Efficient 3He/4He separation in a nanoporous graphenylene membrane.
Helium-3 is a precious noble gas, which is essential in many advanced technologies such as cryogenics, isotope labeling and nuclear weapons. The current imbalance of 3He demand and supply shortage leads to the search for an efficient membrane with high performance for 3He separation. In this study, based on first-principles calculations, we demonstrated that highly efficient 3He harvesting can be achieved in a nanoporous graphenylene membrane with industrially-acceptable selectivity and permeance. The quantum tunneling effect leads to 3He harvesting with high efficiency via kinetic sieving. Both the quantum tunneling effect and zero-point energy (ZPE) determine the 3He/4He separation via thermally-driven equilibrium sieving, where the ZPE effect dominates efficient 3He/4He separation between two reservoirs. The quantum effects revealed in this work suggest that the nanoporous graphenylene membrane is promising for efficient 3He harvesting that can be exploited for industrial applications.


Functional analysis of the white gene of Drosophila by P-factor-mediated transformation.
A 12-kb DNA segment spanning the white (w) locus of Drosophila has been inserted into a P-transposon vector and used for P-factor-mediated germ-line transformation. Several red-eyed transformants were recovered which complement the white mutant phenotype. Analysis of the eye pigments and the interaction with the zeste mutation indicates that the w gene inserted at several new chromosomal sites is expressed normally. The tissue-specific accumulation of w transcripts, as studied by in situ hybridization to tissue sections, is the same in transformant and wild-type larvae. This indicates that all the genetic information specified by the w locus is contained within this 12-kb segment of DNA. By secondary mobilization it was shown that the w sequences have been inserted as a functional P(w) transposon which is capable of further transposition.


Selective receptor neurone responses to E-beta-ocimene, beta-myrcene, E,E-alpha-farnesene and homo-farnesene in the moth Heliothis virescens, identified by gas chromatography linked to electrophysiology.
An important question in olfaction is for which odorants receptor neurones have evolved. In the present study, olfactory receptor neurones on the antennae of the tobacco budworm moth Heliothis virescens were screened for sensitivity to naturally occurring plant-produced volatiles by the use of gas chromatography linked to electrophysiology. Volatiles of host as well as non-host plants collected by headspace techniques were used for stimulating the neurones, sequentially via two columns, one polar and one nonpolar installed in parallel in the gas chromatograph. Three types of neurones presented in this paper responded to one, two or three compounds for which the retention times were determined in both column types. The chemical structures of the active components were determined on the basis of mass spectrometry linked to gas chromatography, indicating E-beta-ocimene and beta-myrcene as stimulants for neurone type 1, E,E-alpha-farnesene for neurone type 2 and homo-farnesene for neurone type 3. Re-testing authentic materials verified the identifications for the type 1 neurones. The results demonstrate a high specificity for the three types of neurones by strong responses to one or two structurally similar compounds out of hundreds present in a large variety of plants. The study exemplifies plant odour detection by narrowly tuned receptor neurones in a polyphagous moth species.


Repetitive hypoxia extends endogenous neurovascular protection for stroke.
Brief systemic hypoxia protects the rodent brain from subsequent ischemic injury, although the protection wanes within days. We hypothesized that the duration of ischemic tolerance could be extended from days to months by repeated intermittent hypoxia of varying magnitude and duration. Infarction volumes following a 60-minute transient middle cerebral artery occlusion were determined in adult male mice 2 days through 8 weeks after completion of a 2-week repetitive hypoxic preconditioning (RHP) protocol. Separate cohorts were studied for the protective effects of RHP on postischemic and cytokine-induced cerebrovascular inflammation, and for potential deleterious effects of the RHP stimulus itself. RHP protection against transient focal stroke persisted for 8 weeks. Leukocyte adherence to cortical venules was attenuated in response to stroke, as well as following tumor necrosis factor-α administration, indicating that reductions in postischemic inflammation were not secondary to smaller infarct volumes. RHP reduced poststroke leukocyte diapedesis concomitant with a long-lasting downregulation of endothelial adhesion molecule mRNAs, and also reduced postischemic blood--brain barrier permeability to endogenous immunoglobulin G. RHP was without effect on hippocampal CA1 pyramidal cell viability, only transiently elevated hematocrit, and did not affect the magnitude of cerebral blood flow during and after ischemia. Taken together, our findings reveal a novel form of epigenetic neurovascular plasticity characterized by a prominent anti-inflammatory phenotype that provides protection against stroke many weeks longer than previously established windows of preconditioning-induced tolerance. Translating these endogenous protective mechanisms into therapeutics could afford sustained periods of cerebroprotection in subpopulations of individuals at identified risk for stroke.


Chronic venous disease treated by ultrasound guided foam sclerotherapy.
To report the outcome of a series of patients with chronic venous disease due to incompetence of saphenous trunks managed by ultrasound guided foam sclerotherapy (UFS). A group of 808 patients comprise this series. CEAP clinical class for limbs was C1: 15%, C2: 81%, C3: 0.5%, C4: 2%, C5: 0.2%, C6: 0.4%. UFS using 1% polidocanol (107 limbs), 1% sodium tetradecyl (102 limbs), 3% sodium tetradecyl (900 limbs) was employed to treat incompetent saphenous trunks. In patients with unilateral varices 1 treatment was required in 43% of patients and 2 treatments in 48% of patients to obliterate incompetent saphenous trunks and varices. For bilateral varices 2 treatments were required in 40% of patients and 3 treatments in 46% of cases. The clinical outcome and patency of treated veins on duplex ultrasonography was assessed at a mean follow-up interval of 11 months. A total of 459 limbs were available for assessment at a follow-up interval of 6 months or greater. The CEAP clinical stage was C0:182 limbs, C1: 241, C2: 22, C3: 0, C4: 11, C5: 2, C6:1. The GSV had remained obliterated in 88% of limbs and the SSV in 82% of limbs. Recurrent venous incompetence following previous surgery was as effectively treated by UFS as primary incompetence. This technique is useful in the management of chronic venous disease as an alternative to surgery.


Structural biology of voltage-gated calcium channels.
Voltage-gated calcium (Cav) channels mediate Ca2+ influx in response to membrane depolarization, playing critical roles in diverse physiological processes. Dysfunction or aberrant regulation of Cav channels can lead to life-threatening consequences. Cav-targeting drugs have been clinically used to treat cardiovascular and neuronal disorders for several decades. This review aims to provide an account of recent developments in the structural dissection of Cav channels. High-resolution structures have significantly advanced our understanding of the working and disease mechanisms of Cav channels, shed light on the molecular basis for their modulation, and elucidated the modes of actions (MOAs) of representative drugs and toxins. The progress in structural studies of Cav channels lays the foundation for future drug discovery efforts targeting Cav channelopathies.


Width of Keratinized Mucosa at Implant Sites in Patients Treated for Generalized Aggressive Periodontitis: A Cohort Study.
The aim of this cohort study was to evaluate the width of keratinized mucosa at implant sites of partially edentulous patients who were treated for generalized aggressive periodontitis. Dental implants were placed in 35 patients who were treated for generalized aggressive periodontitis and 18 periodontally healthy individuals (controls). At baseline, the keratinized mucosa of all implants was ≥ 2 mm. Follow-up examinations were conducted every 3 months over a 4-year period. The implant survival rate was 97.3% in patients with generalized aggressive periodontitis and 100% in the control group. Four years after implant insertion, patients with generalized aggressive periodontitis had significantly higher clinical attachment levels at the teeth and implants compared with the controls. At all time points, in both groups the mean probing depth at the implants was significantly larger than at the teeth. The mean widths of keratinized mucosa and keratinized gingiva were not significantly different between the two groups. In both groups, the widths of keratinized mucosa and keratinized gingiva were significantly higher at the maxilla than at the mandible. Four years after baseline, the implants in the mandible showed the smallest keratinized mucosa (mean: ≤ 1 mm). During the first 4 years after implant placement, no significant changes in the keratinized mucosa at implants could be shown, either in periodontally healthy patients or in patients treated for generalized aggressive periodontitis. The keratinized gingiva at the teeth was generally significantly wider than the keratinized mucosa at the implants.


De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations.
Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.


Significance of leukocytosis after cardiac device implantation.
Infection remains a feared complication after cardiac device implantation. Whether early postprocedural leukocytosis, a recognized marker of infection, is an indicator of impending infection is unclear and was the focus of this study. A retrospective chart review of consecutive patients who underwent implantable cardioverter defibrillator or pacemaker implantation was performed. The association between change in white blood cell (WBC) count and development of infection after device implantation was assessed. Infection was defined as pocket or lead infection or as bacteremia or sepsis <60 days after implantation. Pre- and postprocedural WBC counts were obtained within 48 hours of the procedure. Significant leukocytosis was defined as a ≥50% increase in WBC count; 1,245 device implantations met inclusion criteria. Device-related infections occurred in 8 cases (0.6%). A modest 17.6 ± 30.2% increase in WBC count was observed for the entire cohort. Cases resulting in infection demonstrated minimal change in WBC count (mean +5.5 ± 26.5%). No infections occurred in patients with ≥50% increases in WBC count or postprocedural WBC counts >15,000/μl. Subjects with significant leukocytosis were younger (mean age 61.9 ± 16.5 vs 65.6 ± 15.1 years, p <0.01), had longer procedure times (mean 198 ± 97 vs 170 ± 77 minutes, p <0.001), and received biventricular implantable cardioverter-defibrillators (25% vs 13.9%, p <0.001). In conclusion, after device implantation, a ≥50% increase in WBC count occurred in about 10% to 15% of patients. Age, race, type of device, and procedure time influenced the development of significant leukocytosis. Elevation in WBC count after cardiac device implantation was not associated with an increased risk for early infection.


