Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity.
Natural killer (NK) cells are important early mediators of host immunity to viral infections. The NK activatory receptors NKG2D and NKp80, both C-type lectin-like homodimeric receptors, stimulate NK cell cytotoxicity toward target cells. Like other herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) down-regulates MHC class I molecules to avoid detection by cytotoxic T lymphocytes but renders cells susceptible to NK cell cytotoxicity. We now show that the KSHV immune evasion gene, K5, reduces cell surface expression of the NKG2D ligands MHC class I-related chain A (MICA), MICB, and the newly defined ligand for NKp80, activation-induced C-type lectin (AICL). Down-regulation of both MICA and AICL requires the ubiquitin E3 ligase activity of K5 to target substrate cytoplasmic tail lysine residues. The common MICA *008 allele has a frameshift mutation leading to a premature stop codon and is resistant to down-regulation because of the loss of lysine residues. K5-mediated ubiquitylation signals internalization but not degradation of MICA and causes a potent reduction in NK cell-mediated cytotoxicity. The down-regulation of ligands for both the NKG2D and NKp80 activation pathways provides KSHV with a powerful mechanism for evasion of NK cell antiviral functions.


Inhibitory Effect of Galactooligosaccharide on Skin Pigmentation.
To investigate the effects of ingestion of galactooligosaccharide (GOS) on skin pigmentation, we conducted cell experiments and clinical trials. The effect of GOS on melanin accumulation was assessed in vitro using B16F10 cells. Moreover, melanin and erythema indexes following GOS consumption were explored during a double-blind, randomized, and placebo-controlled study, which included subjects divided by stratified block randomization to placebo or GOS. No cytotoxicity was observed at 70 mg/mL or lower GOS in B16F10 melanoma cells. Melanin accumulation was inhibited at 14 mg/mL or higher GOS. Upon ultraviolet B (UVB) irradiation, the survival of HaCaT cells (control) was reduced to 69.0% lower than baseline. A protective effect of GOS was observed upon treatment with 14~35 mg/mL GOS; however at 70 mg/mL, cells showed 64% viability compared to control cells irradiated with UVB. Delta values (Δ melanin index), which indicate the difference from the baseline melanin level, were significantly different to placebo (P<0.01) after 8 weeks. In the GOS group, delta values (Δ erythema index), which indicate the difference from baseline erythema level, also significantly differed from the placebo group (P<0.05) after 8 weeks. Our results suggest that intake of prebiotic GOS inhibits skin pigmentation and may represent a novel nutritional approach for skin care.


Detailed optical study of the transparent wing membranes of the dragonfly Aeshna cyanea.
The optical properties of transparent single membranes on the wings of the dragonfly Aeshna cyanea have been investigated. These membranes comprise one central thick cuticular layer covered dorsally and ventrally with typical odonatan wax pruinosity. Optical characterisation of individual membranes reveals they can support optical guided modes comprising differential polarisation reflection. We suggest this may offer an intraspecific signalling channel. The guided modes' characteristics depend on membrane thickness and the nature of the wax pruinosity. We accurately modelled multiple optical data sets simultaneously, thereby inaugurally quantifying the roughness of the pruinosity and the complex refractive indices of the wax and the odonatan cuticle.


Case Study: A Bio-Inspired Control Algorithm for a Robotic Foot-Ankle Prosthesis Provides Adaptive Control of Level Walking and Stair Ascent.
Powered ankle-foot prostheses assist users through plantarflexion during stance and dorsiflexion during swing. Provision of motor power permits faster preferred walking speeds than passive devices, but use of active motor power raises the issue of control. While several commercially available algorithms provide torque control for many intended activities and variations of terrain, control approaches typically exhibit no inherent adaptation. In contrast, muscles adapt instantaneously to changes in load without sensory feedback due to the intrinsic property that their stiffness changes with length and velocity. We previously developed a "winding filament" hypothesis (WFH) for muscle contraction that accounts for intrinsic muscle properties by incorporating the giant titin protein. The goals of this study were to develop a WFH-based control algorithm for a powered prosthesis and to test its robustness during level walking and stair ascent in a case study of two subjects with 4-5 years of experience using a powered prosthesis. In the WFH algorithm, ankle moments produced by virtual muscles are calculated based on muscle length and activation. Net ankle moment determines the current applied to the motor. Using this algorithm implemented in a BiOM T2 prosthesis, we tested subjects during level walking and stair ascent. During level walking at variable speeds, the WFH algorithm produced plantarflexion angles (range = -8 to -19°) and ankle moments (range = 1 to 1.5 Nm/kg) similar to those produced by the BiOM T2 stock controller and to people with no amputation. During stair ascent, the WFH algorithm produced plantarflexion angles (range -15 to -19°) that were similar to persons with no amputation and were ~5 times larger on average at 80 steps/min than those produced by the stock controller. This case study provides proof-of-concept that, by emulating muscle properties, the WFH algorithm provides robust, adaptive control of level walking at variable speed and stair ascent with minimal sensing and no change in parameters.


Grow or go? Energetic constraints on shark pup dispersal from pupping areas.
Many sharks and other marine taxa use natal areas to maximize survival of young, meaning such areas are often attributed conservation value. The use of natal areas is often linked to predator avoidance or food resources. However, energetic constraints that may influence dispersal of young and their use of natal areas are poorly understood. We combined swim-tunnel respirometry, calorimetry, lipid class analysis and a bioenergetics model to investigate how energy demands influence dispersal of young in a globally distributed shark. The school shark (a.k.a. soupfin, tope), Galeorhinus galeus, is Critically Endangered due to overfishing and is one of many sharks that use protected natal areas in Australia. Energy storage in neonate pups was limited by small livers, low overall lipid content and low levels of energy storage lipids (e.g. triacylglycerols) relative to adults, with energy stores sufficient to sustain routine demands for 1.3-4 days (mean ± SD: 2.4 ± 0.8 days). High levels of growth-associated structural lipids (e.g. phospholipids) and high energetic cost of growth suggested large investment in growth during residency in natal areas. Rapid growth (~40% in length) between birth in summer and dispersal in late autumn-winter likely increased survival by reducing predation and improving foraging ability. Delaying dispersal may allow prioritization of growth and may also provide energy savings through improved swimming efficiency and cooler ambient temperatures (daily ration was predicted to fall by around a third in winter). Neonate school sharks are therefore ill-equipped for large-scale dispersal and neonates recorded in the northwest of their Australian distribution are likely born locally, not at known south-eastern pupping areas. This suggests the existence of previously unrecorded school shark pupping areas. Integrated bioenergetic approaches as applied here may help to understand dispersal from natal areas in other taxa, such as teleost fishes, elasmobranchs and invertebrates.


Is there subclinical enthesitis in early psoriatic arthritis? A clinical comparison with power doppler ultrasound.
Enthesitis is a recognized feature of spondylarthritides (SpA), including psoriatic arthritis (PsA). Previously, ultrasound imaging has highlighted the presence of subclinical enthesitis in established SpA, but there are little data on ultrasound findings in early PsA. The aim of our study was to compare ultrasound and clinical examination (CE) for the detection of entheseal abnormalities in an early PsA cohort. Forty-two patients with new-onset PsA and 10 control subjects underwent CE of entheses for tenderness and swelling, as well as gray-scale (GS) and power Doppler (PD) ultrasound of a standard set of entheses. Bilateral elbow lateral epicondyles, Achilles tendons, and plantar fascia were assessed by both CE and ultrasound, the latter scored using a semiquantitative (SQ) scale. Inferior patellar tendons were assessed by ultrasound alone. A GS SQ score of >1 and/or a PD score of >0 was used to describe significant ultrasound entheseal abnormality. A total of 24 (57.1%) of 42 patients in the PsA group and 0 (0%) of 10 controls had clinical evidence of at least 1 tender enthesis. In the PsA group, for sites assessed by both CE and ultrasound, 4% (7 of 177) of nontender entheses had a GS score >1 and/or a PD score >0 compared to 24% (9 of 37) of tender entheses. CE overestimated activity in 28 (13%) of 214 of entheses. All the nontender ultrasound-abnormal entheses were in the lower extremity. The prevalence of subclinical enthesitis in this early PsA cohort was low. CE may overestimate active enthesitis. The few subclinically inflamed entheses were in the lower extremity, where mechanical stress is likely to be more significant.


Fourth-order dispersion-limited solitary pulses.
We analyze the performance of a Ti:sapphire self-mode-locked laser with near-zero second- and third-order dispersion. Our simulations show that, in the presence of fourth-order dispersion, solitary laser pulses can be supported within a wide parameter range, close to the experimental values of these parameters. We also conclude that it is possible to generate pulses much shorter than 10 fs if fourth-order dispersion is further reduced.


