appropriate for generation of taxonomy, themes, and theory. Conceptual codes and subcodes facilitate the development of taxonomies. Relationship and perspective codes facilitate the development of themes and theory. Intersectional analyses with data coded for participant characteristics and setting codes can facilitate comparative analyses. Qualitative inquiry can improve the description and explanation of complex, real-world phenomena pertinent to health services research. Greater understanding of the processes of qualitative data analysis can be helpful for health services researchers as they use these methods themselves or collaborate with qualitative researchers from a wide range of disciplines.


Recent advance in very early-onset inflammatory bowel disease.
Recent studies on pediatric inflammatory bowel disease (IBD) have revealed that early-onset IBD has distinct phenotypic differences compared with adult-onset IBD. In particular, very early-onset IBD (VEO-IBD) differs in many aspects, including the disease type, location of the lesions, disease behavior, and genetically attributable risks. Neonatal or infantile-onset IBD develops in less than 1% of pediatric patients. Children with infantile-onset IBD have high rates of affected first-degree relatives and severe disease course. The suspicion of a monogenic cause of VEO-IBD was first confirmed by the discovery of mutations in the genes encoding the interleukin 10 (IL-10) receptors that cause impaired IL-10 signaling. Patients with such mutations typically presented with perianal fistulae, shows a poor response to medical management, and require early surgical interventions in the first year of life. To date, 60 monogenic defects have been identified in children with IBD-like phenotypes. The majority of monogenic defects presents before 6 years of age, and many present before 1 year of age. Next generation sequencing could become an important diagnostic tool in children with suspected genetic defects especially in children with VEO-IBD with severe disease phenotypes. VEO-IBD is a phenotypically and genetically distinct disease entity from adult-onset or older pediatric IBD.


Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.
Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10- 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10- 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10- 12), as well as the TFAM knockout methylation (P = 4.41 × 10- 4) and expression (P = 4.30 × 10- 4) studies. These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.


Axogenesis in the embryonic brain of the grasshopper Schistocerca gregaria: an identified cell analysis of early brain development.
Axogenesis in the embryonic brain was studied at the single cell level in the grasshopper Schistocerca gregaria. A small set of individually identifiable pioneer neurons establishes a primary axon scaffold during early embryogenesis. At the beginning of scaffold formation, pioneering axons navigate along and between glial borders that surround clusters of proliferating neuroblasts. In each brain hemisphere, an axonal outgrowth cascade involving a series of pioneer neurons establishes a pathway from the optic ganglia to the brain midline. At the midline the primary preoral commissural interconnection in the embryonic brain is pioneered by a pair of midline-derived pioneer neurons. A second preoral commissural connection is pioneered by two pairs of pars intercerebralis pioneer neurons. Descending tracts are pioneered by the progeny of identified neuroblasts in the pars intercerebralis, deutocerebrum and tritocerebrum; the postoral tritocerebral commissure is pioneered by a pair of tritocerebral neurons. All of the pioneering brain neurons express the cell adhesion molecule fasciclin I during initial axon outgrowth and fasciculation. Once established, the primary axon scaffold of the brain is used for fasciculation by subsequently differentiating neurons and, by the 40% stage of embryogenesis, axonal projections that characterize the mature brain become evident. The single cell analysis of grasshopper brain development presented here sets the stage for manipulative cell biological experiments and provides the basis for comparative molecular genetic studies of embryonic brain development in Drosophila.


A Screening Rule for ℓ1-Regularized Ising Model Estimation.
We discover a screening rule for ℓ1-regularized Ising model estimation. The simple closed-form screening rule is a necessary and sufficient condition for exactly recovering the blockwise structure of a solution under any given regularization parameters. With enough sparsity, the screening rule can be combined with various optimization procedures to deliver solutions efficiently in practice. The screening rule is especially suitable for large-scale exploratory data analysis, where the number of variables in the dataset can be thousands while we are only interested in the relationship among a handful of variables within moderate-size clusters for interpretability. Experimental results on various datasets demonstrate the efficiency and insights gained from the introduction of the screening rule.


Cellular Internalization of Therapeutic Oligonucleotides by Peptide Amphiphile Nanofibers and Nanospheres.
Oligonucleotides are promising drug candidates due to the exceptionally high specificity they exhibit toward their target DNA and RNA sequences. However, their poor pharmacokinetic and pharmacodynamic properties, in conjunction with problems associated with their internalization by cells, necessitates their delivery through specialized carrier systems for efficient therapy. Here, we investigate the effects of carrier morphology on the cellular internalization mechanisms of oligonucleotides by using self-assembled fibrous or spherical peptide nanostructures. Size and geometry were both found to be important parameters for the oligonucleotide internalization process; direct penetration was determined to be the major mechanism for the internalization of nanosphere carriers, whereas nanofibers were internalized by clathrin- and dynamin-dependent endocytosis pathways. We further showed that glucose conjugation to carrier nanosystems improved cellular internalization in cancer cells due to the enhanced glucose metabolism associated with oncogenesis, and the internalization of the glucose-conjugated peptide/oligonucleotide complexes was found to be dependent on glucose transporters present on the surface of the cell membrane.


Effect of the thickness of undoped GaN interlayers between multiple quantum wells and the p-doped layer on the performance of GaN light-emitting diodes.
InGaN based light-emitting diodes (LEDs) with undoped GaN interlayer of variant thicknesses grown by metal-organic chemical vapor deposition technique have been investigated. It was found that the thickness of undoped GaN interlayers affected LEDs' performance greatly. The LED with 50 nm undoped GaN interlayer showed higher light output power and lower reverse-leakage current compared with the others at 20 mA. Based on electrical and optical characteristics analysis and numerical simulation, these improvements are mainly attributed to the improvement of the quality of depletion region by inserting an undoped GaN layer, as well as reduction of the Shockley-Read-Hall recombination in InGaN/GaN MQWs.


Urinary incontinence and health-related quality of life among older Americans with and without cancer: a cross-sectional study.
Few studies have investigated the impact of urinary incontinence (UI) on health-related quality of life (HRQOL) among cancer survivors. UI is prevalent in the general population and can be both an indicator of cancer and a side effect of cancer treatment. UI and cancer diagnoses have been associated with decreases in HRQOL. This study evaluates the prevalence of UI and the impact on HRQOL among older cancer survivors. The prevalence of UI among cancer survivors (breast, prostate, bladder, colorectal, lung, and endometrial/uterine cancers) and those without cancer was estimated using the SEER-MHOS database. Factors associated with UI were investigated using logistic regression and the impact of UI on SF-36 scores was determined using linear regression. Over 36% of SEER-MHOS beneficiaries without cancer reported UI and higher prevalence was noted among cancer survivors (37%-54% depending on cancer type). History of bladder, breast, endometrial/uterine, or prostate cancer was associated with higher prevalence of UI. UI was independently associated with both lower physical component scores (PCS) (-1.27; 95%CI:-1.34,-1.20) and mental component scores (MCS) (-1.75; 95%CI -1.83, -1.68). A suggested decreasing trend in the prevalence of UI was associated with a longer time since cancer diagnosis. UI was highly prevalent, especially in bladder, endometrial/uterine, and prostate cancer survivors. Improved recognition of UI risk among cancer survivors will help clinicians better anticipate and mediate the effect of UI on individuals' HRQOL.