Internet interventions for chronic pain including headache: A systematic review.
Chronic pain is a major health problem and behavioral based treatments have been shown to be effective. However, the availability of these kinds of treatments is scarce and internet-based treatments have been shown to be promising in this area. The objective of the present systematic review is to evaluate internet-based interventions for persons with chronic pain. The specific aims are to do an updated review with a broad inclusion of different chronic pain diagnoses and to assess disability and pain and also measures of catastrophizing, depression and anxiety. A systematic search identified 891 studies and 22 trials were selected as eligible for review. Two of the selected trials included children/youth and five included individuals with chronic headache and/or migraine. The most frequently measured domain reflected in the primary outcomes was interference/disability, followed by catastrophizing. Result across the studies showed a number of beneficial effects. Twelve trials reported significant effects on disability/interference outcomes and pain intensity. Positive effects were also found on psychological variable such as catastrophizing, depression and anxiety. Several studies (n = 12) were assessed to have an unclear level of risk bias. The attrition levels ranged from 4% to 54% where the headache trials had the highest drop-out levels. However, findings suggest that internet-based treatments based on cognitive behavioural therapy (CBT) are efficacious measured with different outcome variables. Results are in line with trials in clinical settings. Meta-analytic statistics were calculated for interference/disability, pain intensity, catastrophizing and mood ratings. Results showed that the effect size for interference/disability was Hedge's g = - 0.39, for pain intensity Hedge's g = - 0.33, for catastrophizing Hedge's g = - 0.49 and for mood variables (depression) Hedge's g = - 0.26.


Deciphering transcription dysregulation in FSH muscular dystrophy.
DUX4, a homeobox-containing gene present in a tandem array, is implicated in facioscapulohumeral muscular dystrophy (FSHD), a dominant autosomal disease. New findings about DUX4 have raised as many fundamental questions about the molecular pathology of this unique disease as they have answered. This review discusses recent studies addressing the question of whether there is extensive FSHD-related transcription dysregulation in adult-derived myoblasts and myotubes, the precursors for muscle repair. Two models for the role of DUX4 in FSHD are presented. One involves transient pathogenic expression of DUX4 in many cells in the muscle lineage before the myoblast stage resulting in a persistent, disease-related transcription profile ('Majority Rules'), which might be enhanced by subsequent oscillatory expression of DUX4. The other model emphasizes the toxic effects of inappropriate expression of DUX4 in only an extremely small percentage of FSHD myoblasts or myotube nuclei ('Minority Rules'). The currently favored Minority Rules model is not supported by recent studies of transcription dysregulation in FSHD myoblasts and myotubes. It also presents other difficulties, for example, explaining the expression of full-length DUX4 transcripts in FSHD fibroblasts. The Majority Rules model is the simpler explanation of findings about FSHD-associated gene expression and the DUX4-encoded homeodomain-type protein.


The expression of regulated endocrine-specific protein of 18 kDa in peptidergic cells of rat peripheral endocrine tissues and in blood.
We examined the cellular localization of regulated endocrine-specific protein of 18 kDa (RESP18) and mRNA in peripheral endocrine tissues. In situ hybridization and immunocytochemistry identified RESP18 mRNA in most cells of the anterior and intermediate pituitary, with RESP18 protein apparent in many anterior pituitary cells but very few intermediate pituitary cells. In the adrenal medulla and superior cervical ganglion, RESP18 mRNA co-localized with dopamine beta-mono-oxygenase and neuropeptide Y. In the thyroid, RESP18 mRNA was localized to C-cells. RESP18 mRNA was expressed in most of the cells of the pancreatic islets, co-localizing with insulin, glucagon, and somatostatin. No RESP18 mRNA or protein was detected in the adrenal cortex, ovary, neural lobe of the pituitary, parathyroid, exocrine pancreas, thyroid follicular cells, placenta, mammary tissue, liver, lung, or atria. As in the intermediate lobe of the pituitary, high levels of RESP18 mRNA in the pancreatic islets and adrenal medulla did not always correlate with immunodetectable RESP protein, suggesting that post-transcriptional mechanisms are important in controlling RESP18 expression. Western blot analyses identified 18 kDa RESP and higher molecular weight isoforms of RESP in most tissues and in plasma. Subcellular fractionation of the anterior pituitary identified 18 kDa RESP18 in fractions enriched in endoplasmic reticulum and secretory granules, with the higher molecular weight isoforms of RESP18 concentrated in fractions enriched in secretory granules. The broad neuroendocrine distribution of RESP18 suggests that it subserves an important function in the secretory pathway that is common to the production of many secreted peptides.


Critical length scales and strain localization govern the mechanical performance of multi-layer graphene assemblies.
Multi-layer graphene assemblies (MLGs) or fibers with a staggered architecture exhibit high toughness and failure strain that surpass those of the constituent single sheets. However, how the architectural parameters such as the sheet overlap length affect these mechanical properties remains unknown due in part to the limitations of mechanical continuum models. By exploring the mechanics of MLG assemblies under tensile deformation using our established coarse-grained molecular modeling framework, we have identified three different critical interlayer overlap lengths controlling the strength, plastic stress, and toughness of MLGs, respectively. The shortest critical length scale L(C)(S) governs the strength of the assembly as predicted by the shear-lag model. The intermediate critical length L(C)(P) is associated with a dynamic frictional process that governs the strain localization propensity of the assembly, and hence the failure strain. The largest critical length scale L(C)(T) corresponds to the overlap length necessary to achieve 90% of the maximum theoretical toughness of the material. Our analyses provide the general guidelines for tuning the constitutive properties and toughness of multilayer 2D nanomaterials using elasticity, interlayer adhesion energy and geometry as molecular design parameters.


Treatment of endstage heart disease with mechanical circulatory assistance.
A great number of patients suffer and die from the sequelae of acute and chronic heart failure each year. Although advances in medical and surgical therapy have benefited many of these patients, the majority suffer from disease refractory to any definitive therapy. For these patients, cardiac transplantation is the only remaining hope. Unfortunately, because of the increasing demand for donor organs in the face of a fixed and limited supply, this option is only available to a small percentage of these patients. Even in patients accepted for transplantation, a significant waiting list mortality has been observed. A variety of ventricular assist devices (VAD) have been developed since the first successful case of mechanical cardiac assistance over 30 years ago. These devices differ in basic mechanical function, method of insertion, and degree of implantability, and thus have different indications and potential applications. While the intra-aortic balloon pump and centrifugal pumps are effective short-term support modalities, extracorporeal and implantable pulsatile devices have been used successfully for long-term support of patients with reversible and non-reversible cardiac failure. These pumps have most commonly been utilized as bridges to transplantation, but increasing clinical experience has supported the notion of long-term mechanical assistance as a definitive therapy for endstage heart disease. While complications, particularly infection and thromboembolism, pose significant challenges and long-term device reliability remains to be fully determined, available implantable devices seem capable of providing effective long-term support. As data is obtained from currently ongoing trials comparing VAD support to medical therapy for endstage heart failure, ethical and economic issues will assume increasing importance.


Taxonomy of Tricholoma in northern Europe based on ITS sequence data and morphological characters.
Based on molecular and morphological data we investigated the taxonomy and phylogeny of the ectomycorrhizal genus Tricholoma in northern Europe. Our phylogenetic tree confirmed the presence of at least 72 well circumscribed species within the region. Of these, three species, viz. T. boreosulphurescens, T. bryogenum and T. ilkkae are described as new to science, based on morphological, distributional, ecological and molecular data. Several other terminal branches represent putative cryptic taxa nested within classical species or species groups. Molecular type studies and/or designation of sequenced neotypes are needed in these groups, before the taxonomy can be settled. In general our phylogenetic analysis supported previous suprageneric classification systems, but with some substantial changes. Most notably, T. virgatum and allies were found to belong to sect. Tricholoma rather than sect. Atrosquamosa, while T. focale was found to be clearly nested in sect. Genuina rather than in sect. Caligata. In total, ten sections are accepted, with five species remaining unassigned. The combination of morphological and molecular data showed pileus colour, pileipellis structure, presence of clamp connections and spore size to be rather conservative characters within accepted sections, while the presence of a distinct ring, and especially host selection were highly variable within these.


Lipoprotein Particles Interact with Membranes and Transfer Their Cargo without Receptors.
Lipid transfer from lipoprotein particles to cells is essential for lipid homeostasis. High-density lipoprotein (HDL) particles are mainly captured by cell membrane-associated scavenger receptor class B type 1 (SR-B1) from the bloodstream, while low-density and very-low-density lipoprotein (LDL and VLDL, respectively) particles are mostly taken up by receptor-mediated endocytosis. However, the role of the target lipid membrane itself in the transfer process has been largely neglected so far. Here, we study how lipoprotein particles (HDL, LDL, and VLDL) interact with synthetic lipid bilayers and cell-derived membranes and transfer their cargo subsequently. Employing cryo-electron microscopy, spectral imaging, and fluorescence (cross) correlation spectroscopy allowed us to observe integration of all major types of lipoprotein particles into the membrane and delivery of their cargo in a receptor-independent manner. Importantly, the biophysical properties of the target cell membranes change upon delivery of cargo. The concept of receptor-independent interaction of lipoprotein particles with membranes helps us to better understand lipoprotein particle biology and can be exploited for novel treatments of dyslipidemia diseases.


The Alzheimer's Disease Assessment Scale.
This article reviews longitudinal data collected from patients with Alzheimer's disease (AD) that are relevant to the design and interpretation of clinical treatment trials. Longitudinal data from patients tested with the Alzheimer's Disease Assessment Scale demonstrate that cognitive symptoms, including memory loss, dysphasia, and dyspraxia, worsen relentlessly over time with the rate of change depending upon baseline dementia severity. Noncognitive symptoms, such as agitation, depressed mood, and psychosis, are episodic, do not necessarily worsen over time, and tend not to be highly correlated with one another. The reliability of cognitive change measures increases with follow-up duration so that the likelihood of detecting drug effects on the rate of cognitive deterioration is greater with longer treatment trials. Functional measures of activities of daily living are difficult to standardize for AD patients but are important for determining the overall clinical and economic impact of AD treatments.