Creating a Community of Practice to Prevent Suicide Through Multiple Channels: Describing the Theoretical Foundations and Structured Learning of PC CARES.
It is critical to develop practical, effective, ecological, and decolonizing approaches to indigenous suicide prevention and health promotion for the North American communities. The youth suicide rates in predominantly indigenous small, rural, and remote Northern communities are unacceptably high. This health disparity, however, is fairly recent, occurring over the last 50 to 100 years as communities experienced forced social, economic, and political change and intergenerational trauma. These conditions increase suicide risk and can reduce people's access to shared protective factors and processes. In this context, it is imperative that suicide prevention includes--at its heart--decolonization, while also utilizing the "best practices" from research to effectively address the issue from multiple levels. This article describes such an approach: Promoting Community Conversations About Research to End Suicide (PC CARES). PC CARES uses popular education strategies to build a "community of practice" among local and regional service providers, friends, and families that fosters personal and collective learning about suicide prevention in order to spur practical action on multiple levels to prevent suicide and promote health. This article will discuss the theoretical underpinnings of the community intervention and describe the form that PC CARES takes to structure ongoing dialogue, learning, solidarity, and multilevel mobilization for suicide prevention.


Short-term treatment of uterine fibromyomas with danazol.
The aim of this study was to evaluate the effects of danazol in reducing the volume of fibromyomas and in the treatment of associated symptoms. Twenty women (34-42 years) with uterine fibromyomas were treated with 400 mg/day of danazol for 4-month periods. The women underwent ultrasound examination to determine their uterine volume at enrollment in the follicular phase and after 2 and 4 months. The examination was repeated by the same sonographer 3 and 6 months after the end of therapy. Blood samples were taken on the same days for LH, FSH, estradiol and progesterone assays. After therapy, fibromyoma volume decreased significantly (p<0.01) by an average of 23.6+/-5%. All patients experienced partial or complete relief of symptoms while using danazol. Three and six months after the end of treatment the fibromyoma volume had only increased slightly with respect to the volume at the end of therapy, but was still lower than the starting volume. The present study shows the efficacy of danazol at a dose of 400 mg/day for 4 months in reducing the volume of fibromyomas and associated symptoms. The mechanism by which danazol reduces the volume of fibromyomas may be due to reduced estrogen concentrations and to its antiprogesterone effects on uterine myomas.


Human dimensions of forest disturbance by insects: an international synthesis.
Ecological disturbances of forests by insects have a complex array of associated human dimensions presenting complications for natural resource decision making and relationships between stakeholders and managers. This article discusses the human context of forest disturbances by insects by reviewing four cases of bark beetle forest disturbance from British Columbia in Canada, Bavarian Forest National Park in Germany, the Kenai Peninsula in Alaska, and the north central region of Colorado. Findings and lessons learned from these studies are outlined along with their implications for managing forest disturbances by insects in general. Conclusions focus on the need to assess the broad array of impacts and risks perceived by local residents and the capacity for local action and involvement in managing forest disturbances. Communication and interaction between resource managers and local stakeholders can facilitate the identification of management priorities and potentially reduce some of the risks associated with forest disturbances by insects.


Pragmatic cluster randomized trial to evaluate effectiveness and implementation of enhanced EHR-facilitated cancer symptom control (E2C2).
The prevalence of inadequate symptom control among cancer patients is quite high despite the availability of definitive care guidelines and accurate and efficient assessment tools. We will conduct a hybrid type 2 stepped wedge pragmatic cluster randomized clinical trial to evaluate a guideline-informed enhanced, electronic health record (EHR)-facilitated cancer symptom control (E2C2) care model. Teams of clinicians at five hospitals that care for patients with various cancers will be randomly assigned in steps to the E2C2 intervention. The E2C2 intervention will have two levels of care: level 1 will offer low-touch, automated self-management support for patients reporting moderate sleep disturbance, pain, anxiety, depression, and energy deficit symptoms or limitations in physical function (or both). Level 2 will offer nurse-managed collaborative care for patients reporting more intense (severe) symptoms or functional limitations (or both). By surveying and interviewing clinical staff, we will also evaluate whether the use of a multifaceted, evidence-based implementation strategy to support adoption and use of the E2C2 technologies improves patient and clinical outcomes. Finally, we will conduct a mixed methods evaluation to identify disparities in the adoption and implementation of the E2C2 intervention among elderly and rural-dwelling patients with cancer. The E2C2 intervention offers a pragmatic, scalable approach to delivering guideline-based symptom and function management for cancer patients. Since discrete EHR-imbedded algorithms drive defining aspects of the intervention, the approach can be efficiently disseminated and updated by specifying and modifying these centralized EHR algorithms. ClinicalTrials.gov, NCT03892967. Registered on 25 March 2019.


InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions.
After publication of the updated World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues in 2008, the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph) now presents an update of the hierarchical classification of lymphoid neoplasms for epidemiologic research based on the 2001 WHO classification, which we published in 2007. The updated hierarchical classification incorporates all of the major and provisional entities in the 2008 WHO classification, including newly defined entities based on age, site, certain infections, and molecular characteristics, as well as borderline categories, early and "in situ" lesions, disorders with limited capacity for clinical progression, lesions without current International Classification of Diseases for Oncology, 3rd Edition codes, and immunodeficiency-associated lymphoproliferative disorders. WHO subtypes are defined in hierarchical groupings, with newly defined groups for small B-cell lymphomas with plasmacytic differentiation and for primary cutaneous T-cell lymphomas. We suggest approaches for applying the hierarchical classification in various epidemiologic settings, including strategies for dealing with multiple coexisting lymphoma subtypes in one patient, and cases with incomplete pathologic information. The pathology materials useful for state-of-the-art epidemiology studies are also discussed. We encourage epidemiologists to adopt the updated InterLymph hierarchical classification, which incorporates the most recent WHO entities while demonstrating their relationship to older classifications.


Cryptanaerobacter phenolicus gen. nov., sp. nov., an anaerobe that transforms phenol into benzoate via 4-hydroxybenzoate.
An anaerobic bacterium that transforms phenol and 4-hydroxybenzoate (4-OHB) into benzoate, strain LR7.2T, was isolated from a culture originating from a mixture of swamp water, sewage sludge, swine waste and soil. Cells of strain LR7.2T are Gram-positive short rods (1 x 2 microm) that are electron-dense when observed by electron microscopy. The optimum pH and temperature for growth and transformation activity of 4-OHB are 7.5-8.0 and 30-37 degrees C, respectively. The bacterium does not use sulphate, thiosulphate, nitrate, nitrite, FeCl3, fumarate or arsenate as an electron acceptor. It does not normally use sulphite, although stimulation of growth and 4-OHB transformation activity at a low concentration (up to 2 mM) has been reported previously under different culture conditions. The presence of 4-OHB or phenol is essential for growth; transformation of 4-OHB or phenol into benzoate is used to produce energy for growth. Using [6D]-phenol, 4-OHB was shown to be an intermediate in the transformation of phenol into benzoate. No spore was observed. The bacterium has a DNA G+C content of 51 mol% and its major membrane fatty acid is anteiso-C(15 : 0). The 16S rRNA gene sequence of strain LR7.2T shows only 90 % similarity to its closest relative (Pelotomaculum thermopropionicum). From these results, a new taxon is proposed: Cryptanaerobacter phenolicus gen. nov., sp. nov. The type strain is LR7.2T (=ATCC BAA-820T=DSM 15808T).


Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: a stratification tool for prospective clinical trials.
The objective of this study was to develop an algorithm capable of stratifying the survival of patients with metastatic renal cell carcinoma (RCC) after nephrectomy and immunotherapy. The medical records of 173 patients who underwent radical nephrectomy for metastatic RCC and received recombinant interleukin-2 (IL-2)-based immunotherapy between 1989 and 2000 were evaluated. Survival was the primary endpoint and was assessed based on clinical, surgical, and pathologic parameters. The clinical parameters included age, gender, performance status, existing hypertension, thyroid-stimulating hormone (TSH) levels, location of metastases, and presenting symptomatology. The surgical features included the requirement for blood transfusion or adrenalectomy. The pathologic factors involved tumor stage, tumor size, nuclear grade, lymph node status, and histologic subtype. Disease-specific survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used to determine associations between clinical and pathologic features and survival. The median follow-up was 3.2 years (range, 0.2-9.3 years). Death due to RCC occurred in 123 patients (71%) at a median of 13 months (range, from 0.1 months to 8.4 years) after nephrectomy. Multivariate analysis revealed that the following features were associated with survival: lymph node status (P = 0.002), constitutional symptoms (P = 0.005), location of metastases (P < 0.001), sarcomatoid histology (P = 0.003), and TSH level (P = 0.038). A scoring system based on the features in the multivariate model was created to stratify patients into low-risk, intermediate-risk, and high-risk groups. Estimated survival rates at 1 years, 3 years, and 5 years were 92%, 61%, and 41%, respectively, for the low-risk group and 66%, 31%, and 19%, respectively, for the intermediate risk group. The high-risk group had 1% survival at 1 year and no survivors at 3 years. In patients with metastatic RCC who were treated with nephrectomy and IL-2 immunotherapy, regional lymph node status, constitutional symptoms, location of metastases, sarcomatoid histology, and TSH levels were associated with survival. The authors present a scoring algorithm based on these features that can be used to predict survival in patients who present with metastatic RCC and to stratify such patients for prospective clinical trials.


