Increased confusion and memory loss in households, 2011 Behavioral Risk Factor Surveillance System.
Using data from the 2011 Behavioral Risk Factor Surveillance System (BRFSS), we examined households in 13 states (N = 81,012) in which the respondent or another adult household member experienced increased confusion or memory loss (ICML) in the preceding 12 months. A total of 12.6% of households reported at least 1 adult who experienced ICML, and in 5.4% of households all adults experienced ICML. Based on these results, an estimated 4 million households in these 13 states have a member with ICML, potentially affecting more than 10 million people. This study can inform public health communication campaigns aimed at increasing awareness of the signs and symptoms of cognitive decline and augment community planning efforts so that the needs of households in which 1 or more adults has cognitive decline are considered.


UnSplicer: mapping spliced RNA-Seq reads in compact genomes and filtering noisy splicing.
Accurate mapping of spliced RNA-Seq reads to genomic DNA has been known as a challenging problem. Despite significant efforts invested in developing efficient algorithms, with the human genome as a primary focus, the best solution is still not known. A recently introduced tool, TrueSight, has demonstrated better performance compared with earlier developed algorithms such as TopHat and MapSplice. To improve detection of splice junctions, TrueSight uses information on statistical patterns of nucleotide ordering in intronic and exonic DNA. This line of research led to yet another new algorithm, UnSplicer, designed for eukaryotic species with compact genomes where functional alternative splicing is likely to be dominated by splicing noise. Genome-specific parameters of the new algorithm are generated by GeneMark-ES, an ab initio gene prediction algorithm based on unsupervised training. UnSplicer shares several components with TrueSight; the difference lies in the training strategy and the classification algorithm. We tested UnSplicer on RNA-Seq data sets of Arabidopsis thaliana, Caenorhabditis elegans, Cryptococcus neoformans and Drosophila melanogaster. We have shown that splice junctions inferred by UnSplicer are in better agreement with knowledge accumulated on these well-studied genomes than predictions made by earlier developed tools.


Quantification of contralateral differences of the scaphoid: a comparison of bone geometry in three dimensions.
The purpose of this study was to accurately quantify contralateral differences of the scaphoid in three-dimensional space to evaluate the feasibility of using the healthy contralateral bone as a reconstruction template in the preoperative planning of complex mal- or nonunions. Three-dimensional surface models of the left and right scaphoids were reconstructed from computed tomography images and compared in 26 individuals. Left-right differences were quantified with respect to volume, surface area, length, and surface-to-surface deviation. The average left-right differences in volume, surface area, and length were 95.4 mm(3) (SD 66.2 mm(3)), 32.7 mm(2) (SD 22.9 mm(32)), and 0.28 mm (SD 0.4 mm), respectively. The average surface-to-surface deviation between the sides was 0.26 mm (SD 0.2 mm). High statistical correlation (Pearson) between the left and the right side was found in all evaluated measures.


[Methodology of clinical trials for non-muscle infiltrating bladder cancer. Objective evaluation: standardization requirements].
The formulation of proper evaluation criteria after superficial bladder cancer therapy poses several methodological problems that are often peculiar to the disease. The Achilles' heel of many trials is possibly found in the criteria used for the evaluation of the trial outcomes. As a consequence of that, total agreement regarding the criteria for response and the evaluation of response is needed. The adoption of standard response criteria should be given high priority. Uniform response criteria should be chosen because they meet standards of reliability and statistical validity. Thus, the criteria must be reproducible, and they should correlate with some measures of patient's benefit, such as quantity and quality of survival. A proposal of standardization in superficial bladder cancer clinical trials is presented based upon current knowledge on the methodology for conducting clinical trials and upon the experience coming from major clinical research groups.


Patulous upper esophageal sphincter - an unusual endoscopic finding.
The upper esophageal sphincter (UES) has various important functions, such as protection of the airway from aspiration and conduct of bolus into esophagus, which are controlled by complex neuronal mechanisms. The functions will be affected when there is malfunction of the UES due to various etiologies. Here we present an 80-year-old male with non-progressive dysphagia and patulous UES incidentally found on esophagoduodenoscopy. There are no documented cases of idiopathic patulous UES in literature. Endoscopists must be aware of this rare condition while evaluating a patient presenting with oropharyngeal dysphagia.


What are the key factors governing the nucleation of CO2 hydrate?
Microsecond molecular dynamics simulations were performed to provide molecular insights into the nucleation of CO2 hydrate. The adsorption of sufficient CO2 molecules around CO2 hydration shells is revealed to be crucial to effectively stabilize the hydrogen bonds formed therein, catalyzing the hydration shells into hydrate cages and inducing the nucleation. Moreover, a high aqueous CO2 concentration is found to be another key factor governing the nucleation of CO2 hydrate, and only above a critical concentration can the nucleation of CO2 hydrate occur. The 4151062 cages, with size similar to the CO2 hydration shell and an elliptical space closely matching a linear CO2 molecule, play a dominant role in initiating the nucleation and remain the most abundant. The incipient CO2 hydrate is rather amorphous due to the abundance of metastable cages (mostly 4151062).


Melatonin role preventing steatohepatitis and improving liver transplantation results.
Liver steatosis is a prevalent process that is induced due to alcoholic or non-alcoholic intake. During the course of these diseases, the generation of reactive oxygen species, followed by molecular damage to lipids, protein and DMA occurs generating organ cell death. Transplantation is the last-resort treatment for the end stage of both acute and chronic hepatic diseases, but its success depends on ability to control ischemia-reperfusion injury, preservation fluids used, and graft quality. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other because of its efficacy in organs; melatonin has been investigated to improve the outcome of organ transplantation by reducing ischemia-reperfusion injury and due to its synergic effect with organ preservation fluids. Moreover, this indolamine also prevent liver steatosis. That is important because this disease may evolve leading to an organ transplantation. This review summarizes the observations related to melatonin beneficial actions in organ transplantation and ischemic-reperfusion models.


The low-affinity phosphate transporter PitA is dispensable for in vitro growth of Mycobacterium smegmatis.
Mycobacteria have been shown to contain an apparent redundancy of high-affinity phosphate uptake systems, with two to four copies of such systems encoded in all mycobacterial genomes sequenced to date. In addition, all mycobacteria also contain at least one gene encoding the low-affinity phosphate transporter, Pit. No information is available on a Pit system from a Gram-positive microorganism, and the importance of this system in a background of multiple other phosphate transporters is unclear. The aim of this study was to determine the physiological role of the PitA phosphate transporter in Mycobacterium smegmatis. Expression of pitA was found to be constitutive under a variety of growth conditions. An unmarked deletion mutant in pitA of M. smegmatis was created. The deletion did not affect in vitro growth or phosphate uptake of M. smegmatis. Expression of the high-affinity transporters, PstSCAB and PhnDCE, was increased in the pitA deletion strain. PitA is the only low-affinity phosphate transport system annotated in the genome of M. smegmatis. The lack of phenotype of the pitA deletion strain shows that this system is dispensable for in vitro growth of this organism. However, increased expression of the remaining phosphate transporters in the mutant indicates a compensatory mechanism and implies that PitA is indeed used for the uptake of phosphate in M. smegmatis.


Prehospital Anemia Care A Review of Symptoms, Evaluation, and Management.
The ongoing evolution of prehospital medical care continues to advance beyond immediate triage care. Prehospital care is even more important to consider in theaters with extended evacuation times and limited local medical assets. Although blood loss is often associated with settings of acute traumatic hemorrhage in military medicine, the possibility for other hematologic compromise necessitating urgent action requires medics operating in these environments to have a fundamental knowledge of the pathophysiology, manifestations, and stabilization measures of anemia to aid their patients prior to, or in lieu of, evacuation. Continued development of and access to point-of-care testing in increasingly forward-deployed settings further enable medics to perform these tasks. Here, we provide a brief review of hemoglobin function and composition, and presentation and management considerations of anemia, to assist medics in their treatment efforts. We also address specific concerns for battlefield and atraumatic presentations.


The histone deacetylase inhibitor trichostatin A reduces lysosomal pH and enhances cisplatin-induced apoptosis.
High activity of histone deacetylases (HDACs) has been documented in several types of cancer and may be associated with survival advantage. In a head and neck squamous cell carcinoma cell line, cisplatin-induced apoptosis was augmented by pretreatment with the HDAC inhibitor trichostatin A. Apoptosis was accompanied by lysosomal membrane permeabilization (LMP), as shown by immunoblotting of the lysosomal marker protease cathepsin B in extracted cytosol and by immunofluorescence. Moreover, LAMP-2 (lysosomal associated membrane protein-2) was translocated from lysosomal membranes and found in a digitonin extractable fraction together with cytosolic proteins and pretreatment with trichostatin A potentiated the release. Overall, protein level of LAMP-2 was decreased during cell death and, interestingly, inhibition of cysteine cathepsins, by the pan-cysteine cathepsin inhibitor zFA-FMK, prevented loss of LAMP-2. The importance of LAMP-2 for lysosomal membrane stability, was confirmed by showing that LAMP-2 knockout MEFs (mouse embryonic fibroblasts) were more sensitive to cisplatin as compared to the corresponding wildtype cells. Trichostatin A reduced lysosomal pH from 4.46 to 4.25 and cell death was prevented when lysosomal pH was increased by NH(4)Cl, or when inhibiting the activity of lysosomal proteases. We conclude that trichostatin A enhances cisplatin induced cell death by decreasing lysosomal pH, which augments cathepsin activity resulting in reduced LAMP-2 level, and might promote LMP.