Aligned electrospun fibers for neural patterning.
To test a 3D approach for neural network formation, alignment, and patterning that is reproducible and sufficiently stable to allow for easy manipulation. A novel cell culture system was designed by engineering a method for the directional growth of neurons. This uses NG108-15 neuroblastoma x glioma hybrid cells cultured on suspended and aligned electrospun fibers. These fiber networks improved cellular directionality, with alignment angle standard deviations significantly lower on fibers than on regular culture surfaces. Morphological studies found nuclear aspect ratios and cell projection lengths to be unchanged, indicating that cells maintained neural morphology while growing on fibers and forming a 3D network. Furthermore, fibronectin-coated fibers enhanced neurite extensions for all investigated time points. Differentiated neurons exhibited significant increases in average neurite lengths 96 h post plating, and formed neurite extensions parallel to suspended fibers, as visualized through scanning electron microscopy. The developed model has the potential to serve as the basis for advanced 3D studies, providing an original approach to neural network patterning and setting the groundwork for further investigations into functionality.


Evaluation of the Applicability of Solar and Lamp Radiometric Calibrations of a Precision Sun Photometer Operating Between 300 and 1025 nm.
Over a period of 3 years a precision Sun photometer (SPM) operating between 300 and 1025 nm was calibrated four times at three different high-mountain sites in Switzerland, Germany, and the United States by means of the Langley-plot technique. We found that for atmospheric window wavelengths the total error (2varsigma-statistical plus systematic errors) of the calibration constants V(0) (lambda), the SPM voltage in the absence of any attenuating atmosphere, can be kept below 1.6% in the UV-A and blue, 0.9% in the mid-visible, and 0.6% in the near-infrared spectral region. For SPM channels within strong water-vapor or ozone absorption bands a modified Langley-plot technique was used to determine V(0) (lambda) with a lower accuracy. Within the same period of time, we calibrated the SPM five times using irradiance standard lamps in the optical labs of the Physikalisch-Meteorologisches Observatorium Davos and World Radiation Center, Switzerland, and of the Remote Sensing Group of the Optical Sciences Center, University of Arizona, Tucson, Arizona. The lab calibration method requires knowledge of the extraterrestrial spectral irradiance. When we refer the standard lamp results to the World Radiation Center extraterrestrial solar irradiance spectrum, they agree with the Langley results within 2% at 6 of 13 SPM wavelengths. The largest disagreement (4.4%) is found for the channel centered at 610 nm. The results of these intercomparisons change significantly when the lamp results are referred to two different extraterrestrial solar irradiance spectra that have become recently available.


Risk assessment strategies for neuroprotective agents.
Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. Neurotoxic effects may be permanent or reversible, produced by neuropharmacological or neurodegenerative properties of a neurotoxicant, or the result of direct or indirect actions on the nervous system. A multidisciplinary approach is necessary to assess neurotoxicity because of the complexity and diverse functions of the nervous system. Many of the relevant effects can be measured directly by neurochemical, neurophysiological, and neuropathological techniques, whereas, others must be inferred from observed behavior. Some neurotoxicological data can be derived directly from humans. Neurotoxicity in humans is most commonly measured by relatively noninvasive neurophysiologic and neurobehavioral methods that assess cognitive, affective, sensory, and motor function. For most toxicological assessments, however, it is necessary to rely on information derived from animal models. There are many approaches that can be used to assess neurotoxicity, including whole animal (in vivo) and tissue/cell culture (in vitro) testing. Neurotoxicity can be described at multiple levels of organization, including neurochemical, anatomical, physiological, and behavioral. An important aspect of neurotoxic endpoint evaluation involves risk assessment procedures. Risk assessment may be defined as an empirically-based process used to determine the probability that adverse or abnormal effects are associated with exposure to a chemical, physical or biological agent. Risk management, on the other hand, is the process that applies information obtained through the risk assessment process to determine whether the assessed risk should be reduced and, if so, to what extent. For chemicals such as neuroprotective agents and other drugs designed to provide therapeutic benefits, information concerning these benefits is considered during the risk management phase. The risk assessment process usually involves four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. Neurotoxicity risk assessment models of the future may well include biomarkers of both effect and exposure as well as biologically-based mechanistic and pharmacokinetic considerations derived from both epidemiologic and experimental data.


The aetiology of rickets-like lower limb deformities in Malawian children.
Debilitating rickets-like lower limb deformities are common in children throughout the world, particularly in Malawi, Africa where the causes are unknown. We have identified that Blount disease and calcium deficiency rickets are the likely causes of these deformities and propose calcium supplementation as a potential treatment of Malawian rickets. Surgical correction of rickets-like lower limb deformities is the most common paediatric operation performed at Beit Cure Orthopaedic Hospital, Malawi. The aim of this study was to investigate the aetiology of these deformities. Children with a tibio-femoral angle of deformity >20° were enrolled (n = 42, 3.0-15.0 years). Anthropometric and early life and well-being data were collected. Early morning serum and urine samples were collected on the morning of the operation for markers of calcium and phosphate homeostasis. Knee radiographs were obtained, and the children were diagnosed with either Blount (BD, n = 22) or evidence of rickets disease (RD, n = 20). As BD is a mechanical rather than metabolic disease, BD were assumed to be biochemically representative of the local population and thus used as a local reference for RD. There were no differences in anthropometry or early life experiences between BD and RD. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, total alkaline phosphatase and urinary phosphate were significantly higher and serum phosphate, 25-hydroxyvitamin D (25OHD) and tubular maximal reabsorption of phosphate significantly lower in RD than BD. There was no difference in serum calcium, fibroblast growth factor 23 or markers of iron status between groups. All children had 25OHD > 25 nmol/L. Vitamin D deficiency is not implicated in the aetiology of RD or BD in Malawian children. The cause of RD in Malawi is likely to be dietary calcium deficiency leading to elevated PTH resulting in increased losses of phosphate from the bone and glomerular filtrate. The causes of BD remain unclear; there was no evidence in support of previously suggested risk factors such as being overweight or starting to walk early. Prior to surgical intervention, supplementation with calcium should be considered for children with RD.


Improving outcomes in tumour necrosis factor a treatment: comparison of the efficacy of the tumour necrosis factor a blocking agents etanercept and infliximab in patients with active rheumatoid arthritis.
The aim of this study was to evaluate the differences between infliximab and etanercept, in terms of clinical efficacy and rapidity of action. We selected 32 patients with rheumatoid arthritis (RA) with an incomplete response to disease modifying anti-rheumatic drugs (DMARDs), and randomly assigned them to etanercept or infliximab. We evaluated the efficacy after 14, 22, 54 weeks of treatment, using the American College of Rheumatology (ACR) 20, 50 and 70 criteria, and the improvement of quality of life using the Health Assessment Question-naire (HAQ). After 14 weeks, the 54.4% of patients was considered ACR-responders in the etanercept group, whereas, in the infliximab group, the percentage of responders was 74.4%: infliximab gave better results for the tender joint count and for physician's global assessment. After 22 weeks, no significant difference was present. After 54 weeks, etanercept resulted more effective than infliximab for tender joint count (TJC) value, for visual analogic scale (VAS) for pain score, for global disease assessment value, with 74.4% of patients considered ACR-responders in the group treated with etanercept and 60% in the group treated with infliximab. As regards HAQ, patients in the infliximab group presented higher scores at week 14, but in weeks 22 and 54, patients in the etanercept group showed better results. Therefore, both infliximab and etanercept are efficacious in RA, but infliximab is more efficacious than etanercept in week 14. Vice versa, in week 54 etanercept is the most efficacious drug. Physicians have 2 weapons in their armamentarium, with the same target but distinct clinical, pharmacokinetic and pharmacodynamic properties.


Ciguatera: recent advances but the risk remains.
Ciguatera is an important form of human poisoning caused by the consumption of seafood. The disease is characterised by gastrointestinal, neurological and cardiovascular disturbances. In cases of severe toxicity, paralysis, coma and death may occur. There is no immunity, and the toxins are cumulative. Symptoms may persist for months or years, or recur periodically. The epidemiology of ciguatera is complex and of central importance to the management and future use of marine resources. Ciguatera is an important medical entity in tropical and subtropical Pacific and Indian Ocean regions, and in the tropical Caribbean. As reef fish are increasingly exported to other areas, it has become a world health problem. The disease is under-reported and often misdiagnosed. Lipid-soluble, polyether toxins known as ciguatoxins accumulated in the muscles of certain subtropical and tropical marine finfish cause ciguatera. Ciguatoxins arise from biotransformation in the fish of less polar ciguatoxins (gambiertoxins) produced by Gambierdiscus toxicus, a marine dinoflagellate that lives on macroalgae, usually attached to dead coral. The toxins and their metabolites are concentrated in the food chain when carnivorous fish prey on smaller herbivorous fish. Humans are exposed at the end of the food chain. More than 400 species of fish can be vectors of ciguatoxins, but generally only a relatively small number of species are regularly incriminated in ciguatera. Ciguateric fish look, taste and smell normal, and detection of toxins in fish remains a problem. More than 20 precursor gambiertoxins and ciguatoxins have been identified in G. toxicus and in herbivorous and carnivorous fish. The toxins become more polar as they undergo oxidative metabolism and pass up the food chain. The main Pacific ciguatoxin (P-CTX-1) causes ciguatera at levels=0.1 microg/kg in the flesh of carnivorous fish. The main Caribbean ciguatoxin (C-CTX-1) is less polar and 10-fold less toxic than P-CTX-1. Ciguatoxins activate sodium ion (Na ) channels, causing cell membrane excitability and instability. Worldwide coral bleaching is now well documented, and there is a strong association between global warming and the bleaching and death of coral. This, together with natural environmental factors such as earthquakes and hurricanes, and man-made factors such as tourism, dock construction, sewage and eutrophication, may create more favourable environments for G. toxicus. While low levels of G. toxicus are found throughout tropical and subtropical waters, the presence of bloom numbers is unpredictable and patchy. Only certain genetic strains produce ciguatoxins, and environmental triggers for increasing toxin production are unknown.


Incidence of neoplasms in children born after influenza epidemics.
Following a recent report that neoplasia of the lymphatic and haematopoietic tissues is commoner than average in children whose mothers have had influenza in pregnancy, the incidence of neoplasms in 1954-68 in children of the Manchester Hospital Region was examined in relation to date of birth. There were no significant differences between cohorts born in different quinquennia. Incidence among children born after six influenza epidemics in 1951-68 was no higher than among other children born in these years. It is concluded that if there is an association between maternal influenza and childhood neoplasia it is probably due to factors such as immunological deficiencies which may predispose independently to both conditions.