Structure and function of an arabinoxylan-specific xylanase.
The enzymatic degradation of plant cell walls plays a central role in the carbon cycle and is of increasing environmental and industrial significance. The enzymes that catalyze this process include xylanases that degrade xylan, a β-1,4-xylose polymer that is decorated with various sugars. Although xylanases efficiently hydrolyze unsubstituted xylans, these enzymes are unable to access highly decorated forms of the polysaccharide, such as arabinoxylans that contain arabinofuranose decorations. Here, we show that a Clostridium thermocellum enzyme, designated CtXyl5A, hydrolyzes arabinoxylans but does not attack unsubstituted xylans. Analysis of the reaction products generated by CtXyl5A showed that all the oligosaccharides contain an O3 arabinose linked to the reducing end xylose. The crystal structure of the catalytic module (CtGH5) of CtXyl5A, appended to a family 6 noncatalytic carbohydrate-binding module (CtCBM6), showed that CtGH5 displays a canonical (α/β)(8)-barrel fold with the substrate binding cleft running along the surface of the protein. The catalytic apparatus is housed in the center of the cleft. Adjacent to the -1 subsite is a pocket that could accommodate an l-arabinofuranose-linked α-1,3 to the active site xylose, which is likely to function as a key specificity determinant. CtCBM6, which adopts a β-sandwich fold, recognizes the termini of xylo- and gluco-configured oligosaccharides, consistent with the pocket topology displayed by the ligand-binding site. In contrast to typical modular glycoside hydrolases, there is an extensive hydrophobic interface between CtGH5 and CtCBM6, and thus the two modules cannot function as independent entities.


The Utah paradigm of skeletal physiology: an overview of its insights for bone, cartilage and collagenous tissue organs.
In a 1960 paradigm of skeletal physiology, effector cells (chondroblasts, fibroblasts, osteoblasts, osteoclasts, etc.) regulated by nonmechanical agents wholly determined the architecture, strength, and health of bones, joints, fascia, ligaments, and tendons. Biomechanical and tissue-level phenomena had no roles in that paradigm. Subsequent studies and evidence slowly revealed skeletal tissue-level mechanisms and their functions, including biomechanical ones, as well as "game rules" that seem to govern them. That slow discovery process found that effector cells are only parts of tissue-level mechanisms, as kidney cells are only parts of nephrons and wheels are only parts of cars. Normally all those things help to determine skeletal architecture, strength, and health, and adding them to the 1960 paradigm led to the still-evolving Utah paradigm of skeletal physiology that concerns, in part, how load-bearing skeletal organs adapt to the voluntary mechanical loads on them. That caused controversies this article does not try to resolve; instead, it describes some issues they concern. In that regard, controversy can depend on how one assesses the relevance of facts to a problem more than on their accuracy. If a paradigm added new facts to a former one and the new one's advocates viewed all those facts as relevant, but the former's advocates questioned the relevance of some of the new facts, their views about a problem could differ even though each view depended on accurate facts. Readers would make their own judgments about the bearing of those ideas on this article's content.


Growth differentiation factor 11 locally controls anterior-posterior patterning of the axial skeleton.
Growth and differentiation factor 11 (GDF11) is a transforming growth factor β family member that has been identified as the central player of anterior-posterior (A-P) axial skeletal patterning. Mice homozygous for Gdf11 deletion exhibit severe anterior homeotic transformations of the vertebrae and craniofacial defects. During early embryogenesis, Gdf11 is expressed predominantly in the primitive streak and tail bud regions, where new mesodermal cells arise. On the basis of this expression pattern of Gdf11 and the phenotype of Gdf11 mutant mice, it has been suggested that GDF11 acts to specify positional identity along the A-P axis either by local changes in levels of signaling as development proceeds or by acting as a morphogen. To further investigate the mechanism of action of GDF11 in the vertebral specification, we used a Cdx2-Cre transgene to generate mosaic mice in which Gdf11 expression is removed in posterior regions including the tail bud, but not in anterior regions. The skeletal analysis revealed that these mosaic mice display patterning defects limited to posterior regions where Gdf11 expression is deficient, whereas displaying normal skeletal phenotype in anterior regions where Gdf11 is normally expressed. Specifically, the mosaic mice exhibited seven true ribs, a pattern observed in wild-type (wt) mice (vs. 10 true ribs in Gdf11-/- mice), in the anterior axis and nine lumbar vertebrae, a pattern observed in Gdf11 null mice (vs. six lumbar vertebrae in wt mice), in the posterior axis. Our findings suggest that GDF11, rather than globally acting as a morphogen secreted from the tail bud, locally regulates axial vertebral patterning.


Screening for blunt cerebrovascular injuries is cost-effective.
Screening for blunt carotid and vertebral injury (BCVI) is increasing without a clear understanding of whether the chosen screening approach is cost-effective. We hypothesized that screening for BCVI using computed tomography angiography (CTA) was cost-effective in populations at high risk for BCVI. A decision analysis was performed modeling current BCVI screening approaches: no screening, duplex ultrasound, magnetic resonance angiography, angiography, and CTA. Treatment options included antiplatelet therapy, anticoagulation, stents for pseudoaneurysm, and no treatment. Probability estimates for incidence of injury and stroke, sensitivity and specificity of the screening modality, and type of treatment were taken from published data. Average wholesale price and medicare reimbursement costs were used. Two populations were analyzed; high-risk and overall blunt trauma populations. Two perspectives were taken; societal (including lifetime stroke costs) and institutional (ignoring lifetime stroke costs). In the high-risk population, from a societal perspective, CTA has the lowest cost and stroke rate; $3,727 per patient screened with a 1% stroke rate. No treatment has the highest cost and stroke rate. From an institutional perspective, no screening is the least costly option but has an 11% stroke rate. Duplex ultrasound is the most cost-effective screening modality; $8,940 per stroke prevented. From the societal perspective, CTA is the most cost-effective screening strategy for patients at high risk for BCVI. From an institutional perspective, CTA prevents the most strokes at a reasonable cost.