Evaluating scaling models in biology using hierarchical Bayesian approaches.
Theoretical models for allometric relationships between organismal form and function are typically tested by comparing a single predicted relationship with empirical data. Several prominent models, however, predict more than one allometric relationship, and comparisons among alternative models have not taken this into account. Here we evaluate several different scaling models of plant morphology within a hierarchical Bayesian framework that simultaneously fits multiple scaling relationships to three large allometric datasets. The scaling models include: inflexible universal models derived from biophysical assumptions (e.g. elastic similarity or fractal networks), a flexible variation of a fractal network model, and a highly flexible model constrained only by basic algebraic relationships. We demonstrate that variation in intraspecific allometric scaling exponents is inconsistent with the universal models, and that more flexible approaches that allow for biological variability at the species level outperform universal models, even when accounting for relative increases in model complexity.


Immunological relatedness of the LamB proteins among members of Enterobacteriaceae.
We have studied the immunological relatedness of LamB proteins from a wide range of enterobacterial species, using antibodies directed against denatured Escherichia coli K12 and Klebsiella pneumoniae LamB proteins (LamBE.c. and LamBK.p., respectively), and anti-peptide antibodies directed against 10 distinct loops of LamB from E. coli K12 predicted to protrude either side of the outer membrane. We have shown that a protein immunologically related to LamBE.c. and LamBK.p. was present in all members of Enterobacteriaceae tested. A protein recognized by several anti-peptide antibodies was identified in E. coli, Shigella sonnei, Salmonella typhimurium and Kleb. pneumoniae, as well as in two Citrobacter species, two Enterobacter species and Kluyvera ascorbata. The recognition patterns obtained with the anti-peptide antibodies were in agreement with the LamB protein sequence data available. They indicated that the cell surface and also the periplasmic loops of LamB are subject to great antigenic variability.


A review on chemical composition, mechanical properties, and manufacturing work flow of additively manufactured current polymers for interim dental restorations.
Additive manufacturing (AM) technologies can be used to fabricate 3D-printed interim dental restorations. The aim of this review is to report the manufacturing workflow, its chemical composition, and the mechanical properties that may support their clinical application. These new 3D-printing provisional materials are typically composed of monomers based on acrylic esters or filled hybrid material. The most commonly used AM methods to manufacture dental provisional restorations are stereolithography (SLA) and material jetting (MJ) technologies. To the knowledge of the authors, there is no published article that analyzes the chemical composition of these new 3D-printing materials. Because of protocol disparities, technology selected, and parameters of the printers and material used, it is notably difficult to compare mechanical properties results obtained in different studies. Although there is a growing demand for these high-tech restorations, additional information regarding the chemical composition and mechanical properties of these new provisional printed materials is required. Additive manufacturing technologies are a current option to fabricate provisional dental restorations; however, there is very limited information regarding its chemical composition and mechanical properties that may support their clinical application.


Quantitative fluorescence in situ hybridization of microbial communities in the rumens of cattle fed different diets.
At present there is little quantitative information on the identity and composition of bacterial populations in the rumen microbial community. Quantitative fluorescence in situ hybridization using newly designed oligonucleotide probes was applied to identify the microbial populations in liquid and solid fractions of rumen digesta from cows fed barley silage or grass hay diets with or without flaxseed. Bacteroidetes, Firmicutes, and Proteobacteria were abundant in both fractions, constituting 31.8 to 87.3% of the total cell numbers. They belong mainly to the order Bacteroidales (0.1 to 19.2%), hybridizing with probe BAC1080; the families Lachnospiraceae (9.3 to 25.5%) and Ruminococcaceae (5.5 to 23.8%), hybridizing with LAC435 and RUM831, respectively; and the classes Deltaproteobacteria (5.8 to 28.3%) and Gammaproteobacteria (1.2 to 8.2%). All were more abundant in the rumen communities of cows fed diets containing silage (75.2 to 87.3%) than in those of cows fed diets containing hay (31.8 to 49.5%). The addition of flaxseed reduced their abundance in the rumens of cows fed silage-based diets (to 45.2 to 58.7%) but did not change markedly their abundance in the rumens of cows fed hay-based diets (31.8 to 49.5%). Fibrolytic species, including Fibrobacter succinogenes and Ruminococcus spp., and archaeal methanogens accounted for only a small proportion (0.4 to 2.1% and 0.2 to 0.6%, respectively) of total cell numbers. Depending on diet, between 37.0 and 91.6% of microbial cells specifically hybridized with the probes used in this study, allowing them to be identified in situ. The identities of other microbial populations (8.4 to 63.0%) remain unknown.


Family size and old-age wellbeing: effects of the fertility transition in Mexico.
The present study aims to determine how family size affects psycho-social, economic and health wellbeing in old age differently across two cohorts with declining fertility. The data are from the 2012 Mexican Health and Ageing Study (MHAS) including respondents aged 50+ (N = 13,102). Poisson (standard and zero-inflated) and logistic regressions are used to model determinants of wellbeing in old age: psycho-social (depressive symptoms), economic (consumer durables and insurance) and health (chronic conditions). In the younger cohort, having fewer children is associated with fewer depressive symptoms and chronic conditions, and better economic well-being. For the older cohort, having fewer children is associated with lower economic wellbeing and higher odds of being uninsured. Lower fertility benefited the younger cohort (born after 1937), whereas the older cohort (born in 1937 or earlier) benefited from lower fertility only in chronic conditions. Further research is needed to continue exploring the old-age effects of the fertility transition.


Evaluation of the kinetics and mechanism of action of anti-integration host factor-mediated disruption of bacterial biofilms.
The extracellular polymeric substance produced by many human pathogens during biofilm formation often contains extracellular DNA (eDNA). Strands of bacterial eDNA within the biofilm matrix can occur in a lattice-like network wherein a member of the DNABII family of DNA-binding proteins is positioned at the vertex of each crossed strand. To date, treatment of all biofilms tested with antibodies directed against one DNABII protein, Integration Host Factor (IHF), results in significant disruption. Here, using non-typeable Haemophilus influenzae as a model organism, we report that this effect was rapid, IHF-specific and mediated by binding of transiently dissociated IHF by anti-IHF even when physically separated from the biofilm by a nucleopore membrane. Further, biofilm disruption fostered killing of resident bacteria by previously ineffective antibiotics. We propose the mechanism of action to be the sequestration of IHF upon dissociation from the biofilm eDNA, forcing an equilibrium shift and ultimately, collapse of the biofilm. Further, antibodies against a peptide positioned at the DNA-binding tips of IHF were as effective as antibodies directed against the native protein. As incorporating eDNA and associated DNABII proteins is a common strategy for biofilms formed by multiple human pathogens, this novel therapeutic approach is likely to have broad utility.


Requirement of the inositol trisphosphate receptor for activation of store-operated Ca2+ channels.
The coupling mechanism between endoplasmic reticulum (ER) calcium ion (Ca2+) stores and plasma membrane (PM) store-operated channels (SOCs) is crucial to Ca2+ signaling but has eluded detection. SOCs may be functionally related to the TRP family of receptor-operated channels. Direct comparison of endogenous SOCs with stably expressed TRP3 channels in human embryonic kidney (HEK293) cells revealed that TRP3 channels differ in being store independent. However, condensed cortical F-actin prevented activation of both SOC and TRP3 channels, which suggests that ER-PM interactions underlie coupling of both channels. A cell-permeant inhibitor of inositol trisphosphate receptor (InsP3R) function, 2-aminoethoxydiphenyl borate, prevented both receptor-induced TRP3 activation and store-induced SOC activation. It is concluded that InsP3Rs mediate both SOC and TRP channel opening and that the InsP3R is essential for maintaining coupling between store emptying and physiological activation of SOCs.


Auditory and audiovisual inhibition of return.
Two experiments examined any inhibition-of-return (IOR) effects from auditory cues and from preceding auditory targets upon reaction times (RTs) for detecting subsequent auditory targets. Auditory RT was delayed if the preceding auditory cue was on the same side as the target, but was unaffected by the location of the auditory target from the preceding trial, suggesting that response inhibition for the cue may have produced its effects. By contrast, visual detection RT was inhibited by the ipsilateral presentation of a visual target on the preceding trial. In a third experiment, targets could be unpredictably auditory or visual, and no peripheral cues intervened. Both auditory and visual detection RTs were now delayed following an ipsilateral versus contralateral target in either modality on the preceding trial, even when eye position was monitored to ensure central fixation throughout. These data suggest that auditory target-target IOR arises only when target modality is unpredictable. They also provide the first unequivocal evidence for cross-modal IOR, since, unlike other recent studies (e.g., Reuter-Lorenz, Jha, & Rosenquist, 1996; Tassinari & Berlucchi, 1995; Tassinari & Campara, 1996), the present cross-modal effects cannot be explained in terms of response inhibition for the cue. The results are discussed in relation to neurophysiological studies and audiovisual links in saccade programming.


Role of Goosecoid, Xnot and Wnt antagonists in the maintenance of the notochord genetic programme in Xenopus gastrulae.
The Xenopus trunk organiser recruits neighbouring tissues into secondary trunk axial and paraxial structures and itself differentiates into notochord. The inductive properties of the trunk organiser are thought to be mediated by the secretion of bone morphogenetic protein (BMP) antagonists. Ectopic repression of BMP signals on the ventral side is sufficient to mimic the inductive properties of the trunk organiser. Resultant secondary trunks contain somite and neural tube, but no notochord. We show that inhibition of BMP signalling is sufficient for the initiation of the trunk organiser genetic programme at the onset of gastrulation. During late gastrulation, however, this programme is lost, due to an invasion of secreted Wnts from neighbouring tissues. Maintenance of this programme requires co-repression of BMP and Wnt signalling within the presumptive notochord region. To shed light on the molecular cascade that leads to the repression of the Wnt pathway, we looked for individual organiser genes whose overexpression could complement the inhibition of BMP signalling to promote notochord formation in the secondary trunks. Two genes, gsc and Xnot, were thus identified and shown to act in different ways. Xnot acts as a transcriptional repressor within the mesodermal region. Gsc acts in deeper vegetal cells, where it regulates Frzb expression to maintain Xnot expression in the neighbouring notochord territory. These results suggest that, during gastrulation, the necessary repression of Wnt/beta-catenin signalling in notochord precursors is achieved by the action of secreted inhibitors, such as Frzb, emitted by gsc-expressing dorsal vegetal cells.