In vivo reflectance-mode confocal microscopy provides insights in human skin microcirculation and histomorphology.
Various approaches are used to study microcirculation, however, no modality evaluates microcirculation and histomorphology on cellular levels. We hypothesized that reflectance-mode confocal microscopy (RCM) enables simultaneous evaluation in vivo of both microcirculation and histomorphology. The forearm of 20 volunteers was exposed to either local heat stress (HS-group), or to local cold stress (CS-group). RCM was performed prior and after temperature stress to evaluate quantitative blood-cell flow, capillary loop diameter, granular cell size, and basal layer thickness. In the HS-group, we observed significant increase in capillary loop diameter and increased blood-cell flow after heat stress. In the CS-group, significant decreases of capillary loop diameter and in blood-cell flow were determined following cold stress. Granular cell size and basal layer thickness differed insignificantly prior and after local temperature stress. RCM provides real-time and in vivo high resolution imaging of temperature-dependent changes in the human skin microcirculation and histomorphology on cellular levels.


The importance of reactive oxygen species on the aqueous phototransformation of sulfonamide antibiotics: kinetics, pathways, and comparisons with direct photolysis.
Sulfonamide antibiotics (SAs) are increasingly detected as aquatic contaminants and exist as different dissociated species depending on the pH of the water. Their removal in sunlit surface waters is governed by photochemical transformation. Here we report a detailed examination of the hydroxyl radical (•OH) and singlet oxygen (1O2) mediated photooxidation of nine SAs: sulfamethoxazole, sulfisoxazole, sulfamethizole, sulfathiazole, sulfamethazine, sulfamerazine, sulfadiazine, sulfachloropyridazine and sulfadimethoxine. Both •OH and 1O2 oxidation kinetics varied depending on the dominant protonated states of the SA in question (H2SAs+, HSAs0 and SAs-) as a function of pH. Based on competition kinetic experiments and matrix deconvolution calculations, HSAs0 or SAs- (pH ∼5-8) were observed to be more highly reactive towards •OH, while SAs- (pH ∼8) react the fastest with 1O2 for most of the SAs tested. Using the empirically derived rates of reaction for the speciated forms at different pHs, the environmental half-lives were determined using typical 1O2 and •OH concentrations observed in the environment. This approach suggests that photochemical 1O2 oxidation contributes more than •OH oxidation and direct photolysis to the overall phototransformation of SAs in sunlit waters. Based on the identification of key photointermediates using tandem mass spectrometry, 1O2 oxidation generally occurred at the amino moiety on the molecule, whereas •OH reaction experienced multi-site hydroxylation. Both these reactions preserve the basic parent structure of the compounds and raise concerns that the routes of phototransformation give rise to intermediates with similar antimicrobial potency as the parent SAs. We therefore recommend that these phototransformation pathways are included in risk assessments concerning the presence and fate of SAs in waste and surface waters.


The Technique, Resources and Costs of Stereotactic Body Radiotherapy of Prostate Cancer: A Comparison of Dose Regimens and Delivery Systems.
Robotic system has been used for stereotactic body radiotherapy (SBRT) of prostate cancer. Arc-based and fixed-gantry systems are used for hypofractionated regimens (10-20 fractions) and the standard regimen (39 fractions); they may also be used to deliver SBRT. Studies are currently underway to compare efficacy and safety of these systems and regimens. Thus, we describe the technique and required resources for the provision of robotic SBRT in relation to the standard regimen and other systems to guide investment decisions. Using administrative data of resource volumes and unit prices, we computed the cost per patient, cost per cure and cost per quality adjusted life year (QALY) of four regimens (5, 12, 20 and 39 fractions) and three delivery systems (robotic, arc-based and fixed-gantry) from a payer's perspective. We performed sensitivity analyses to examine the effects of daily hours of operation and in-room treatment delivery times on cost per patient. In addition, we estimated the budget impact when a robotic system is preferred over an arc-based or fixed-gantry system. Costs of SBRT were $6333/patient (robotic), $4368/patient (arc-based) and $4443/patient (fixed-gantry). When daily hours of operation were varied, the cost of robotic SBRT varied from $9324/patient (2 hours daily) to $5250/patient (10 hours daily). This was comparable to the costs of 39 fraction standard regimen which were $5935/patient (arc-based) and $7992/ patient (fixed-gantry). In settings of moderate to high patient volume, robotic SBRT is cost effective compared to the standard regimen. If SBRT can be delivered with equivalent efficacy and safety, the arc-based system would be the most cost effective system.


Single-atom spin-flip spectroscopy.
We demonstrate the ability to measure the energy required to flip the spin of single adsorbed atoms. A low-temperature, high-magnetic field scanning tunneling microscope was used to measure the spin excitation spectra of individual manganese atoms adsorbed on Al2O3 islands on a NiAl surface. We find pronounced variations of the spin-flip spectra for manganese atoms in different local environments.


Acoustic, mechanical and near-infrared profiling of osteoarthritic progression in bovine joints.
Early-stage treatments for osteoarthritis are attracting considerable interest as a means to delay, or avoid altogether, the pain and lack of mobility associated with late-stage disease, and the considerable burden that it places on the community. With the development of these treatments comes a need to assess the tissue to which they are applied, both in trialling of new treatments and as an aid to clinical decision making. Here, we measure a range of mechanical indentation, ultrasound and near-infrared spectroscopy parameters in normal and osteoarthritic bovine joints in vitro to describe the role of different physical phenomena in disease progression, using this as a basis to investigate the potential value of the techniques as clinical tools. Based on 72 samples we found that mechanical and ultrasound parameters showed differences between fibrillated tissue, macroscopically normal tissue in osteoarthritic joints, and normal tissue, yet did were unable to differentiate degradation beyond that which was visible to the naked eye. Near-infrared spectroscopy showed a clear progression of degradation across the visibly normal osteoarthritic joint surface and as such, was the only technique considered useful for clinical application.


Bovine papillomavirus in Brazil: detection of coinfection of unusual types by a PCR-RFLP method.
Bovine papillomavirus (BPV) is recognized as a causal agent of benign and malignant tumors in cattle. Thirteen types of BPV are currently characterized and classified into three distinct genera, associated with different pathological outcomes. The described BPV types as well as other putative ones have been demonstrated by molecular biology methods, mainly by the employment of degenerated PCR primers. Specifically, divergences in the nucleotide sequence of the L1 gene are useful for the identification and classification of new papillomavirus types. On the present work, a method based on the PCR-RFLP technique and DNA sequencing was evaluated as a screening tool, allowing for the detection of two relatively rare types of BPV in lesions samples from a six-year-old Holstein dairy cow, chronically affected with cutaneous papillomatosis. These findings point to the dissemination of BPVs with unclear pathogenic potential, since two relatively rare, new described BPV types, which were first characterized in Japan, were also detected in Brazil.


Childhood Cancer Survivor Study participants' perceptions and understanding of the Affordable Care Act.
The Patient Protection and Affordable Care Act (ACA) established provisions intended to increase access to affordable health insurance and thus increase access to medical care and long-term surveillance for populations with pre-existing conditions. However, childhood cancer survivors' coverage priorities and familiarity with the ACA are unknown. Between May 2011 and April 2012, we surveyed a randomly selected, age-stratified sample of 698 survivors and 210 siblings from the Childhood Cancer Survivor Study. Overall, 89.8% of survivors and 92.1% of siblings were insured. Many features of insurance coverage that survivors considered "very important" are addressed by the ACA, including increased availability of primary care (94.6%), no waiting period before coverage initiation (79.0%), and affordable premiums (88.1%). Survivors were more likely than siblings to deem primary care physician coverage and choice, protections from costs due to pre-existing conditions, and no start-up period as "very important" (P < .05 for all). Only 27.3% of survivors and 26.2% of siblings reported familiarity with the ACA (12.1% of uninsured v 29.0% of insured survivors; odds ratio, 2.86; 95% CI, 1.28 to 6.36). Only 21.3% of survivors and 18.9% of siblings believed the ACA would make it more likely that they would get quality coverage. Survivors' and siblings' concerns about the ACA included increased costs, decreased access to and quality of care, and negative impact on employers and employees. Although survivors' coverage preferences match many ACA provisions, survivors, particularly uninsured survivors, were not familiar with the ACA. Education and assistance, perhaps through cancer survivor navigation, are critically needed to ensure that survivors access coverage and benefits.


Hoyeraal-Hreidarsson Syndrome: An Extremely Rare Dyskeratosis Congenita Phenotype.
Hoyeraal-Hreidarsson syndrome is a rare telomere biology disorder that is recognized as a severe variant of dyskeratosis congenita. We present a Libyan boy with hematologic and neurologic abnormalities with typical dermatologic manifestations of dyskeratosis congenita. Death usually occurs before the age of 4 years as a result of pancytopenia or malignant transformation of mucocutaneous lesions. The boy presented survived longer than 5 years. Early recognition and appropriate genetic counseling are crucial because of the high mortality of this genetic disorder.


Severe spruelike enteropathy associated with olmesartan.
To report the response to discontinuation of olmesartan, an angiotensin II receptor antagonist commonly prescribed for treatment of hypertension, in patients with unexplained severe spruelike enteropathy. All 22 patients included in this report were seen at Mayo Clinic in Rochester, Minnesota, between August 1, 2008, and August 1, 2011, for evaluation of unexplained chronic diarrhea and enteropathy while taking olmesartan. Celiac disease was ruled out in all cases. To be included in the study, the patients also had to have clinical improvement after suspension of olmesartan. The 22 patients (13 women) had a median age of 69.5 years (range, 47-81 years). Most patients were taking 40 mg/d of olmesartan (range, 10-40 mg/d). The clinical presentation was of chronic diarrhea and weight loss (median, 18 kg; range, 2.5-57 kg), which required hospitalization in 14 patients (64%). Intestinal biopsies showed both villous atrophy and variable degrees of mucosal inflammation in 15 patients, and marked subepithelial collagen deposition (collagenous sprue) in 7. Tissue transglutaminase antibodies were not detected. A gluten-free diet was not helpful. Collagenous or lymphocytic gastritis was documented in 7 patients, and microscopic colitis was documented in 5 patients. Clinical response, with a mean weight gain of 12.2 kg, was demonstrated in all cases. Histologic recovery or improvement of the duodenum after discontinuation of olmesartan was confirmed in all 18 patients who underwent follow-up biopsies. Olmesartan may be associated with a severe form of spruelike enteropathy. Clinical response and histologic recovery are expected after suspension of the drug.