The impact of mass gatherings and holiday traveling on the course of an influenza pandemic: a computational model.
During the 2009 H1N1 influenza pandemic, concerns arose about the potential negative effects of mass public gatherings and travel on the course of the pandemic. Better understanding the potential effects of temporal changes in social mixing patterns could help public officials determine if and when to cancel large public gatherings or enforce regional travel restrictions, advisories, or surveillance during an epidemic. We develop a computer simulation model using detailed data from the state of Georgia to explore how various changes in social mixing and contact patterns, representing mass gatherings and holiday traveling, may affect the course of an influenza pandemic. Various scenarios with different combinations of the length of the mass gatherings or traveling period (range: 0.5 to 5 days), the proportion of the population attending the mass gathering events or on travel (range: 1% to 50%), and the initial reproduction numbers R0 (1.3, 1.5, 1.8) are explored. Mass gatherings that occur within 10 days before the epidemic peak can result in as high as a 10% relative increase in the peak prevalence and the total attack rate, and may have even worse impacts on local communities and travelers' families. Holiday traveling can lead to a second epidemic peak under certain scenarios. Conversely, mass traveling or gatherings may have little effect when occurring much earlier or later than the epidemic peak, e.g., more than 40 days earlier or 20 days later than the peak when the initial R0 = 1.5. Our results suggest that monitoring, postponing, or cancelling large public gatherings may be warranted close to the epidemic peak but not earlier or later during the epidemic. Influenza activity should also be closely monitored for a potential second peak if holiday traveling occurs when prevalence is high.


Knowledge, Attitudes and Practice Behaviour of Midwives Concerning Periodontal Health of Pregnant Patients.
Maternal gum disease is associated with adverse pregnancy outcomes such as preterm birth and low birthweight. This study aims to evaluate the knowledge, attitudes and practice behaviour of Australian midwives regarding the periodontal health of pregnant women to inform interprofessional antenatal care. This was an observational, cross-sectional study. We circulated an online questionnaire to Australian midwives from August 2018 to February 2019. Key outcome variables were knowledge, attitudes, and practice behaviours related to oral health. Key predictor variables were years of practice, practice location, and dental history. We summarized responses with frequency tables and assigned tallied scores for analysis using non-parametric statistical tests. 100 responses were analysed, including from rural (n = 23) and urban (n = 77) midwives. Eighty percent of midwives agreed that maternal dental care can positively affect pregnancy outcomes. Fluoridated toothpaste use (19.1%) was incorrectly answered to prevent gum disease more often than psychological stress control (7.9%), a correct answer. Rural midwives demonstrated a significantly higher knowledge score (p = 0.001) and significantly more positive practice behaviours towards oral health (p = 0.014) than urban midwives. Australian midwives have positive attitudes towards antenatal oral health but misunderstand gum disease aetiology and prevention. This study highlights areas to improve interprofessional education for optimal oral health and pregnancy outcomes.


Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization.
Nitric oxide synthase (NOS) produces nitric oxide, a mediator of potential importance in numerous physiologic and inflammatory processes in the lung. We localized constitutive NOS (c-NOS) and inducible NOS (i-NOS) within lung tissue by immunoperoxidase labeling with specific antibodies or by histochemical demonstration of the characteristic NADPH diaphorase activity of NOS. We analyzed human airway (n = 4) or parenchyma (n = 10) specimens obtained from uninvolved areas of surgical tumor resections. We also studied human fetal lung samples (n = 6) and normal or inflamed (16 h after intratracheal LPS instillation) rat lung tissue. Immunostaining with anti-c-NOS identified c-NOS antigen in rat lung nerves, endothelium, and airway epithelium. Normal or inflamed rat macrophages were not stained. Human nerve elements and large-vessel endothelium showed immunostaining with the anti-c-NOS, but no labeling of the airway or alveolar epithelium was seen. Immunostaining with anti-i-NOS showed strong labeling of rat macrophages after LPS treatment, in vivo or in vitro, while normals were negative. Human alveolar macrophages were occasionally positive for i-NOS, especially in areas of chronic inflammation, which also showed focal immunolabeling of endothelium. Uniform labeling of epithelium in large, cartilaginous airways was found with anti-i-NOS in both human bronchi and normal rat trachea samples, suggesting a constitutive role for a NOS that shares epitope(s) with or is highly homologous to the inducible, macrophage type of NOS. Histochemical staining for NADPH diaphorase activity was consistent with immunolocalization of NOS antigens.(ABSTRACT TRUNCATED AT 250 WORDS)


GoDental! Enhancing flipped classroom experience with game-based learning.
To investigate the use of game-based learning (GBL) to enhance students' experience of the flipped classroom (FC) in dental education. Students participated in three sessions organised as FC, implemented either as conventional FC or FC augmented with the GoDental! game. In the pre-class phase, sessions 1 and 2 were organised as instructor-made video lectures, plus a questionnaire. These activities were supplemented with the individual development of questions and answers for the game in session 3. In the in-class phase, group and plenary discussions were used during sessions 1 and 2 and were replaced by game activities in session 3. Perceptions of session 3 compared to that of sessions 1 and 2 were explored via a questionnaire with both open-ended and Likert-scale items. Most students (29, 97%) perceived the FC session augmented with the GoDental! game as enjoyable. The game augmented session was perceived as more enjoyable compared to the conventional FC sessions. Students agreed that GBL augmented FC compared to conventional FC increased engagement (25, 83%), motivation (24, 83%), their integration in the social environment (23, 77%) and concentration (22, 73%), helped them learn more about the topic (24, 80%) and was a good learning method (25, 83%). There was a positive correlation between the degree of enjoyment and concentration and the feeling that the game helped them learn more about the topic. Game-based learning augmented FC proved to enhance students' experience, resulting in increased enjoyment compared to the conventional FC setup. Future studies should explore whether the use of GBL in FC has the potential to increase examination performance.


Eurotiomycetes: Eurotiomycetidae and Chaetothyriomycetidae.
The class Eurotiomycetes (Ascomycota, Pezizomycotina) is a monophyletic group comprising two major clades of very different ascomycetous fungi: (i) the subclass Eurotiomycetidae, a clade that contains most of the fungi previously recognized as Plectomycetes because of their mostly enclosed ascomata and prototunicate asci; and (ii) the subclass Chaetothyriomycetidae, a group of fungi that produce ascomata with an opening reminiscent of those produced by Dothideomycetes or Sordariomycetes. In this paper we use phylogenetic analyses based on data available from the Assembling the Fungal Tree of Life project (AFTOL), in addition to sequences in GenBank, to outline this important group of fungi. The Eurotiomycetidae include producers of toxic and useful secondary metabolites, fermentation agents used to make food products and enzymes, xerophiles and psychrophiles, and the important genetics model Aspergillus nidulans. The Chaetothyriomycetidae include the common black yeast fungi, some of which are pathogens of humans and animals, as well as some primarily lichenized groups newly found to be phylogenetically associated with this group. The recently proposed order Mycocaliciales shows a sister relationship with Eurotiomycetes. The great majority of human pathogenic Pezizomycotina are Eurotiomycetes, particularly in Eurotiales, Onygenales and Chaetothyriales. Due to their broad importance in basic research, industry and public health, several genome projects have focused on species in Onygenales and Eurotiales.


Executive control and felt concentrative engagement following intensive meditation training.
Various forms of mental training have been shown to improve performance on cognitively demanding tasks. Individuals trained in meditative practices, for example, show generalized improvements on a variety of tasks assessing attentional performance. A central claim of this training, derived from contemplative traditions, posits that improved attentional performance is accompanied by subjective increases in the stability and clarity of concentrative engagement with one's object of focus, as well as reductions in felt cognitive effort as expertise develops. However, despite frequent claims of mental stability following training, the phenomenological correlates of meditation-related attentional improvements have yet to be characterized. In a longitudinal study, we assessed changes in executive control (performance on a 32-min response inhibition task) and retrospective reports of task engagement (concentration, motivation, and effort) following one month of intensive, daily Vipassana meditation training. Compared to matched controls, training participants exhibited improvements in response inhibition accuracy and reductions in reaction time variability. The training group also reported increases in concentration, but not effort or motivation, during task performance. Critically, increases in concentration predicted improvements in reaction time variability, suggesting a link between the experience of concentrative engagement and ongoing fluctuations in attentional stability. By incorporating experiential measures of task performance, the present study corroborates phenomenological accounts of stable, clear attentional engagement with the object of meditative focus following extensive training. These results provide initial evidence that meditation-related changes in felt experience accompany improvements in adaptive, goal-directed behavior, and that such shifts may reflect accurate awareness of measurable changes in performance.


Protein secondary structure determination by constrained single-particle cryo-electron tomography.
Cryo-electron microscopy (cryo-EM) is a powerful technique for 3D structure determination of protein complexes by averaging information from individual molecular images. The resolutions that can be achieved with single-particle cryo-EM are frequently limited by inaccuracies in assigning molecular orientations based solely on 2D projection images. Tomographic data collection schemes, however, provide powerful constraints that can be used to more accurately determine molecular orientations necessary for 3D reconstruction. Here, we propose "constrained single-particle tomography" as a general strategy for 3D structure determination in cryo-EM. A key component of our approach is the effective use of images recorded in tilt series to extract high-resolution information and correct for the contrast transfer function. By incorporating geometric constraints into the refinement to improve orientational accuracy of images, we reduce model bias and overrefinement artifacts and demonstrate that protein structures can be determined at resolutions of ∼8 Å starting from low-dose tomographic tilt series.