How deaths can help clinicians and policy-makers understand the risks of novel psychoactive substances.
Novel psychoactive substances (NPS), especially those newly created, are largely an unknown quantity, particularly in terms of their potential serious adverse effects. This means that policy-makers and clinicians are under-informed about appropriate responses. Collation of detailed information on deaths related to NPS use can help in providing knowledge and understanding these aspects of the NPS phenomenon. The purpose of this review is to outline the role(s) which such evidence-based data can play in this respect. UK NPS-related cases demonstrate differences in definitions used by the General Mortality Registers, and differences between countries, not only in terms of the type of NPS implicated in deaths, but the number and extent of such deaths over time. NPS deaths are continuing to increase numerically and as a proportion of all drug-poisoning deaths. In order to better understand how specific molecules contribute to and/or cause death, detailed information collected by Special Mortality Registers can provide examples of substances' modes of action, adverse effects, symptomatology, treatment interventions, mechanisms of death, etc. This information can provide clinicians and policy-makers with objective information on the serious harms from such emerging molecules. Such evidence-based advice informs public health interventions, service provision and policy decisions on regulation and control of NPS. However, without reliable, accurate and complete information that is correctly collated, scientifically analysed and disseminated in a timely manner, an understanding of the phenomenon of what deaths can be ascribed to NPS, their characteristics and nature will remain unachieved, and thus limit what can be done to reduce them.


Sensitivity of ID NOW and RT-PCR for detection of SARS-CoV-2 in an ambulatory population.
Diagnosis of SARS-CoV-2 (COVID-19) requires confirmation by reverse transcription-polymerase chain reaction (RT-PCR). Abbott ID NOW provides fast results but has been criticized for low sensitivity. Here we determine the sensitivity of ID NOW in an ambulatory population presented for testing. The study enrolled 785 symptomatic patients, of whom 21 were positive by both ID NOW and RT-PCR, and 2 only by RT-PCR. All 189 asymptomatic patients tested negative. The positive percent agreement between the ID NOW assay and the RT-PCR assay was 91.3%, and negative percent agreement was 100%. The results from the current study were included into a larger systematic review of literature where at least 20 subjects were simultaneously tested using ID NOW and RT-PCR. The overall sensitivity for ID NOW assay was calculated at 84% (95% confidence interval 55-96%) and had the highest correlation to RT-PCR at viral loads most likely to be associated with transmissible infections.


[History and biology: possible dialogues, necessary distances].
Evolution has often been rejected as a theory incompatible with proper historical reflection. While there are undoubtedly insurmountable barriers between biology and the study of man and society, a rigorous analysis of Darwinist theory demonstrates epistemological areas of contact between history and evolutionary biology. The amazing temporal perspective shared by both areas of knowledge points to some bridges of communication, like the importance of the event and of creation processes, the rejection of teleology and the idea of progress, the complexity of events between chance and necessity, and the impossibility of making predictions. This affords an opportunity for a transdisciplinary approach at a moment of various contemporary challenges.


Opinions regarding the effectiveness of non-pharmacological measures in prevention of cardiovascular disease in the Czech Republic.
Cardiovascular diseases are the most common cause of deaths. Cardiovascular mortality is influenced by several factors that can be changed by our behaviour. The goal of this study was to survey the opinions of physicians and nurses on the topic of preventative cardiovascular risk factors. The inquiry was carried out using a standardized structured interviewer-respondent interview (face-to-face). The final form of the interview was based on the results of a pre-investigation. The study was anonymous, participation was voluntary, and the actual interview did not contain any controversial ethical questions. To meet these goals, a non-standardized questionnaire for nurses and physicians was developed. The questions evaluated the interest, coping difficulties, and efficiency of multimodal interventions in practice. The study sample included 1000 physicians and 1000 nurses. The results were statistically evaluated. The survey of physician and nurse opinions showed that patients were primarily interested in interventions in the area of nutrition, weight loss, and coping with pharmacotherapy; however, the overall lack of interest in smoking cessation was a surprising result. Physicians and nurses viewed smoking cessation as the most difficult risk factors to influence, followed by nutrition changes, and weight loss. It was noteworthy that more than half of the interviewed physicians and nurses were of the opinion that behavioral interventions were only sometimes or rarely effective. The results of our study show that nurses and physicians largely agree on behavioral risk factors and how to influence them. Nurses and physicians in Czech health care generally agree that patients are interested in influencing the above risk factors, being least interested in exercise and smoking cessation. Nurses and physicians also consider smoking reduction and weight loss as particularly difficult risk factors to manage. Results from this study will contributed to the overall goal of preparing and implementing short-term and long-term interventions in preventive cardiology.


Writing social determinants into and out of cancer control: an assessment of policy practice.
A large literature concurs that social determinants of health (SDH) are demonstrable, important, and insufficiently attended to in policy and practice. A resulting priority for research should be to determine how the social determinants of health can best be addressed. In this paper we support the more effective transfer of social determinants research into policy by: (1) describing a qualitative analysis of thirty-two cancer control policy documents from six English-speaking OECD countries and two transnational organizations, demonstrating great variability in the treatment of social determinants in these policies; (2) critiquing these various policy practices in relation to their likely impact on social determinants of health; and (3) advancing a tool that policy writers can use to assess the way in which social determinants of health have been addressed in their work. In the sample of policy documents, the distinction between structural and intermediate determinants, population-based and targeted interventions, and their respective relationships to equity were not always clear. The authors identified four approaches to social determinants (acknowledging SDH, auditing SDH, stating aims regarding SDH and setting out actions on SDH), and five ways of writing about the relationship between social determinants and cancer risk. These five discourses implied, respectively: that group membership was intrinsically risky; that not enough was known about SDH; that risk arose from choices made by individuals; that groups were constrained by circumstance; or that structural change was necessary. Socio-cultural factors were generally presented negatively, though New Zealand policies modeled a possible alternative. Based on their empirical work, the authors propose a matrix and a set of questions to guide the development and assessment of health policy.


Invasive papillary carcinoma of male breast.
Breast carcinoma is uncommon in males and constitutes less than one per cent of all cancers in men. Invasive papillary carcinoma is a rare morphological type of breast cancer. Since papillary carcinoma has a favorable prognosis as compared to other histopathological subtypes, an accurate diagnosis is essential. We report two cases of this rare histological type of male breast cancer. A 62-year-old man presented with a lump in the central quadrant of right breast and underwent simple mastectomy. Histological examination showed features of invasive papillary carcinoma. The other case was of an 81-year-old male patient with a subareolar mass in the right breast. Wide local excision of the lump showed features of an intracystic invasive papillary carcinoma. The patient subsequently underwent simple mastectomy, however, no residual tumor was found in the resection specimen. Both the patients were free of disease at one year of follow-up. Invasive papillary carcinoma is an uncommon morphological type of breast cancer in males. The intracystic variant of papillary carcinoma is extremely unusual and may be missed on cytological examination. A thorough sampling is essential for an accurate diagnosis of invasion in these cases.


An interactive visualization tool and data model for experimental design in systems biology.
Experimental design is important, but is often under-supported, in systems biology research. To improve experimental design, we extend the visualization of complex sphingolipid pathways to study biosynthetic origin in SphinGOMAP. We use the ganglio-series sphingolipid dataset as a test bed and the Java Universal Network / Graph Framework (JUNG) visualization toolkit. The result is an interactive visualization tool and data model for experimental design in lipid systems biology research. We improve the current SphinGOMAP in terms of interactive visualization by allowing (i) choice of four different network layouts, (ii) dynamic addition / deletion of on-screen molecules and (iii) mouse-over to reveal detailed molecule data. Future work will focus on integrating various lipid-relevant data systematically i.e. SphinGOMAP biosynthetic data, Lipid Bank molecular data (Japan) and Lipid MAPS metabolic pathway data (USA). We aim to build a comprehensive and interactive communication platform to improve experimental design for scientists globally in high-throughput lipid systems biology research.


The often overlooked posterior dislocation of the shoulder.
Unlike most shoulder dislocations, the posterior dislocation is truly a diagnostic challenge to the treating physician because it may be missed more often than it is recognized. In fact, more than 60% of posterior dislocations are misdiagnosed initially by the treating orthopedic surgeon, and the correct diagnosis is often delayed for months or years. A history of seizures, electroshock, or a fall onto a flexed, adducted arm should alert the physician to the possibility of posterior dislocation. A careful physical examination with comparison to the unaffected arm must be performed with particular attention given to subtle posterior fullness and anterior flatness of the shoulder, along with a lack of external rotation and abduction. A radiographic trauma series made in the scapular plane must always be obtained in cases of shoulder trauma to rule out posterior dislocation. A computed tomographic scan may also be necessary. The correct diagnosis of this injury will facilitate proper orthopedic evaluation and treatment and will reduce the incidence of missed posterior shoulder dislocation and its associated morbidity.


Electron microscopy of cartilage and bone matrix at the distal epiphyseal line of the femur in the newborn infant.
An examination of the fine structure of cartilage and bone matrix at the distal epiphyseal line of the femur of a newborn infant has revealed the following information. Cartilage matrix is composed of a network of widely spaced fibers without obvious periodic banding. Calcification is first seen about the level of the third chondrocyte capsule distal to the furthest penetration of the capillaries. It starts as a haphazard deposition of crystals which have no obvious relationship to the location of the fibers. The process of calcification is completed before ossification commences but the central zone of matrix remains only partly mineralized. Bone matrix is formed over a bar of calcified cartilage. Fibers, recognizable as collagen, are deposited in a loose network in a narrow zone between the osteoblasts and cartilage. These fibers are 2 to 5 times as wide as the fibers in epiphyseal cartilage. Calcification then begins in the osteoid, crystals being first laid down irregularly on or close to the fibers. As they increase in number, the crystals tend to line up along the fibers and eventually are arranged so that the periodicity of the underlying collagen is emphasized. In such an area the fibers are more tightly packed than when uncalcified. There is no change observed in the calcified cartilage at this level. The extracellular matrices of this epiphyseal cartilage and bone can be distinguished from one another in the electron microscope.