Diet and its relationship with grip strength in community-dwelling older men and women: the Hertfordshire cohort study.
To examine relationships between diet and grip strength in older men and women and to determine whether prenatal growth modifies these relationships. Cross-sectional and retrospective cohort study. Hertfordshire, United Kingdom. Two thousand nine hundred eighty-three men and women aged 59 to 73 who were born and still living in Hertfordshire, United Kingdom. Weight at birth recorded in Health Visitor ledgers; current food and nutrient intake assessed using an administered food frequency questionnaire; and grip strength measured using a handheld dynamometer. Grip strength was positively associated with height and weight at birth and inversely related to age (all P<.001). Of the dietary factors considered in relation to grip strength, the most important was fatty fish consumption. An increase in grip strength of 0.43 kg (95% confidence interval (CI)=0.13-0.74) in men (P=.005) and 0.48 kg (95% CI=0.24-0.72) in women (P<.001) was observed for each additional portion of fatty fish consumed per week. These relationships were independent of adult height, age, and birth weight, each of which had additive effects on grip strength. There was no evidence of interactive effects of weight at birth and adult diet on grip strength. These data suggest that fatty fish consumption can have an important influence on muscle function in older men and women. This raises the possibility that the antiinflammatory actions of omega-3 fatty acids may play a role in the prevention of sarcopenia.


Multiframe deconvolution with space-variant point-spread functions by use of inverse filtering and fast Fourier transform.
A procedure for deconvolution of multiple images of the same object with space-variant point-spread functions (PSFs) is presented. It is based on expressing deconvolution with inverse filtering as convolution with kernels corresponding to inverse PSFs. Sets of basis functions are made from these inverse PSFs, given at discrete sample points, through Karhunen-Loève (K-L) decomposition. The entire field of view can then be convolved with the K-L kernels. Coadding the results using continuous maps of expansion weights, interpolated for every pixel between the sample points, results in an image that is deconvolved with smoothly varying PSFs that match the discrete measurements. A demonstration data set is used to show how the transition between the grid points improves deconvolutions compared to piecewise deconvolution and mosaicking by avoiding the blending of discontinuities at the interfaces between adjacent subfields.


Out-of-Sample Extension for Dimensionality Reduction of Noisy Time Series.
This paper proposes an out-of-sample extension framework for a global manifold learning algorithm (Isomap) that uses temporal information in out-of-sample points in order to make the embedding more robust to noise and artifacts. Given a set of noise-free training data and its embedding, the proposed framework extends the embedding for a noisy time series. This is achieved by adding a spatio-temporal compactness term to the optimization objective of the embedding. To the best of our knowledge, this is the first method for out-of-sample extension of manifold embeddings that leverages timing information available for the extension set. Experimental results demonstrate that our out-of-sample extension algorithm renders a more robust and accurate embedding of sequentially ordered image data in the presence of various noise and artifacts when compared with other timing-aware embeddings. Additionally, we show that an out-of-sample extension framework based on the proposed algorithm outperforms the state of the art in eye-gaze estimation.


Development of a multivariate model to predict the likelihood of carcinoma in patients with indeterminate peripheral lung nodules after a nondiagnostic bronchoscopic evaluation.
Studies have shown that fluorescence in situ hybridization (FISH) testing increases lung cancer detection on cytology specimens in peripheral nodules. The goal of this study was to determine whether a predictive model using clinical features and routine cytology with FISH results could predict lung malignancy after a nondiagnostic bronchoscopic evaluation. Patients with an indeterminate peripheral lung nodule that had a nondiagnostic bronchoscopic evaluation were included in this study (N = 220). FISH was performed on residual bronchial brushing cytology specimens diagnosed as negative (n = 195), atypical (n = 16), or suspicious (n = 9). FISH results included hypertetrasomy (n = 30) and negative (n = 190). Primary study end points included lung cancer status along with time to diagnosis of lung cancer or date of last clinical follow-up. Hazard ratios (HRs) were calculated using Cox proportional hazards regression model analyses, and P values < .05 were considered statistically significant. The mean age of the 220 patients was 66.7 years (range, 35-91), and most (58%) were men. Most patients (79%) were current or former smokers with a mean pack year history of 43.2 years (median, 40; range, 1-200). After multivariate analysis, hypertetrasomy FISH (HR = 2.96, P < .001), pack years (HR = 1.03 per pack year up to 50, P = .001), age (HR = 1.04 per year, P = .02), atypical or suspicious cytology (HR = 2.02, P = .04), and nodule spiculation (HR = 2.36, P = .003) were independent predictors of malignancy over time and were used to create a prediction model (C-statistic = 0.78). These results suggest that this multivariate model including test results and clinical features may be useful following a nondiagnostic bronchoscopic examination.


The CAPN2/CAPN8 Locus on Chromosome 1q Is Associated with Variation in Serum Alpha-Carotene Concentrations.
Alpha-carotene is a provitamin A carotenoid present in fruits and vegetables. Higher serum concentrations of α-carotene have been associated with lower risk of cancer and all-cause mortality. Previous studies have suggested that genetic variants influence serum concentrations of provitamin A carotenoids, but to date no variants have been robustly associated with serum α-carotene concentrations. The aim of this study was to identify genetic associations with serum α-carotene concentrations using the genome-wide association study (GWAS) approach. A GWAS of serum α-carotene concentrations was conducted in 433 Old Order Amish adults who had consumed a 6-day controlled diet. Linear regression models adjusting for age, gender, and family structure were utilized to evaluate associations between genetic variants and serum α-carotene concentrations. Genome-wide significant associations with α-carotene concentrations were observed for loci on chromosome 1q41 between the genes CAPN2 and CAPN8 (rs12137025, p = 3.55 × 10-8), chromosome 2p21 in PRKCE (rs2594495, p = 1.01 × 10-8), and chromosome 4q34 (rs17830069, p = 2.89 × 10-8). We identified 3 novel loci associated with serum α-carotene concentrations among a population that consumed a controlled diet. While replication is necessary, the CAPN2/CAPN8 locus provides compelling evidence for an association with serum α-carotene concentrations and may suggest a relationship with the development and progression of cancers.


Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: report of the ISPOR Task Force for Translation and Cultural Adaptation.
In 1999, ISPOR formed the Quality of Life Special Interest group (QoL-SIG)--Translation and Cultural Adaptation group (TCA group) to stimulate discussion on and create guidelines and standards for the translation and cultural adaptation of patient-reported outcome (PRO) measures. After identifying a general lack of consistency in current methods and published guidelines, the TCA group saw a need to develop a holistic perspective that synthesized the full spectrum of published methods. This process resulted in the development of Translation and Cultural Adaptation of Patient Reported Outcomes Measures--Principles of Good Practice (PGP), a report on current methods, and an appraisal of their strengths and weaknesses. The TCA Group undertook a review of evidence from current practice, a review of the literature and existing guidelines, and consideration of the issues facing the pharmaceutical industry, regulators, and the broader outcomes research community. Each approach to translation and cultural adaptation was considered systematically in terms of rationale, components, key actors, and the potential benefits and risks associated with each approach and step. The results of this review were subjected to discussion and challenge within the TCA group, as well as consultation with the outcomes research community at large. Through this review, a consensus emerged on a broad approach, along with a detailed critique of the strengths and weaknesses of the differing methodologies. The results of this review are set out as "Translation and Cultural Adaptation of Patient Reported Outcomes Measures--Principles of Good Practice" and are reported in this document.


Treatment patterns, health care resource utilization, and costs in Japanese adults with attention-deficit hyperactivity disorder treated with atomoxetine.
To describe the characteristics and medication treatment patterns of adult patients with attention-deficit/hyperactivity disorder (ADHD) prescribed atomoxetine in Japan. A retrospective analysis of insurance claims data was conducted using the Japan Medical Data Center database. Adults (≥18 years) with ADHD who had ≥1 atomoxetine claim from January 1, 2013 to December 31, 2014, and ≥180 to ≤900 days of follow-up were included. First atomoxetine claim defined the index date. Patient characteristics included age, gender, and comorbid conditions. Treatment patterns assessed included rates of atomoxetine discontinuation, switching, persistence, adherence (assessed via the medication possession ratio), and use of concomitant medications. A total of 457 adults met all the inclusion criteria. Mean (SD) age was 32.7 (10.4) years, and 61.0% of patients were male. Nearly 72.0% of the patients had at least one comorbid mental health condition in the baseline period; depression (43.8%) and insomnia (40.7%) were the most common mental health comorbidities. Most common physical comorbidities were chronic obstructive pulmonary disease (14.4%) and diabetes (12.9%). Non-ADHD-specific psychotropics were prescribed to 59.7% of patients during the baseline period and to 65.9% during the follow-up period; 6.6% were prescribed non-ADHD-specific psychotropics concomitantly with atomoxetine. Overall, 40.0% of adults discontinued atomoxetine during the entire follow-up period and 65.9% were persistent with atomoxetine therapy at 3 months post-index date. Mean (SD) atomoxetine medication possession ratio was 0.57 (0.25), and 25.4% switched to an alternative ADHD therapy; methylphenidate (22.4%) and non-ADHD-specific psychotropics (77.6%) were the most common medication alternatives. Nearly 8% augmented atomoxetine with methylphenidates, non-stimulants, or non-ADHD-specific psychotropics. In this observational study, a majority of adults with ADHD treated with atomoxetine were still persistent with therapy at 3 months post-index date, with one quarter switching to alternative ADHD therapy. High proportions of mental health comorbidities, along with high use of non-ADHD-specific psychotropic medications in both the baseline and follow-up periods, were observed among patients with ADHD prescribed atomoxetine.


