Clinical evaluation of NucliSENS magnetic extraction and NucliSENS analytical specific reagents for the real-time detection of respiratory syncytial virus (RSV) in paediatric respiratory specimens.
To evaluate the combination of NucliSENS magnetic extraction and NucliSENS analytical specific reagents (bioMérieux, Marcy L'Etoile, France) for the detection of respiratory syncytial virus (RSV) from a variety of respiratory samples. Nucleic acids (NA) from paediatric samples (n = 603) and an RSV-specific inhibition control (R-IC) were coextracted using the miniMAG and/or the easyMAG. Nucleic-acid-sequence-based amplification (NASBA) and molecular beacon detection of RSV and R-IC were performed using NucliSENS analyte-specific reagents (NRSVA) and the NucliSENS EasyQ Analyzer. NRSVA results were compared with R-Mix culture and direct fluorescent antibody detection (DFA). The NRSVA analytical specificity was 100%, and the NRSVA limit of detection was 5-20 RNA copies/reaction. The prediscordant analysis, sensitivity, specificity, PPV and NPV were, respectively, for R-Mix (64.7%, 100%, 100%, 94.5%); DFA (98.8%, 99.0%, 94.4%, 99.8%); NRSVA (94.1%, 95%, 75.5%, 99%). After discordant analysis, sensitivity, specificity, PPV and NPV were, respectively, for R-Mix (56.7%, 100%, 100%, 92.3%); DFA (87.6%, 99.2%, 95.5%, 97.7%); NRSVA (93.8%, 97%, 85.9%, 99%). RSV was detected in 17.8% of the samples and in seven coinfections. Children with proven RSV infection, compared with children without a pathogen identified, had shorter median hospitalisation stays (2 days vs 3 days, p = 0.035), used fewer antibiotics (54% vs 69%) and had shorter durations of antibiotic therapy (6.2 days vs 9.3 days, p = 0.021), respectively. NRSVA is sensitive and specific for RSV detection in respiratory samples. The R-IC monitored the test process, including NA extraction, target amplification and detection. The rapid detection of respiratory pathogens can foster appropriate patient management.


A novel method for pulmonary embolism detection in CTA images.
In this paper, we propose a new computer-aided detection (CAD) - based method to detect pulmonary embolism (PE) in computed tomography angiography images (CTAI). Since lung vessel segmentation is the main objective to provide high sensitivity in PE detection, this method performs accurate lung vessel segmentation. To concatenate clogged vessels due to PEs, the starting region of PEs and some reference points (RPs) are determined. These RPs are detected according to the fixed anatomical structures. After lung vessel tree is segmented, the region, intensity, and size of PEs are used to distinguish them. We used the data sets that have heart disease or abnormal tissues because of lung disease except PE in this work. According to the results, 428 of 450 PEs, labeled by the radiologists from 33 patients, have been detected. The sensitivity of the developed system is 95.1% at 14.4 false positive per data set (FP/ds). With this performance, the proposed CAD system is found quite useful to use as a second reader by the radiologists.


Sodium ferrous citrate and 5-aminolevulinic acid improve type 2 diabetes by maintaining muscle and mitochondrial health.
Improving mitochondrial function is a promising strategy for intervention in type 2 diabetes mellitus. This study investigated the preventive effects of sodium ferrous citrate (SFC) and 5-aminolevulinic acid phosphate (ALA) on several metabolic dysfunctions associated with obesity because they have been shown to alleviate abnormal glucose metabolism in humans. Six-week-old male C57BL/6J mice were fed with a normal diet, a high-fat diet, or a high-fat diet supplemented with SFC and ALA for 15 weeks. The simultaneous supplementation of SFC + ALA to high-fat diet-fed mice prevented loss of muscle mass, improved muscle strength, and reduced obesity and insulin resistance. SFC + ALA prevented abnormalities in mitochondrial morphology and reverted the diet effect on the skeletal muscle transcriptome, including the expression of glucose uptake and mitochondrial oxidative phosphorylation-related genes. In addition, SFC + ALA prevented the decline in mitochondrial DNA copy number by enhancing mitochondrial DNA maintenance and antioxidant transcription activity, both of which are impaired in high-fat diet-fed mice during long-term fasting. These findings suggest that SFC + ALA supplementation exerts its preventive effects in type 2 diabetes mellitus via improved skeletal muscle and mitochondrial health, further validating its application as a promising strategy for the prevention of obesity-induced metabolic disorders.


Urinary stone composition in Oman: with high incidence of cystinuria.
Urinary stones are a common problem in Oman and their composition is unknown. The aim of this study is to analyze the components of urinary stones of Omani patients and use the obtained data for future studies of etiology, treatment, and prevention. Urinary stones of 255 consecutive patients were collected at the Sultan Qaboos University Hospital. Stones were analyzed by Fourier transform infrared spectrophotometer. The biochemical, metabolic, and radiological data relating to the patients and stones were collected. The mean age was 41 years, with M:F ratio of 3.7:1. The common comorbidities associated with stone formation were hypertension; diabetes, benign prostate hyperplasia; urinary tract infection; obesity; and atrophic kidney. The common presentation was renal colic and flank pain (96%). Stones were surgically retrieved in 70% of patients. Mean stone size was 9 ± 0.5 mm (range 1.3-80). Stone formers had a BMI ≥ 25 in 56% (P = 0.006) and positive family history of stones in 3.8%. The most common stones in Oman were as follows: Calcium Oxalates 45% (114/255); Mixed calcium phosphates & calcium oxalates 22% (55/255); Uric Acid 16% (40/255); and Cystine 4% (10/255). The most common urinary stones in Oman are Calcium Oxalates. Overweight is an important risk factor associated with stone formation. The hereditary Cystine stones are three times more common in Oman than what is reported in the literature that needs further genetic studies.


Systematic literature review of determinants of sedentary behaviour in older adults: a DEDIPAC study.
Older adults are the most sedentary segment of society and high sedentary time is associated with poor health and wellbeing outcomes in this population. Identifying determinants of sedentary behaviour is a necessary step to develop interventions to reduce sedentary time. A systematic literature review was conducted to identify factors associated with sedentary behaviour in older adults. Pubmed, Embase, CINAHL, PsycINFO and Web of Science were searched for articles published between 2000 and May 2014. The search strategy was based on four key elements: (a) sedentary behaviour and its synonyms; (b) determinants and its synonyms (e.g. correlates, factors); (c) types of sedentary behaviour (e.g. TV viewing, sitting, gaming) and (d) types of determinants (e.g. environmental, behavioural). Articles were included in the review if specific information about sedentary behaviour in older adults was reported. Studies on samples identified by disease were excluded. Study quality was rated by means of QUALSYST. The full review protocol is available from PROSPERO (PROSPERO 2014: CRD42014009823). The analysis was guided by the socio-ecological model framework. Twenty-two original studies were identified out of 4472 returned by the systematic search. These included 19 cross-sectional, 2 longitudinal and 1 qualitative studies, all published after 2011. Half of the studies were European. The study quality was generally high with a median of 82 % (IQR 69-96 %) using Qualsyst tool. Personal factors were the most frequently investigated with consistent positive association for age, negative for retirement, obesity and health status. Only four studies considered environmental determinants suggesting possible association with mode of transport, type of housing, cultural opportunities and neighbourhood safety and availability of places to rest. Only two studies investigated mediating factors. Very limited information was available on contexts and sub-domains of sedentary behaviours. Few studies have investigated determinants of sedentary behaviour in older adults and these have to date mostly focussed on personal factors, and qualitative studies were mostly lacking. More longitudinal studies are needed as well as inclusion of a broader range of personal and contextual potential determinants towards a systems-based approach, and future studies should be more informed by qualitative work.


The Effect of Time, Roasting Temperature, and Grind Size on Caffeine and Chlorogenic Acid Concentrations in Cold Brew Coffee.
The extraction kinetics and equilibrium concentrations of caffeine and 3-chlorogenic acid (3-CGA) in cold brew coffee were investigated by brewing four coffee samples (dark roast/medium grind, dark roast/coarse grind, medium roast/medium grind, medium roast/coarse grind) using cold and hot methods. 3-CGA and caffeine were found at higher concentrations in cold brew coffee made with medium roast coffees, rather than dark roast. The grind size did not impact 3-CGA and caffeine concentrations of cold brew samples significantly, indicating that the rate determining step in extraction for these compounds did not depend on surface area. Caffeine concentrations in cold brew coarse grind samples were substantially higher than their hot brew counterparts. 3-CGA concentrations and pH were comparable between cold and hot brews. This work suggests that the difference in acidity of cold brew coffee is likely not due to 3-CGA or caffeine concentrations considering that most acids in coffee are highly soluble and extract quickly. It was determined that caffeine and 3-CGA concentrations reached equilibrium according to first order kinetics between 6 and 7 hours in all cold brew samples instead of 10 to 24 hours outlined in typical cold brew methods.


The roots of diversity: below ground species richness and rooting distributions in a tropical forest revealed by DNA barcodes and inverse modeling.
Plants interact with each other, nutrients, and microbial communities in soils through extensive root networks. Understanding these below ground interactions has been difficult in natural systems, particularly those with high plant species diversity where morphological identification of fine roots is difficult. We combine DNA-based root identification with a DNA barcode database and above ground stem locations in a floristically diverse lowland tropical wet forest on Barro Colorado Island, Panama, where all trees and lianas >1 cm diameter have been mapped to investigate richness patterns below ground and model rooting distributions. DNA barcode loci, particularly the cpDNA locus trnH-psba, can be used to identify fine and small coarse roots to species. We recovered 33 species of roots from 117 fragments sequenced from 12 soil cores. Despite limited sampling, we recovered a high proportion of the known species in the focal hectare, representing approximately 14% of the measured woody plant richness. This high value is emphasized by the fact that we would need to sample on average 13 m(2) at the seedling layer and 45 m(2) for woody plants >1 cm diameter to obtain the same number of species above ground. Results from inverse models parameterized with the locations and sizes of adults and the species identifications of roots and sampling locations indicates a high potential for distal underground interactions among plants. DNA barcoding techniques coupled with modeling approaches should be broadly applicable to studying root distributions in any mapped vegetation plot. We discuss the implications of our results and outline how second-generation sequencing technology and environmental sampling can be combined to increase our understanding of how root distributions influence the potential for plant interactions in natural ecosystems.