Quantifying the mechanisms of domain gain in animal proteins.
Protein domains are protein regions that are shared among different proteins and are frequently functionally and structurally independent from the rest of the protein. Novel domain combinations have a major role in evolutionary innovation. However, the relative contributions of the different molecular mechanisms that underlie domain gains in animals are still unknown. By using animal gene phylogenies we were able to identify a set of high confidence domain gain events and by looking at their coding DNA investigate the causative mechanisms. Here we show that the major mechanism for gains of new domains in metazoan proteins is likely to be gene fusion through joining of exons from adjacent genes, possibly mediated by non-allelic homologous recombination. Retroposition and insertion of exons into ancestral introns through intronic recombination are, in contrast to previous expectations, only minor contributors to domain gains and have accounted for less than 1% and 10% of high confidence domain gain events, respectively. Additionally, exonization of previously non-coding regions appears to be an important mechanism for addition of disordered segments to proteins. We observe that gene duplication has preceded domain gain in at least 80% of the gain events. The interplay of gene duplication and domain gain demonstrates an important mechanism for fast neofunctionalization of genes.


Temporal trends in ambulance diversion in a mid-sized metropolitan area.
To evaluate the amount of ambulance diversion in an emergency medical services (EMS) system and to investigate potential predictive factors. Ambulance diversion status of hospitals in the four-county metropolitan Portland, Oregon, area has been recorded for approximately 15 years. These data are used by EMS transporting agencies to determine appropriate hospital destination for their patients. The authors calculated the total yearly hospital ambulance diversion time for "Total Ambulance Divert (TAD)" and "Critical Care Divert (CCD)" for the time period between January 1, 1996, and December 31, 1999. Yearly EMS 9-1-1-generated patient transport volume, hospital emergency department (ED) census volume, total population, amount of health maintenance organization (HMO) penetration, and number of licensed and available hospital beds were calculated for each yearly interval. Kendall's tau-b correlation was used to determine significant secular trends. Potential predictive factors for the amount of ambulance diversion were tested using Pearson's correlation. Total TAD increased 122.5% (p = 0.04), total CCD increased 64.4% (p = 0.50), total EMS transport volume increased 16.1% (p = 0.04), total ED census increased 9.4% (p = 0.04), total licensed beds decreased 5.7% (p = 0.17), total available beds decreased 15.8% (p = 0.17), HMO penetration increased 4.7% (p = 0.04), and total population increased 9.7% (p = 0.04) over the four-year study period. CCD and TAD were not significantly related to each other (p = 0.50). The only significant factor associated with the increase in TAD was number of available beds (p = 0.03). There were no significant factors associated with CCD. TAD increased significantly over time and was associated only with the decrease in available hospital beds.


Ru(ii)-Catalyzed C-H activation and annulation of salicylaldehydes with monosubstituted and disubstituted alkynes.
The Ru(ii)-catalyzed C-H activation and annulation reaction of salicylaldehydes and disubstituted alkynes affords chromones in high yields. This reaction also works with terminal alkynes and tolerates a wide range of sensitive functional groups. The selectivity pattern of this Ru(ii)-catalyzed annulation reaction is different from the known Au(i), Rh(iii)-catalyzed annulation reactions of salicylaldehydes and terminal alkynes.


Small Molecule Inhibitors of NFkB Reverse Iron Overload and Hepcidin Deregulation in a Zebrafish Model for Hereditary Hemochromatosis Type 3.
Hereditary hemochromatosis (HH) is one of the most common genetic disorders in Caucasian populations, with no viable therapeutic options except phlebotomy. We describe a zebrafish model of human HH (HH) created by targeted mutagenesis of the gene encoding transferrin receptor 2 ( tfr2). TFR2 mutations in humans lead to HH Type 3, a rare but severe form of the disease. The tfr2 mutant model in zebrafish recapitulates the defining features of HH3: iron overload and suppression of hepcidin, the iron regulatory hormone. Using in vivo chemical screens in zebrafish embryos, we identify a new small molecule inducer of hepcidin: SC-514, a specific chemical inhibitor of NFkB signaling. Using independent small molecule inhibitors of the NFkB pathway, we demonstrate that inhibition of NFkB signaling causes induction of hepcidin transcription and reduction of iron overload in the HH3 model. This first successful chemical intervention for hereditary hemochromatosis may also have relevance in treatment of other very prevalent iron regulatory iron overload disorders such as thalassemia.


Unintended durotomy in lumbar degenerative spinal surgery: a 10-year systematic review of the literature.
OBJECT Unintended durotomy is a common occurrence during lumbar spinal surgery, particularly in surgery for degenerative spinal conditions, with the reported incidence rate ranging from 0.3% to 35%. The authors performed a systematic literature review on unintended lumbar spine durotomy, specifically aiming to identify the incidence of durotomy during spinal surgery for lumbar degenerative conditions. In addition, the authors analyzed the incidence of durotomy when minimally invasive surgical approaches were used as compared with that following a traditional midline open approach. METHODS A MEDLINE search using the term "lumbar durotomy" (under the 2015 medical subject heading [MeSH] "cerebrospinal fluid leak") was conducted on May 13, 2015, for English-language medical literature published in the period from January 1, 2005, to May 13, 2015. The resulting papers were categorized into 3 groups: 1) those that evaluated unintended durotomy rates during open-approach lumbar spinal surgery, 2) those that evaluated unintended durotomy rates during minimally invasive spine surgery (MISS), and 3) those that evaluated durotomy rates in comparable cohorts undergoing MISS versus open-approach lumbar procedures for similar lumbar pathology. RESULTS The MEDLINE search yielded 116 results. A review of titles produced 22 potentially relevant studies that described open surgical procedures. After a thorough review of individual papers, 19 studies (comprising 15,965 patients) pertaining to durotomy rates during open-approach lumbar surgery were included for analysis. Using the Oxford Centre for Evidence-Based Medicine (CEBM) ranking criteria, there were 7 Level 3 prospective studies and 12 Level 4 retrospective studies. In addition, the authors also included 6 studies (with a total of 1334 patients) that detailed rates of durotomy during minimally invasive surgery for lumbar degenerative disease. In the MISS analysis, there were 2 prospective and 4 retrospective studies. Finally, the authors included 5 studies (with a total of 1364 patients) that directly compared durotomy rates during open-approach versus minimally invasive procedures. Studies of open-approach surgery for lumbar degenerative disease reported a total of 1031 durotomies across all procedures, for an overall durotomy rate of 8.11% (range 2%-20%). Prospectively designed studies reported a higher rate of durotomy than retrospective studies (9.57% vs 4.32%, p = 0.05). Selected MISS studies reported a total of 93 durotomies for a combined durotomy rate of 6.78%. In studies of matched cohorts comparing open-approach surgery with MISS, the durotomy rates were 7.20% (34 durotomies) and 7.02% (68), respectively, which were not significantly different. CONCLUSIONS Spinal surgery for lumbar degenerative disease carries a significant rate of unintended durotomy, regardless of the surgical approach selected by the surgeon. Interpretation of unintended durotomy rates for lumbar surgery is limited by a lack of prospective and cohort-matched controlled studies.


Induction of hair follicle dermal papilla cell properties in human induced pluripotent stem cell-derived multipotent LNGFR(+)THY-1(+) mesenchymal cells.
The dermal papilla (DP) is a specialised mesenchymal component of the hair follicle (HF) that plays key roles in HF morphogenesis and regeneration. Current technical difficulties in preparing trichogenic human DP cells could be overcome by the use of highly proliferative and plastic human induced pluripotent stem cells (hiPSCs). In this study, hiPSCs were differentiated into induced mesenchymal cells (iMCs) with a bone marrow stromal cell phenotype. A highly proliferative and plastic LNGFR(+)THY-1(+) subset of iMCs was subsequently programmed using retinoic acid and DP cell activating culture medium to acquire DP properties. The resultant cells (induced DP-substituting cells [iDPSCs]) exhibited up-regulated DP markers, interacted with human keratinocytes to up-regulate HF related genes, and when co-grafted with human keratinocytes in vivo gave rise to fibre structures with a hair cuticle-like coat resembling the hair shaft, as confirmed by scanning electron microscope analysis. Furthermore, iDPSCs responded to the clinically used hair growth reagent, minoxidil sulfate, to up-regulate DP genes, further supporting that they were capable of, at least in part, reproducing DP properties. Thus, LNGFR(+)THY-1(+) iMCs may provide material for HF bioengineering and drug screening for hair diseases.


Time-variable expression levels of mazF, atlE, sdrH, and bap genes during biofilm formation in Staphylococcus epidermidis.
Staphylococcus epidermidis is an opportunistic pathogen causing infections related to the usage of implants and medical devices. Pathogenicity of this microorganism is mainly linked to its capability to form biofilm structures. Biofilm formation vastly depends on several factors including different proteins. We studied the expression levels of three proteins including SdrH, Bap, AtlE, and MazF at different time intervals during the course of biofilm formation. In this study, a catheter-derived S. epidermidis isolate with strong ability of biofilm formation was selected. PCR assay was used to detect sdrH, bap, atlE, and mazF genes in this isolate. Real-time PCR was used to determine the expression levels of these genes after 4, 8, and 20 h during the course of biofilm formation. The studied genes showed different expression levels at different time intervals during biofilm formation by real-time PCR method. Expression levels of atlE and sdrH genes were the highest at 4 h, whereas bap gene showed the highest expression level at 8 h during the course of biofilm formation. In addition, the expression level of mazF gene peaked at 4 h and then progressively decreased at 8 and 20 h. Our results suggest the importance of AtlE, SdrH, and MazF proteins in the establishment and development of the biofilm structure. In addition, our results showed the important role of protein Bap in the accumulation of biofilm structure. Future studies are required to understand the exact role of MazF in the process of biofilm formation.