A Case of Primary Mammary Analog Secretory Carcinoma (MASC) of the Thyroid Masquerading as Papillary Thyroid Carcinoma: Potentially More than a One Off.
We present the second reported mammary analog secretory carcinoma (MASC) apparently arising in the thyroid and propose a potential close relationship to ETV6-NTRK3 fusion papillary thyroid carcinoma. The patient, a 36 year old woman, presented with a neck mass of 1 year's duration. Imaging studies showed a tumor involving most of the thyroid with enlarged regional lymph nodes. FNA biopsy yielded a diagnosis of "papillary thyroid carcinoma". Resection revealed a 4.5 cm infiltrative tumor. Final diagnosis was "papillary thyroid carcinoma (PTC) consistent with diffuse sclerosing variant" with positive lymph nodes (2+/4) and margins. Histologic features included mixed microcystic, solid, follicular and papillary architecture, prominent nucleoli, abundant nuclear grooves and rare nuclear pseudo-inclusions. Despite radioactive iodine, radiotherapy and multiagent chemotherapy, the patient progressed over 6 years with local recurrence and additional lymph node involvement finally developing widespread distant metastases. Prompted by the breast carcinoma-like histopathology of a metastasis, immunohistochemical staining was performed and revealed strong expression of GATA3 and mammaglobin with no reactivity for thyroglobulin or TTF-1. The original tumor was then tested and showed the same immunoprofile. RT-PCR confirmed the presence of an ETV6-NTRK3 fusion consistent with a diagnosis of MASC. Our patient's clinical, imaging and morphologic features remarkably mimicked papillary thyroid carcinoma. At the molecular level, the ETV6-NTRK3 fusion in this patient involved exons reported in the rare "papillary thyroid carcinoma" with this translocation. Given the immunophenotype of this case, it is possible that at least some ETV6-NTRK3 fusion positive PTC are actually MASC masquerading as papillary thyroid carcinoma.


Preliminary in Vitro Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug-Drug Interactions.
EST64454 is a selective sigma-1 receptor ligand intended for orally administered pain treatment that showed a promising profile in the lead optimization process. As part of the preliminary compound profiling, the potential for future drug-drug interactions was explored in vitro. Both direct and time-dependent CYP inhibition for CYP1A2, 2C9, 2C19, 2D6 and 3A4 was studied in human liver microsomes. EST64454 showed a low potential for CYP inhibition (IC50 between 100 and 1000 µM) and as time-dependent inhibitor (IC50 shift mainly around 1). CYP induction studies with HepaRG™ cells revealed no CYP induction at concentrations ≤50 µM, as shown by the CYP1A2, 3A4 and 2B6 activities measured. Reaction phenotyping was assessed after incubation with recombinant human enzymes. Although a very low metabolism was observed, several enzymes catalyzed the formation of metabolites, including CYP3A4, 2C19 and flavin monooxygenases (FMO) 1 and 3. EST64454 was not a P-glycoprotein (P-gp) substrate and was highly permeable in Caco-2 cells. P-gp inhibition was only observed at 200 µM, the highest concentration studied. Preliminary studies suggest that neither CYP nor P-gp interaction of EST64454 would be of any concern for further development. At later stages, the interaction kinetics and the clinical relevance of these findings will be thoroughly evaluated.


The pyruvate kinase isoenzyme M2 (Tu M2-PK) as a tumour marker for renal cell carcinoma.
The M2 isoenzyme of pyruvate kinase (M2-PK) is specially expressed by tumour cells (Tu M2-PK) and has been detected in the peripheral blood of patients with renal cell carcinoma (RCC). We analysed the benefit of using Tu M2-PK as a tumour marker for primary detection of RCC by receiver operating characteristic (ROC) analysis. The area under the curve was 0.674, and the sensitivity, specificity and positive predictive value (PPV) were 44.4%, 87.5% and 88%, respectively, at the ROC optimal cut-off of 28.2 kU/L. We examined 71 patients. Since the marker sensitivity for detection of the early stages T1 and T2 was only 47% it is not suggested to use this marker for primary diagnosis of RCC. Its use as part of the confirmatory preoperative evaluation might be considered in view of its high PPV.


Can we control tuberculosis in high HIV prevalence settings?
The overlap between the epidemiology of HIV and tuberculosis and consequent rapid rise in numbers of patients with tuberculosis in many African countries has put a huge burden on health systems. The stigma of HIV has increased the existing stigma surrounding tuberculosis. There are three mechanisms by which we may reduce the number of cases of tuberculosis in a community: reducing transmission of tuberculosis, reducing reactivation of latent tuberculosis infection and reducing HIV transmission. Reinforcing the existing health service to find more cases, active case-finding in communities or enhanced case-finding in specific groups will reduce transmission of tuberculosis. However, health services that find it difficult to find cases efficiently will also find it difficult to support patients throughout treatment to achieve a cure. Partnership with traditional healers, community-based organizations and private practitioners could reduce this burden. Reactivation of tuberculosis among people living with HIV can be reduced by tuberculosis preventive therapy or by antiretroviral therapy. Programmes that identify people living with HIV can also implement enhanced tuberculosis case-finding increasing the benefits of the programme. However, the impact of widespread use of antiretroviral therapy may be to increase the number of people in a community who are mildly immunocompromised and the incidence of tuberculosis at a community level might rise. Any strategy that successfully reduces HIV transmission will benefit tuberculosis control, since around a third of all HIV-positive individuals will develop tuberculosis before they die. To control tuberculosis in high HIV prevalence settings, we must strengthen health systems to include not only expansion of the DOTS strategy but also full-blooded implementation of voluntary counselling and testing, enhanced and active tuberculosis case-finding, preventive therapy and better care for people living with HIV including antiretroviral therapy. The approach needed to control tuberculosis needs also to be integrated into broader development and poverty reduction goals.


Deep sequencing and genome-wide analysis reveals the expansion of MicroRNA genes in the gall midge Mayetiola destructor.
MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating post transcriptional gene expression. Gall midges encompass a large group of insects that are of economic importance and also possess fascinating biological traits. The gall midge Mayetiola destructor, commonly known as the Hessian fly, is a destructive pest of wheat and model organism for studying gall midge biology and insect - host plant interactions. In this study, we systematically analyzed miRNAs from the Hessian fly. Deep-sequencing a Hessian fly larval transcriptome led to the identification of 89 miRNA species that are either identical or very similar to known miRNAs from other insects, and 184 novel miRNAs that have not been reported from other species. A genome-wide search through a draft Hessian fly genome sequence identified a total of 611 putative miRNA-encoding genes based on sequence similarity and the existence of a stem-loop structure for miRNA precursors. Analysis of the 611 putative genes revealed a striking feature: the dramatic expansion of several miRNA gene families. The largest family contained 91 genes that encoded 20 different miRNAs. Microarray analyses revealed the expression of miRNA genes was strictly regulated during Hessian fly larval development and abundance of many miRNA genes were affected by host genotypes. The identification of a large number of miRNAs for the first time from a gall midge provides a foundation for further studies of miRNA functions in gall midge biology and behavior. The dramatic expansion of identical or similar miRNAs provides a unique system to study functional relations among miRNA iso-genes as well as changes in sequence specificity due to small changes in miRNAs and in their mRNA targets. These results may also facilitate the identification of miRNA genes for potential pest control through transgenic approaches.


Effect of Size and Shape of Nitrogen-Containing Aromatics on Conformational Preferences of DNA Containing Damaged Guanine.
The present work investigates the effects of the size and shape of the nitrogen-containing aromatic (NCA) skeleton on the structure of DNA damaged through adduct formation at C8 of 2'-deoxyguanosine (dG), a common DNA lesion associated with chemical carcinogenesis. Specifically, density functional theory (DFT) calculations (B3LYP-D3) and molecular dynamics (MD) simulations (AMBER) are performed on seven model adducts with systematic expansion of the NCA moiety. DFT calculations reveal that the NCA moiety shape affects the structure at the nucleobase-carcinogen linkage. Approximately 4.5 μs of MD simulations on damaged oligonucleotides adopting three established conformational themes (namely, B, W, and S) illustrate that the structure and lesion-site stabilization strongly depend on the NCA moiety shape and size, which provides insight into the repair propensity of C8-dG adducted DNA. Our results add bulky moiety shape to the growing list of previously established effects on the conformational and repair outcomes of damaged DNA (i.e., size, ionization state, substitution, linker type, and DNA sequence). Furthermore, this work illustrates the utility of a systematic set of model DNA lesions for understanding the structure-activity relationship for DNA damaged by carcinogens of different sizes and shapes, which should be used in future studies of the cellular processing of damaged DNA.