Relationship between serum adiponectin concentration, pulse wave velocity and nonalcoholic fatty liver disease.
We aimed to investigate the relationship between nonalcoholic fatty liver disease (NAFLD), serum adiponectin concentration and brachial-ankle pulse wave velocity (baPWV) as a risk marker for atherosclerosis. A total of 213 nonalcoholic subjects (67 males, 146 females) participated in this study. Division of subjects into the NAFLD group or the normal group was based on the existence of fatty liver detected by sonography. Serum adiponectin levels in the NAFLD group were significantly lower than those in the normal group. After adjusting for age, body-mass index (BMI) and the homeostasis model of assessment (HOMA), there was a significant negative correlation between NAFLD and serum adiponectin level only in females (r = -0.22, P = 0.008). Multiple logistic regression analysis showed a tendency of inverse correlation between NAFLD and serum adiponectin level in females (P = 0.055). After adjustment for age, BMI and HOMA value, serum adiponectin levels were inversely correlated with serum alanine aminotransferase (ALT) and gamma-glutamyltranspeptidase (GGT) levels (r = -0.199 (P = 0.004) and r = -0.282 (P < 0.001)). On the other hand, baPWV in the NAFLD group was also significantly higher than that in the normal group in females (P = 0.005). Individual levels of serum ALT, aspatate aminotransferase (AST), alkaline phosphatase (ALP) and GGT were positively correlated with baPWV after adjusting for age, sex, BMI, HOMA and systolic blood pressure (P < 0.05). Serum adiponectin level and baPWV were significantly associated with NAFLD and various liver enzymes, especially in females.


IVAN: intelligent van for the distribution of pharmaceutical drugs.
This paper describes a telematic system based on an intelligent van which is capable of tracing pharmaceutical drugs over delivery routes from a warehouse to pharmacies, without altering carriers' daily conventional tasks. The intelligent van understands its environment, taking into account its location, the assets and the predefined delivery route; with the capability of reporting incidences to carriers in case of failure according to the established distribution plan. It is a non-intrusive solution which represents a successful experience of using smart environments and an optimized Radio Frequency Identification (RFID) embedded system in a viable way to resolve a real industrial need in the pharmaceutical industry. The combination of deterministic modeling of the indoor vehicle, the implementation of an ad-hoc radiating element and an agile software platform within an overall system architecture leads to a competitive, flexible and scalable solution.


Long-term outcome in orbital meningiomas: progression-free survival after targeted resection combined with early or postponed postoperative radiotherapy.
In meningiomas involving the orbit and optic canal, surgery is the mainstay of therapy. However, radical resection is often limited to avoid functional damage, so multidisciplinary treatment concepts are implemented. Data on the timing and value of early postoperative radiotherapy (PORT) are scarce. This retrospective study analyzes outcomes in patients who underwent targeted resection alone or in combination with early PORT. Patients undergoing resection of orbit-associated WHO grade I meningiomas from January 1999 to December 2013 who presented to the authors' department at least twice for follow-up were included. Clinical and radiological findings were analyzed retrospectively. Patients were stratified into two cohorts: follow-up with MRI scans at regular intervals, i.e., the watch and wait (W&W) group, and a PORT group receiving PORT within 6 months after surgery in addition to MRI follow-up. Patients in the W&W group were scheduled for treatment when tumor progression was detected by imaging. One hundred twenty-two patients were included. The mean follow-up was 70 months. The most common symptoms at presentation were visual disturbances; 87.7% of patients received Simpson grade II-III targeted partial resection. Twenty-three patients received PORT, and 99 patients were regularly observed with MRI scans (W&W group). Tumor recurrence/progression occurred significantly later (76.3 vs 40.7 months) and less frequently in the PORT group (13%) than in the W&W group (46.5%). Cases of recurrence were diagnosed an average of 39 months after initial surgery in both groups. PORT patients demonstrated significantly less visual impairment at last follow-up. These results indicate that receiving PORT early after targeted partial resection might help to postpone tumor recurrence and the need for additional treatment, while preserving or even improving visual outcome.


Allelic loss on chromosome 8p12-21 in microdissected prostatic intraepithelial neoplasia.
The development and progression of human prostate cancer is associated with genetic abnormalities in tumor cells. Inactivation of tumor suppressor genes due to allelic loss is thought to be an important mechanism of gene alteration in prostatic neoplasms. In this study we examined allelic loss on chromosome 8p12-21 in microdissected samples of normal prostatic epithelium, high grade prostatic intraepithelial neoplasia (PIN), and invasive prostate carcinoma from the same patients. Tissue microdissection under direct microscopic visualization procures pure populations of cells of interest, including small lesions such as PIN. Among 30 patients with concomitant cancer and PIN, we found loss of heterozygosity on chromosome 8p12-21 in 63% (34 of 54) of foci of PIN examined and 90.6% (29 of 32) of tumors, suggesting that abnormalities on chromosome 8p12-21 may be important in the early stages of prostatic carcinoma development. Several cases in which multiple foci of PIN from the same patient were sampled showed different patterns of allelic loss. Fifty-five % (16 of 29) of the prostate carcinomas contained a potential precursor PIN focus based on allelic loss pattern. Our results are consistent with the hypothesis that PIN arises multifocally within the prostate gland, and that a subset of these lesions progress to become carcinoma.


Learning in the tutorial group: a balance between individual freedom and institutional control.
The study investigates factors in problem-based learning tutorial groups which promote or inhibit learning. The informants were tutors and students from speech-language pathology and physiotherapy programmes. Semi-structured focus-group interviews and individual interviews were used. Results revealed three themes: Responsibility. Time and Support. Under responsibility, the delicate balance between individual and institutional responsibility and control was shown. Time included short and long-term perspectives on learning. Under support, supporting documents, activities and personnel resources were mentioned. In summary, an increased control by the program and tutors decreases student's motivation to assume responsibility for learning. Support in tutorial groups needs to adapt to student progression and to be well aligned to tutorial work to have the intended effect. A lifelong learning perspective may help students develop a meta-awareness regarding learning that could make tutorial work more meaningful.


Laying a Community-Based Foundation for Data-Driven Semantic Standards in Environmental Health Sciences.
Despite increasing availability of environmental health science (EHS) data, development, and implementation of relevant semantic standards, such as ontologies or hierarchical vocabularies, has lagged. Consequently, integration and analysis of information needed to better model environmental influences on human health remains a significant challenge. We aimed to identify a committed community and mechanisms needed to develop EHS semantic standards that will advance understanding about the impacts of environmental exposures on human disease. The National Institute of Environmental Health Sciences sponsored the "Workshop for the Development of a Framework for Environmental Health Science Language" hosted at North Carolina State University on 15-16 September 2014. Through the assembly of data generators, users, publishers, and funders, we aimed to develop a foundation for enabling the development of community-based and data-driven standards that will ultimately improve standardization, sharing, and interoperability of EHS information. Creating and maintaining an EHS common language is a continuous and iterative process, requiring community building around research interests and needs, enabling integration and reuse of existing data, and providing a low barrier of access for researchers needing to use or extend such a resource. Recommendations included developing a community-supported web-based toolkit that would enable a) collaborative development of EHS research questions and use cases, b) construction of user-friendly tools for searching and extending existing semantic resources, c) education and guidance about standards and their implementation, and d) creation of a plan for governance and sustainability. Mattingly CJ, Boyles R, Lawler CP, Haugen AC, Dearry A, Haendel M. 2016. Laying a community-based foundation for data-driven semantic standards in environmental health sciences. Environ Health Perspect 124:1136-1140; http://dx.doi.org/10.1289/ehp.1510438.


Multiscale temporal neural dynamics predict performance in a complex sensorimotor task.
Ongoing neuronal oscillations are pivotal in brain functioning and are known to influence subjects' performance. This modulation is usually studied on short time scales whilst multiple time scales are rarely considered. In our study we show that Long-Range Temporal Correlations (LRTCs) estimated from the amplitude of EEG oscillations over a range of time-scales predict performance in a complex sensorimotor task, based on Brain-Computer Interfacing (BCI). Our paradigm involved eighty subjects generating covert motor responses to dynamically changing visual cues and thus controlling a computer program through the modulation of neuronal oscillations. The neuronal dynamics were estimated with multichannel EEG. Our results show that: (a) BCI task accuracy may be predicted on the basis of LRTCs measured during the preceding training session, and (b) this result was not due to signal-to-noise ratio of the ongoing neuronal oscillations. Our results provide direct empirical evidence in addition to previous theoretical work suggesting that scale-free neuronal dynamics are important for optimal brain functioning.