Schisandrin B inhibits the proliferation of human lung adenocarcinoma A549 cells by inducing cycle arrest and apoptosis.
Lung cancer is the leading cause of cancer death in the world. Schizandrin B (Sch B) is one of the main dibenzocyclooctadiene lignans present in the fruit of Schisandra chinensis (Schisandraceae). Sch B has multiple functions against cancer. The aim of this study was to determine the effect of Sch B on the proliferation, cell cycling, apoptosis and invasion of lung adenocarcinoma A549 cells by MTT, flow cytometry, wound healing and transwell invasion assays. Treatment with Sch B inhibited the proliferation of A549 cells in a dose-dependent manner. Sch B induced cell cycle arrest at G0/G1 phase by down-regulating the expression of cyclin D1, cyclin-dependent kinase (CDK)4, and CDK6, but up-regulating p53 and p21 expression in A549 cells. Furthermore, Sch B triggered A549 cell apoptosis by increasing Bax, cleaved caspase-3, 9, Cyto C, but decreasing Bcl-2 and PCNA expression. In addition, Sch B inhibited the invasion and migration of A549 cells by down-regulating the expressions of HIF-1, VEGF, MMP-9 and MMP-2. Therefore, Sch B has potent anti-tumor activity and may be a promising traditional Chinese medicine for human lung carcinoma.


Methods to identify and prioritize research projects and perform embedded research in learning healthcare systems.
The Embedded Healthcare Research Conference aimed to promote and enhance research-operations partnerships in diverse health care settings. Within this conference, the Priorities and Methods Workgroup set out to define a vision of embedded research that leverages diverse methods to address clearly articulated research questions of importance to health systems. The Workgroup session involved a combination of small and large group discussions around three broadly focused topics: the integration of embedded research within the existing quality improvement (QI) ecosystem; the identification, prioritization and formulation of embedded research questions; the creation of an embedded research "tool kit." Workgroup participants envisioned a future for embedded research that is characterized by authentic engagement between researchers and health system leaders; seamless integration between research, QI and clinical operations; clear and explicit articulation of research questions; an appropriate balance between rigor and relevance in applied methodology; alignment between study design, available resources and the importance of the knowledge to be gained; efficient processes; and bi-directional communication. Important barriers to achieving this vision include limited access to executive leaders, silos that discourage integration of research and QI, generally low tolerance for disruption in high-risk clinical settings, limited access to data, and limited availability of researchers with requisite skills and training. Embedded research holds potential to enhance the relevance, value and use of research, while also creating generalizable knowledge. Key recommendations include building authentic relationships, discouraging silos, encouraging innovation and experimentation, and expanding opportunities for funding research in delivery systems.


Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function.
Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β-NAD+. Hence, mice lacking PARP-1 or PARP-2 show DNA perturbations ranging from altered DNA integrity to impaired DNA repair. These effects stem from the central role that PARP-1 and PARP-2 have on the cellular response to DNA damage. Failure to mount a proper response culminates in cell death. Accordingly, PARP inhibitors are emerging as promising drugs in cancer therapy. However, the full impact of these inhibitors on immunity, including B-cell antibody production, remains elusive. Given that mice carrying dual PARP-1 and PARP-2 deficiency develop early embryonic lethality, we crossed PARP-1-deficient mice with mice carrying a B-cell-conditional PARP-2 gene deletion. We found that the resulting dually PARP-1 and PARP-2-deficient mice had perturbed bone-marrow B-cell development as well as profound peripheral depletion of transitional and follicular but not marginal zone B-cells. Of note, bone-marrow B-cell progenitors and peripheral mature B-cells were conserved in mice carrying either PARP-1 or PARP-2 deficiency. In dually PARP-1 and PARP-2-deficient mice, B-cell lymphopenia was associated with increased DNA damage and accentuated death in actively proliferating B-cells. Moreover, dual PARP-1 and PARP-2 deficiency impaired antibody responses to T-independent carbohydrate but not to T-dependent protein antigens. Notwithstanding the pivotal role of PARP-1 and PARP-2 in DNA repair, combined PARP-1 and PARP-2 deficiency did not perturb the DNA-editing processes required for the generation of a protective antibody repertoire, including Ig V(D)J gene recombination and IgM-to-IgG class switching. These findings provide key information as to the potential impact of PARP inhibitors on humoral immunity, which will facilitate the development of safer PARP-targeting regimens against cancer.


Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study.
The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. We aimed to investigate the relation between QuantiFERON-TB Gold In-Tube (QFT) conversion interferon-γ values and risk of subsequent active tuberculosis disease and of QFT reversion. We analysed data from a reported vaccine efficacy trial of the tuberculosis vaccine MVA85A in South Africa. QFT negative, HIV uninfected young children aged 18-24 weeks were enrolled. We stratified participants by quantitative QFT result (interferon-γ <0·35 IU/mL, 0·35-4·00 IU/mL, and >4·00 IU/mL) at the intermediate study visit (day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6-24 months. No QFT differences were observed between placebo and MVA85A groups at day 336 or end of study; therefore, both groups were included in analyses. Study clinicians were not masked to QFT values, but strict case definitions were used that excluded QFT results. We used generalised additive models to evaluate the quantitative relation between day 336 QFT value and subsequent disease risk, and we compared disease rates between QFT strata using a two-sample Poisson test. Among 2512 young children with QFT tests done at day 336, 172 (7%) were positive; 87 (7%) of 1267 in placebo group and 85 (7%) of 1245 in the MVA85A group (p=1·00). Compared with QFT non-converters (tuberculosis disease incidence 0·7 per 100 person-years [95% CI 0·4-1·1]), children with QFT conversion at interferon-γ values between 0·35-4·00 IU/mL did not have significantly increased risk of disease (2·5 per 100 person-years [95% CI 0·4-9·4]; incidence rate ratio (IRR) 3·7 (95% CI 0·4-15·8; p=0·23). However, QFT conversion at interferon-γ values higher than 4·00 IU/mL was associated with substantially increased disease incidence (28·0 per 100 person-years [95% CI 14·9-45·7]) compared with non-converters (IRR 42·5 [95% CI 17·2-99·7]; p<0·0001), and compared with children with interferon-γ values between 0·35-4·00 IU/mL (IRR 11·4 [95% CI 2·4-107·2]; p=0·00047). Among 91 QFT converters who were given a repeat test, 53 (58%) reverted from positive to negative. QFT reversion risk was inversely associated with interferon-γ value at QFT conversion and was highest with interferon-γ values less than 4·00 IU/mL (47 [77%] of 61). In young children, tuberculosis disease risk was not significantly increased, and QFT reversion was common, following QFT conversion at interferon-γ values up to 10 times the recommended test threshold (0·35 IU/mL). By contrast, QFT conversion at very high interferon-γ values (>4·00 IU/mL) warrants intensified diagnostic and preventive intervention because of the extremely high risk of tuberculosis disease in these young children. Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC) were the funders of the MVA85A 020 Trial. National Institute of Allergy and Infectious Diseases supported this analysis.


An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia.
CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6-/- mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations.


Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1.
Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder characterized by sphingolipid and cholesterol storage in the late endocytic system. In common with other neurodegenerative diseases, activation of the innate immune system occurs in the brain resulting in neuro-inflammation. Targeting inflammation in the brain therefore represents a potential clinical intervention strategy that aims to slow the rate of disease progression and improve quality of life. We evaluated non-steroidal anti-inflammatory drugs (NSAIDs) and an anti-oxidant to determine whether these agents are disease modifying in an acute mouse model of NPC1. NSAIDs significantly prolonged the lifespan of NPC1 mice and slowed the onset of clinical signs. However, anti-oxidant therapy was of no significant benefit. Combining NSAID therapy with substrate reduction therapy (SRT) resulted in additive benefit. These data suggest that anti-inflammatory therapy may be a useful adjunctive treatment in the clinical management of NPC1, alone or combined with SRT.


Pulmonary Drug Delivery Following Continuous Vibrating Mesh Nebulization and Inspiratory Synchronized Vibrating Mesh Nebulization During Noninvasive Ventilation in Healthy Volunteers.
A breath-synchronized nebulization option that could potentially improve drug delivery during noninvasive positive pressure ventilation (NIPPV) is currently not available on single-limb circuit bilevel ventilators. The aim of this study was to compare urinary excretion of amikacin following aerosol delivery with a vibrating mesh nebulizer coupled to a single-limb circuit bilevel ventilator, using conventional continuous (Conti-Neb) and experimental inspiratory synchronized (Inspi-Neb) nebulization modes. A crossover clinical trial involving 6 noninvasive ventilated healthy volunteers (mean age of 32.3 ± 9.5 y) randomly assigned to both vibrating mesh nebulization modes was conducted: Inspi-Neb delivered aerosol during only the whole inspiratory phase, whereas Conti-Neb delivered aerosol continuously. All subjects inhaled amikacin solution (500 mg/4 mL) during NIPPV using a single-limb bilevel ventilator (inspiratory positive airway pressure: 12 cm H2O, and expiratory positive airway pressure: 5 cm H2O). Pulmonary drug delivery of amikacin following both nebulization modes was compared by urinary excretion of drug for 24 hours post-inhalation. The total daily amount of amikacin excreted in the urine was significantly higher with Inspi-Neb (median: 44.72 mg; interquartile range [IQR]: 40.50-65.13) than with Conti-Neb (median: 40.07 mg; IQR: 31.00-43.73), (p = 0.02). The elimination rate constant of amikacin (indirect measure of the depth of drug penetration into the lungs) was significantly higher with Inspi-Neb (median: 0.137; IQR: 0.113-0.146) than with Conti-Neb (median: 0.116; IQR: 0.105-0.130), (p = 0.02). However, the mean pulmonary drug delivery rate, expressed as the ratio between total daily urinary amount of amikacin and nebulization time, was significantly higher with Conti-Neb (2.03 mg/min) than with Inspi-Neb (1.09 mg/min) (p < 0.01). During NIPPV with a single-limb circuit bilevel ventilator, the use of inspiratory synchronized vibrating mesh nebulization may improve pulmonary drug delivery compared with conventional continuous vibrating mesh nebulization.