Patients' negative emotional cues and concerns in hospital consultations: a video-based observational study.
Little is known about the frequency and occurrence of patients' negative emotional cues and concerns (NECC) across specialties in hospital departments. Ninety-six consultations were videotaped in a general hospital. The VR-CoDES (Verona Coding Definitions of Emotional Sequences) were used to code the patients' NECC. Cohen's kappa was used to establish reliability between coders. Cohen's kappa was above 0.60. NECC were observed in more than half of the consultations. The number of NECC in the consultations was 163, with 109 negative emotional cues and 54 concerns. The mean number of NECC in the consultations was 1.69, with a median of 1. The first NECC in consultations were stated after a median duration of 5min 21s. We could not find significant differences related to the gender and age of the patient or the physician, or the specialty of the physician. More than half of the concerns were not preceded by a negative emotional cue. Few consultations contained more than 3 NECC, and NECC tended to be expressed relatively early. Patients' expressions of emotional issues are few, and most of them are subtle. Physicians should be thoroughly trained to identify and respond to them.


Improving Color Quality of Nanowire White Light-Emitting Diodes with Mn4+ Doped Fluoride Nanosheets.
A two-dimensional nanostructured fluoride red-emitting phosphor with an excellent quantum yield of ~91% is studied for cost-effective and high-color quality nanowire white light-emitting diodes (WLEDs). K2TiF6:Mn4+ phosphors are synthesized via an emulsification method using surfactants as sodium dodecyl sulphonate and oleic acid. The K2TiF6:Mn4+ phosphors in ultra-thin and nanosheet crystals are observed via scanning electron microscopy and high-resolution transmission electron microscopy. The surfactants are found to play a key role in inhibition of KTFM crystal growth process and stabilization of Mn4+ ions doping into the K2TiF6 host. The prepared phosphors exhibited intensive red emission at approximately 632 nm and excellent thermal stability in the range of 300-500 K upon 460 nm light excitation. Moreover, the K2TiF6:Mn4+ nanosheets were integrated on InGaN/AlGaN nanowire WLEDs for color quality study. The results show that the nanowire WLEDs with red-emitting phosphor exhibit unprecedentedly high color rendering index ~96.4, and correlated color temperature ~4450 K.


Bridging the gap between self-directed learning of nurse educators and effective student support.
Self-directed learning requires the ability to identify one's own learning needs, develop and implement a plan to gain knowledge and to monitor one's own progress. A lifelong learning approach cannot be forced, since it is in essence an internally driven process. Nurse educators can, however, act as role models to empower their students to become independent learners by modelling their own self-directed learning and applying a number of techniques in supporting their students in becoming ready for self-directed learning. The aim of the article is to describe the manifestations and implications of the gap between self-directed learning readiness of nurse educators and educational trends in supporting students. An instrumental case study design was used to gain insight into the manifestations and implications of self-directed learning of nurse educators. Based on the authentic foci of various critical incidents and literature, data were collected and constructed into a fictitious case. The authors then deductively analysed the case by using the literature on self-directed learning readiness as departure point. Four constructs of self-directed learning were identified, namely internal motivation, planning and implementation, self-monitoring and interpersonal communication. Supportive strategies were identified from the available literature. Nine responses by nurse educators based on the fictitious case were analysed.Analysis showed that readiness for self-directed learning in terms of the identified constructswas interrelated and not mutually exclusive of one other. The success of lifelong learning is the ability to engage in self-directed learning which requires openness to learning opportunities, good self-concept, taking initiative and illustrating independence in learning. Conscientiousness, an informed acceptance of a responsibility for one's own learning and creativity, is vital to one's future orientation towards goal-directed learning. Knowledge and understanding of one's own and students' selfdirected learning abilities are critical for nurse educators. In the nursing profession, it has been shown that self-directed learning by the nurse educators has a direct relationship towards the development of a lifelong learning approach by their students. Supporting students towards becoming self-directed learners throughout their professional life, in turn, will impact directly on the quality of nursing and midwifery practice. (Article to follow).


Sensitized solar cells with colloidal PbS-CdS core-shell quantum dots.
We report on the fabrication of PbS-CdS (core-shell) quantum dot (QD)-sensitized solar cells by direct adsorption of core-shell QDs on mesoporous TiO2 followed by 3-mercaptopropionic acid ligand exchange. PbS-CdS QD-sensitized solar cells show 4 times higher efficiency with respect to solar cells sensitized with PbS QDs. The significantly enhanced mean electron lifetime and electron diffusion length provide crucial evidence for the higher efficiency of the cell. The average electron lifetime increases with the thickness of the CdS shell, demonstrating that the CdS shell plays an important role in preventing carrier recombination. However, owing to the barrier provided by the offset between the conduction bands of CdS and the PbS core, the CdS shell also hinders carrier injection from PbS to TiO2. Herein, we studied the effect of the shell thickness on cell's performance, showing a power conversion efficiency of 1.28% for PbS QDs with a 0.5 nm CdS shell. In addition, we demonstrate that the CdS shell effectively prevents photo-corrosion of PbS, resulting in devices with highly stable photocurrent.


Optical conformal mapping.
An invisibility device should guide light around an object as if nothing were there, regardless of where the light comes from. Ideal invisibility devices are impossible, owing to the wave nature of light. This study develops a general recipe for the design of media that create perfect invisibility within the accuracy of geometrical optics. The imperfections of invisibility can be made arbitrarily small to hide objects that are much larger than the wavelength. With the use of modern metamaterials, practical demonstrations of such devices may be possible. The method developed here can also be applied to escape detection by other electromagnetic waves or sound.


Erbin regulates NRG1 signaling and myelination.
Neuregulin 1 (NRG1) plays a critical role in myelination. However, little is known about regulatory mechanisms of NRG1 signaling. We show here that Erbin, a protein that contains leucine-rich repeats (LRR) and a PSD95-Dlg-Zol (PDZ) domain and that interacts specifically with ErbB2, is necessary for NRG1 signaling and myelination of peripheral nervous system (PNS). In Erbin null mice, myelinated axons were hypomyelinated with reduced expression of P0, a marker of mature myelinating Schwann cells (SCs), whereas unmyelinated axons were aberrantly ensheathed in Remak bundles, with increased numbers of axons in the bundles and in pockets. The morphological deficits were associated with decreased nerve conduction velocity and increased sensory threshold to mechanistic stimulation. These phenotypes were duplicated in erbin(DeltaC/DeltaC) mice, in which Erbin lost the PDZ domain to interact with ErbB2. Moreover, ErbB2 was reduced at protein levels in both Erbin mutant sciatic nerves, and ErbB2 became unstable and NRG1 signaling compromised when Erbin expression was suppressed. These observations indicate a critical role of Erbin in myelination and identify a regulatory mechanism of NRG1 signaling. Our results suggest that Erbin, via the PDZ domain, binds to and stabilizes ErbB2, which is necessary for NRG1 signaling that has been implicated in tumorigenesis, heart development, and neural function.