In vivo magnetic resonance imaging tracking of C6 glioma cells labeled with superparamagnetic iron oxide nanoparticles.
The aim of the current study was to monitor the migration of superparamagnetic iron oxide nanoparticle (SPION)-labeled C6 cells, which were used to induce glioblastoma tumor growth in an animal model, over time using magnetic resonance imaging (MRI), with the goal of aiding in tumor prognosis and therapy. Two groups of male Wistar rats were used for the tumor induction model. In the first group (n=3), the tumors were induced via the injection of SPION-labeled C6 cells. In the second group (n=3), the tumors were induced via the injection of unlabeled C6 cells. Prussian Blue staining was performed to analyze the SPION distribution within the C6 cells in vitro. Tumor-inducing C6 cells were injected into the right frontal cortex, and subsequent tumor monitoring and SPION detection were performed using T2- and T2*-weighted MRI at a 2T field strength. In addition, cancerous tissue was histologically analyzed after performing the MRI studies. The in vitro qualitative evaluation demonstrated adequate distribution and satisfactory cell labeling of the SPIONs. At 14 or 21 days after C6 injection, a SPION-induced T2- and T2*-weighted MRI signal reduction was observed within the lesion located in the left frontal lobe on parasagittal topography. Moreover, histological staining of the tumor tissue with Prussian Blue revealed a broad distribution of SPIONs within the C6 cells. MRI analyses exhibit potential for monitoring the tumor growth of C6 cells efficiently labeled with SPIONs.


Capsaicin-evoked CGRP release from rat buccal mucosa: development of a model system for studying trigeminal mechanisms of neurogenic inflammation.
Many of the physiological hallmarks associated with neurogenic inflammatory processes in cutaneous tissues are similarly present within orofacial structures. Such attributes include the dependence upon capsaicin-sensitive sensory neurons and the involvement of certain inflammatory mediators derived therein, including calcitonin gene-related peptide (CGRP). However, there are also important differences between the trigeminal and spinal nervous systems, and the potential contributions of neurogenic processes to inflammatory disease within the trigeminal system have yet to be fully elucidated. We present here a model system that affords the ability to study mechanisms regulating the efferent functions of peptidergic terminals that may subserve neurogenic inflammation within the oral cavity. Freshly dissected buccal mucosa tissue from adult, male, Sprague-Dawley rats was placed into chambers and superfused with oxygenated, Krebs buffer. Serial aliquots of the egressing superfusate were acquired and analysed by radioimmunoassay for immunoreactive CGRP (iCGRP). Addition of the selective excitotoxin, capsaicin (10-300 microm), to the superfusion buffer resulted in a significant, concentration-dependent increase in superfusate levels of iCGRP. Similarly, release of iCGRP from the buccal mucosa could also be evoked by a depolarizing concentration of potassium chloride (50 mm) or by the calcium ionophore A23187 (1 microm). The specific, capsaicin receptor antagonist, capsazepine (300 microm), completely abolished the capsaicin-evoked release of iCGRP while having no effect whatsoever on the potassium-evoked release. Moreover, capsaicin-evoked release was dependent upon the presence of extracellular calcium ions and was significantly, though incompletely, attenuated by neonatal capsaicin denervation. Collectively, these data indicate that the evoked neurosecretion of iCGRP in response to capsaicin occurs via a vanilloid receptor-mediated, exocytotic mechanism. The model system described here should greatly facilitate future investigations designed to identify and characterize the stimuli that regulate the release of CGRP or other neurosecretory substances in isolated tissues. This system may also be used to elucidate the role of these mediators in the aetiology of inflammatory processes within the trigeminal field of innervation.


The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice.
Aging is associated with functional decline in the immune system and increases the risk of chronic diseases owing to smoldering inflammation. In the present study, we demonstrated an age-related increase in the accumulation of Programmed Death-1 (PD-1)+ memory-phenotype T cells that are considered "senescence-associated T cells" in both the visceral adipose tissue and spleen. As caloric restriction is an established intervention scientifically proven to exert anti-aging effects and greatly affects physiological and pathophysiological alterations with advanced age, we evaluated the effect of caloric restriction on the increase in this T-cell subpopulation and glucose tolerance in aged mice. Long-term caloric restriction significantly decreased the number of PD-1+ memory-phenotype cluster of differentiation (CD) 4+ and CD8+ T cells in the spleen and visceral adipose tissue, decreased M1-type macrophage accumulation in visceral adipose tissue, and improved insulin resistance in aged mice. Furthermore, the immunological depletion of PD-1+ T cells reduced adipose inflammation and improved insulin resistance in aged mice. Taken together with our previous report, these results indicate that senescence-related T-cell subpopulations are involved in the development of chronic inflammation and insulin resistance in the context of chronological aging and obesity. Thus, long-term caloric restriction and specific deletion of senescence-related T cells are promising interventions to regulate age-related chronic diseases.


Viral entry route determines how human plasmacytoid dendritic cells produce type I interferons.
Although plasmacytoid dendritic cells (pDCs) represent a rare immune cell type, they are the most important source of type I interferons (IFNs) upon viral infection. Phagocytosed RNA viruses and RNA virus-infected cells are detected by pDCs with the endosomal pattern recognition receptor (PRR) toll-like receptor 7 (TLR7). We showed that replication of the yellow fever live vaccine YF-17D in human pDCs and pDC-like cell lines stimulated type I IFN production through RIG-I (retinoic acid-inducible gene I), a member of the RIG-I-like receptor (RLR) family of cytosolic PRRs. Thus, human pDCs sense replicative viral RNA. In contrast, direct contact between pDCs and YF-17D-infected cells stimulated a TLR7-dependent, viral replication-independent production of type I IFN. We also showed that the RLR pathway was dampened by the activities of interleukin-1 receptor-associated kinases 1 and 4 (IRAK1 and IRAK4), which are downstream effectors of the TLR7 pathway, suggesting that both kinases play opposing roles downstream of specific PRRs. Together, these data suggest that a virus can stimulate either TLR or RLR signaling in the same cell, depending on how its nucleic acid content is delivered.


Psilocybin-Assisted Group Therapy and Attachment: Observed Reduction in Attachment Anxiety and Influences of Attachment Insecurity on the Psilocybin Experience.
Attachment insecurity is determined early in life, is a risk factor for psychopathology, and can be measured on two separate continuous dimensions: attachment anxiety and attachment avoidance. Therapeutic changes toward more secure attachment correlate with reduction in psychiatric symptoms. Psilocybin-assisted psychotherapy has demonstrated promise in the treatment of psychopathology, such as treatment-resistant depression and substance use disorders. We hypothesized that psilocybin-assisted psychotherapy would reduce attachment anxiety and attachment avoidance, thus increasing attachment security. We also hypothesized that baseline measures of attachment insecurity, which can reflect a diminished capacity for trust and exploration, would inform the quality of the psilocybin session. Participants were male long-term AIDS survivors with moderate-severe demoralization (n = 18). Using the Experiences in Close Relationships scale, we measured attachment insecurity at baseline as well as immediately, and 3 months, after completion of a brief group therapy course, which included a single midtreatment open-label psilocybin session conducted individually. Clinically important aspects of the psilocybin session were assessed using the revised Mystical Experience Questionnaire and the Challenging Experience Questionnaire the day following psilocybin administration. Self-reported ratings of attachment anxiety decreased significantly from baseline to 3-months post-intervention, t(16) = -2.2; p = 0.045; d rm = 0.45; 95% CI 0.01, 0.87. Attachment avoidance did not change significantly. Baseline attachment anxiety was strongly correlated with psilocybin-occasioned mystical-type experiences, r(15) = 0.53, p = 0.029, and baseline attachment avoidance was strongly correlated with psilocybin-related challenging experiences, r(16) = 0.62, p = 0.006. These findings have important implications for the general treatment of psychopathology as well as optimizing psilocybin-assisted psychotherapy as a broadly applicable treatment modality.


The Tomaj mutant alleles of alpha Tubulin67C reveal a requirement for the encoded maternal specific tubulin isoform in the sperm aster, the cleavage spindle apparatus and neurogenesis during embryonic development in Drosophila.
The three dominant TomajD and their eleven revertant (TomajR) alleles have been localized to the alpha Tubulin67C gene of Drosophila melanogaster. Although the meiotic divisions are normally completed in eggs laid by TomajD/+, TomajD/-, TomajR/- females, embryogenesis arrests prior to the gonomeric division. The arrest is caused by: (1) the failure of prominent sperm aster formation; and (2) a consequent lack of female pronuclear migration towards the male pronucleus. Concomitant with the sperm aster defect, the four female meiotic products fuse (tetra-fusion), similar to what is seen in eggs of wild-type virgin females. In eggs of females heterozygous for weaker TomajR alleles, embryogenesis comes to a cessation before or shortly after cortical migration of cleavage nuclei. The apparent source of embryonic defect is the cleavage spindle apparatus. One of the three TomajD alleles is cold-sensitive and its cold-sensitive period coincides with the completion of female meiosis and pronuclear migration. Disorganized central and peripheral nervous systems are also characteristic of embryos derived from the temperature-sensitive TomajD/+ females. The Tomaj mutant phenotypes indicate an involvement of the normal alpha Tubulin67C gene product in: (1) the formation of the sperm aster; (2) cleavage spindle apparatus formation/function; and (3) the differentiation of the embryonic nervous system. The TomajD alleles encode a normal-sized alpha Tubulin67C isotype. Sequence analyses of the TomajD alleles revealed the replacement in different positions of a single negatively charged or neutral amino acid with a positively charged one. These residues presumably identify important functional sites.


Arterial pre-hypertension and hypertension in intracranial versus extracranial cerebrovascular stenosis.
Since it has remained unclear whether arterial pre-hypertension is a risk factor for cerebrovascular diseases, potential associations between arterial pre-hypertension and intracranial arterial stenosis (ICAS) and extracranial arterial stenosis (ECAS) were assessed. The population-based Asymptomatic Polyvascular Abnormalities in Community Study was a sub-study of employees and retirees of the coal mining industry in China. Our study examined asymptomatic polyvascular abnormalities in a general population and with an age of 40+ years without history of stroke, transient ischaemic attacks and coronary heart disease. ICAS was diagnosed by transcranial Doppler sonography and was defined by peak flow velocity criteria; ECAS was diagnosed by carotid duplex sonography and was defined by the diameter of the common carotid artery or internal carotid artery. Out of 4422 study participants, 711 (16.1%) subjects showed an asymptomatic ICAS and 292 (6.6%) showed an asymptomatic ECAS. After adjusting for relevant risk factors, higher prevalence of ICAS was significantly associated with higher prevalence of pre-hypertension [odds ratio (OR) 1.55; 95% confidence interval (CI) 1.11, 2.16; P = 0.010] and hypertension (OR 1.80; 95% CI 1.53, 2.11; P < 0.001). Stratified by gender, the association was stronger for men than for women. Asymptomatic ECAS was not significantly associated with the prevalence of pre-hypertension (OR 0.78; 95% CI 0.55, 1.10) or of hypertension (OR 1.06; 95% CI 0.91, 1.24). The results suggest that arterial pre-hypertension in addition to hypertension is associated with a higher prevalence of asymptomatic ICAS, more in men.