A randomized trial of a low-carbohydrate diet for obesity.
Despite the popularity of the low-carbohydrate, high-protein, high-fat (Atkins) diet, no randomized, controlled trials have evaluated its efficacy. We conducted a one-year, multicenter, controlled trial involving 63 obese men and women who were randomly assigned to either a low-carbohydrate, high-protein, high-fat diet or a low-calorie, high-carbohydrate, low-fat (conventional) diet. Professional contact was minimal to replicate the approach used by most dieters. Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months (mean [+/-SD], -6.8+/-5.0 vs. -2.7+/-3.7 percent of body weight; P=0.001) and 6 months (-7.0+/-6.5 vs. -3.2+/-5.6 percent of body weight, P=0.02), but the difference at 12 months was not significant (-4.4+/-6.7 vs. -2.5+/-6.3 percent of body weight, P=0.26). After three months, no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations. The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study. Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load. The low-carbohydrate diet produced a greater weight loss (absolute difference, approximately 4 percent) than did the conventional diet for the first six months, but the differences were not significant at one year. The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease. Adherence was poor and attrition was high in both groups. Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate, high-protein, high-fat diets.


Uptake of ouabain by isolated hepatocytes from livers of developing rats.
The kinetics of uptake of [3H]ouabain were studied in hepatocytes isolated from livers of rats of various ages. Accumulation of ouabain in hepatocytes was measured at 1-min intervals for 4 min of incubation. Uptake of the drug was found to increase with the age of the animal. Although Vmax increased with age, there was no discernible difference in Km values. The uptake of [3H]ouabain into hepatocytes isolated from livers of 12-day-old rats could be stimulated by pretreatment of the animal with pregnenolone-16 alpha-carbonitrile. Uptake of [3H]taurocholate into isolated rat hepatocytes did not show a continuous age related pattern similar to that for ouabain. The age dependence of ouabain uptake into isolated rat hepatocytes demonstrated in this study is evidence that a low hepatic uptake capacity is the mechanism by which ouabain exhibits greater toxicity in the newborn rat.


Selective targeting of antiapoptotic BCL-2 proteins in cancer.
Circumvention of apoptotic machinery is one of the distinctive properties of carcinogenesis. Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apoptosis regulator BCL-2) proteins, determine the response of cancer cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL-2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, milestone achievements in the development of selective antiapoptotic BCL-2 proteins inhibitors for BCL-2, BCL-XL (BCL-2-like protein 1), and MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1) were summarized and their future implications were discussed. In the first section, the design and development of BCL-2/BCL-XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL-2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL-XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summarized. In the second section, MCL-1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL-1. Explicitly, studies leading to the identification of MCL-1, nonselective and selective targeting of MCL-1, and recently initiated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increasing selectivity in the design of prosurvival BCL-2 member inhibitors.


Genetics of alcohol dependence.
Alcohol dependence (AD), a genetically influenced phenotype, is extremely costly to individuals and to society in the United States and throughout the world, contributing to morbidity and mortality and a host of economic, interpersonal, and societal problems. Although until recently the only genes established to affect risk for AD were those encoding several alcohol metabolizing enzymes, there are now several other genes that can be regarded as confirmed risk loci, discovered through linkage and candidate gene association studies. While the mechanism of action of the effects of alcohol-metabolizing enzymes on AD risk is thought to be well understood, we are still in the early stages of understanding the physiology of other risk loci. Further, it is clear that only a small number of the many genes that influence risk for AD have been identified. Newer methodologies (e.g., genomewide association, study of copy number variation, and deep sequencing of candidate loci to identify rare risk variants) that have improved our understanding of other complex traits hold the promise of identifying a greater set of AD susceptibility loci.


The utility of supine radiographs in the assessment of thoracic flexibility and risk of proximal junctional kyphosis.
Supine radiographs have successfully been used for preoperative planning of lumbar deformity corrections. However, they have not been used to assess thoracic flexibility, which has recently garnered attention as a potential contributor to proximal junctional kyphosis (PJK). The purpose of this study was to compare supine to standing radiographs to assess thoracic flexibility and to determine whether thoracic flexibility is associated with PJK. A retrospective study was conducted of a single-institution database of patients with adult spinal deformity (ASD). Sagittal alignment parameters were compared between standing and supine and between pre- and postoperative radiographs. Thoracic flexibility was determined as the change between preoperative standing thoracic kyphosis (TK) and preoperative supine TK, and these changes were measured over the overall thoracic spine and the fused portion of the thoracic spine (i.e., TK fused). A case-control analysis was performed to compare thoracic flexibility between patients with PJK and those without (no PJK). The cohort was also stratified into three groups based on thoracic flexibility: kyphotic change (increased TK), lordotic change (decreased TK), and no change. The PJK rate was compared between the cohorts. A total of 101 patients (mean 63 years old, 82.2% female, mean BMI 27.4 kg/m2) were included. Preoperative Scoliosis Research Society-Schwab ASD classification showed moderate preoperative deformity (pelvic tilt 27.7% [score ++]; pelvic incidence-lumbar lordosis mismatch 44.6% [score ++]; sagittal vertical axis 42.6% [score ++]). Postoperatively, the average offset from age-adjusted alignment goals demonstrated slight overcorrection in the study sample (-8.5° ± 15.6° pelvic incidence-lumbar lordosis mismatch, -29.2 ± 53.1 mm sagittal vertical axis, -5.4 ± 10.8 pelvic tilt, and -7.6 ± 11.7 T1 pelvic angle). TK decreased between standing and supine radiographs and increased postoperatively (TK fused: -25.3° vs -19.6° vs -29.9°; all p < 0.001). The overall rate of radiographic PJK was 23.8%. Comparisons between PJK and no PJK demonstrated that offsets from age-adjusted alignment goals were similar (p > 0.05 for all). There was a significant difference in the PJK rate when stratified by thoracic flexibility cohorts (kyphotic: 0.0% vs no change: 18.4% vs lordotic: 35.0%; p = 0.049). Logistic regression revealed thoracic flexibility (p = 0.045) as the only independent correlate of PJK. Half of patients with ASD experienced significant changes in TK during supine positioning, a quality that may influence surgical strategy. Increased thoracic flexibility is associated with PJK, possibly secondary to fusing the patient's spine in a flattened position intraoperatively.


Factors predisposing women to chronic pelvic pain: systematic review.
To evaluate factors predisposing women to chronic and recurrent pelvic pain. DESIGN, DATA SOURCES, AND METHODS: Systematic review of relevant studies without language restrictions identified through Medline, Embase, PsycINFO, Cochrane Library. SCISEARCH, conference papers, and bibliographies of retrieved primary and review articles. Two reviewers independently extracted data on study characteristics, quality, and results. Exposure to risk factors was compared between women with and without pelvic pain. Results were pooled within subgroups defined by type of pain and risk factors. There were 122 studies (in 111 articles) of which 63 (in 64,286 women) evaluated 54 risk factors for dysmenorrhoea, 19 (in 18,601 women) evaluated 14 risk factors for dyspareunia, and 40 (in 12,040 women) evaluated 48 factors for non-cyclical pelvic pain. Age < 30 years, low body mass index, smoking, earlier menarche (< 12 years), longer cycles, heavy menstrual flow, nulliparity, premenstrual syndrome, sterilisation, clinically suspected pelvic inflammatory disease, sexual abuse, and psychological symptoms were associated with dysmenorrhoea. Younger age at first childbirth, exercise, and oral contraceptives were negatively associated with dysmenorrhoea. Menopause, pelvic inflammatory disease, sexual abuse, anxiety, and depression were associated with dyspareunia. Drug or alcohol abuse, miscarriage, heavy menstrual flow, pelvic inflammatory disease, previous caesarean section, pelvic pathology, abuse, and psychological comorbidity were associated with an increased risk of non-cyclical pelvic pain. Several gynaecological and psychosocial factors are strongly associated with chronic pelvic pain. Randomised controlled trials of interventions targeting these potentially modifiable factors are needed to assess their clinical relevance in chronic pelvic pain.


Characterizing ultrabroadband attosecond lasers.
Recent progress in sub-laser-cycle gating of high-order harmonic generation promises to push the limits on optical pulse durations below the atomic unit of time, 24 as, which corresponds to a bandwidth broader than 75 eV. However, the available techniques for attosecond pulse measurement are valid only for narrow-bandwidth spectra, due to one of the key approximations made in the phase retrieval. Here we report a new technique for characterizing attosecond pulses, whereby the spectral phase of the attosecond pulse is extracted from the oscillation component with the dressing laser frequency in the photoelectron spectrogram. This technique, termed PROOF (Phase Retrieval by Omega Oscillation Filtering), can be applied to characterizing attosecond pulses with ultrabroad bandwidths.