Lipopolysaccharide reduces electrical coupling in microvascular endothelial cells by targeting connexin40 in a tyrosine-, ERK1/2-, PKA-, and PKC-dependent manner.
Electrical coupling along the endothelium is central in the arteriolar conducted response and in control of vascular resistance. It has been shown that exposure of endothelium to lipopolysaccharide (LPS, an initiating factor in sepsis) reduces intercellular communication in vitro and in vivo. The molecular basis for this reduction is not known. We examined the effect of LPS on electrical coupling in monolayers of cultured mouse microvascular endothelial cells (MMEC) derived from the mouse hindlimb skeletal muscle. To assess coupling, we measured the spread of electrical current injected into the monolayer and computed the monolayer intercellular resistance (inverse measure of coupling). LPS (10 microg/ml, 1 h) reduced coupling (i.e., increased resistance) in MMEC isolated from wild-type, connexin37 (Cx37) null and Cx43(G60S) (nonfunctional mutant) mice, but not in MMEC derived from Cx40 null mice. LPS also activated JNK1/2, p38 and ERK1/2 MAP kinases. Pretreatment of WT monolayers with ERK1/2 inhibitor U0126 (20 microM, 1 h) prevented the LPS-induced decrease in coupling, while inhibition of JNK1/2 with SP600125 (20 microM, 1 h) and p38 with a p38 inhibitor (10 nM, 1 h) had no effect. Furthermore, inhibition of tyrosine kinases with PP-2 (10 nM, 1 h), activation of PKA by 8-bromo-cAMP (1 mM, 5 min), and activation of PKC by bryostatin-2 (10 nM, 1 h) also prevented the reduction in coupling. We propose that LPS reduces inter-endothelial electrical coupling via tyrosine-, ERK1/2-, PKA-, and PKC-dependent signaling that targets Cx40. We suggest that this mechanism contributes to compromised arteriolar function following LPS exposure.


OBSERVING THE INFLUENCE OF MINDFULNESS AND ATTACHMENT STYLES THROUGH MOTHER AND INFANT INTERACTION: A LONGITUDINAL STUDY.
The cross-generational influence of attachment security or insecurity on caregiving is well-established. Recently, research has focused on mindfulness as a potential variable to interrupt the transmission of insecure attachment and disrupt its effect across generations. Thirty-six pregnant female participants completed the Five Facets Mindfulness Questionnaire and Relationship Questionnaire-Clinical Version at 30 weeks' gestation. Following the infant's birth, mothers and their babies participated in a video-recorded feeding session at 7 to 10 weeks' postpartum. It was predicted that a secure attachment style and higher levels of mindfulness measured prenatally would be associated with greater maternal responsiveness postpartum. The hypothesis was supported for both the secure and insecure (fearful and profoundly distrustful) attachment styles. Mindfulness did not mediate the relationship between attachment and maternal distress. The mindfulness subscale Non-Reacting was significantly associated with maternal response to distress. These findings support the role of prenatal mindfulness skills and attachment security for later postnatal maternal sensitivity to baby.


Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial.
Tubal ectopic pregnancy can be surgically treated by salpingectomy, in which the affected Fallopian tube is removed, or salpingotomy, in which the tube is preserved. Despite potentially increased risks of persistent trophoblast and repeat ectopic pregnancy, salpingotomy is often preferred over salpingectomy because the preservation of both tubes is assumed to offer favourable fertility prospects, although little evidence exists to support this assumption. We aimed to assess whether salpingotomy would improve rates of ongoing pregnancy by natural conception compared with salpingectomy. In this open-label, multicentre, international, randomised controlled trial, women aged 18 years and older with a laparoscopically confirmed tubal pregnancy and a healthy contralateral tube were randomly assigned via a central internet-based randomisation program to receive salpingotomy or salpingectomy. The primary outcome was ongoing pregnancy by natural conception. Differences in cumulative ongoing pregnancy rates were expressed as a fecundity rate ratio with 95% CI, calculated by Cox proportional-hazards analysis with a time horizon of 36 months. Secondary outcomes were persistent trophoblast and repeat ectopic pregnancy (expressed as relative risks [RRs] with 95% CIs) and ongoing pregnancy after ovulation induction, intrauterine insemination, or IVF. The researchers who collected data for fertility outcomes were masked to the assigned intervention, but patients and the investigators who analysed the data were not. All endpoints were analysed by intention to treat. We also did a (non-prespecified) meta-analysis that included the findings from the present trial. This trial is registered, number ISRCTN37002267. 446 women were randomly assigned between Sept 24, 2004, and Nov 29, 2011, with 215 allocated to salpingotomy and 231 to salpingectomy. Follow-up was discontinued on Feb 1, 2013. The cumulative ongoing pregnancy rate was 60·7% after salpingotomy and 56·2% after salpingectomy (fecundity rate ratio 1·06, 95% CI 0·81-1·38; log-rank p=0·678). Persistent trophoblast occurred more frequently in the salpingotomy group than in the salpingectomy group (14 [7%] vs 1 [<1%]; RR 15·0, 2·0-113·4). Repeat ectopic pregnancy occurred in 18 women (8%) in the salpingotomy group and 12 (5%) women in the salpingectomy group (RR 1·6, 0·8-3·3). The number of ongoing pregnancies after ovulation induction, intrauterine insemination, or IVF did not differ significantly between the groups. 43 (20%) women in the salpingotomy group were converted to salpingectomy during the initial surgery because of persistent tubal bleeding. Our meta-analysis, which included our own results and those of one other study, substantiated the results of the trial. In women with a tubal pregnancy and a healthy contralateral tube, salpingotomy does not significantly improve fertility prospects compared with salpingectomy. Netherlands Organisation for Health Research and Development (ZonMW), Region Västra Götaland Health & Medical Care Committee.


The Building Blocks of Interoperability. A Multisite Analysis of Patient Demographic Attributes Available for Matching.
Patient matching is a key barrier to achieving interoperability. Patient demographic elements must be consistently collected over time and region to be valuable elements for patient matching. We sought to determine what patient demographic attributes are collected at multiple institutions in the United States and see how their availability changes over time and across clinical sites. We compiled a list of 36 demographic elements that stakeholders previously identified as essential patient demographic attributes that should be collected for the purpose of linking patient records. We studied a convenience sample of 9 health care systems from geographically distinct sites around the country. We identified changes in the availability of individual patient demographic attributes over time and across clinical sites. Several attributes were consistently available over the study period (2005-2014) including last name (99.96%), first name (99.95%), date of birth (98.82%), gender/sex (99.73%), postal code (94.71%), and full street address (94.65%). Other attributes changed significantly from 2005-2014: Social security number (SSN) availability declined from 83.3% to 50.44% (p<0.0001). Email address availability increased from 8.94% up to 54% availability (p<0.0001). Work phone number increased from 20.61% to 52.33% (p<0.0001). Overall, first name, last name, date of birth, gender/sex and address were widely collected across institutional sites and over time. Availability of emerging attributes such as email and phone numbers are increasing while SSN use is declining. Understanding the relative availability of patient attributes can inform strategies for optimal matching in healthcare.