Misfolded α-synuclein causes hyperactive respiration without functional deficit in live neuroblastoma cells.
The misfolding and aggregation of the largely disordered protein, α-synuclein, is a central pathogenic event that occurs in the synucleinopathies, a group of neurodegenerative disorders that includes Parkinson's disease. While there is a clear link between protein misfolding and neuronal vulnerability, the precise pathogenic mechanisms employed by disease-associated α-synuclein are unresolved. Here, we studied the pathogenicity of misfolded α-synuclein produced using the protein misfolding cyclic amplification (PMCA) assay. To do this, previous published methods were adapted to allow PMCA-induced protein fibrillization to occur under non-toxic conditions. Insight into potential intracellular targets of misfolded α-synuclein was obtained using an unbiased lipid screen of 15 biologically relevant lipids that identified cardiolipin (CA) as a potential binding partner for PMCA-generated misfolded α-synuclein. To investigate whether such an interaction can impact the properties of α-synuclein misfolding, protein fibrillization was carried out in the presence of the lipid. We show that CA both accelerates the rate of α-synuclein fibrillization and produces species that harbour enhanced resistance to proteolysis. Because CA is virtually exclusively expressed in the inner mitochondrial membrane, we then assessed the ability of these misfolded species to alter mitochondrial respiration in live non-transgenic SH-SY5Y neuroblastoma cells. Extensive analysis revealed that misfolded α-synuclein causes hyperactive mitochondrial respiration without causing any functional deficit. These data give strong support for the mitochondrion as a target for misfolded α-synuclein and reveal persistent, hyperactive respiration as a potential upstream pathogenic event associated with the synucleinopathies.This article has an associated First Person interview with the first author of the paper.


Very low birth weight and perinatal periods of risk: disparities in St. Louis.
Very low birth weight (VLBW) is a significant issue in St. Louis, Missouri. Our study evaluated risk factors associated with VLBW in this predominantly urban community. From 2000 to 2009, birth and fetal death certificates were evaluated (n = 160, 189), and mortality rates were calculated for perinatal periods of risk. The Kitagawa method was used to explore fetoinfant mortality rates (FIMR) in terms of birth weight distribution and birthweight specific mortality. Multivariable logistic regression was used to assess the magnitude of association of selected risk factors with VLBW. VLBW contributes to 50% of the excess FIMR in St. Louis City and County. The highest proportion of VLBW can be attributed to black maternal race (40.6%) in St. Louis City, inadequate prenatal care (19.8%), and gestational hypertension (12.0%) among black women. Medicaid was found to have a protective effect for VLBW among black women (population attributable risk (PAR) = -14.5). Interventions targeting the health of women before and during conception may be most successful at reducing the disparities in VLBW in this population. Interventions geared towards smoking cessation and improvements in Medicaid and prenatal care access for black mothers and St. Louis City residents can greatly reduce VLBW rates.


Remapping the cognitive and neural profiles of children who struggle at school.
Our understanding of learning difficulties largely comes from children with specific diagnoses or individuals selected from community/clinical samples according to strict inclusion criteria. Applying strict exclusionary criteria overemphasizes within group homogeneity and between group differences, and fails to capture comorbidity. Here, we identify cognitive profiles in a large heterogeneous sample of struggling learners, using unsupervised machine learning in the form of an artificial neural network. Children were referred to the Centre for Attention Learning and Memory (CALM) by health and education professionals, irrespective of diagnosis or comorbidity, for problems in attention, memory, language, or poor school progress (n = 530). Children completed a battery of cognitive and learning assessments, underwent a structural MRI scan, and their parents completed behavior questionnaires. Within the network we could identify four groups of children: (a) children with broad cognitive difficulties, and severe reading, spelling and maths problems; (b) children with age-typical cognitive abilities and learning profiles; (c) children with working memory problems; and (d) children with phonological difficulties. Despite their contrasting cognitive profiles, the learning profiles for the latter two groups did not differ: both were around 1 SD below age-expected levels on all learning measures. Importantly a child's cognitive profile was not predicted by diagnosis or referral reason. We also constructed whole-brain structural connectomes for children from these four groupings (n = 184), alongside an additional group of typically developing children (n = 36), and identified distinct patterns of brain organization for each group. This study represents a novel move toward identifying data-driven neurocognitive dimensions underlying learning-related difficulties in a representative sample of poor learners.


Spectral and phase-amplitude coupling signatures in human deep brain oscillations during propofol-induced anaesthesia.
Both the cerebral cortex and subcortical structures play important roles in consciousness. Some evidence points to general anaesthesia-induced unconsciousness being associated with distinct patterns of superficial cortical electrophysiological oscillations, but how general anaesthetics influence deep brain neural oscillations and interactions between oscillations in humans is poorly understood. Local field potentials were recorded in discrete deep brain regions, including anterior cingulate cortex, sensory thalamus, and periaqueductal grey, in humans with implanted deep brain electrodes during induction of unconsciousness with propofol. Power-frequency spectra, phase-amplitude coupling, coherence, and directed functional connectivity analysis were used to characterise local field potentials in the awake and unconscious states. An increase in alpha (7-13 Hz) power and decrease in gamma (30-90 Hz) power were observed in both deep cortical (ACC, anterior cingulate cortex) and subcortical (sensory thalamus, periaqueductal grey) areas during propofol-induced unconsciousness. Robust alpha-low gamma (30-60 Hz) phase-amplitude coupling induced by general anaesthesia was observed in the anterior cingulate cortex but not in other regions studied. Moreover, alpha oscillations during unconsciousness were highly coherent within the anterior cingulate cortex, and this rhythm exhibited a bidirectional information flow between left and right anterior cingulate cortex but stronger left-to-right flow. Propofol increases alpha oscillations and attenuates gamma oscillations in both cortical and subcortical areas. The alpha-gamma phase-amplitude coupling and the functional connectivity of alpha oscillations in the anterior cingulate cortex could be specific markers for loss of consciousness.


Small bowel liposarcoma--a rare cause of small bowel perforation.
A 76-year-old patient was admitted with right-sided lower abdominal pain. CT scan of the abdomen demonstrated a fatty mass arising around the bowel in the left iliac fossa causing local distortion of the vasculature. His clinical condition rapidly deteriorated with worsening abdominal signs necessitating an exploratory laparotomy. A segment of perforated small bowel associated with mesenteric mass was excised and the patient died 3 days later. The histology demonstrated a well-differentiated liposarcoma. Liposarcomas are the most common soft tissue sarcomas in adults but occurrence in the gastrointestinal tract is extremely rare. The clinical presentation of these tumours is frequently non-specific and commonest symptoms are generalised, intermittent abdominal pain. Surgical resection with clear margins is the treatment of choice for primary liposarcomas. They are moderately radiosensitive and chemotherapy is non-effective. Although gastrointestinal liposarcomas have been previously reported, this is the first reported case of a primary liposarcoma associated with a small bowel perforation.


Quantitative analysis of iron concentration and expression of ferroportin 1 in the cortex and hippocampus of rats induced by cerebral ischemia.
Iron overload induced by brain ischemia has been shown to be involved in neurodegenerative disease. Little is known about the relationship between brain ischemia and ferroportin 1 (FP1). The aims of this study are: (i) to determine whether iron accumulation in the brain is induced by cerebral hypoperfusion; and (ii) to test whether expression of FP1 is influenced by cerebral ischemia. The common carotid arteries (CCA) of rats were ligated bilaterally to induce cerebral ischemia, and the iron concentration of the cortex and hippocampus was measured by graphite furnace atomic absorption spectrometry. Iron was stained by Perl's method. The expression of FP1 mRNA and protein was shown by the reverse transcriptase polymerase chain reaction and immunohistochemical methods. The iron concentration in the cortex and hippocampus of ischemic rats had increased on day 7 (CCA7) and significantly on day 28 (CCA28) compared to control rats. More iron granules had been deposited in the cerebral cortex and hippocampus in rats with bilaterally ligated CCA on CCA7 and CCA28. In ischemic rats, FP1 expression in the cerebral cortex and hippocampus was decreased by CCA7 and this was more marked by CCA28 compared to control rats. We therefore concluded that iron deposition in the cerebral cortex and hippocampus of rats is induced by cerebral ischemia. Iron deposition may be attributed to the decrease in FP1 expression, and this inhibition of FP1 expression could be a major contributor to the formation of iron deposits in cerebral ischemia.