Genetic Properties of a Nested Association Mapping Population Constructed With Semi-Winter and Spring Oilseed Rapes.
Nested association mapping (NAM) populations have been widely applied to dissect the genetic basis of complex quantitative traits in a variety of crops. In this study, we developed a Brassica napus NAM (BN-NAM) population consisting of 15 recombination inbred line (RIL) families with 2,425 immortal genotypes. Fifteen high-density genetic linkage maps were constructed by genotyping by sequencing (GBS) based on all RIL families, with further integration into a joint linkage map (JLM) having 30,209 unique markers in common with multiple linkage maps. Furthermore, an ultra-density whole-genome variation map was constructed by projecting 4,444,309 high-quality variants onto the JLM. The NAM population captured a total of 88,542 recombination events (REs). The uneven distribution of recombination rate along chromosomes is positively correlated with the densities of genes and markers, but negatively correlated with the density of transposable elements and linkage disequilibrium (LD). Analyses of population structure and principal components revealed that the BN-NAM population could be divided into three groups with weak stratification. The LD decay distance across genome varied between 170 and 2,400 Kb, with LD decay more rapid in the A than in the C sub-genome. The pericentromeric regions contained large LD blocks, especially in the C sub-genome. This NAM population provides a valuable resource for dissecting the genetic basis of important traits in rapeseed, especially in semi-winter oilseed rape.


Composition of human low density lipoprotein: effects of postprandial triglyceride-rich lipoproteins, lipoprotein lipase, hepatic lipase and cholesteryl ester transfer protein.
A preponderance of small, dense low density lipoprotein (LDL) particles has been linked to increased risk of myocardial infarction, and a dense and protein-rich LDL has proved to be a characteristic of patients with manifest coronary heart disease (CHD). The present study focused on metabolic determinants of the LDL subfraction distribution with the emphasis placed on alimentary lipaemia. The relations of plasma levels and composition of light (1.019 < d < 1.040 kg/l) and dense (1.040 < d < 1.063 kg/l) LDL subfractions to postprandial triglyceride-rich lipoproteins (TGRL), postheparin plasma lipase activities and the activity of cholesteryl ester transfer protein (CETP) were studied in 32 men with angiographically ascertained premature coronary atherosclerosis (age 48.8 +/- 3.2 years) and in 10 age matched healthy control men. LDL subfractions were separated by equilibrium density gradient ultracentrifugation of fasting plasma drawn before participants were subjected to an oral fat tolerance test of a mixed meal type. The response of TGRL to the oral fat load was determined by measuring plasma triglycerides, and the apolipoprotein (apo) B-48 and apo B-100 content of Sf 60-400 and Sf 20-60 lipoprotein fractions. At a second visit plasma samples were taken for determination of postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities and for measurement of CETP activity. Hypertriglyceridaemic patients had a preponderance of dense LDL particles compared with normotriglyceridaemic patients and controls. The magnitude of the response of TGRL to the oral fat load showed a positive association with the dense LDL apo B concentration (r = 0.32-0.52, P < 0.05), whereas the LPL activity correlated positively with the free (r = 0.50, P < 0.001) and esterified cholesterol (r = 0.45, P < 0.01) and apo B (r = 0.42, P < 0.01) content of the light LDL fraction. The HL activity was found to be inversely associated with the plasma level of light LDL triglycerides (r = -0.38, P < 0.05). In contrast, no relations were noted between CETP activity and plasma concentrations of LDL constituents. Multiple stepwise linear regression analysis with the proportion of total LDL apo B contained in the dense LDL subfraction (% dense LDL apo B) used as the dependent variable indicated that the combined effect of LPL activity and postprandial plasma levels of TGRL (areas under the curve for plasma triglycerides or Sf 60-400 apo B-48) accounted for around 50% of the variability in the distribution of LDL particles between light and dense subfractions.(ABSTRACT TRUNCATED AT 400 WORDS)


Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse.
Colony stimulating factor-1 (CSF-1) regulates the survival, proliferation and differentiation of mononuclear phagocytes. The osteopetrotic (op/op) mutant mouse is devoid of CSF-1 due to an inactivating mutation in the CSF-1 gene and is deficient in several mononuclear phagocyte subpopulations. To analyze more fully the requirement for CSF-1 in the establishment and maintenance of mononuclear phagocytes, the postnatal development of cells bearing the macrophage marker antigens F4/80 and MOMA-1, in op/op mice and their normal (+/op or +/+) littermates, were studied during the first three months of life. In normal mice, maximum expression of tissue F4/80+ cells was generally correlated with the period of maximum organogenesis and/or cell turnover. Depending on the tissue, the F4/80+ cell density either decreased, transiently increased or gradually increased with age. In op/op mice, tissues that normally contain F4/80+ cells could be classified into those in which F4/80+ cells were absent and those in which the F4/80+ cell densities were either reduced, normal or initially normal then subsequently reduced. To assess which F4/80+ populations were regulated by circulating CSF-1 in normal mice, op/op mice in which the circulating CSF-1 concentration was restored to above normal levels by daily subcutaneous injection of human recombinant CSF-1 from day 3 were analyzed. These studies suggest that circulating CSF-1 exclusively regulates both the F4/80+ cells in the liver, spleen and kidney and the MOMA-1+ metallophilic macrophages in the spleen. Macrophages of the dermis, bladder, bone marrow and salivary gland, together with a subpopulation in the gut, were partially restored by circulating CSF-1, whereas macrophages of the muscle, tendon, periosteum, synovial membrane, adrenals and the macrophages intimately associated with the epithelia of the digestive tract, were not corrected by restoration of circulating CSF-1, suggesting that they are exclusively locally regulated by this growth factor. Langerhans cells, bone marrow monocytes and macrophages of the thymus and lymph nodes were not significantly affected by circulating CSF-1 nor decreased in op/op mice, consistent with their regulation by other growth factors. These results indicate that important differences exist among mononuclear phagocytes in their dependency on CSF-1 and the way in which CSF-1 is presented to them. They also suggest that the prevalent role of CSF-1 is to influence organogenesis and tissue turnover by stimulating the production of tissue macrophages with local trophic and/or scavenger (physiological) functions. Macrophages involved in inflammatory and immune (pathological) responses appear to be dependent on other factors for their ontogenesis and function.(ABSTRACT TRUNCATED AT 400 WORDS)


Facial Dermatitis in Male Patients Referred for Patch Testing: Retrospective Analysis of North American Contact Dermatitis Group Data, 1994 to 2016.
Facial dermatitis in women is well characterized. However, recent shifts in the men's grooming industry may have important implications for male facial dermatitis. To characterize male patients with facial dermatitis. A 22-year retrospective cross-sectional analysis (1994-2016) of North American Contact Dermatitis Group (NACDG) data, including 50 507 patients who underwent patch testing by a group of dermatology board-certified patch test experts at multiple centers was carried out. Facial dermatitis was defined as involvement of the eyes, eyelids, lips, nose, or face (not otherwise specified). The main outcome was to compare characteristics (including demographics and allergens) between male patients with facial dermatitis (MFD) and those without facial dermatitis (MNoFD) using statistical analysis (relative risk, CIs). Secondary outcomes included sources of allergic and irritant contact dermatitis and, for occupationally related cases, specific occupations and industries in MFD. Overall, 1332 male patients (8.0%) were included in the MFD group and 13 732 male patients (82.0%) were included in MNoFD. The mean (SD) age of participants was 47 (17.2) years in the MFD group and 50 (17.6) years in the MNoFD group. The most common facial sites were face (not otherwise specified, 817 [48.9%]), eyelids (392 [23.5%]), and lips (210 [12.6%]). Participants in the MFD group were significantly younger than MNoFD (mean age, 47 vs 50 years; P < .001). Those in the MFD group were less likely to be white (relative risk [RR], 0.92; 95% CI, -0.90 to 0.95) or have occupationally related skin disease (RR, 0.49; 95% CI, -0.42 to 0.58; P < .001) than MNoFD. The most common allergens that were associated with clinically relevant reactions among MFD included methylisothiazolinone (n = 113; 9.9%), fragrance mix I (n = 27; 8.5%), and balsam of Peru (n = 90; 6.8%). Compared with MNoFD, MFD were more likely to react to use of dimethylaminopropylamine (RR, 2.49; 95% CI, -1.42 to 4.37]) and paraphenylenediamine (RR, 1.43; 95% CI, -1.00 to 2.04; P < .001). Overall, 60.5% of NACDG allergen sources were personal care products. Although many allergens were similar in both groups, MFD were more likely to react to use of dimethylaminopropylamine and paraphenylenediamine, presumably owing to their higher prevalence in hair products. Most sources of allergic and irritant contact dermatitis in MFD were personal care products. This study provides insight into the risks and exposures of the increasing number of grooming products used by male dermatology patients. This will enable clinicians to better identify male patients who would benefit from patch testing and treat those with facial dermatitis.


Current Treatment Modalities of JIA-associated Uveitis and its Complications: Literature Review.
Uveitis is a common and serious complication of juvenile idiopathic arthritis. Up to 75% of all cases of anterior uveitis in childhood are associated with juvenile idiopathic arthritis. Despite the remarkable progress in early detection and treatment of inflammation, vision-threatening complications of uveitis still occur in almost 60% of patients. Structural complications include band keratopathy, maculopathy (macular edema, macular cysts, and epiretinal membrane), glaucomatous optic neuropathy, and cataracts. The management of complications in juvenile idiopathic arthritis is usually complex and requires early surgical intervention. In this paper, we review the general concepts of common ocular complications seen in patients with JIA-associated uveitis, with special attention to the recent diagnostic and preferred treatment approaches at the Massachusetts Eye Research and Surgery Institution. Received 9 March 2015; revised 30 September 2015; accepted 30 October 2015; published online 14 January 2016.