Short-term Suicide Risk After Psychiatric Hospital Discharge.
Although psychiatric inpatients are recognized to be at increased risk for suicide immediately after hospital discharge, little is known about the extent to which their short-term suicide risk varies across groups with major psychiatric disorders. To describe the risk for suicide during the 90 days after hospital discharge for adults with first-listed diagnoses of depressive disorder, bipolar disorder, schizophrenia, substance use disorder, and other mental disorders in relation to inpatients with diagnoses of nonmental disorders and the general population. This national retrospective longitudinal cohort included inpatients aged 18 to 64 years in the Medicaid program who were discharged with a first-listed diagnosis of a mental disorder (depressive disorder, bipolar disorder, schizophrenia, substance use disorder, and other mental disorder) and a 10% random sample of inpatients with diagnoses of nonmental disorders. The cohort included 770 643 adults in the mental disorder cohort, 1 090 551 adults in the nonmental disorder cohort, and 370 deaths from suicide from January 1, 2001, to December 31, 2007. Data were analyzed from March 5, 2015, to June 6, 2016. Suicide rates per 100 000 person-years were determined for each study group during the 90 days after hospital discharge and the demographically matched US general population. Adjusted hazard ratios (ARHs) of short-term suicide after hospital discharge were also estimated by Cox proportional hazards regression models. Information on suicide as a cause of death was obtained from the National Death Index. In the overall population of 1 861 194 adults (27% men; 73% women; mean [SD] age, 35.4 [13.1] years), suicide rates for the cohorts with depressive disorder (235.1 per 100 000 person-years), bipolar disorder (216.0 per 100 000 person-years), schizophrenia (168.3 per 100 000 person-years), substance use disorder (116.5 per 100 000 person-years), and other mental disorders (160.4 per 100 000 person-years) were substantially higher than corresponding rates for the cohort with nonmental disorders (11.6 per 100 000 person-years) or the US general population (14.2 per 100 000 person-years). Among the cohort with mental disorders, AHRs of suicide were associated with inpatient diagnosis of depressive disorder (AHR, 2.0; 95% CI, 1.4-2.8; reference cohort, substance use disorder), an outpatient diagnosis of schizophrenia (AHR, 1.6; 95% CI, 1.1-2.2), an outpatient diagnosis of bipolar disorder (AHR, 1.6; 95% CI, 1.2-2.1), and an absence of any outpatient health care in the 6 months preceding hospital admission (AHR, 1.7; 95% CI, 1.2-2.5). After psychiatric hospital discharge, adults with complex psychopathologic disorders with prominent depressive features, especially patients who are not tied into a system of health care, appear to have a particularly high short-term risk for suicide.


Antifungal activity of the essential oil of Melaleuca alternifolia (tea tree oil) against pathogenic fungi in vitro.
The in vitro antifungal activity of tea oil, the essential oil of Melaleuca alternifolia, has been evaluated against 26 strains of various dermatophyte species, 54 yeasts, among them 32 strains of Candida albicans and other Candida sp. as well as 22 different Malassezia furfur strains. Minimum inhibitory concentrations (MIC) of tea tree oil were measured by agar dilution technique. Tea tree oil was found to be able to inhibit growth of all clinical fungal isolates. For the investigated dermatophytes MIC values from 1,112.5 to 4,450.0 micrograms/ml with a geometric mean of 1,431.5 micrograms/ml were demonstrated. Both C. albicans strains and the other strains belonging to the genus Candida and Trichosporon appeared to be slightly less susceptible to tea tree oil in vitro. However, their MIC values, which varied from 2,225.0 to 4,450.0 micrograms/ml (geometric mean 4,080 micrograms/ml), indicated moderate susceptibility to the essential oil of M. alternifolia. The lipophilic yeast M. furfur seemed to be most susceptible to tea tree oil. MIC values between 556.2 and 4,450.0 micrograms/ml (geometric mean 1,261.5 micrograms/ml) were found against the tested M. furfur strains. However, when calculated as percentage tea tree oil of the agar, the above-mentioned concentrations correspond to 0.5-0.44% tea tree oil content. These values are far below the usual relatively high therapeutic concentrations of the agent; approximately 5-10% solution or even the concentrated essential oil are used for external treatment. In comparison with tea tree oil, in vitro susceptibility against miconazole, an established topical antifungal, was tested. As expected, very low MIC values for miconazole were found for dermatophytes (geometric mean 0.2 microgram/ml), yeasts (geometric mean 1.0 microgram/ml), and M. furfur (geometric mean 2.34 micrograms/ml). It is suggested that the in vivo effect of tea tree oil ointment in the therapy of fungal infections of the skin and mucous membranes as well as in the treatment of dandruff, a mild form of seborrheic dermatitis, may be at least partly due to an antifungal activity of tea tree oil.


GADOXETATE DISODIUM (GD-EOB-DTPA) CONTRAST ENHANCED MAGNETIC RESONANCE IMAGING CHARACTERISTICS OF HEPATOCELLULAR CARCINOMA IN DOGS.
Hepatocellular carcinoma is the most common primary hepatic tumor in dogs and is amenable to surgical resection in many cases. Unfortunately, overlap of sonographic findings between benign and malignant hepatic lesions typically requires more invasive diagnostic tests to be performed (e.g., biopsy for histopathology). The availability of a noninvasive diagnostic test to identify hepatocellular carcinoma would be beneficial. The use of a liver-specific magnetic resonance imaging (MRI) contrast agent such as gadoxetate disodium (Gd-EOB-DTPA; Eovist® or Primovist®) has improved lesion detection in human patients. In this descriptive study, gadoxetate disodium contrast-enhanced MRI characteristics in dogs were evaluated in seven dogs (total of eight lesions). The imaging characteristics were variable with the exception of all lesions being hypointense to surrounding normal hepatic parenchyma on 3D T1-weighted gradient recalled echo images at all postcontrast time points. All lesions displayed signal intensity ratios less than 1, consistent with retained but impaired hepatocyte function. Hepatic lesions not identified on previous imaging were found in 3/7 patients which may affect surgical planning. In two patients, several hepatic nodules were identified during surgery which had not been visualized on MRI and were found to be benign on histopathology. This descriptive study reports the MRI characteristics of hepatocellular carcinoma in dogs using the liver-specific contrast agent gadoxetate disodium.


Emotional and behaviour difficulties in teenagers with permanent childhood hearing loss.
It is known that during the middle childhood years those with permanent childhood hearing loss (PCHL) are at increased risk of showing emotional and behaviour difficulties (EBD). It has yet to be established whether this risk continues into the late teenage years. There is a paucity of longitudinal studies on the association between PCHL and EBD. The Strengths and Difficulties Questionnaire (SDQ) was used to measure EBD based on parent, teacher and self-ratings in 76 teenagers with PCHL and 38 in a hearing comparison group (HCG) from a population sample of children that was followed up from birth to adolescence. On parent-rated SDQ, the PCHL group had significantly higher Total Difficulties score than the HCG (Standardised mean difference (SMD) = +0.39, 95%CI 0.00 to 0.79). Amongst the PCHL group the presence of disabilities other than hearing loss had a substantial impact on the level of parent-rated EBD (SMD = +1.68, 1.04 to 2.33). There was a relationship between receptive language ability and EBD in both the HCG (r = -0.33, 95%CI -0.59 to -0.01) and the PCHI group (r = -0.33, 95%CI -0.53 to -0.02). The effect of PCHL on EBD became non-significant when receptive language was included as a covariate (F = 0.12, df = 1,95, p = 0.729). Early confirmation of hearing loss (i.e. before 9 months of age) did not have a significant effect on EBD scores (SMD = +0.31, 95%CI -0.15 to 0.77). PCHL continues to be associated with elevated EBD scores as measured by parent rated SDQ into the late teenage years but the degree of this elevation is less than in childhood and is not apparent on teacher or self-ratings. Poor receptive language ability appeared to account for these elevated EBD scores in the group with PCHL. Particular attention needs to be paid to the mental health of children and adolescents with PCHL that is accompanied by other disabilities and to those with poor receptive language ability. However, the majority of teenagers with PCHL do not show clinically significant elevated levels of EBD.


Notch1 regulated autophagy controls survival and suppressor activity of activated murine T-regulatory cells.
Cell survival is one of several processes regulated by the Notch pathway in mammalian cells. Here we report functional outcomes of non-nuclear Notch signaling to activate autophagy, a conserved cellular response to nutrient stress, regulating survival in murine natural T-regulatory cells (Tregs), an immune subset controlling tolerance and inflammation. Induction of autophagy required ligand-dependent, Notch intracellular domain (NIC) activity, which controlled mitochondrial organization and survival of activated Tregs. Consistently, NIC immune-precipitated Beclin and Atg14, constituents of the autophagy initiation complex. Further, ectopic expression of an effector of autophagy (Atg3) or recombinant NIC tagged to a nuclear export signal (NIC-NES), restored autophagy and suppressor function in Notch1(-/-) Tregs. Furthermore, Notch1 deficiency in the Treg lineage resulted in immune hyperactivity, implicating Notch activity in Treg homeostasis. Notch1 integration with autophagy, revealed in these experiments, holds implications for Notch regulated cell-fate decisions governing differentiation.


Caregiver Perceptions of a Telehealth Wellness Program.
We sought to understand caregivers' experience of an education-based wellness program delivered using telehealth. In this qualitative pilot study, 4 caregivers participated in a focus group after completing a 6-wk telehealth program. Data analysis involved open coding, thematic analysis, and coding triangulation. Two major themes emerged. The first, "I feel like I am now prepared," included the subthemes of strategies for caregiver self-maintenance, the understanding that caregiving is a normal process, and the value of a group experience. The second theme, "It was just a good interaction," included the subthemes of benefits of telehealth, challenges of telehealth, and process of learning the technology. Participant discussion of the content learned and the value of group support indicated that telehealth was effective in both promoting learning and facilitating relationships. Even with challenges, participants reported an overall positive experience. Telehealth holds promise for increasing access to health promotion programs.