The Asia-Pacific consensus on ulcerative colitis.
Inflammatory bowel disease (IBD) is increasing in many parts of the Asia-Pacific region. There is a need to improve the awareness of IBD and develop diagnostic and management recommendations relevant to the region. This evidence-based consensus focuses on the definition, epidemiology and management of ulcerative colitis (UC) in Asia. A multi-disciplinary group developed the consensus statements, reviewed the relevant literature, and voted on them anonymously using the Delphi method. The finalized statements were reviewed to determine the level of consensus, evidence quality and strength of recommendation. Infectious colitis must be excluded prior to diagnosing UC. Typical histology and macroscopic extent of the disease seen in the West is found in the Asia-Pacific region. Ulcerative colitis is increasing in many parts of Asia with gender distribution and age of diagnosis similar to the West. Extra-intestinal manifestations including primary sclerosing cholangitis are rarer than in the West. Clinical stratification of disease severity guides management. In Japan, leukocytapheresis is a treatment option. Access to biologic agents remains limited due to high cost and concern over opportunistic infections. The high endemic rates of hepatitis B virus infection require stringent screening before initiating immune-suppressive agents. Vaccination and prophylactic therapies should be initiated on a case-by-case basis and in accordance with local practice. Colorectal cancer complicates chronic colitis. A recent increase in UC is reported in the Asia-Pacific region. These consensus statements aim to improve the recognition of UC and assist clinicians in its management with particular relevance to the region.


Arteriolosclerotic ulcer of Martorell.
In 1945, Martorell described ischaemic leg ulcers in patients with hypertension. He suggested that the ischaemic necrosis was secondary to a hypertensive arteriolar disease and referred to them as 'hypertensive ischaemic ulcers'. In recent years, the specific entity of these ulcers has been questioned. Others claim they have a much higher incidence, but presume the diagnosis is frequently missed. Almost 900 cases of Martorell's ulcers have been reported in literature since the first description. A systematic review and comprehensive search of literature (evidence-based) was needed to characterize this type of ulcer. Based on aetiology and histopathology, it seems to be justified to maintain the name 'arteriolosclerotic ulcer of Martorell'. We conclude that the arteriolosclerotic ulcer of Martorell is a specific entity with its own clinical and histological diagnostic keys, wound management and preventive measures. We introduce a set of criteria that may be used to facilitate diagnosing arteriolosclerotic ulcer of Martorell as well as a flowchart that includes diagnosis, treatment and prevention of this particular type of vascular leg ulcer.


Improving Human Induced Pluripotent Stem Cell-Derived Megakaryocyte Differentiation and Platelet Production.
Several protocols exist for generating megakaryocytes (MKs) and platelets from human induced pluripotent stem cells (hiPSCs) with limited efficiency. We observed previously that mesoderm induction improved endothelial and stromal differentiation. We, therefore, hypothesized that a protocol modification prior to hemogenic endothelial cell (HEC) differentiation will improve MK progenitor (MKP) production and increase platelet output. We further asked if basic media composition affects MK maturation. In an iterative process, we first compared two HEC induction protocols. We found significantly more HECs using the modified protocol including activin A and CHIR99021, resulting in significantly increased MKs. MKs released comparable platelet amounts irrespective of media conditions. In a final validation phase, we obtained five-fold more platelets per hiPSC with the modified protocol (235 ± 84) compared to standard conditions (51 ± 15; p < 0.0001). The regenerative potency of hiPSC-derived platelets was compared to adult donor-derived platelets by profiling angiogenesis-related protein expression. Nineteen of 24 angiogenesis-related proteins were expressed equally, lower or higher in hiPSC-derived compared to adult platelets. The hiPSC-platelet's coagulation hyporeactivity compared to adult platelets was confirmed by thromboelastometry. Further stepwise improvement of hiPSC-platelet production will, thus, permit better identification of platelet-mediated regenerative mechanisms and facilitate manufacture of sufficient amounts of functional platelets for clinical application.


Multiple Cosmic Sources for Meteorite Macromolecules?
The major organic component in carbonaceous meteorites is an organic macromolecular material. The Murchison macromolecular material comprises aromatic units connected by aliphatic and heteroatom-containing linkages or occluded within the wider structure. The macromolecular material source environment remains elusive. Traditionally, attempts to determine source have strived to identify a single environment. Here, we apply a highly efficient hydrogenolysis method to liberate units from the macromolecular material and use mass spectrometric techniques to determine their chemical structures and individual stable carbon isotope ratios. We confirm that the macromolecular material comprises a labile fraction with small aromatic units enriched in (13)C and a refractory fraction made up of large aromatic units depleted in (13)C. Our findings suggest that the macromolecular material may be derived from at least two separate environments. Compound-specific carbon isotope trends for aromatic compounds with carbon number may reflect mixing of the two sources. The story of the quantitatively dominant macromolecular material in meteorites appears to be made up of more than one chapter.


Characteristics of Japanese inflammatory bowel disease susceptibility loci.
There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD. For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta-analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls. We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA-DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA-DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFα to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24). Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.


Focal adhesion kinase is involved in rabies virus infection through its interaction with viral phosphoprotein P.
The rabies virus (RABV) phosphoprotein P is a multifunctional protein: it plays an essential role in viral transcription and replication, and in addition, RABV P has been identified as an interferon antagonist. Here, a yeast two-hybrid screen revealed that RABV P interacts with the focal adhesion kinase (FAK). The binding involved the 106-to-131 domain, corresponding to the dimerization domain of P and the C-terminal domain of FAK containing the proline-rich domains PRR2 and PRR3. The P-FAK interaction was confirmed in infected cells by coimmunoprecipitation and colocalization of FAK with P in Negri bodies. By alanine scanning, we identified a single mutation in the P protein that abolishes this interaction. The mutant virus containing a substitution of Ala for Arg in position 109 in P (P.R109A), which did not interact with FAK, is affected at a posttranscriptional step involving protein synthesis and viral RNA replication. Furthermore, FAK depletion inhibited viral protein expression in infected cells. This provides the first evidence of an interaction of RABV with FAK that positively regulates infection. Rabies virus exhibits a small genome that encodes a limited number of viral proteins. To maintain efficient virus replication, some of them are multifunctional, such as the phosphoprotein P. We and others have shown that P establishes complex networks of interactions with host cell components. These interactions have revealed much about the role of P and about host-pathogen interactions in infected cells. Here, we identified another cellular partner of P, the focal adhesion kinase (FAK). Our data shed light on the implication of FAK in RABV infection and provide evidence that P-FAK interaction has a proviral function.