Inhibitory-excitatory synaptic balance is shifted toward increased excitation in magnocellular neurosecretory cells of heart failure rats.
Despite the well-established contribution of neurohumoral activation to morbidity and mortality in heart failure (HF) patients, relatively little is known about the underlying central nervous system mechanisms. In this study, we aimed to determine whether changes in GABAergic inhibitory and glutamatergic excitatory synaptic function contribute to altered hypothalamic magnocellular neurosecretory cell (MNC) activity in HF rats. Patch-clamp recordings were obtained from MNCs in brain slices from sham and HF rats. Glutamate excitatory (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) were simultaneously recorded, and changes in their strengths, as well as their interactions, were evaluated. We found a diminished GABAergic synaptic strength in MNCs of HF rats, reflected as faster decaying IPSCs and diminished mean IPSC charge transfer. Opposite changes were observed in glutamate EPSC synaptic strength, resulting in a shift in the GABA-glutamate balance toward a relatively stronger glutamate influence in HF rats. The prolongation of glutamate EPSCs during HF was mediated, at least in part, by an enhanced contribution of AMPA receptor desensitization to the EPSC decay time course. EPSC prolongation, and consequently increased unitary strength, resulted in a stronger AMPA receptor-mediated excitatory drive to firing discharge in MNCs of HF rats. Blockade of GABA(A) synaptic activity diminished the EPSC waveform variability observed among events in sham rats, an effect that was blunted in HF rats. Together, our results suggest that opposing changes in postsynaptic properties of GABAergic and glutamatergic synaptic function contribute to enhanced magnocellular neurosecretory activity in HF rats.


The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis.
The objectives of this study are to review the long-term consequences of injuries to the anterior cruciate ligament and menisci, the pathogenic mechanisms, and the causes of the considerable variability in outcome. Injuries of the anterior cruciate ligament and menisci are common in both athletes and the general population. At 10 to 20 years after the diagnosis, on average, 50% of those with a diagnosed anterior cruciate ligament or meniscus tear have osteoarthritis with associated pain and functional impairment: the young patient with an old knee. These individuals make up a substantial proportion of the overall osteoarthritis population. There is a lack of evidence to support a protective role of repair or reconstructive surgery of the anterior cruciate ligament or meniscus against osteoarthritis development. A consistent finding in a review of the literature is the often poor reporting of critical study variables, precluding data pooling or a meta-analysis. Osteoarthritis development in the injured joints is caused by intra-articular pathogenic processes initiated at the time of injury, combined with long-term changes in dynamic joint loading. Variation in outcome is reinforced by additional variables associated with the individual such as age, sex, genetics, obesity, muscle strength, activity, and reinjury. A better understanding of these variables may improve future prevention and treatment strategies. In evaluating medical treatment, we now expect large randomized clinical trials complemented by postmarketing monitoring. We should strive toward a comparable level of quality of evidence in surgical treatment of knee injuries. In instances in which a randomized clinical trial is not feasible, natural history and other observational cohort studies need to be as carefully designed and reported as the classic randomized clinical trial, to yield useful information.


Referral of mothers and infants for intensive care.
During 1975-7, 96 mothers were referred to University College Hospital for delivery from 39 other hospitals because their pregnancies were considered to be at very high risk. One hundred of the 111 infants born to the 96 mothers weighed 2500 g or less and 60 weighed 1500 g or less. A high proportion of the infants developed serious illnesses necessitating intensive care. The birth-weight-specific neonatal mortality rates of the infants were much lower than those of infants born in England and Wales as a whole and were also lower than those of the 370 infants transported to this hospital for intensive care after delivery elsewhere. Whenever possible mothers with very high-risk pregnancies should be referred for delivery to centres with full facilities for the intensive care of the mother, fetus, and newborn infant.


MicroRNA Expression Profiling of Human Respiratory Epithelium Affected by Invasive Candida Infection.
Invasive candidiasis is potentially life-threatening systemic fungal infection caused by Candida albicans (C. albicans). Candida enters the blood stream and disseminate throughout the body and it is often observed in hospitalized patients, immunocompromised individuals or those with chronic diseases. This infection is opportunistic and risk starts with the colonization of C. albicans on mucocutaneous surfaces and respiratory epithelium. MicroRNAs (miRNAs) are small non-coding RNAs which are involved in the regulation of virtually every cellular process. They regulate and control the levels of mRNA stability and post-transcriptional gene expression. Aberrant expression of miRNAs has been associated in many disease states, and miRNA-based therapies are in progress. In this study, we investigated possible variations of miRNA expression profiles of respiratory epithelial cells infected by invasive Candida species. For this purpose, respiratory epithelial tissues of infected individuals from hospital laboratory were accessed before their treatment. Invasive Candida infection was confirmed by isolation of Candia albicans from the blood cultures of the same infected individuals. The purity of epithelial tissues was assessed by flow cytometry (FACSCalibur cytometer; BD Biosciences, Heidelberg, Germany) using statin antibody (S-44). TaqMan quantitative real-time PCR (in a TaqMan Low Density Array format) was used for miRNA expression profiling. MiRNAs investigated, the levels of expression of 55 miRNA were significantly altered in infected tissues. Some miRNAs showed dramatic increase (miR-16-1) or decrease of expression (miR-17-3p) as compared to control. Gene ontology enrichment analysis of these miRNA-targeted genes suggests that Candidal infection affect many important biological pathways. In summary, disturbance in miRNA expression levels indicated the change in cascade of pathological processes and the regulation of respiratory epithelial functions following invasive Candidal infection. These findings contribute to our understanding of host cell response to Candidal systemic infections.


Coherent hollow-core waveguide bundles for thermal imaging.
There has been very little work done in the past to extend the wavelength range of fiber image bundles to the IR range. This is due, in part, to the lack of IR transmissive fibers with optical and mechanical properties analogous to the oxide glass fibers currently employed in the visible fiber bundles. Our research is aimed at developing high-resolution hollow-core coherent IR fiber bundles for transendoscopic infrared imaging. We employ the hollow glass waveguide (HGW) technology that was used successfully to make single-HGWs with Ag/AgI thin film coatings to form coherent bundles for IR imaging. We examine the possibility of developing endoscopic systems to capture thermal images using hollow waveguide fiber bundles adjusted to the 8-10?mum spectral range and investigate the applicability of such systems. We carried out a series of measurements in order to characterize the optical properties of the fiber bundles. These included the attenuation, resolution, and temperature response. We developed theoretical models and simulation tools that calculate the light propagation through HGW bundles, and which can be used to calculate the optical properties of the fiber bundles. Finally, the HGW fiber bundles were used to transmit thermal images of various heated objects; the results were compared with simulation results. The experimental results are encouraging, show an improvement in the resolution and thermal response of the HGW fiber bundles, and are consistent with the theoretical results. Nonetheless, additional improvements in the attenuation of the bundles are required in order to be able to use this technology for medical applications.


Identifying type 2 diabetes risk classification systems and recommendations for review of podiatric care in an Australian Aboriginal health clinic.
There are several risk classification systems developed to facilitate diabetic foot assessments and prioritise diabetes patients for foot prevention services according to risk factors. Utilisation of both The University of Texas Diabetic Foot Risk Classification System (UTDFRCS) and The National Evidence-Based Guideline on Prevention, Identification and Management of Foot Complications in Diabetes (Part of the Guidelines on Management of Type 2 Diabetes), allows guidance for the podiatrist in terms of review timeframes for future assessments and treatment. The aim of this clinical audit was to classify Aboriginal type 2 diabetes subjects' risk status according to UTDFRCS and identify if evidence based standards are being met for podiatry services at the Albury-Wodonga Aboriginal Health Service in New South Wales, Australia. A retrospective clinical audit over a twenty six month period was undertaken at the Albury-Wodonga Aboriginal Health Service, New South Wales. This is a primary health care facility that started podiatry services in August 2011. The primary variables of interest were the UTDFRCS for each subject and whether those participants met or did not meet the National Evidence-Based Guideline for review appointment timeframes. Other variables of interest include age, gender, duration of diabetes, occasions of visits and cancelled and failure to attend appointments to the podiatry service over the data collection period. There was excellent overall adherence (94 %) of this sample population (n = 729) to the National Evidence-Based Guideline for podiatric review timeframes according to their risk status. Males were reported to be less likely to comply with the review timeframes compared to women. There was no association between risk status and age (OR = 1.04, p = 0.11), duration of diabetes (OR = 1.03, p = 0.71) or gender (OR = 0.77, p = 0.67). Regular foot examinations aid in stratifying patients according to risk status, guiding podiatry interventions to reduce the likelihood of ulceration and amputation. This primary health care setting has achieved podiatric evidence based standards for Aboriginal people with type 2 diabetes, demonstrated by acceptable timeframes for review appointments.


Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore.
p53 is a Zn(2+)-dependent tumor suppressor inactivated in >50% of human cancers. The most common mutation, R175H, inactivates p53 by reducing its affinity for the essential zinc ion, leaving the mutant protein unable to bind the metal in the low [Zn(2+)]free environment of the cell. The exploratory cancer drug zinc metallochaperone-1 (ZMC1) was previously demonstrated to reactivate this and other Zn(2+)-binding mutants by binding Zn(2+) and buffering it to a level such that Zn(2+) can repopulate the defective binding site, but how it accomplishes this in the context of living cells and organisms is unclear. In this study, we demonstrated that ZMC1 increases intracellular [Zn(2+)]free by functioning as a Zn(2+) ionophore, binding Zn(2+) in the extracellular environment, diffusing across the plasma membrane, and releasing it intracellularly. It raises intracellular [Zn(2+)]free in cancer (TOV112D) and noncancer human embryonic kidney cell line 293 to 15.8 and 18.1 nM, respectively, with half-times of 2-3 minutes. These [Zn(2+)]free levels are predicted to result in ∼90% saturation of p53-R175H, thus accounting for its observed reactivation. This mechanism is supported by the X-ray crystal structure of the [Zn(ZMC1)2] complex, which demonstrates structural and chemical features consistent with those of known metal ionophores. These findings provide a physical mechanism linking zinc metallochaperone-1 in both in vitro and in vivo activities and define the remaining critical parameter necessary for developing synthetic metallochaperones for clinical use.