Role of yoga and physical activity in work-related musculoskeletal disorders among dentists.
Work-related musculoskeletal pain is one of the occupational hazards in dentists. To find the prevalence and severity of musculoskeletal pain in dentists, to compare musculoskeletal pain among dentists practicing yoga, those practicing physical activities, and those without any physical activity, and also to know the effects of sex, age, and workload on musculoskeletal pain. A self-reporting work-related questionnaire and the Nordic questionnaire for analysis of musculoskeletal disorders were given to graduated dentists attending Indian dental conference in Mumbai, to know the musculoskeletal pain experienced in the last 12 months and feedback was obtained from 220 dentists. The prevalence of musculoskeletal pain in dentists was 34.5%. Prevalence of musculoskeletal pain was 10.5%, 21.7%, and 45.6% in dentists with regular yoga practice, other physical activity, and no physical activity, respectively. There was statistically significant difference in the prevalence of musculoskeletal pain among dentists who were practicing yoga when compared with those in no regular activity group. Within the limitations of the study, there was significant role of physical activity on the quality and quantity of work-related musculoskeletal disorders experienced by dentists. Yoga was found to be more effective than other modes of physical activities. More research is needed on musculoskeletal problems in dentists, with an emphasis on larger sample sizes and correlating other factors like age and sex of the dentists, duration of practice, years of practicing yoga, and working hours per week.


International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study.
Chronic obstructive pulmonary disease (COPD) is a growing cause of morbidity and mortality worldwide, and accurate estimates of the prevalence of this disease are needed to anticipate the future burden of COPD, target key risk factors, and plan for providing COPD-related health services. We aimed to measure the prevalence of COPD and its risk factors and investigate variation across countries by age, sex, and smoking status. Participants from 12 sites (n=9425) completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors. COPD prevalence estimates based on the Global Initiative for Chronic Obstructive Lung Disease staging criteria were adjusted for the target population. Logistic regression was used to estimate adjusted odds ratios (ORs) for COPD associated with 10-year age increments and 10-pack-year (defined as the number of cigarettes smoked per day divided by 20 and multiplied by the number of years that the participant smoked) increments. Meta-analyses provided pooled estimates for these risk factors. The prevalence of stage II or higher COPD was 10.1% (SE 4.8) overall, 11.8% (7.9) for men, and 8.5% (5.8) for women. The ORs for 10-year age increments were much the same across sites and for women and men. The overall pooled estimate was 1.94 (95% CI 1.80-2.10) per 10-year increment. Site-specific pack-year ORs varied significantly in women (pooled OR=1.28, 95% CI 1.15-1.42, p=0.012), but not in men (1.16, 1.12-1.21, p=0.743). This worldwide study showed higher levels and more advanced staging of spirometrically confirmed COPD than have typically been reported. However, although age and smoking are strong contributors to COPD, they do not fully explain variations in disease prevalence-other factors also seem to be important. Although smoking cessation is becoming an increasingly urgent objective for an ageing worldwide population, a better understanding of other factors that contribute to COPD is crucial to assist local public-health officials in developing the best possible primary and secondary prevention policies for their regions.


The role of autoantibodies in the pathogenesis of lupus nephritis.
Despite intensive research over the past three decades, the events leading to pathogenic autoantibody production and immune deposit formation in individuals with systemic lupus erythematosus continues to be debated. The controversy is fueled by the clinical observations that individual patients with lupus have variable expression of disease, and that it is often difficult to completely distinguish the events involved in the initiation of nephritis from the processes leading to progressive disease and organ failure. This review focuses on the mechanisms of immune deposition in individuals with lupus nephritis. Recent evidence derived from both analysis of spontaneously occurring animal models of lupus nephritis and human lupus nephritis suggests that direct binding of autoantibodies to glomerular antigens is an important mechanism in lupus and other immune complex nephritides. In situ deposition of circulating autoantigens and autoantibodies also may play a role. These findings, taken together with observations from analysis of other autoimmune diseases, suggest that autoantigen ligation by autoantibodies may contribute to the inflammatory/fibrogenic response through either direct stimulation of cells or interruption of cell-cell or cell matrix interactions. The nature of these type of interactions in individual patients therefore may have disease-modulating effects. For example, the predominant autoantibody response likely influences the glomerular response to immune deposition and the ensuing inflammation. The evidence for, and implications of, this hypothesis are discussed.


Amiloride kills malignant glioma cells independent of its inhibition of the sodium-hydrogen exchanger.
Previously, we demonstrated that malignant glioma cell lines have increased intracellular pH (pHi) as a result of increased activities of the type I sodium/hydrogen exchanger (NHE1). This alkalotic pHi of 7.2 to 7.4 is favorable for augmented glycolysis, DNA synthesis, and cell cycle progression. Conversely, reductions in pHi have been associated with reduced rates of proliferation in transformed cell types. The effects of reducing pHi directly and by NHE1 inhibition on human malignant glioma cells were systematically compared with those on primary rat astrocytes. Neither cariporide, nor direct acidification to pHi 6.9 altered the proliferative rates or viabilities of human U87 or U118 malignant glioma cell lines. However, amiloride significantly impaired glioma cell proliferation and viability while not affecting astrocytes at concentrations (500 microM) that exceeded its inhibition of NHE1 in glioma cells (IC50 = 17 microM). Preventing a reduction of pHi did not alter the drug's antiproliferative and cytotoxic effects on glioma cells. These findings indicated that amiloride's cytotoxic effects on glioma cells are independent of its ability to inhibit NHE1 or to reduce intracellular pHi. The amiloride derivative 2,4 dichlorobenzamil (DCB) inhibits the sodium-calcium exchanger (NCX) and was both antiproliferative and cytotoxic to glioma cells at low doses (20 microM). By contrast, KB-R7943 [(2-[2-[4-nitrobenzyloxy]phenyl]ethyl)-isothioureamethanesulfonate] preferentially blocks sodium-dependent calcium influx by NCX (reverse mode) and was nontoxic to glioma cells. It is proposed that DCB (20 microM) and amiloride (500 microM) impair calcium efflux by NCX, leading to elevations of intracellular calcium that initiate a morphologically necrotic, predominantly caspase-independent glioma cell death.


A minimal stress model for the assessment of electroacupuncture analgesia in rats under halothane.
The use of anesthetics in acupuncture analgesia is controversial. We evaluate a steady-state light anesthesia model to test whether minimal stress manipulation and reliable measurement of analgesia could be simultaneously achieved during electroacupuncture (EA) in animals. A series of experiments were performed. Firstly, EA compliance and tail-flick latencies (TFL) were compared in rats under 0.1%, 0.3%, 0.5%, 0.7%, or 1.1% halothane for 120min. Under 0.5% halothane, TFL were then measured in groups receiving EA at intensity of 3, 10 or 20 volt (V), 1 or 2mg/kg morphine, 20V EA plus naloxone, or control. Subsequently, the effect of EA on formalin-induced hyperalgesia was tested and c-fos expression in the spinal dorsal horn was analyzed. Rats exhibited profound irritable behaviors and highly variable TFL under 0.1% or 0.3% halothane, as well as a time-dependent increase of TFL under 0.7% or 1.1% halothane. TFL remained constant at 0.5% halothane, and needle insertion and electrical stimulation were well tolerated. Under 0.5% halothane, EA increased TFL and suppressed formalin-induced hyperalgesia in an intensity-dependent and naloxone-reversible manner. EA of 20V prolonged TFL by 74%, suppressed formalin-induced hyperalgesia by 32.6% and decreased c-fos expression by 29.7% at the superficial and deep dorsal horn with statistically significant difference. In conclusion, 0.5% halothane provides a steady-state anesthetic level which enables the humane application of EA stimulus with the least interference on analgesic assessment. This condition serves as a minimal stress EA model in animals devoid of stress-induced analgesia while maintaining physiological and biochemical response in the experiment.


Continuous Sign Language Recognition through a Context-Aware Generative Adversarial Network.
Continuous sign language recognition is a weakly supervised task dealing with the identification of continuous sign gestures from video sequences, without any prior knowledge about the temporal boundaries between consecutive signs. Most of the existing methods focus mainly on the extraction of spatio-temporal visual features without exploiting text or contextual information to further improve the recognition accuracy. Moreover, the ability of deep generative models to effectively model data distribution has not been investigated yet in the field of sign language recognition. To this end, a novel approach for context-aware continuous sign language recognition using a generative adversarial network architecture, named as Sign Language Recognition Generative Adversarial Network (SLRGAN), is introduced. The proposed network architecture consists of a generator that recognizes sign language glosses by extracting spatial and temporal features from video sequences, as well as a discriminator that evaluates the quality of the generator's predictions by modeling text information at the sentence and gloss levels. The paper also investigates the importance of contextual information on sign language conversations for both Deaf-to-Deaf and Deaf-to-hearing communication. Contextual information, in the form of hidden states extracted from the previous sentence, is fed into the bidirectional long short-term memory module of the generator to improve the recognition accuracy of the network. At the final stage, sign language translation is performed by a transformer network, which converts sign language glosses to natural language text. Our proposed method achieved word error rates of 23.4%, 2.1% and 2.26% on the RWTH-Phoenix-Weather-2014 and the Chinese Sign Language (CSL) and Greek Sign Language (GSL) Signer Independent (SI) datasets, respectively.