Genetic variant in the glucose transporter type 2 is associated with higher intakes of sugars in two distinct populations.
Glucose sensing in the brain has been proposed to be involved in regulating food intake, but the mechanism is not known. Glucose transporter type 2 (GLUT2)-null mice fail to control their food intake in response to glucose, suggesting a potential role for this transporter as a glucose sensor in the brain. Here we show that individuals with a genetic variation in GLUT2 (Thr110Ile) have a higher daily intake of sugars in two distinct populations. In the first population, compared with individuals with the Thr/Thr genotype, carriers of the Ile allele had a significantly higher intake of sugars as assessed from 3-day food records administered on two separate visits (visit 1: 112 +/- 9 vs. 86 +/- 4 g/day, P = 0.01; visit 2: 111 +/- 8 vs. 82 +/- 4 g/day, P = 0.003), demonstrating within-population reproducibility. In a second population, carriers of the Ile allele also reported consuming a significantly greater intake of sugars (131 +/- 5 vs. 115 +/- 3 g/day, P = 0.007) over a 1-mo period as measured from a food frequency questionnaire. GLUT2 genotypes were not associated with fat, protein, or alcohol intake in either population. These observations were consistent across older and younger adults as well as among subjects with early Type 2 diabetes and healthy individuals. Taken together, our findings show that a genetic variation in GLUT2 is associated with habitual consumption of sugars, suggesting an underlying glucose-sensing mechanism that regulates food intake.


Low dose of Bisphenol A enhance the susceptibility of thyroid carcinoma stimulated by DHPN and iodine excess in F344 rats.
Thyroid carcinoma (TC) is the most common endocrine neoplasm. The risk of TC as a second primary malignancy (SPM) of breast cancer is significantly increased. Bisphenol A (BPA) is a widely contacted xenoestrogen and increases susceptibility to breast cancer through binding to estrogen receptor alpha (ERα). However, the effect of BPA on thyroid carcinogenesis has not been fully demonstrated. This present study aimed to characterize the effects of BPA on the development of TC using a Fischer 344 (F344) rat model. In this study, we established a TC model using female F344 rats pretreated with N-Bis (2-hydroxypropyl) nitrosamine (DHPN) at a single dose of 2800 mg/kg (the DA group) or without DHPN (the DN group), followed by stimulation with BPA at the level of 250 μg/kg (BPA250) or 1000 μg/kg (BPA1000) and a basic diet containing potassium iodine (KI, 1000 μg/L) for 64 weeks. We demonstrated that the incidence of TC in the BPA250 + KI of DA groups reached the highest at 50%, the incidence of thyroid hyperplasia lesions (including both tumors and focal hyperplasia lesions) in the BPA1000 + KI of DA groups reached 100% (P < 0.05). ERα protein and immunochemistry expression was upregulated in the BPA-exposed groups and the immunochemistry scores were positively correlated with PCNA. Thus, the present results indicate that BPA could enhance the susceptibility to TC stimulated by DHPN and iodine excess. ERα is probably involved in the proliferation effect of BPA. BPA or KI alone could not increase TC incidence.


Overeating and obesity from damage to a noradrenergic system in the brain.
A discrete, ascending fiber system that supplies the hypothalamus with most of its noradrenergic terminals was destroyed at midbrain level, both electrolytically and with local injections of 6-hydroxydopamine, a destructive agent specific for catecholaminergic neurons. The result was hyperphagia leading to obesity. Fluorescence histochemical analysis showed that loss of noradrenergic terminals in ventral bundle termination areas such as the hypothalamus was necessary for hyperphagia. Damage to dorsal bundle or dopaminergic projections was not. Prior treatment with desmethylimipramine to selectively block uptake of 6-hydroxydopamine into noradrenergic neurons prevented both hyperphagia and loss of norepinephrine fluorescence. The lesions that produced hyperphagia also reduced the potency of d-amphetamine as an appetite suppressant. It is concluded that this noradrenergic bundle normally mediates suppression of feeding, thereby influences body weight, and serves as a substrate for d-amphetamine-induced loss of appetite.


Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice.
The receptor tyrosine kinase ret protooncogene (RET) is implicated in the pathogenesis of several diseases and in several developmental defects, particularly those in neural crest-derived structures and the genitourinary system. In order to further elucidate RET-mediated mechanisms that contribute to these diseases and decipher the basis for specificity in the pleiotropic effects of RET, we characterized development of the enteric and autonomic nervous systems in mice expressing RET9 or RET51 isoforms harboring mutations in tyrosine residues that act as docking sites for the adaptors Plcgamma, Src, Shc, and Grb2. Using this approach, we found that development of the genitourinary system and the enteric and autonomic nervous systems is dependent on distinct RET-stimulated signaling pathways. Thus, mutation of RET51 at Y1062, a docking site for multiple adaptor proteins including Shc, caused distal colon aganglionosis reminiscent of Hirschsprung disease (HSCR). On the other hand, this mutation in RET9, which encodes an isoform that lacks the Grb2 docking site present in RET51, produced severe abnormalities in multiple organs. Mutations that abrogate RET-Plcgamma binding, previously shown to produce features reminiscent of congenital anomalies of kidneys or urinary tract (CAKUT) syndrome, produced only minor abnormalities in the nervous system. Abrogating RET51-Src binding produced no major defects in these systems. These studies provide insight into the basis of organotypic specificity and redundancy in RET signaling within these unique systems and in diseases such as HSCR and CAKUT.


Training health care professionals in root cause analysis: a cross-sectional study of post-training experiences, benefits and attitudes.
Root cause analysis (RCA) originated in the manufacturing engineering sector but has been adapted for routine use in healthcare to investigate patient safety incidents and facilitate organizational learning. Despite the limitations of the RCA evidence base, healthcare authorities and decision makers in NHS Scotland - similar to those internationally - have invested heavily in developing training programmes to build local capacity and capability, and this is a cornerstone of many organizational policies for investigating safety-critical issues. However, to our knowledge there has been no systematic attempt to follow-up and evaluate post-training experiences of RCA-trained staff in Scotland. Given the significant investment in people, time and funding we aimed to capture and learn from the reported experiences, benefits and attitudes of RCA-trained staff and the perceived impact on healthcare systems and safety. We adapted a questionnaire used in a published Australian research study to undertake a cross sectional online survey of health care professionals (e.g. nursing & midwifery, medical doctors and pharmacists) formally trained in RCA by a single territorial health board region in NHS Scotland. A total of 228/469 of invited staff completed the survey (48%). A majority of respondents had yet to participate in a post-training RCA investigation (n=127, 55.7%). Of RCA-experience staff, 71 had assumed a lead investigator role (70.3%) on one or more occasions. A clear majority indicated that their improvement recommendations were generally or partly implemented (82%). The top three barriers to RCA success were cited as: lack of time (54.6%), unwilling colleagues (34%) and inter-professional differences (31%). Differences in agreement levels between RCA-experienced and inexperienced respondents were noted on whether a follow-up session would be beneficial after conducting RCA (65.3% v 39.4%) and if peer feedback on RCA reports would be of educational value (83.2% v 37.0%). Comparisons with the previous research highlighted significant differences such as less reported difficulties within RCA teams (P<0.001) and a greater proportion of respondents taking on RCA leadership roles in this study (P<0.001). This study adds to our knowledge and understanding of the need to improve the effectiveness of RCA training and frontline practices in healthcare settings. The overall evidence points to a potential organisational learning need to provide RCA-trained staff with continuous development opportunities and performance feedback. Healthcare authorities may wish to look more critically at whom they train in RCA, and how this is delivered and supported educationally to maximize cost-benefits, organizational learning and safer patient care.


Outcome after gastrectomy in gastric cancer patients with type 2 diabetes.
To evaluate the prognosis of type II diabetes mellitus (T2DM) after gastrectomy and related factors in gastric cancer patients. 403 gastric cancer patients with T2DM were studied, who underwent gastrectomy between May 2003 and September 2009. A review of medical records and telephone interviews was performed in this cross-sectional study. The factors included in the statistical analysis were as follows: gender, age, type of surgery, preoperative body mass index (BMI), current BMI, BMI reduction ratio, preoperative insulin or oral diabetic medicine requirement, follow-up duration, and current state of diabetes. Assessment of diabetes status after surgery was classified into four categories according to the change in hypoglycemic agents after surgery and present status of T2DM: resolution, improvement, same, and worse. The mean follow-up duration was 33.7 mo (± 20.6 mo), preoperative BMI was 24.7 kg/m(2) (± 3.0 kg/m(2)), and BMI reduction ratio was 9.8% (± 8.6%). After surgery, T2DM was cured in 58 patients (15.1%) and was improved in 117 patients (30.4%). According to the type of surgery, the BMI reduction ratio was significantly higher in the total gastrectomy and Roux-en-Y reconstruction group [14.2% ± 9.2% vs 9.2% ± 7.7% (Billroth II group), P < 0.001] and significantly lower in the subtotal gastrectomy and Billroth I reconstruction group [7.6% ± 8.0%, 9.2% ± 7.7% (Billroth II group), P < 0.001]. The BMI reduction ratio, follow-up duration after surgery, type of surgery, extent of gastrectomy, and performance of duodenal bypass were significantly correlated to the course of T2DM (P < 0.05). The BMI reduction ratio was the most influential factor on T2DM status. In a subgroup analysis of patients with a BMI reduction ratio of 10% or less (n = 206), T2DM was cured in 15 (7.6%) patients and was improved in 57 (28.8%) patients after surgery, and only the duration of surgery was significantly correlated to T2DM status (P = 0.022). The course of T2DM was significantly correlated to the BMI reduction ratio but not to the type of surgery without a significant change in BMI.