Recontacting Pediatric Research Participants for Consent When They Reach the Age of Majority.
Because children are presumed to have insufficient cognitive ability to consent to participate in research, pediatric research raises particular ethical and legal issues. For children who have not reached the age of consent stipulated by law or policy, parents (or legal guardians) must authorize their participation. This paper explores the issue of whether, to satisfy the ethical and legal norms of consent for research, participants in pediatric studies who attain the age of majority after their parents or guardians enrolled them in a study should be "recontacted" to obtain their consent to remain in the study. Using three different contexts (longitudinal studies, clinical trials, and newborn screening), we argue that distinctions should be made between the risks and benefits involved in recontacting for consent before determining the potential duties of researchers. An obligation to recontact should always be balanced with the feasibility and cost of such efforts in each particular research context and with consideration for the existence or lack of an ongoing relationship with the participant.


Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha.
Transgenic mice expressing tumor necrosis factor-alpha (TNF-alpha) in cardiac myocytes develop dilated cardiomyopathy, but the temporal progression to cardiac dysfunction is not well characterized. We asked (1) Does magnetic resonance imaging (MRI) provide a reproducible assessment of cardiac output in mice that correlates with invasive measurements obtained with thermodilution? (2) What is the time course of left ventricular (LV) remodeling in transgenic mice with myocardial expression of TNF-alpha? Transgenic mice from 2 different lineages with differing amounts of myocardial TNF-alpha expression [lineage 1 (L1) and lineage 2 (L2)] and littermate controls (LC) were studied. In protocol 1, cardiac output (CO) and stroke volume (SV) were measured by MRI and thermodilution (TD) in 15 mice (3 L1, 4 L2, 8 LC). In protocol 2, 23 mice (7 L1, 8 L2, 8 LC) were scanned at 1 month of life and every 4 weeks thereafter. In both protocols, cine-MRI was performed with the use of a 1.5-T clinical system (1.5-mm slices, 195x195 microm in-plane resolution). MRI CO and SV correlated well with TD [COTD (mL/min)=0.94*COMRI+0.72, r=0.84; SVTD( microL)=1. 01*SVMRI-1.07, r=0.94]. Serial MRI studies showed significant increase in LV mass and volumes over time and a significant decrease in ejection fraction in transgenic mice when compared with littermate controls. Compared with lineage 2, lineage 1 showed significantly larger LV mass and volumes and significantly lower ejection fraction. MRI assessment of cardiac function in mice correlates well with invasive measurements. Serial MRI studies in the TNF-alpha mouse model demonstrate that the rate of progression and severity of LV dysfunction are dependent on the degree of TNF-alpha overexpression.


An assessment of the toxicity of polypropylene microplastics in human derived cells.
Environmental pollution caused by plastic waste is a growing global problem. Discarded plastic products and debris (microplastic particles) in the oceans detrimentally affect marine ecosystems and may impact human. Humans are exposed to plastic debris via the consumption of seafood and drinking water, contact with food packaging, or inhalation of particles. The accumulation of microplastic particles in humans has potential health risks such as cytotoxicity, hypersensitivity, unwanted immune response, and acute response like hemolysis. We investigated the cellular responses of secondary polypropylene microplastics (PP particles) of approximately ~20 μm and 25-200 μm in different condition and size to normal cells, immune cells, blood cells, and murine immune cells by cytokine analysis, ROS assay, polarization assay and proliferation assay. We found that PP particles showed low cytotoxicity effect in size and concentration manner, however, a high concentration, small sized, DMSO method of PP particles stimulated the immune system and enhanced potential hypersensitivity to PP particles via an increase in the levels of cytokines and histamines in PBMCs, Raw 264.7 and HMC-1 cells.


Postnatal depression and mother and infant outcomes after infant massage.
Postnatal depression can be a long lasting condition which affects both the mother and her baby. A pilot study indicated that attending baby massage improved maternal depression and mother-infant interactions. The current study further investigates any benefits of baby massage for mothers with postnatal depression and their infants. Mothers scoring (3)13 on the Edinburgh Postnatal Depression Scale (EPDS) at 4 weeks postpartum were randomly assigned to attend baby massage classes (n=31) or a support group (n=31). They completed depression, anxiety and Infant Characteristics Questionnaires and were filmed interacting with their infants before and after 6 intervention sessions, and at one year. Thirty four non-depressed mothers also completed the study. More of the massage than support group mothers showed a clinical reduction in EPDS scores between four weeks and outcome (p<0.05). At one year, massage-group mothers had non-depressed levels of sensitivity of interaction with their babies, whereas the support group did not. There were no other differences in either mother or child between the two intervention groups. Depressed mothers did not achieve control depression or anxiety scores at one year. For ethical reasons, the study did not include a control group of depressed mothers who did not receive an intervention. Both intervention groups showed reductions in depression scores across the study period, but the massage group did better on some indices. They also had somewhat better interactions with their infants at one year, but these effects were limited.


The Impact of Internal Medicine Clerkship Characteristics and NBME Subject Exams on USMLE Step 2 Clinical Knowledge Exam Performance.
Residency program directors will likely emphasize the United States Medical Licensing Exam (USMLE) Step 2 clinical knowledge (CK) exam more during residency application given the recent USMLE Step 1 transition to pass/fail scoring. We examined how internal medicine clerkship characteristics and NBME subject exam scores affect USMLE Step 2 CK performance. The authors used univariable and multivariable generalized estimating equations to determine associations between Step 2 CK performance and internal medicine clerkship characteristics and NBME subject exams. The sample had 21,280 examinees' first Step 2 CK scores for analysis. On multivariable analysis, Step 1 performance (standardized β = 0.45, p < .001) and NBME medicine subject exam performance (standardized β = 0.40, p < .001) accounted for approximately 60% of the variance in Step 2 CK performance. Students who completed the internal medicine clerkship last in the academic year scored lower on Step 2 CK (Mdiff = -3.17 p < .001). Students who had a criterion score for passing the NBME medicine subject exam scored higher on Step 2 CK (Mdiff = 1.10, p = .03). There was no association between Step 2 CK performance and other internal medicine clerkship characteristics (all p > 0.05) nor with the total NBME subject exams completed (β=0.05, p = .78). Despite similarities between NBME subject exams and Step 2 CK, the authors did not identify improved Step 2 CK performance for students who had more NBME subject exams. The lack of association of Step 2 CK performance with many internal medicine clerkship characteristics and more NBME subject exams has implications for future clerkship structure and summative assessment. The improved Step 2 CK performance in students that completed their internal medicine clerkship earlier warrants further study given the anticipated increase in emphasis on Step 2 CK.


Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer.
Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is not well-established. Currently, there are no small-molecule inhibitors of gp130 under clinical development. In this study, we show that gp130 is an attractive drug target in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-molecule gp130 inhibitor. SC144 shows greater potency in human ovarian cancer cell lines than in normal epithelial cells. SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and further inhibits the expression of downstream target genes. In addition, SC144 shows potent inhibition of gp130 ligand-triggered signaling. Oral administration of SC144 delays tumor growth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues.


Triple combination MPT vaginal microbicide using curcumin and efavirenz loaded lactoferrin nanoparticles.
We report that a combination of anti-HIV-1 drug efavirenz (EFV), anti-microbial-spermicidal curcumin (Cur) and lactoferrin nanoparticles (ECNPs) act as MPT formulation. These nanoparticles are of well dispersed spherical shape with 40-70 nm size, with encapsulation efficiency of 63 ± 1.9% of Cur &61.5% ± 1.6 of EFV, significantly higher than that of single drug nanoparticles (Cur, 59 ± 1.34%; EFV: 58.4 ± 1.79). ECNPs were found to be sensitive at pH 5 and 6 and have not effected viability of vaginal micro-flora, Lactobacillus. Studies in rats showed that ECNPs delivers 88-124% more drugs in vaginal lavage as compared to its soluble form, either as single or combination of EFV and Cur. The ECNPs also shows 1.39-4.73 fold lower concentration of absorption in vaginal tissue and plasma compared to soluble EFV + Cur. Furthermore, ECNPs show significant reduction in inflammatory responses by 1.6-3.0 fold in terms of IL-6 and TNF-α in vaginal tissue and plasma compared to soluble EFV + Cur. ECNPs showed improved pharmacokinetics profiles in vaginal lavage with more than 50% of enhancement in AUC, AUMC, Cmax and t1/2 suggesting longer exposure of Cur and EFV in vaginal lavage compared to soluble EFV + Cur. Histopathological analysis of vaginal tissue shows remarkably lower toxicity of ECNPs compared to soluble EFV + Cur. In conclusion, ECNPs are significantly safe and exhibit higher bioavailability thus constitute an effective MPT against HIV.


A comparative study of hydrolysis and transglycosylation activities of fungal β-glucosidases.
β-glucosidases (BGs) from Aspergillus fumigatus, Aspergillus niger, Aspergillus oryzae, Magnaporthe grisea, Neurospora crassa, and Penicillium brasilianum were purified to homogeneity, and investigated for their (simultaneous) hydrolytic and transglycosylation activity in samples with high concentrations of either cellobiose or glucose. The rate of the hydrolytic process (which converts one cellobiose to two glucose molecules) shows a maximum around 10-15 mM cellobiose and decreases with further increase in the concentration of substrate. At the highest investigated concentration (100 mM cellobiose), the hydrolytic activity for the different enzymes ranged from 10% to 55% of the maximum value. This decline in hydrolysis was essentially compensated by increased transglycosylation (which converts two cellobiose to one glucose and one trisaccharide). Hence, it was concluded that the hydrolytic slowdown at high substrate concentrations solely relies on an increased flow through the transglycosylation pathway and not an inhibition that delays the catalytic cycle. Transglycosylation was also detected at high product (glucose) concentrations, but in this case, it was not a major cause for the slowdown in hydrolysis. The experimental data was modeled to obtain kinetic parameters for both hydrolysis and transglycosylation. These parameters were subsequently used in calculations that quantified the negative effects on BG activity of respectively transglycosylation and product inhibition. The kinetic parameters and the mathematical method presented here allow estimation of these effects, and we suggest that this may be useful for the evaluation of BGs for industrial use.