'Born before arrival': user and provider perspectives on health facility childbirths in Kapiri Mposhi district, Zambia.
Maternal mortality remains high in sub-Saharan Africa. Health facility intra-partum strategies with skilled birth attendance have been shown to be most effective to address maternal mortality. In Zambia, the health policy for pregnant women is to have facility childbirth, but less than half of the women utilize the facilities for delivery. 'Born before arrival' (BBA) describes childbirth that occurs outside health facility. With the aim to increase our understanding of trust in facility birth care we explored how users and providers perceived the low utilization of health facilities during childbirth. A qualitative study was conducted in Kapiri Mposhi, Zambia. Focus group discussions with antenatal clinic and outpatient department attendees were conducted in 2008 as part of the Response to Accountable priority setting and Trust in health systems project, (REACT). In-depth interviews conducted with women who delivered at home, their husbands, community leaders, traditional birth attendants, and midwives were added in 2011. Information was collected on perceptions and experiences of home and health facility childbirth, and reasons for not utilizing a facility at delivery. Data were analysed by inductive content analysis. Perspectives of users and providers were grouped under themes that included experiences related to promotion of facility childbirth, responsiveness of health care providers, and giving birth at home. Trust and quality of care were important when individuals seek facility childbirth. Safety, privacy and confidentiality encouraged facility childbirth. Poor attitudes of health providers, long distances and lack of transport to facilities, costs to buy delivery kits, and cultural ideals that local herbs speed up labour and women should exhibit endurance at childbirth discouraged facility childbirth. Trust and perceived quality of care were important and influenced health care seeking at childbirth. Interventions that include both the demand and supply sides of services with prioritizing needs of the community could substantially improve trust and utilization of facilities at childbirth, and accelerate efforts to achieve MDG5.


The neural correlates of emotion regulation by implementation intentions.
Several studies have investigated the neural basis of effortful emotion regulation (ER) but the neural basis of automatic ER has been less comprehensively explored. The present study investigated the neural basis of automatic ER supported by 'implementation intentions'. 40 healthy participants underwent fMRI while viewing emotion-eliciting images and used either a previously-taught effortful ER strategy, in the form of a goal intention (e.g., try to take a detached perspective), or a more automatic ER strategy, in the form of an implementation intention (e.g., "If I see something disgusting, then I will think these are just pixels on the screen!"), to regulate their emotional response. Whereas goal intention ER strategies were associated with activation of brain areas previously reported to be involved in effortful ER (including dorsolateral prefrontal cortex), ER strategies based on an implementation intention strategy were associated with activation of right inferior frontal gyrus and ventro-parietal cortex, which may reflect the attentional control processes automatically captured by the cue for action contained within the implementation intention. Goal intentions were also associated with less effective modulation of left amygdala, supporting the increased efficacy of ER under implementation intention instructions, which showed coupling of orbitofrontal cortex and amygdala. The findings support previous behavioural studies in suggesting that forming an implementation intention enables people to enact goal-directed responses with less effort and more efficiency.


Single-molecule Force Spectroscopy Reveals the Calcium Dependence of the Alternative Conformations in the Native State of a βγ-Crystallin Protein.
Although multidomain proteins predominate the proteome of all organisms and are expected to display complex folding behaviors and significantly greater structural dynamics as compared with single-domain proteins, their conformational heterogeneity and its impact on their interaction with ligands are poorly understood due to a lack of experimental techniques. The multidomain calcium-binding βγ-crystallin proteins are particularly important because their deterioration and misfolding/aggregation are associated with melanoma tumors and cataracts. Here we investigate the mechanical stability and conformational dynamics of a model calcium-binding βγ-crystallin protein, Protein S, and elaborate on its interactions with calcium. We ask whether domain interactions and calcium binding affect Protein S folding and potential structural heterogeneity. Our results from single-molecule force spectroscopy show that the N-terminal (but not the C-terminal) domain is in equilibrium with an alternative conformation in the absence of Ca(2+), which is mechanically stable in contrast to other proteins that were observed to sample a molten globule under similar conditions. Mutagenesis experiments and computer simulations reveal that the alternative conformation of the N-terminal domain is caused by structural instability produced by the high charge density of a calcium binding site. We find that this alternative conformation in the N-terminal domain is diminished in the presence of calcium and can also be partially eliminated with a hitherto unrecognized compensatory mechanism that uses the interaction of the C-terminal domain to neutralize the electronegative site. We find that up to 1% of all identified multidomain calcium-binding proteins contain a similarly highly charged site and therefore may exploit a similar compensatory mechanism to prevent structural instability in the absence of ligand.


Current concepts and systematic review of vascularized composite allotransplantation of the abdominal wall.
Abdominal wall vascularized composite allotransplantation (AW-VCA) is a rarely utilized technique for large composite abdominal wall defects. The goal of this article is to systematically review the literature and current concepts of AW-VCA, outline the challenges ahead, and provide an outlook for the future. Systematic review of the literature was performed using MEDLINE, EMBASE, and PubMed to identify relevant articles discussing results of AW-VCA. Cadaver and animal studies were excluded from the systematic review, but selectively included in the discussion. The resultant five papers report their results on AW-VCA(Transplantation, 85, 2008, 1607; Am J Transplant, 7, 2007, 1304; Transplant Proc, 41, 2009, 521; Transplant Proc, 36, 2004, 1561; Lancet, 361, 2003, 2173). These papers represent the result of two study groups in which a total of 18 AW-VCA were performed in 17 patients. Two different operative approaches were used. Overall flap/graft survival was 88%. No mortality related to the transplant was reported. One cadaver study and two animal models were identified and separately presented (Transplant Proc, 43, 2011, 1701; Transplantation, 90, 2010, 1590; Journal of Surgical Research, 162, 2010, 314). Literature review reports AW-VCA is technically feasible with low morbidity and mortality. Functional outcomes are not reported and minimally considered. With advancements in vascularized composite allotransplantation research and decreasing toxicity of immunosuppression therapies and immunomodulatory regimens, AW-VCA can be applied in circumstances beyond conjunction with visceral transplantation.


Therapy-Related Acute Myeloid Leukemia Following TCHP Chemotherapy in Two HER2+ Breast Cancer Patients.
Increased risk for the development of therapy-induced myeloid leukemia following the treatment of breast cancer has typically been associated with the use of regimens containing anthracyclines or alkylating agents. We present two cases of estrogen receptor-positive/progesterone receptor-positive/human epidermal growth factor receptor 2-positive (ER+/PR+/HER2+) breast cancer patients, treated with a non-anthracycline, non-alkylating regimen of trastuzumab, carboplatin, docetaxel, and pertuzumab (TCHP), who developed therapy-related acute myeloid leukemia (t-AML) within 30 months of the completion of treatment. Both patients had marked cytogenetic abnormalities, including deletions of chromosomes 5 and 7, and highly aggressive disease that resulted in a poor prognosis. While platinum and taxane-based chemotherapy regimens have been previously linked to the development of t-AML or therapy-related myelodysplastic syndrome (t-MDS) following treatment for ovarian cancer, they have not yet been shown to increase the risk of t-AML/t-MDS after their use for breast cancer therapy. As TCHP is widely used for the treatment of HER2/neu overexpressed breast cancer, these cases highlight the need to further evaluate the link between taxane and platinum-based chemotherapeutics for breast cancer and the development of t-AML/t-MDS.


Terahertz quantitatively distinguishing gasoline mixtures using multiparameter-combined analysis.
Refined oil mixtures can be quantified using terahertz-absorption-coefficient spectra and dualistic linear regression fitting. However, when this method was used to quantify mixtures of 90# and 97# gasolines, the absolute error between the real and fitted value was large (25%), and this was due to the component similarity between 90# and 97# gasolines. To solve this problem, the present research addresses the possibility of developing a method that would allow direct, simple, and accurate determination of the 97# gasoline content in gasoline mixtures using a terahertz time-domain pulse coupled to a multiparameter-combined analysis. The multiparameter represents the time delay and amplitude of the first transmission dip and peak in the time-domain pulse. The relationship between these four parameters and the 97# gasoline content in gasoline mixtures was thoroughly investigated, and four distinct calibration models for quantifying gasoline mixtures were built using least square fitting. To enable the development of an informative and accurate calibration model, the four individual models were given proper weights and combined. The weight was determined by the cosine-optimal method, which aimed to determine the most proper weight under the condition of the cosine of the angle between the fitted content vector and the real content vector that reaches the maximum. This method allows the determination of 97# gasoline content in gasoline mixtures with a low absolute error (6%), resulting in predictions that are more accurate and precise than those obtained by the terahertz-absorption-coefficient spectra and dualistic linear regression fitting.


Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages.
Macrophages participate in inflammatory and repair processes in part through the selective release of cytokines that contribute to tissue remodeling. Extracellular matrix components generated at inflammatory sites may influence tissue remodeling by effects on leukocyte adherence and local cytokine production. In murine bone marrow-derived macrophages, we found that soluble hyaluronic acid stimulated IL-1 beta, TNF alpha, and insulin-like growth factor-1 (IGF-1) mRNA transcript expression as well as IGF-1 protein synthesis. Monoclonal antibodies to the hyaluronic acid receptor CD44 blocked the effects of hyaluronic acid on IL-1 beta, TNF alpha, and IGF-1 expression. TNF alpha and IL-1 beta mRNA expression preceded IGF-1 protein synthesis, and TNF alpha, but not IL-1 beta, was found to directly stimulate IGF-1. Furthermore, IGF-1 induction was dependent on endogenous TNF alpha production since IGF-1 protein synthesis was inhibited in the presence of anti-TNF alpha antiserum. In addition, IL-1 beta was found to exert a regulatory role on IGF-1 production by enhancing the TNF alpha effect. IL-1 beta and TNF alpha mRNA transcript expression as well as IGF-1 protein synthesis were also stimulated by chrysotile asbestos. Anti-CD44 antibodies had no effect whereas anti-TNF alpha antiserum blocked asbestos-stimulated IGF-1 production. These results indicate that hyaluronate activation of CD44 induces cytokine expression and macrophage-derived IGF-1 production is dependent on TNF alpha expression.


Spectral optimized asymmetric segmented phase-only correlation filter.
We suggest a new type of optimized composite filter, i.e., the asymmetric segmented phase-only filter (ASPOF), for improving the effectiveness of a VanderLugt correlator (VLC) when used for face identification. Basically, it consists in merging several reference images after application of a specific spectral optimization method. After segmentation of the spectral filter plane to several areas, each area is assigned to a single winner reference according to a new optimized criterion. The point of the paper is to show that this method offers a significant performance improvement on standard composite filters for face identification. We first briefly revisit composite filters [adapted, phase-only, inverse, compromise optimal, segmented, minimum average correlation energy, optimal trade-off maximum average correlation, and amplitude-modulated phase-only (AMPOF)], which are tools of choice for face recognition based on correlation techniques, and compare their performances with those of the ASPOF. We illustrate some of the drawbacks of current filters for several binary and grayscale image identifications. Next, we describe the optimization steps and introduce the ASPOF that can overcome these technical issues to improve the quality and the reliability of the correlation-based decision. We derive performance measures, i.e., PCE values and receiver operating characteristic curves, to confirm consistency of the results. We numerically find that this filter increases the recognition rate and decreases the false alarm rate. The results show that the discrimination of the ASPOF is comparable to that of the AMPOF, but the ASPOF is more robust than the trade-off maximum average correlation height against rotation and various types of noise sources. Our method has several features that make it amenable to experimental implementation using a VLC.


The Pathogenic Role of Low Range Repeats in SCA17.
SCA17 is an autosomal dominant cerebellar ataxia with expansion of the CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene. SCA17 can have various clinical presentations including parkinsonism, ataxia, chorea and dystonia. SCA17 is diagnosed by detecting the expanded CAG repeats in the TBP gene; however, in the literature, pathologic repeat numbers as low as 41 overlap with normal repeat numbers. The subjects in this study included patients with involuntary movement disorders such as cerebellar ataxia, parkinsonism, chorea and dystonia who visited Seoul National University Hospital between Jan. 2006 and Apr. 2014 and were screened for SCA17. Those who were diagnosed with other genetic diseases or nondegenerative diseases were excluded. DNA from healthy subjects who did not have a family history of parkinsonism, ataxia, psychiatric symptoms, chorea or dystonia served as the control. In total, 5242 chromosomes from 2099 patients and 522 normal controls were analyzed. The total number of patients included in the analysis was 2099 (parkinsonism, 1706; ataxia, 345; chorea, 37; and dystonia, 11). In the normal control, up to 44 repeats were found. In the 44 repeat group, there were 7 (0.3%) patients and 1 (0.2%) normal control. In 43 repeat group, there were 8 (0.4%) patients and 2 (0.4%) normal controls. In the 42 repeat group, there were 16 (0.8%) patients and 3 (0.6%) normal controls. In 41 repeat group, there were 48 (2.3%) patients and 8 (1.5%) normal controls. Considering the overlaps and non-significant differences in allelic frequencies between the patients and the normal controls with low-expansions, we could not determine a definitive cutoff value for the pathologic CAG repeat number of SCA17. Because the statistical analysis between the normal controls and patients with low range expansions failed to show any differences so far, we must consider that clinical cases with low range expansions could be idiopathic movement disorders showing coincidental CAG/CAA expansions. Thus, we need to reconsider the pathologic role of low range expansions (41-42). Long term follow up and comprehensive investigations using autopsy and imaging studies in patients and controls with low range expansions are necessary to determine the cutoff value for the pathologic CAG repeat number of SCA17.


Managing uncertainty around HIV/AIDS in an urban setting: private medical providers and their patients in Pune, India.
Changing epidemiological patterns and the advent of new rapid diagnostic technologies and therapies have created considerable uncertainty for providers working in HIV. In India, the demand for HIV care is increasingly being met by private practitioners (PPs), yet little is known about how they deal with the challenges of managing HIV patients. To explore HIV management practices in the private medical sector, a survey was conducted with 215PPs in Pune, India, followed by in-depth interviews focusing on the social context of practice among a sub-set of 27PPs. Drawing primarily on interview data, this paper illustrates a number of uncertainties that underlie the reported actions of providers in a competitive medical market. PPs perceive HIV as a 'new' and challenging disease for which they lack adequate knowledge and skills. Combined with the perceived high cost and complexity of antiretroviral treatment, preconceptions about HIV patients' social, financial and mental capacity lead to highly individualistic management practices. While these fall short of clinical 'best practice' guidelines, they reflect adaptive responses to the wider uncertainties surrounding HIV care in urban India. By highlighting contextual issues in PPs' management of HIV patients, the paper suggests the need to explicitly acknowledge the social, moral and economic bases of uncertainty beyond the clinical setting.


Great ape Y Chromosome and mitochondrial DNA phylogenies reflect subspecies structure and patterns of mating and dispersal.
The distribution of genetic diversity in great ape species is likely to have been affected by patterns of dispersal and mating. This has previously been investigated by sequencing autosomal and mitochondrial DNA (mtDNA), but large-scale sequence analysis of the male-specific region of the Y Chromosome (MSY) has not yet been undertaken. Here, we use the human MSY reference sequence as a basis for sequence capture and read mapping in 19 great ape males, combining the data with sequences extracted from the published whole genomes of 24 additional males to yield a total sample of 19 chimpanzees, four bonobos, 14 gorillas, and six orangutans, in which interpretable MSY sequence ranges from 2.61 to 3.80 Mb. This analysis reveals thousands of novel MSY variants and defines unbiased phylogenies. We compare these with mtDNA-based trees in the same individuals, estimating time-to-most-recent common ancestor (TMRCA) for key nodes in both cases. The two loci show high topological concordance and are consistent with accepted (sub)species definitions, but time depths differ enormously between loci and (sub)species, likely reflecting different dispersal and mating patterns. Gorillas and chimpanzees/bonobos present generally low and high MSY diversity, respectively, reflecting polygyny versus multimale-multifemale mating. However, particularly marked differences exist among chimpanzee subspecies: The western chimpanzee MSY phylogeny has a TMRCA of only 13.2 (10.8-15.8) thousand years, but that for central chimpanzees exceeds 1 million years. Cross-species comparison within a single MSY phylogeny emphasizes the low human diversity, and reveals species-specific branch length variation that may reflect differences in long-term generation times.


Ceramic membrane fouling during ultrafiltration of oil/water emulsions: roles played by stabilization surfactants of oil droplets.
Oil/water (O/W) emulsion stabilized by surfactants is the part of oily wastewater that is most difficult to handle. Ceramic membrane ultrafiltration presently is an ideal process to treat O/W emulsions. However, little is known about the fouling mechanism of the ceramic membrane during O/W emulsion treatment. This paper investigated how stabilization surfactants of O/W emulsions influence the irreversible fouling of ceramic membranes during ultrafiltration. An unexpected phenomenon observed was that irreversible fouling was much less when the charge of the stabilization surfactant of O/W emulsions is opposite to the membrane. The less ceramic membrane fouling in this case was proposed to be due to a synergetic steric effect and demulsification effect which prevented the penetration of oil droplets into membrane pores and led to less pore blockage. This proposed mechanism was supported by cross section images of fouled and virgin ceramic membranes taken with scanning electron microscopy, regression results of classical fouling models, and analysis of organic components rejected by the membrane. Furthermore, this mechanism was also verified by the existence of a steric effect and demulsification effect. Our finding suggests that ceramic membrane oppositely charged to the stabilization surfactant should be applied in ultrafiltration of O/W emulsions to alleviate irreversible membrane fouling. It could be a useful rule for ceramic membrane ultrafiltration of oily wastewater.