Intravascular oxygen sensors with novel applications for bedside respiratory monitoring.
Measurement allows us to quantify various parameters and variables in natural systems. In addition, by measuring the effect by which a perturbation of one part of the system influences the system as a whole, insights into the functional mechanisms of the system can be inferred. Clinical monitoring has a different role to that of scientific measurement. Monitoring describes measurements whose prime purpose is not to give insights into underlying mechanisms, but to provide information to 'warn' of imminent events. What is often more important is the description of trends in measured variables. In this article, we give some examples - focussed around oxygen sensors - of how new sensors can make important measurements and might in the future contribute to improved clinical management.


The Ret(C620R) mutation affects renal and enteric development in a mouse model of Hirschsprung's disease.
In rare families RET tyrosine kinase receptor substitutions located in exon 10 (especially at positions 609, 618, and 620) can concomitantly cause the MEN 2A (multiple endocrine neoplasia type 2A) or FMTC (familial medullary thyroid carcinoma) cancer syndromes, and Hirschsprung's disease (HSCR). No animal model mimicking the co-existence of the MEN 2 pathology and HSCR is available, and the association of these activating mutations with a developmental defect still represents an unresolved problem. The aim of this work was to investigate the significance of the RET(C620R) substitution in the pathogenesis of both gain- and loss-of-function RET-associated diseases. We report the generation of a line of mice carrying the C620R mutation in the Ret gene. Although Ret(C620R) homozygotes display severe defects in kidney organogenesis and enteric nervous system development leading to perinatal lethality. Ret(C620R) heterozygotes recapitulate features characteristic of HSCR including hypoganglionosis of the gastrointestinal tract. Surprisingly, heterozygotes do not show any defects in the thyroid that might be attributable to a gain-of-function mutation. The Ret(C620R) allele is responsible for HSCR and affects the development of kidneys and the enteric nervous system (ENS). These mice represent an interesting model for studying new therapeutic approaches for the treatment of HSCR disease.


Anti-inflammatory activity of leaf essential oil from Cinnamomum longepaniculatum (Gamble) N. Chao.
The anti-inflammatory activity of the essential oil from C. longepaniculatum was evaluated by three experimental models including the dimethyl benzene-induced ear edema in mice, the carrageenan-induced paw edema in rat and the acetic acid-induced vascular permeability in mice. The influence of the essential oil on histological changes and prostaglandin E2 (PGE2), histamine and 5-hydroxytryptamine (5-HT) production associated with carrageenan-induced rat paw edema was also investigated. The essential oil (0.5, 0.25, 0.13 ml/kg b.w.) showed significantly inhibition of inflammation along with a dose-dependent manner in the three experimental models. The anti-inflammatory activity of essential oil was occurred both in early and late phase and peaked at 4 h after carrageenan injection. The essential oil resulted in a dose dependent reduction of the paw thickness, connective tissue injury and the infiltration of inflammatory cell. The essential oil also significantly reduced the production of PGE2, histamine and 5-HT in the exudates of edema paw induced by carrageenan. Both the essential oil and indomethacin resulted relative lower percentage inhibition of histamine and 5-HT than that of PGE2 at 4 h after carrageenan injection.


Effect of deer velvet on sexual function in men and their partners: a double-blind, placebo-controlled study.
The use of alternative medicines and herbal remedies is an increasing trend in Western societies. For years, people have taken products made of deer velvet for their alleged beneficial effects on sexual function. There has been no scientific investigation of the effects of deer velvet powder on the sexual functioning of human males. This study investigated sexual function in men during a 12-week double-blind, placebo-controlled trial of deer velvet. Thirty-two volunteer male participants, aged 45-65 years, and their partners, were randomly assigned to either the deer velvet or placebo study group. The males took capsules containing ground deer velvet or placebo everyday for 12 weeks. Two sexual function questionnaires (the International Index of Erectile Function and the Brief Index of Sexual Function for Women) used at pre- and posttreatment assessed changes in sexual functioning in males and their partners. Blood tests at baseline, and end of study, determined levels of sex-related hormones in male participants. There were no significant differences in the sexual behavior of the men taking deer velvet compared with the men taking placebo capsules. There were no significant hormone changes from baseline to the end of the study in either group of men. We conclude that in normal males there was no advantage in taking deer velvet to enhance sexual function. All alternative health products or nutritional supplements should be subjected to randomized placebo-controlled trials to determine efficacy.


Precision rehabilitation for aphasia by patient age, sex, aphasia severity, and time since stroke? A prespecified, systematic review-based, individual participant data, network, subgroup meta-analysis.
Stroke rehabilitation interventions are routinely personalized to address individuals' needs, goals, and challenges based on evidence from aggregated randomized controlled trials (RCT) data and meta-syntheses. Individual participant data (IPD) meta-analyses may better inform the development of precision rehabilitation approaches, quantifying treatment responses while adjusting for confounders and reducing ecological bias. We explored associations between speech and language therapy (SLT) interventions frequency (days/week), intensity (h/week), and dosage (total SLT-hours) and language outcomes for different age, sex, aphasia severity, and chronicity subgroups by undertaking prespecified subgroup network meta-analyses of the RELEASE database. MEDLINE, EMBASE, and trial registrations were systematically searched (inception-Sept2015) for RCTs, including ⩾ 10 IPD on stroke-related aphasia. We extracted demographic, stroke, aphasia, SLT, and risk of bias data. Overall-language ability, auditory comprehension, and functional communication outcomes were standardized. A one-stage, random effects, network meta-analysis approach filtered IPD into a single optimal model, examining SLT regimen and language recovery from baseline to first post-intervention follow-up, adjusting for covariates identified a-priori. Data were dichotomized by age (⩽/> 65 years), aphasia severity (mild-moderate/ moderate-severe based on language outcomes' median value), chronicity (⩽/> 3 months), and sex subgroups. We reported estimates of means and 95% confidence intervals. Where relative variance was high (> 50%), results were reported for completeness. 959 IPD (25 RCTs) were analyzed. For working-age participants, greatest language gains from baseline occurred alongside moderate to high-intensity SLT (functional communication 3-to-4 h/week; overall-language and comprehension > 9 h/week); older participants' greatest gains occurred alongside low-intensity SLT (⩽ 2 h/week) except for auditory comprehension (> 9 h/week). For both age-groups, SLT-frequency and dosage associated with best language gains were similar. Participants ⩽ 3 months post-onset demonstrated greatest overall-language gains for SLT at low intensity/moderate dosage (⩽ 2 SLT-h/week; 20-to-50 h); for those > 3 months, post-stroke greatest gains were associated with moderate-intensity/high-dosage SLT (3-4 SLT-h/week; ⩾ 50 hours). For moderate-severe participants, 4 SLT-days/week conferred the greatest language gains across outcomes, with auditory comprehension gains only observed for ⩾ 4 SLT-days/week; mild-moderate participants' greatest functional communication gains were associated with similar frequency (⩾ 4 SLT-days/week) and greatest overall-language gains with higher frequency SLT (⩾ 6 days/weekly). Males' greatest gains were associated with SLT of moderate (functional communication; 3-to-4 h/weekly) or high intensity (overall-language and auditory comprehension; (> 9 h/weekly) compared to females for whom the greatest gains were associated with lower-intensity SLT (< 2 SLT-h/weekly). Consistencies across subgroups were also evident; greatest overall-language gains were associated with 20-to-50 SLT-h in total; auditory comprehension gains were generally observed when SLT > 9 h over ⩾ 4 days/week. We observed a treatment response in most subgroups' overall-language, auditory comprehension, and functional communication language gains. For some, the maximum treatment response varied in association with different SLT-frequency, intensity, and dosage. Where differences were observed, working-aged, chronic, mild-moderate, and male subgroups experienced their greatest language gains alongside high-frequency/intensity SLT. In contrast, older, moderate-severely impaired, and female subgroups within 3 months of aphasia onset made their greatest gains for lower-intensity SLT. The acceptability, clinical, and cost effectiveness of precision aphasia rehabilitation approaches based on age, sex, aphasia severity, and chronicity should be evaluated in future clinical RCTs.