Linking DNA methyltransferases to epigenetic marks and nucleosome structure genome-wide in human tumor cells.
DNA methylation, mediated by the combined action of three DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), is essential for mammalian development and is a major contributor to cellular transformation. To elucidate how DNA methylation is targeted, we mapped the genome-wide localization of all DNMTs and methylation, and examined the relationships among these markers, histone modifications, and nucleosome structure in a pluripotent human tumor cell line in its undifferentiated and differentiated states. Our findings reveal a strong link between DNMTs and transcribed loci, and that DNA methylation is not a simple sum of DNMT localization patterns. A comparison of the epigenomes of normal and cancerous stem cells, and pluripotent and differentiated states shows that the presence of at least two DNMTs is strongly associated with loci targeted for DNA hypermethylation. Taken together, these results shed important light on the determinants of DNA methylation and how it may become disrupted in cancer cells.


Design of a prototype flow microreactor for synthetic biology in vitro.
As a reference platform for in vitro synthetic biology, we have developed a prototype flow microreactor for enzymatic biosynthesis. We report the design, implementation, and computer-aided optimisation of a three-step model pathway within a microfluidic reactor. A packed bed format was shown to be optimal for enzyme compartmentalisation after experimental evaluation of several approaches. The specific substrate conversion efficiency could significantly be improved by an optimised parameter set obtained by computational modelling. Our microreactor design provides a platform to explore new in vitro synthetic biology solutions for industrial biosynthesis.


Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology.
The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.


Gender and metabolic differences of gallstone diseases.
To investigate the risk factors for gallstone disease in the general population of Chengdu, China. This study was conducted at the West China Hospital. Subjects who received a physical examination at this hospital between January and December 2007 were included. Body mass index, blood pressure, fasting plasma glucose, serum lipid and lipoproteins concentrations were analyzed. Gallstone disease was diagnosed by ultrasound or on the basis of a history of cholecystectomy because of gallstone disease. Unconditional logistic regression analysis was used to investigate the risk factors for gallstone disease, and the Chi-square test was used to analyze differences in the incidence of metabolic disorders between subjects with and without gallstone disease. A total of 3573 people were included, 10.7% (384/3573) of whom had gallstone diseases. Multiple logistic regression analysis indicated that the incidence of gallstone disease in subjects aged 40-64 or >or= 65 years was significantly different from that in those aged 18-39 years (P < 0.05); the incidence was higher in women than in men (P < 0.05). In men, a high level of fasting plasma glucose was obvious in gallstone disease (P < 0.05), and in women, hypertriglyceridemia or obesity were significant in gallstone disease (P < 0.05). We assume that age and sex are profoundly associated with the incidence of gallstone disease; the metabolic risk factors for gallstone disease were different between men and women.


Association of polymorphisms in pharmacogenetic candidate genes (OPRD1, GAL, ABCB1, OPRM1) with opioid dependence in European population: a case-control study.
It is becoming increasingly evident that genetic variants contribute to the development of opioid addiction. An elucidation of these genetic factors is crucial for a better understanding of this chronic disease and may help to develop novel therapeutic strategies. In recent years, several candidate genes were implicated in opioid dependence. However, most study findings have not been replicated and additional studies are required before reported associations can be considered robust. Thus, the major objective of this study was to replicate earlier findings and to identify new genetic polymorphisms contributing to the individual susceptibility to opioid addiction, respectively. Therefore, a candidate gene association study was conducted including 142 well-phenotyped long-term opioid addicts undergoing opioid maintenance therapy and 142 well-matched healthy controls. In both study groups, 24 single nucleotide polymorphisms predominantly located in pharmacogenetic candidate genes have been genotyped using an accurate mass spectrometry based method. The most significant associations with opioid addiction (remaining significant after adjustment for multiple testing) were observed for the rs948854 SNP in the galanin gene (GAL, p = 0.001) and the rs2236861 SNP in the delta opioid receptor gene (OPRD1, p = 0.001). Moreover, an association of the ATP binding cassette transporter 1 (ABCB1) variant rs1045642 and the Mu Opioid receptor (OPRM1) variant rs9479757 with opioid addiction was observed. The present study provides further support for a contribution of GAL and OPRD1 variants to the development of opioid addiction. Furthermore, our results indicate a potential contribution of OPRM1 and ABCB1 SNPs to the development of this chronic relapsing disease. Therefore it seems important that these genes are addressed in further addiction related studies.


Free energy analysis along the stalk mechanism of membrane fusion.
The free energy profile of the stalk model of membrane fusion has been calculated using coarse-grained molecular dynamics simulations. The proposed method guides the lipid configuration using a guiding wall potential to make the transition from two apposed membranes to a stalk and a fusion pore. The free energy profile is obtained with a thermodynamic integration scheme using the mean force working on the guiding wall as a response of the system. We applied the method to two apposed flat bilayers composed of dioleoyl phosphatidylethanolamine/dioleoyl phosphatidylcholine expanding over the simulation box under the periodic boundary conditions. The two transition states are identified as pre-stalk and pre-pore states. The free energy barrier for the latter is confirmed to be in good agreement with that estimated by the pulling method. The present method provides a practical way to calculate the free energy profile along the stalk mechanism.


Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients.
A high density of tumor-infiltrating CD8+ T cells and CD20+ B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP+ DCs is robustly associated with an immune contexture characterized by TH1 polarization and cytotoxic activity. We showed that both mature DCs and CD20+ B cells play a critical role in the generation of a clinically-favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naïve HGSC patients. Our findings suggest that the presence of mature, DC-LAMP+ DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically-relevant anticancer immunity.


Feedback in hypothesis testing: an ERP study.
We used event-related potentials (ERPs) to probe the effects of feedback in a hypothesis testing (HT) paradigm. Thirteen college students serially tested hypotheses concerning a hidden rule by judging its presence or absence in triplets of digits and revised them on the basis of an exogenous performance feedback. ERPs time-locked to performance feedback were then examined. The results showed differences between responses to positive and negative feedback at all cortical sites. Negative feedback, indicating incorrect performance, was associated to a negative deflection preceding a P300-like wave. Spatiotemporal principal component analysis (PCA) showed the interplay between early frontal components and later central and posterior ones. Lateralization of activity was selectively detectable at frontal sites, with a left frontal dominance for both positive and negative feedback. These results are discussed in terms of a proposed computational model of trial-to-trial feedback in HT in which the cognitive and emotive aspects of feedback are explicitly linked to putative mediating brain mechanisms. The properties of different feedback types and feedback-related deficits in depression are also discussed.


The differentiation and movement of presomitic mesoderm progenitor cells are controlled by Mesogenin 1.
Somites are formed from the presomitic mesoderm (PSM) and give rise to the axial skeleton and skeletal muscles. The PSM is dynamic; somites are generated at the anterior end, while the posterior end is continually renewed with new cells entering from the tailbud progenitor region. Which genes control the conversion of tailbud progenitors into PSM and how is this process coordinated with cell movement? Using loss- and gain-of-function experiments and heat-shock transgenics we show in zebrafish that the transcription factor Mesogenin 1 (Msgn1), acting with Spadetail (Spt), has a central role. Msgn1 allows progression of the PSM differentiation program by switching off the progenitor maintenance genes ntl, wnt3a, wnt8 and fgf8 in the future PSM cells as they exit from the tailbud, and subsequently induces expression of PSM markers such as tbx24. msgn1 is itself positively regulated by Ntl/Wnt/Fgf, creating a negative-feedback loop that might be crucial to regulate homeostasis of the progenitor population until somitogenesis ends. Msgn1 drives not only the changes in gene expression in the nascent PSM cells but also the movements by which they stream out of the tailbud into the PSM. Loss of Msgn1 reduces the flux of cells out of the tailbud, producing smaller somites and an enlarged tailbud, and, by delaying exhaustion of the progenitor population, results in supernumerary tail somites. Through its combined effects on gene expression and cell movement, Msgn1 (with Spt) plays a key role both in genesis of the paraxial mesoderm and in maintenance of the progenitor population from which it derives.


The association of cyclophosphamide and dexamethasone in advanced refractory multiple myeloma patients.
VAD is the most active regimen in refractory myeloma patients; however, the role of vincristine and doxorubicin remains unclear. Relatively high doses of cyclophosphamide (3.6 g/sqm) increased the response rate and survival in resistant MM. Cyclophosphamide and dexamethasone were administered to 28 patients with advanced refractory myeloma. Thirteen patients received cyclophosphamide 1.2 g/sqm on days 1 and 3 and dexamethasone 40 mg/day from day 1 to day 4, every 4 weeks for 6 cycles (schedule A); 15 patients were treated with cyclophosphamide 0.5 g/sqm on days 1 and 3 and dexamethasone 40 mg/day from day 1 to day 4, every two weeks for 12 cycles (schedule B). Overall, 21 patients (75%) responded and 10 achieved an objective response (36%), while 11 reached a partial response. Twenty patients died (68%), most of them of disease progression, and 8 are still alive (32%). Median length of response and survival is 6 and 8 months, respectively. Therapy was easily applied and well tolerated. The overall response rate (75%) compares favorably with the best published results in this setting. The two schedules proved to be equally effective but patients treated with schedule B had more infections, which may have been related to the higher dosage of steroids.