Abscess volume and ultrasound characteristics of community-associated methicillin-resistant Staphylococcus aureus infection.
Skin abscesses may vary in volume and inflammation based on organism, although this has not been evaluated using emergency ultrasonography (EUS). The objective of this study was to examine the utility of EUS in discerning skin abscess volume and inflammation by infecting organism. This was a secondary analysis of prospectively enrolled subjects 2 months to 19 years presenting for a skin abscess. Subjects with a prior drainage procedure, multiple lesions, incomplete EUS measurements, or lack of an abscess culture were excluded. Abscess cavity dimensions in the x, y, and z planes and signs of local inflammation (cobblestoning, hyperechoic, or thickened dermis) were determined. Abscess volume was calculated using the ellipsoid formula: 4/3 π · (rx) · (ry) · (rz). One hundred eighty-eight subjects met the inclusion criteria. Mean age was 7.7 ± 6.2 years; 39.9% were male. The gluteal region was most commonly involved (33.0%), and lesions were present for a mean 4.2 days (95% confidence interval [CI], 3.8-4.6 days). Methicillin-resistant Staphylococcus aureus (MRSA) was isolated from 125 (66.5%); methicillin-sensitive S. aureus (21.8%) was most common among non-MRSA lesions. Abscess volume was smaller in MRSA (1.12 cm3) compared with non-MRSA (2.46 cm3) lesions (mean difference, -1.33 cm; 95% CI, -2.21 to -0.47 cm3). No differences between MRSA and non-MRSA lesions were present for EUS signs of inflammation. When adjusting for age, duration of lesion, and spontaneous drainage, smaller abscess volumes were associated with MRSA infection (odds ratio, 0.83; 95% CI, 0.71-0.97). Using an optimal threshold value of 1.32 cm3, sensitivity and specificity for non-MRSA lesion were 50.8% and 81.5%, respectively. Methicillin-resistant S. aureus infection is statistically negatively associated with abscess volume, although of limited predictive ability. Findings using EUS suggest that MRSA does not differ from other organisms with respect to size and inflammation. Clinicians should not consider unique treatment for the presence of MRSA abscess based on these EUS findings.


Ontogeny of arterial macrophages defines their functions in homeostasis and inflammation.
Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease.


Steroidal isomers with uniform mass spectra of their per-TMS derivatives: synthesis of 17-hydroxyandrostan-3-ones, androst-1-, and -4-ene-3,17-diols.
In human sports doping control analysis most of the steroids are analyzed after enzymatic hydrolysis of the glucuronides as per-trimethylsilyl (TMS) derivatives applying gas chromatography-mass spectrometry (GC-MS). According to the recommendations of the World Anti-Doping Agency the identification of analytes should be based on retention time and on mass spectrometric characterization. This study shows that the bis-TMS derivatives of 16 specific C19 steroids, namely the stereoisomers of 5xi-androst-1-ene-3xi,17xi-diol (8 isomers), androst-4-ene-3xi,17xi-diol (4 isomers), and 17xi-hydroxy-5xi-androstan-3-one (4 isomers), reveal very similar mass spectra. As a rule, when taking the retention times, which are provided as Kovac indices for all these isomers, into account, a restriction to two or three possible isomers is possible. Reliable identification should additionally include a comparison of the retention times of the analytes with the reference compounds measured concomitantly. In some cases standard addition may be appropriate. Due to the limited availability, the above mentioned isomers were synthesized by reduction of the corresponding alpha,beta-unsaturated oxo steroids either with K-Selectride or by catalytic hydrogenation (Pd/C as catalyst). The products of the reactions were identified by means of nuclear magnetic resonance (NMR) characterization and by further reduction to the corresponding 5xi-androstane-3xi,17xi-diols and GC-MS comparison with commercially available reference standards.


Idiopathic non-traumatic spontaneous renal hemorrhage/laceration: a case report and review of the literature.
The majority of patients presenting with renal and/or peri-renal hemorrhage are diagnosed with an underlying etiology. Non-traumatic spontaneous idiopathic renal hemorrhage is an infrequently reported entity. Management of these patients is critical; diagnosis is established only once any surgically correctable etiology is excluded. A 57 year old Caucasian female with no significant past medical history presented to an outside emergency department with a one day history of right lower back pain and fatigue. An abdominal and pelvic computed tomography (CT) at the time revealed a grade IV right renal laceration. We present this unusual case of a previously healthy woman with a low probability for a spontaneous idiopathic non traumatic grade IV renal laceration with perirenal hemorrhage. Though most renal and perirenal hemorrhages are associated with an underlying etiology, in rare circumstances idiopathic non traumatic spontaneous renal laceration manifests with insignificant symptomatology. It is critical for clinicians in the Emergency Department to be aware of this entity to avoid diagnostic error. Prior to categorizing an injury as idiopathic, appropriate evaluation to rule out rare etiologic basis is crucial.


Resolving transient time profile in ToF imaging via log-sum sparse regularization.
Multi-frequency time-of-flight (ToF) cameras have been used to recover the transient time profiles of optical responses such that multipath interference can be separated. The resolution of the recovered time profiles is limited by the highest modulation frequency. Here, we demonstrate a method based on log-sum sparsity regularization to recover transient time profiles of specular reflections. We show that it improves the ability of separating pulses better than the state-of-the-art regularization methods. As an application, we demonstrate the encoding and decoding of hidden images using mirror reflections.


Nuciferine, extracted from Nelumbo nucifera Gaertn, inhibits tumor-promoting effect of nicotine involving Wnt/β-catenin signaling in non-small cell lung cancer.
The leaves of Nelumbo nucifera Gaertn are recorded in the earliest written documentation of traditional Chinese medicinal as "Ben Cao Gang Mu", a medicinal herb for blood clotting, dysentery and dizziness. Recently, nuciferine (NF), one of N. nucifera Gaertn leaf extracts has been shown to possess several pharmacological properties, including anti-viral and anti-cancer. The aim of this study is to investigate the underlying molecular mechanism of the anti-cancer activity of NF in NSCLC progression induced by nicotine The effect of NF on proliferation of A549 (human lung adenocarcinoma epithelial cell line) pretreated with or without nicotine was detected by tumor cell proliferation assay. TOP-Flash reporter assay was applied to investigate the activity of Wnt/β-catenin signaling in tumor cells in the presence of NF and/or nicotine. Apoptosis was measured using a FITC-Annexin V and PI detection kit by flow cytometry. In addition, mRNA or protein expression levels were respectively tested by quantitative RT-PCR or western blot. In vivo experiments, tumor samples were fixed in formalin and embedded in paraffin for additional analyses by immunohistochemistry and TUNEL staining. NF significantly inhibited the proliferation of NSCLC cells in the presence of nicotine, suppressed the activity of Wnt/β-catenin signaling, enhanced the stabilization of Axin, and induced apoptosis. NF down-regulated the expression levels of β-catenin and its downstream targets including c-myc, cyclin D and VEGF-A. NF also decreased the ratio of Bcl-2/Bax, which may explain the pro-apoptosis effect of NF. In tumor xenograft nude mice, NF not only inhibited the growth of non-small cell lung cancer (NSCLC) cells, but also remarkably alleviated the injury induced by nicotine in liver function. NF has the remarkable effect to inhibit nicotine-induced NSCLC progression, which was due to its ability to reduce the activity of Wnt/β-catenin signaling. Thus, the work stated here emphasizes the importance of this traditional medicine and presents a potential novel alternative to NSCLC prevention and therapy.


The role of lysosomal enzymes in killing of mammalian cells by the lysosomotropic detergent N-dodecylimidazole.
The sensitivity of cultured human and hamster fibroblast cells to killing by the lysosomotropic detergent N-dodecylimidazole (C12-Im) was investigated as a function of cellular levels of general lysosomal hydrolase activity, and specifically of cysteine cathepsin activity. Fibroblasts from patients with mucolipidosis II (I-cell disease) lack mannose-6-phosphate-containing proteins, and therefore possess only 10-15% of the normal level of most lysosomal hydrolases. I-cell fibroblasts are about one-half as sensitive to killing by C12-Im as are normal human fibroblasts. Overall lysosomal enzyme levels of CHO cells were experimentally manipulated in several ways without affecting cell viability: Growth in the presence of 10 mM ammonium chloride resulted in a gradual decrease in lysosomal enzyme content to 10-20% of control values within 3 d. Subsequent removal of ammonium chloride from the growth medium resulted in an increase in lysosomal enzymes, to approximately 125% of control values within 24 h. Treatment with 80 mM sucrose caused extensive vacuolization within 2 h; lysosomal enzyme levels remained at control levels for at least 6 h, but increased 15-fold after 24 h of treatment. Treatment with concanavalin A (50 micrograms/ml) also caused rapid (within 2 h) vacuolation with a sevenfold rise in lysosomal enzyme levels occurring only after 24 h. The sensitivity of these experimentally manipulated cells to killing by C12-Im always paralleled the measured intracellular lysosomal enzyme levels: lower levels were associated with decreased sensitivity while higher levels were associated with increased sensitivity, regardless of the degree of vacuolization of the cells. The cytotoxicity of the cysteine proteases (chiefly cathepsin L in our cells) was tested by inactivating them with the irreversible inhibitor E-64 (100 micrograms/ml). Cell viability, protein levels, and other lysosomal enzymes were unaffected, but cysteine cathepsin activity was reduced to less than 20% of control values. E-64-treated cells were almost completely resistant to C12-Im treatment, although lysosomal disruption appeared normal by fluorescent visualization of Lucifer Yellow CH-loaded cells. It is concluded that cysteine cathepsins are the major or sole cytotoxic agents released from lysosomes by C12-Im. These observations also confirm the previous conclusions that C12-Im kills cells as a consequence of lysosomal disruption.