Combination of Phospholipid Complex and Submicron Emulsion Techniques for Improving Oral Bioavailability and Therapeutic Efficacy of Water-Insoluble Drug.
Water-insoluble drugs cannot be absorbed effectively through the gastrointestinal tract due to insufficient solubility and often face the problems of low bioavailability and poor therapeutic efficacy. To overcome these biopharmaceutical challenges, lipid-based formulations were suggested and have been researched in recent years. In this study, we used atorvastatin as a model drug to prepare a phospholipid complex prodrug system to upgrade its lipophilicity and further developed a drug loaded submicron emulsion to improve its in vivo bioavailability. The mean particle size and zeta potential of submicron emulsion were 122.7 nm and -22.7 mV. Intestinal absorption of atorvastatin from submicron emulsion was significantly improved compared with free drug, and the absorption rate constant ( Ka) and apparent permeability coefficients ( Papp) increase 2.88-fold and 2.45-fold, respectively. After oral administration, the atorvastatin plasma concentration of the emulsion group was much higher than that of free drug and the area under the curve (AUC) reached to 4.033 mg/L·h (2.58-fold). In vivo pharmacodynamics results revealed that atorvastatin submicron emulsion showed excellent antihyperlipidemia efficacy by reducing the total cholesterol, triglyceride, and low density lipoprotein cholesterol (LDL-cholesterol) levels and simultaneously increasing the high density lipoprotein cholesterol (HDL-cholesterol) level in comparison with Lipitor. In conclusion, drug-phospholipid complex loaded submicron emulsion was a promising oral delivery system for improving in vivo absorption behavior and therapeutic efficacy for water-insoluble drugs.


The orally available, synthetic ether lipid edelfosine inhibits T cell proliferation and induces a type I interferon response.
The drug edelfosine is a synthetic analog of 2-lysophosphatidylcholine. Edelfosine is incorporated by highly proliferating cells, e.g. activated immune cells. It acts on cellular membranes by selectively aggregating the cell death receptor Fas in membrane rafts and interference with phosphatidylcholine (PC) synthesis with subsequent induction of apoptosis. Edelfosine has been proposed for the treatment of autoimmune diseases like multiple sclerosis (MS). Earlier studies on the animal model of MS, experimental autoimmune encephalomyelitis (EAE), have generated first evidence for the efficacy of edelfosine treatment. However, it is unknown if the previously described mechanisms for edelfosine action, which are derived from in vitro studies, are solely responsible for the amelioration of EAE or if edelfosine may exert additional effects, which may be beneficial in the context of autoimmunity. Since it was the purpose of our studies to assess the potential usefulness of edelfosine for the treatment of MS, we examined its mechanism/s of action on immune functions in human T cells. Low doses of edelfosine led to a decrease in homeostatic proliferation, and further studies of the mechanism/s of action by genome-wide transcriptional profiling showed that edelfosine reduces the expression of MHC class II molecules, of molecules involved in MHC class II-associated processing and presentation, and finally upregulated a series of type I interferon-associated genes. The inhibition of homeostatic proliferation, as well as the effects on MHC class II expression and -presentation, and the induction of type I interferon-associated genes are novel and interesting in the context of developing edelfosine for clinical use in MS and possibly also other T cell-mediated autoimmune diseases.


Establishing a minimum standard for collaborative research in federal environmental agencies.
There is a general consensus that-given the magnitude of the challenges facing our nation's natural resource managers-the rate, efficiency, and effectiveness of linking research to decision making must be enhanced. Many reports have touched on this issue, most of them culminating with the exhortation to "foster more interactions between scientists and users," but very few documents provide details or assign responsibility to drive the interactions that most agree should happen. As a result, many natural science and engineering programs "talk the talk"-that is, they say they do collaborative research with intended users; however, upon inspection, few of them "walk the walk" by effectively supporting collaboration throughout the research process. Moreover, when called to support transition to application in specific ways, research agencies often balk, most often objecting that research programs cannot afford to take any support away from funding more research. They may also argue that science works best for society when it is freed from concerns related to application. In this paper we will 1) review the cultural conflict that often underlies disagreements about collaborative research, 2) offer details on the basic ingredients required to achieve a minimum standard for collaborative research, 3) suggest an approach for determining the appropriate level of support for collaborative research, given various research goals, and 4) recommend specific steps for motivating scientists and stakeholders to participate in collaborative research.


Bloodstream infections in mechanical circulatory support device recipients in the International Society of Heart and Lung Transplantation Mechanically Assisted Circulation Support Registry: Epidemiology, risk factors, and mortality.
We used multicenter international data from the International Society of Heart and Lung Transplantation Mechanically Assisted Circulation Support (IMACS) registry to determine bloodstream infection (BSI) event rate, independent risk factors, and association with mortality. Included were patients registered in IMACS from January 2013 through December 2015, assessed BSI event rate of mechanical circulatory support (MCS) and non-MCS-related BSIs, and conducted univariate and multivariate analyses between BSI with baseline characteristics and mortality. We documented 1,606 BSIs in 1,231 of 10,171 MCS recipients (12%), with an event rate of 2.43 BSIs/100 patient-months within 3 months after implant (early onset) and 1.03 BSIs/100 patient-months after 3 months (late onset). Of these episodes, 1,378 (85.8%) were non- MCS-related BSI. Increasing body mass index and bilirubin were independent correlates of MCS-related BSI. Independent correlates of non-MCS-related BSI included older age, higher body mass index, previous cardiac surgery, baseline chronic renal disease and dialysis, pre-implant frailty, presence of biventricular assist device, total artificial heart or right ventricular assist device, and Interagency Registry for Mechanically Assisted Circulatory Support category 1. Survival after 3 months after implant of patients who developed early-onset BSI was 56.9% at 24 months vs 77.4% in patients without early-onset BSI (p < 0.001). Early-onset BSI was an independent correlate of mortality at 3 months after implantation (hazard ratio, 2.56; 95% confidence interval, 2.09-3.15; p < 0.001). Early-onset BSI was associated with significantly increased 24-month mortality. More than 85% of these BSIs were not device related. There is an opportunity for infection prevention practices to decrease the BSI event rate, which may affect 24-month survival. These data can also serve as benchmarking for individual institutions.