Prevalence of thyroid autoimmunity in children with celiac disease compared to healthy 12-year olds.
Objectives. Studies have suggested a correlation between untreated celiac disease and risk for other autoimmune diseases. We investigated the prevalence of thyroid autoimmunity in 12-year-old children (i) with symptomatic celiac disease diagnosed and treated with a gluten-free diet, (ii) with screening-detected untreated celiac disease, and (iii) without celiac disease. Methods. Blood samples from 12632 children were collected. All celiac disease cases, previously diagnosed and newly screening-detected, were identified. Per case, 4 referents were matched. Blood samples were analyzed for autoantibodies against thyroid peroxidase (TPOAb). The cut-off value for TPO positivity was set to 100 U/mL. Results. Altogether, 335 celiac disease cases were found. In the entire celiac disease group, 7.2% (24/335) had elevated titers of TPOAb compared to 2.8% (48/1695) of the referents. Among the previously diagnosed celiac disease cases, 7.5% (7/93, OR 2.8, 95% CI 1.2-6.4) was TPOAb positive and among screening-detected cases, 7.0% (17/242, OR 2.6, 95% CI 1.5-4.6) was TPOAb positive. Conclusion. Children with celiac disease showed a higher prevalence of thyroid autoimmunity. We could not confirm the hypothesis that untreated celiac disease is associated with increased risk of developing thyroid autoimmunity. Early initiation of celiac disease treatment might not lower the risk for other autoimmune diseases.


Anoctamin 2 identified as an autoimmune target in multiple sclerosis.
Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.


The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling.
The human uterus includes the complex endometrial mucosa, the endometrium that undergoes dynamic, hormone-dependent alterations throughout the life of fertile females. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to analyze gene expression patterns in the normal endometrium. Human endometrial tissues from five women were used for deep sequencing (RNA-Seq). The mRNA and protein expression data from the endometrium were compared to 31 (RNA) and 44 (protein) other normal tissue types, to identify genes with elevated expression in the endometrium and to localize the expression of corresponding proteins at a cellular resolution. Based on the expression levels of transcripts, we could classify all putative human protein coding genes into categories defined by expression patterns and found altogether 101 genes that showed an elevated pattern of expression in the endometrium, with only four genes showing more than five-fold higher expression levels in the endometrium compared to other tissues. In conclusion, our analysis based on transcriptomics and antibody-based protein profiling reports here comprehensive lists of genes with elevated expression levels in the endometrium, providing important starting points for a better molecular understanding of human reproductive biology and disease.


Two classes of matrix metalloproteinases reciprocally regulate synaptogenesis.
Synaptogenesis requires orchestrated intercellular communication between synaptic partners, with trans-synaptic signals necessarily traversing the extracellular synaptomatrix separating presynaptic and postsynaptic cells. Extracellular matrix metalloproteinases (Mmps) regulated by secreted tissue inhibitors of metalloproteinases (Timps), cleave secreted and membrane-associated targets to sculpt the extracellular environment and modulate intercellular signaling. Here, we test the roles of Mmp at the neuromuscular junction (NMJ) model synapse in the reductionist Drosophila system, which contains just two Mmps (secreted Mmp1 and GPI-anchored Mmp2) and one secreted Timp. We found that all three matrix metalloproteome components co-dependently localize in the synaptomatrix and show that both Mmp1 and Mmp2 independently restrict synapse morphogenesis and functional differentiation. Surprisingly, either dual knockdown or simultaneous inhibition of the two Mmp classes together restores normal synapse development, identifying a reciprocal suppression mechanism. The two Mmp classes co-regulate a Wnt trans-synaptic signaling pathway modulating structural and functional synaptogenesis, including the GPI-anchored heparan sulfate proteoglycan (HSPG) Wnt co-receptor Dally-like protein (Dlp), cognate receptor Frizzled-2 (Frz2) and Wingless (Wg) ligand. Loss of either Mmp1 or Mmp2 reciprocally misregulates Dlp at the synapse, with normal signaling restored by co-removal of both Mmp classes. Correcting Wnt co-receptor Dlp levels in both Mmp mutants prevents structural and functional synaptogenic defects. Taken together, these results identify an Mmp mechanism that fine-tunes HSPG co-receptor function to modulate Wnt signaling to coordinate synapse structural and functional development.


Acid fog and hospital visits for asthma: an epidemiological study.
The aim of this study was to elucidate the adverse respiratory effects of naturally occurring acid fog. In total, 102 adult asthmatic patients (44 nonatopic and 58 atopic) were studied for a 2 yr period (January 1992 to December 1993) in Kushiro, a city with only a small industrial area, located in the northern-most island in Japan. Fog occurred on 378 out of 731 days, and the acidity of the fog ranged from pH 3.32 to 6.91 (mean pH 4.95). The association between hospital visits for asthma and meteorological factors or air pollutants was investigated. In nonatopic patients, fog, high ozone and water vapour pressure, low day-to-day temperature differences, low concentrations of atmospheric NO and NO2 contributed significantly (p<0.05) to increasing hospital visits. In atopic subjects, fog, high water vapour pressure, low levels of atmospheric NO2 and SO2 contributed significantly to hospital visits (p<0.05). In Poisson regression analysis the remaining factors of significance (p<0.01) for nonatopic asthma were fog and low NO and for atopic asthma were high water vapour pressure and low SO2 (p<0.05). A weak but significant correlation was observed between the number of hospital visits and the mean pH of the foggy day (r=-0.38, p<0.05) in nonatopic asthmatic patients, not in atopic asthma. On foggy days, gaseous air pollutant levels were significantly (p<0.01) lower than on fog-free days. It was concluded that, naturally occurring acid fog may have a weak bronchoconstrictive effect which appears to be more influential in nonatopic asthmatic subjects than in atopic subjects.


Urease-positive bacteriuria and obstruction of long-term urinary catheters.
Long-term urethral catheterization (greater than or equal to 30 days), a management technique for urinary incontinence, results in polymicrobial bacteriuria. We frequently found urease-producing bacteria: of 1,135 weekly urine specimens from 32 long-term-catheterized patients, 86% had urease-positive bacterial species at greater than or equal to 10(5) CFU/ml. The most common species were Proteus mirabilis and Morganella morganii, each found in over half the specimens. P. mirabilis, but not other urease-positive species, was significantly associated with the 67 obstructions observed in 23 patients. M. morganii had a more complex association and in some way may protect the catheter from obstruction.


Large-scale climatic phenomena drive fluctuations in macroinvertebrate assemblages in lowland tropical streams, Costa Rica: The importance of ENSO events in determining long-term (15y) patterns.
Understanding how environmental variables influence the distribution and density of organisms over relatively long temporal scales is a central question in ecology given increased climatic variability (e.g., precipitation, ENSO events). The primary goal of our study was to evaluate long-term (15y time span) patterns of climate, as well as environmental parameters in two Neotropical streams in lowland Costa Rica, to assess potential effects on aquatic macroinvertebrates. We also examined the relative effects of an 8y whole-stream P-enrichment experiment on macroinvertebrate assemblages against the backdrop of this long-term study. Climate, environmental variables and macroinvertebrate samples were measured monthly for 7y and then quarterly for an additional 8y in each stream. Temporal patterns in climatic and environmental variables showed high variability over time, without clear inter-annual or intra-annual patterns. Macroinvertebrate richness and abundance decreased with increasing discharge and was positively related to the number of days since the last high discharge event. Findings show that fluctuations in stream physicochemistry and macroinvertebrate assemblage structure are ultimately the result of large-scale climatic phenomena, such as ENSO events, while the 8y P-enrichment did not appear to affect macroinvertebrates. Our study demonstrates that Neotropical lowland streams are highly dynamic and not as stable as is commonly presumed, with high intra- and inter-annual variability in environmental parameters that change the structure and composition of freshwater macroinvertebrate assemblages.


Techniques and devices to restore cognition.
Executive planning, the ability to direct and sustain attention, language and several types of memory may be compromised by conditions such as stroke, traumatic brain injury, cancer, autism, cerebral palsy and Alzheimer's disease. No medical devices are currently available to help restore these cognitive functions. Recent findings about the neurophysiology of these conditions in humans coupled with progress in engineering devices to treat refractory neurological conditions imply that the time has arrived to consider the design and evaluation of a new class of devices. Like their neuromotor counterparts, neurocognitive prostheses might sense or modulate neural function in a non-invasive manner or by means of implanted electrodes. In order to paint a vision for future device development, it is essential to first review what can be achieved using behavioral and external modulatory techniques. While non-invasive approaches might strengthen a patient's remaining intact cognitive abilities, neurocognitive prosthetics comprised of direct brain-computer interfaces could in theory physically reconstitute and augment the substrate of cognition itself.


Diabetes risks and outcomes in chronic obstructive pulmonary disease patients: Two nationwide population-based retrospective cohort studies.
The relationship between chronic obstructive pulmonary disease (COPD) and diabetes remains incompletely understood. This study evaluated diabetes risk and post-diabetes outcomes in COPD patients with and without exacerbations. We identified 4671 adults newly diagnosed with COPD exacerbations and 9342 adults newly diagnosed with COPD without exacerbations during 2000-2008 using Taiwan's National Health Insurance Research Database. A comparison cohort of 18684 adults without COPD, matched by age and sex, was randomly selected from the same dataset for the control group. Diabetes events during 2000-2013 were ascertained from medical claims during the follow-up period. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of diabetes associated with COPD with or without exacerbations were calculated. We conducted another nested cohort study of 395516 patients with diabetes hospitalization during 2002-2013 and calculated adjusted odds ratios (ORs) and 95% CIs of histories of COPD and COPD exacerbations associated with adverse events after diabetes admission. During the follow-up period, the incidences of diabetes for patients without COPD and for patients with COPD without or with exacerbations were 3.4, 4.1 and 7.4 per 1000 person-years, respectively (P < 0.0001). Increased risk of diabetes for patients with COPD without exacerbations (HR 1.09, 95% CI 1.02-1.17) and COPD with exacerbations (HR 2.18, 95% CI 1.88-2.52) was noted. Post-diabetes pneumonia (OR 3.28, 95% CI 3.13-3.43), intensive care admission (OR 1.32, 95% CI 1.26-1.39) and mortality (OR 2.06, 95% CI 1.88-2.25) were associated with COPD exacerbations. Prevention and intervention strategies for diabetes and post-diabetes outcomes are needed for this susceptible population.