Reorganisation of Hoxd regulatory landscapes during the evolution of a snake-like body plan.
Within land vertebrate species, snakes display extreme variations in their body plan, characterized by the absence of limbs and an elongated morphology. Such a particular interpretation of the basic vertebrate body architecture has often been associated with changes in the function or regulation of Hox genes. Here, we use an interspecies comparative approach to investigate different regulatory aspects at the snake HoxD locus. We report that, unlike in other vertebrates, snake mesoderm-specific enhancers are mostly located within the HoxD cluster itself rather than outside. In addition, despite both the absence of limbs and an altered Hoxd gene regulation in external genitalia, the limb-associated bimodal HoxD chromatin structure is maintained at the snake locus. Finally, we show that snake and mouse orthologous enhancer sequences can display distinct expression specificities. These results show that vertebrate morphological evolution likely involved extensive reorganisation at Hox loci, yet within a generally conserved regulatory framework.


Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. San Diego, Calif., November 17-23, 1996.
Sixteen research groups participated in the ISOBM TD-4 Workshop in which the reactivity and specificity of 56 monoclonal antibodies against the MUC1 mucin was investigated using a diverse panel of target antigens and MUC1 mucin-related synthetic peptides and glycopeptides. The majority of antibodies (34/56) defined epitopes located within the 20-amino acid tandem repeat sequence of the MUC1 mucin protein core. Of the remaining 22 antibodies, there was evidence for the involvement of carbohydrate residues in the epitopes for 16 antibodies. There was no obvious relationship between the type of immunogen and the specificity of each antibody. Synthetic peptides and glycopeptides were analyzed for their reactivity with each antibody either by assay of direct binding (e.g. by ELISA or BiaCore) or by determining the capacity of synthetic ligands to inhibit antibody binding interactions. There was good concordance between the research groups in identifying antibodies reactive with peptide epitopes within the MUC1 protein core. Epitope mapping tests were performed using the Pepscan analysis for antibody reactivity against overlapping synthetic peptides, and results were largely consistent between research groups. The dominant feature of epitopes within the MUC1 protein core was the presence, in full or part, of the hydrophilic sequence of PDTRAPAP. Carbohydrate epitopes were less easily characterized and the most useful reagents in this respect were defined oligosaccharides, rather than purified mucin preparations enriched in particular carbohydrate moieties. It was evident that carbohydrate residues were involved in many epitopes, by regulating epitope accessibility or masking determinants, or by stabilizing preferred conformations of peptide epitopes within the MUC1 protein core. Overall, the studies, highlight concordance between groups rather than exposing inconsistencies which gives added confidence to the results of analyses of the specificity of antimucin monoclonal antibodies.


Novel RNA-based strategies for therapeutic gene silencing.
The past decade has seen intense scientific interest in non-coding RNAs. In particular, the discovery and subsequent exploitation of gene silencing via RNA interference (RNAi) has revolutionized the way in which gene expression is now studied and understood. It is now well established that post-transcriptional gene silencing (PTGS) by the microRNA (miRNA) and other RNAi-associated pathways represents an essential layer of complexity to gene regulation. Gene silencing using RNAi additionally demonstrates huge potential as a therapeutic strategy for eliminating pathogenic gene expression. Yet despite the early promise and excitement of gene-specific silencing, several critical hurdles remain to be overcome before widespread clinical adoption. These include off-target effects, toxicity due to saturation of the endogenous RNAi functions, limited duration of silencing, and effective targeted delivery. In recent years, a range of novel strategies for producing RNA-mediated silencing have been developed that can circumvent many of these hurdles, including small internally segmented interfering RNAs, tandem hairpin RNAs, and pri-miRNA cluster mimics. This review discusses RNA-mediated silencing in light of this recent research, and highlights the benefits and limitations conferred by these novel gene-silencing strategies.


Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease.
Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).


Neural antecedents of the endowment effect.
The "endowment effect" refers to the tendency to place greater value on items that one owns-an anomaly that violates the reference-independence assumption of rational choice theories. We investigated neural antecedents of the endowment effect in an event-related functional magnetic resonance imaging (fMRI) study. During scanning, 24 subjects considered six products paired with 18 different prices under buying, choosing, or selling conditions. Subjects showed greater nucleus accumbens (NAcc) activation for preferred products across buy and sell conditions combined, but greater mesial prefrontal cortex (MPFC) activation in response to low prices when buying versus selling. During selling, right insular activation for preferred products predicted individual differences in susceptibility to the endowment effect. These findings are consistent with a reference-dependent account in which ownership increases value by enhancing the salience of the possible loss of preferred products.


Cloning and characterization of the mouse interleukin enhancer binding factor 3 (Ilf3) homolog in a screen for RNA binding proteins.
In a screen for RNA-binding proteins expressed during murine spermatogenesis, we have identified a cDNA that encodes a protein of 911 amino acids that contains two copies of the double-stranded RNA-binding motif and has 80% identity with human Interleukin Enhancer Binding Factor 3 (ILF3). Linkage and cytogenetic analyses localized the Ilf3 cDNA to a portion of mouse Chr 9, which shows conserved synteny with a region of human Chr 19 where the human ILF3 gene had been previously localized, supporting that we had cloned the murine homolog of ILF3. Northern analysis indicated the Ilf3 gene is ubiquitously expressed in mouse adult tissues with high levels of expression in the brain, thymus, testis, and ovary. Polyclonal antibodies detected multiple protein species in a subset of the tissues expressing Ilf3 RNA. Immunoreactive species are present at high levels in the thymus, testis, ovary, and the spleen to a lesser extent. The high degree of sequence similarity between the mouse ILF3 protein and other dsRNA binding motif-containing proteins suggests a role in RNA metabolism, while the differential expression indicates the mouse ILF3 protein predominantly functions in tissues containing developing lymphocyte and germ cells.


Assessing spatial and temporal biases and gaps in the publicly available distributional information of Iberian mosses.
One of the most valuable initiatives on massive availability of biodiversity data is the Global Biodiversity Information Facility, which is creating new opportunities to develop and test macroecological knowledge. However, the potential uses of these data are limited by the gaps and biases associated to large-scale distributional databases (the so-called Wallacean shortfall). Describing and quantifying these limitations are essential to improve knowledge on biodiversity, especially in poorly-studied groups, such as mosses. Here we assess the coverage of the publicly-available distributional information on Iberian mosses, defining its eventual biases and gaps. For this purpose, we compiled IberBryo v1.0, a database that comprises 82,582 records after processing and checking the geospatial and taxonomical information. Our results show the limitations of data and metadata of the publicly-available information. Particularly, ca. 42% of the records lacked collecting date information, which limits data usefulness for time coverage analyses and enlarges the existing knowledge gaps. Then we evaluated the overall coverage of several aspects of the spatial, temporal and environmental variability of the Iberian Peninsula. Through this assessment, we demonstrate that the publicly-available information on Iberian mosses presents significant biases. Inventory completeness is strongly conditioned by the recorders' survey bias, particularly in northern Portugal and eastern Spain and the spatial pattern of surveys is also biased towards mountains. Besides, the temporal pattern of survey effort intensifies from 1970 onwards, encompassing a progressive increase in the geographic coverage of the Iberian Peninsula. Although we just found 5% of well-surveyed cells of 30' of resolution over the 1970-2018 period, they cover about a fifth of the main climatic gradients of the Iberian Peninsula, which provides a fair - though limited - coverage. Yet, the well-surveyed cells are biased towards anthropised areas and some of them are located in areas under intense land-use changes, mainly due to the wood-fires of the last decade. Despite the overall increase, we found a noticeable gap of information in the south-west of Iberia, the Ebro river basin and the inner plateaus. All these gaps and biases call for a careful use of the available distributional data of Iberian mosses for biogeographical and ecological modelling analysis. Further, our results highlight the necessity of incorporating several good practices to increase the coverage of high-quality information. These good practices include digitalisation of specimens and metadata information, improvement on the protocols to get accurate data and metadata or revisions of the vouchers and recorders' field notebooks. These procedures are essential to improve the quality and coverage of the data. Finally, we also encourage Iberian bryologists to establish a series of re-surveys of classical localities that would allow updating the information on the group, as well as to design their future surveys considering the most important information gaps on IberBryo.


Sex education as health promotion: what does it take?
Health promotion should be evidence-based, needs driven, subject to evaluation, and ecological in perspective. How can this be achieved in the context of school-based sex education? Adopting new behaviors and giving up old habits involves common decision-making, planning, motivational control, and goal prioritization processes. Consequently, despite the particular nature of sexual behavior, models of cognitive change applied to other health-related behaviors also apply to the promotion of safer sex practice. Young people are less likely to have unprotected sexual intercourse if they have acquired a variety of social skills relevant to dealing with romantic and sexual relationships. Many of these social skills and the methods employed to facilitate their development are also important to the promotion of other health behaviors. However, teaching social skills relevant to sexual behavior in classroom settings requires specialist expertise both in program design and in delivery by teachers or facilitators. Theory- and evidence-based programs designed to promote such skills and modified on the basis of effectiveness evaluations are most likely to have an impact on the rate of pregnancies and sexually transmitted infections among young people. Yet, such programs may not be used in schools because of policy and cultural constraints. When this is the case, optimally effective health promotion cannot be delivered. Health promoters should acknowledge these challenges and facilitate the adoption and implementation of effective sexual health promotion programs by targeting communities and legislators.


Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A.
Fast desensitization is an important regulatory mechanism of neuronal NMDA receptor function. Only recombinant NMDA receptors composed of NR1/NR2A exhibit a fast component of desensitization similar to neuronal NMDA receptors. Here we report that the fast desensitization of NR1/NR2A receptors is caused by ambient zinc, and that a positive allosteric interaction occurs between the extracellular zinc-binding site located in the amino terminal domain and the glutamate-binding domain of NR2A. The relaxation of macroscopic currents reflects a shift to a new equilibrium due to increased zinc affinity after binding of glutamate. We also show a similar interaction between the ifenprodil binding site and the glutamate binding site of NR1/NR2B receptors. These data raise the possibility that there is an allosteric interaction between the amino terminal domain and the ligand-binding domain of other glutamate receptors. Our findings may provide insight into how zinc and other extracellular modulators regulate NMDA receptor function.