Variability in individual activity bursts improves ant foraging success.
Using experimental and computational methods, we study the role of behavioural variability in activity bursts (or temporal activity patterns) for individual and collective regulation of foraging in A. senilis ants. First, foraging experiments were carried out under special conditions (low densities of ants and food and absence of external cues or stimuli) where individual-based strategies are most prevalent. By using marked individuals and recording all foraging trajectories, we were then able to precisely quantify behavioural variability among individuals. Our main conclusions are that (i) variability of ant trajectories (turning angles, speed, etc.) is low compared with variability of temporal activity profiles, and (ii) this variability seems to be driven by plasticity of individual behaviour through time, rather than the presence of fixed behavioural stereotypes or specialists within the group. The statistical measures obtained from these experimental foraging patterns are then used to build a general agent-based model (ABM) which includes the most relevant properties of ant foraging under natural conditions, including recruitment through pheromone communication. Using the ABM, we are able to provide computational evidence that the characteristics of individual variability observed in our experiments can provide a functional advantage (in terms of foraging success) to the group; thus, we propose the biological basis underpinning our observations. Altogether, our study reveals the potential utility of experiments under simplified (laboratory) conditions for understanding information-gathering in biological systems.


Aspects on evolution of fungal beta-lactam biosynthesis gene clusters and recruitment of trans-acting factors.
Penicillins and cephalosporins are beta-lactam antibiotics. The formation of hydrophobic penicillins has been reported in fungi only, notably Penicillium chrysogenum and Aspergillus (Emericella) nidulans, whereas the hydrophilic cephalosporins are produced by both fungi, e.g., Acremonium chrysogenum (cephalosporin C), and bacteria. The producing bacteria include Gram-negatives and Gram-positives, e.g., Streptomyces clavuligerus (cephamycin C) and Lysobacter lactamgenus (cephabacins), respectively. The evolutionary origin of beta-lactam biosynthesis genes has been the subject of discussion for many years, and two main hypotheses have been proposed: (i) horizontal gene transfer (HGT) from bacteria to fungi or (ii) vertical decent. There are strong arguments in favour of HGT, e.g., unlike most other fungal genes, beta-lactam biosynthesis genes are clustered and some of these genes lack introns. In contrast to S. clavuligerus, all regulators of fungal beta-lactam biosynthesis genes represent wide-domain regulators that are not part of the gene cluster. If bacterial regulators were co-transferred with the gene cluster from bacteria to fungi, most likely they would have been non-functional in eukaryotes and lost during evolution. Recently, the penicillin biosynthesis gene aatB was discovered, which is not part of the penicillin biosynthesis gene cluster and is even located on a different chromosome. The aatB gene is regulated by the same regulators AnCF and AnBH1 as the penicillin biosynthesis gene aatA (penDE). Data suggest that aatA and aatB are paralogues derived by duplication of a common ancestor gene. This data supports a model in which part of the beta-lactam biosynthesis gene cluster was transferred to some fungi, i.e., the acvA and ipnA gene without a regulatory gene. We propose that during the assembly of aatA and acvA-ipnA into a single gene cluster, recruitment of transcriptional regulators occurred along with acquisition of the duplicated aatA ancestor gene and its cis-acting sites.


Molecular diagnostic experience of whole-exome sequencing in adult patients.
Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults. We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms. Molecular diagnoses were reported for 17.5% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2%; P = 0.0003); the diagnostic rate was higher (23.9%) for those 18-30 years of age compared to patients older than 30 years (10.4%; P = 0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses. Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.Genet Med 18 7, 678-685.


Seamless image stitching by minimizing false edges.
Various applications such as mosaicing and object insertion require stitching of image parts. The stitching quality is measured visually by the similarity of the stitched image to each of the input images, and by the visibility of the seam between the stitched images. In order to define and get the best possible stitching, we introduce several formal cost functions for the evaluation of the stitching quality. In these cost functions the similarity to the input images and the visibility of the seam are defined in the gradient domain, minimizing the disturbing edges along the seam. A good image stitching will optimize these cost functions, overcoming both photometric inconsistencies and geometric misalignments between the stitched images. We study the cost functions and compare their performance for different scenarios both theoretically and practically. Our approach is demonstrated in various applications including generation of panoramic images, object blending and removal of compression artifacts. Comparisons with existing methods show the benefits of optimizing the measures in the gradient domain.


Culturally competent evidence-based behavioral health services for the transgender community: Progress and challenges.
The presence of individuals who identify as transgender has emerged into public awareness in the United States in recent years. Celebrities who publicly transition have expanded the national conversation about gender variation beyond gender and women's studies classrooms and certain specialty health and mental health services. This increased public visibility has been accompanied by increased visibility in the mental health literature, including the publishing of competencies or guidelines for working with clients who identify as transgender by various professional organizations. However, rapid societal changes and increased understanding of the experience of being transgender in our society means literature can rapidly become dated. This commentary identifies key points that will move forward professional competency, both of the field and of individual practitioners, in the provision of psychological services. Topics discussed include (1) how mental health has contributed to trans stigma, (2) why more than good intentions are needed, (3) a research agenda for the development of high-quality evidence-based behavioral health care for the trans community, and (4) clinician recommendations. (PsycINFO Database Record


Knowing What We're Doing: Why Specification of Treatment Methods Is Critical for Evidence-Based Practice in Speech-Language Pathology.
The purpose of this clinical focus article is to describe the conceptual framework of the multidisciplinary rehabilitation treatment taxonomy (RTT) and illustrate its potential use in speech-language pathology (SLP) clinical practice and research. The method used was a critical discussion. Current methods of defining and classifying SLP and other rehabilitation interventions maintain the "black box" of rehabilitation by referring to hours or days of therapy or using problem-oriented labels (e.g., naming treatment) to describe treatments, none of which reveal what is actually done to effect desired changes in patient functioning. The RTT framework uses treatment targets, ingredients, and mechanisms of action defined by treatment theory to specify SLP and other rehabilitation interventions with greater precision than current methods of treatment labeling and classification. It also makes a distinction between the target of treatment at which ingredients are directed and broader aims of treatment, which may be downstream effects explained instead by enablement/disablement theory. Future application of the RTT conceptual scheme to SLP intervention may enhance clinical practice, research, and knowledge translation as well as training and program evaluation efforts.


Grammatical agreement processing in reading: ERP findings and future directions.
In the domain of written sentence comprehension, the computation of agreement dependencies is generally considered as a form-driven processing routine whose domain is syntactic in nature. In the present review we discuss the main findings emerging in the Event-Related Potential (ERP) literature on sentence comprehension, focusing on the different dimensions of agreement patterns (features, values, constituents involved and language): Agreement mismatches usually evoke a biphasic electrophysiological pattern (Left Anterior Negativity - LAN, 300-450 msec and P600 after 500 msec). This ERP pattern is assumed to reflect rule-based computations sensitive to formal (inflectional) covariations of related words (trigger-target). Here we claim that agreement processing is sensitive to both the type of feature involved and the constituents that express the agreement dependency. More specifically, LAN could reflect violation of expectancy (elicited by the trigger) for the target functional morphology; later, trigger and target are structurally integrated at the sentence level (early P600). However, morphosyntactic information could trigger the activation of higher-level representations that are not strictly syntactic in nature. The recruitment of this additional non-syntactic information (mirrored by N400-like effects) indicates that rule-based computations of agreement dependencies are not blind to non-syntactic information but are often recruited to establish sentence-level relations.


Identification of a PD-L1+Tim-1+ iNKT subset that protects against fine particulate matter-induced airway inflammation.
Although air pollutants such as fine particulate matter (PM2.5) are associated with acute and chronic lung inflammation, the etiology of PM2.5-induced airway inflammation remains poorly understood. Here we report that PM2.5 triggered airway hyperreactivity (AHR) and neutrophilic inflammation with concomitant increases in Th1 and Th17 responses and epithelial cell apoptosis. We found that γδ T cells promoted neutrophilic inflammation and AHR through IL-17A. Unexpectedly, we found that invariant natural killer T (iNKT) cells played a protective role in PM2.5-induced pulmonary inflammation. Specifically, PM2.5 activated a suppressive CD4- iNKT cell subset that coexpressed Tim-1 and programmed cell death ligand 1 (PD-L1). Activation of this suppressive subset was mediated by Tim-1 recognition of phosphatidylserine on apoptotic cells. The suppressive iNKT subset inhibited γδ T cell expansion and intrinsic IL-17A production, and the inhibitory effects of iNKT cells on the cytokine-producing capacity of γδ T cells were mediated in part by PD-1/PD-L1 signaling. Taken together, our findings underscore a pathogenic role for IL-17A-producing γδ T cells in PM2.5-elicited inflammation and identify PD-L1+Tim-1+CD4- iNKT cells as a protective subset that prevents PM2.5-induced AHR and neutrophilia by inhibiting γδ T cell function.


Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from Royal College of General Practitioners' oral contraception study.
To describe the long term effects of the use of oral contraceptives on mortality. Cohort study with 25 year follow up. Details of oral contraceptive use and of morbidity and mortality were reported six monthly by general practitioners. 75% of the original cohort was "flagged" on the NHS central registers. 1400 general practices throughout Britain. 46 000 women, half of whom were using oral contraceptives at recruitment in 1968-9. Median age at end of follow up was 49 years. Relative risks of death adjusted for age, parity, social class, and smoking. Over the 25 year follow up 1599 deaths were reported. Over the entire period of follow up the risk of death from all causes was similar in ever users and never users of oral contraceptives (relative risk=1.0, 95% confidence interval 0.9 to 1.1; P=0.7) and the risk of death for most specific causes did not differ significantly in the two groups. However, among current and recent (within 10 years) users the relative risk of death from ovarian cancer was 0.2 (0.1 to 0.8; P=0.01), from cervical cancer 2.5 (1.1 to 6.1; P=0.04), and from cerebrovascular disease 1.9 (1.2 to 3.1, P=0.009). By contrast, for women who had stopped use >/= 10 years previously there were no significant excesses or deficits either overall or for any specific cause of death. Oral contraceptives seem to have their main effect on mortality while they are being used and in the 10 years after use ceases. Ten or more years after use ceases mortality in past users is similar to that in never users.