Real-world variability in dabigatran levels in patients with atrial fibrillation.
In clinical practice, physicians are given the choice of selecting one of two dabigatran doses based on patient characteristics, with the lower dose typically used in patients at a higher risk of bleeding. The objectives of the study were to (i) estimate the inter- and intra-patient variability in dabigatran levels with 110 mg (DE110) and 150 mg (DE150) doses, (ii) examine the effect of physicians' dose selection on levels in DE110 and DE150 subgroups, and (iii) explore whether a single trough measurement identifies patients with extreme levels on subsequent visits. In this prospective observational study of 100 patients with atrial fibrillation (AF), peak and trough levels of dabigatran were measured with the Hemoclot(®) assay at baseline and every 2 months thereafter (maximum four visits). Inter-patient variability in dabigatran levels (geometric coefficient of variation [gCV], 51-64%) was greater than intra-patient variability (gCV, 32-40%). Similar medians and distributions of levels were observed in DE110 and DE150 subgroups. Patients receiving DE110 were older, had lower renal function and weighed less than those receiving DE150. Up to 40% of patients whose trough levels were in the upper extremes, and up to 80% of patients whose trough levels were in the lower extremes at baseline, showed subsequent levels that fell in the middle quartiles. Our data support the practice of selecting the dabigatran dose based upon clinical characteristics because it results in similar levels of drug exposure in patients given DE110 or DE150. They do not support the concept that a single Hemoclot(®) measurement reliably identifies patients with consistently high or low values.


Management of anaphylaxis in an austere or operational environment.
We present a case report of a Special Operations Soldier who developed anaphylaxis as a consequence of a bee sting, resulting in compromise of the operation. We review the current literature as it relates to the pathophysiology of the disease process, its diagnosis, and its management. An evidence-based field treatment algorithm is suggested.


Occupational Therapy Interventions to Improve Activities of Daily Living for Community-Dwelling Older Adults: A Systematic Review.
This systematic review aimed to synthesize the effects of interventions within the scope of occupational therapy to improve performance of activities of daily living (ADLs) in community-dwelling older adults. Searches were conducted in CINAHL, the Cochrane Database of Systematic Reviews, MEDLINE, PsycINFO, and OTseeker. Empirical studies published between 1995 and 2015 were individually screened and appraised by two reviewers. Forty-three studies met the review inclusion and exclusion criteria. Physical exercise was the most common intervention approach. Physical exercise interventions for frail older adults showed a moderate benefit, but no benefits were found for older adults without noticeable difficulty in ADLs. For older adults with difficulty in ADLs, there was a high benefit of using home-based intervention. The findings of this systematic review highlight the importance of addressing older adults' living environment in intervention to promote independence in ADLs.


Assessment of the allosteric interactions of the bisquaternary heptane-1,7-bis(dimethyl-3'-phthalimidopropyl)ammonium bromide at M1 and M2 muscarine receptors.
The interaction of the allosteric muscarine receptor antagonist heptane-1,7-bis(dimethyl-3'-phthalimidopropyl)ammonium bromide (C7/3-phth) with M1 muscarine receptors in rat cerebral cortex and rabbit vas deferens and M2 muscarine receptors in guinea pig atria was investigated. In atria, C7/3-phth completely inhibited the dissociation of N-[3H]methylscopolamine ([3H]NMS) in the presence of excess unlabeled NMS and slowed the washout of NMS in functional experiments. C7/3-phth also produced supra-additive inhibition of the negative inotropic effects of carbachol when combined with NMS. This latter phenomenon was less pronounced when pirenzepine (PZP) was used in place of NMS. Cooperativity factors for the interaction of C7/3-phth with other antagonists were obtained by fitting the data to a theoretical model for interaction between an agonist, a competitive antagonist, and an allosteric antagonist. The values obtained indicate that C7/3-phth exhibits a greater degree of negative heterotropic cooperativity with PZP than with NMS at the M2 muscarine receptor. In the rat cerebral cortex, C7/3-phth slowed the dissociation of [3H]NMS and [3H]quinuclidinyl benzilate from the M1 receptor to the same extent but appeared not to affect the dissociation of [3H]PZP. In rabbit vas deferens, the inhibitory effect of the combination of C7/3-phth and atropine on the responses to McN-A-343 at the M1 receptor was more pronounced than that of the combination of C7/3-phth and PZP. Comparison of the findings for both central and peripheral M1 receptors with those obtained for the cardiac M2 receptor suggests that the allosteric interaction of C7/3-phth is less evident at the M1 receptor, particularly in the case of PZP.


Do juvenile developmental and adult body characteristics differ among genotypes at the doublesex locus that controls female-limited Batesian mimicry polymorphism in Papilio memnon?: A test for the "cost of mimicry" hypothesis.
Female-limited Batesian mimicry may have evolved because of stronger predation pressure on females than on males, but some physiological costs of mimicry may also hinder the evolution of mimicry in males. In Papilio memnon, which possesses a female-limited Batesian mimicry polymorphism, two alleles at the doublesex (dsx) locus strictly control female phenotypes. To examine whether there are physiological costs associated with mimetic genotypes in the juvenile stage, we compered mortality, juvenile growth and development, and the resultant adult characteristics among three dsx genotypes (HH, Hh, hh) at a constant temperature (25 °C) and two differing day lengths (LD 14:10 and LD 12:12; the latter might induce pupal diapause) by crossing individuals heterozygous (Hh) for the dsx allele. All pupae emerged directly without diapause irrespective of day length. The genotype frequencies of the emerged individuals were consistent with the expected 1:2:1 ratio of HH:Hh:hh. The sex ratio was significantly male-biased in one of two families, but not in the other. We found no effect of genotype on any developmental or adult characteristic, although there were sex differences in most traits. The larval development time was longer and growth rate higher in females than in males; pupal weight, forewing length, and total dry mass of the thorax and abdomen were greater in females, whereas the thoracic mass/abdominal mass ratio was greater in males. We also found that the growth rate was higher and pupal period longer with a short day than with a long day. Overall, we found no evidence for physiological costs associated with the mimetic genotypes. However, it is too early to conclude that no physiological cost of mimicry affects the evolution and maintenance of this female-limited Batesian mimicry polymorphism because we have not studied the adults of different genotypes.


Using videoconsultations to deliver dietary advice to children with chronic kidney disease: a qualitative study of parent and child perspectives.
Children with chronic kidney disease require specialist renal paediatric dietetic care, regardless of disease severity or geographical location; however, under-resourcing makes this challenging. Videoconsultation may offer a solution but research exploring its acceptability is limited. The present study explored parent/carer and child perspectives of videoconsultation as an alternative or supplement to existing regional dietetic care. Children and families using a regional paediatric nephrology service were recruited through purposeful sampling techniques. Renal paediatric dietitians used existing hospital software to host videoconsultations with families. Perspectives were subsequently explored in telephone interviews with the children, their parents and separately with the renal dietitians. Data were transcribed verbatim and an inductive framework analysis conducted. Twelve families took part in the study, comprising 13 parents and five children (aged 9 months to 14 years). Two renal dietitians were also interviewed. Six themes emerged which were 'Logistics', 'Understanding Information', 'Family Engagement', 'Establishing Trust', 'Willingness to Change' and 'Preferences'. Satisfaction with the videoconsultations was high, with no data security fears and only minor privacy concerns. Parents reported that screen-sharing software enhanced their understanding, generating greater discussion and engagement compared to clinic and telephone contacts. Parents praised efficiencies and improved access to specialist advice, requesting that videoconsultations supplement care. Children preferred videoconsultations outright. Dietetic videoconsultations were acceptable to families and perceived to be a feasible, high-quality complement to regional specialist dietetic care. Enhanced understanding and engagement might improve self-care in adolescents. The acceptability and feasibility of videoconsultations could address inequitable regional service provision.


Adaptation to human populations is revealed by within-host polymorphisms in HIV-1 and hepatitis C virus.
CD8(+) cytotoxic T-lymphocytes (CTLs) perform a critical role in the immune control of viral infections, including those caused by human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). As a result, genetic variation at CTL epitopes is strongly influenced by host-specific selection for either escape from the immune response, or reversion due to the replicative costs of escape mutations in the absence of CTL recognition. Under strong CTL-mediated selection, codon positions within epitopes may immediately "toggle" in response to each host, such that genetic variation in the circulating virus population is shaped by rapid adaptation to immune variation in the host population. However, this hypothesis neglects the substantial genetic variation that accumulates in virus populations within hosts. Here, we evaluate this quantity for a large number of HIV-1- (n > or = 3,000) and HCV-infected patients (n > or = 2,600) by screening bulk RT-PCR sequences for sequencing "mixtures" (i.e., ambiguous nucleotides), which act as site-specific markers of genetic variation within each host. We find that nonsynonymous mixtures are abundant and significantly associated with codon positions under host-specific CTL selection, which should deplete within-host variation by driving the fixation of the favored variant. Using a simple model, we demonstrate that this apparently contradictory outcome can be explained by the transmission of unfavorable variants to new hosts before they are removed by selection, which occurs more frequently when selection and transmission occur on similar time scales. Consequently, the circulating virus population is shaped by the transmission rate and the disparity in selection intensities for escape or reversion as much as it is shaped by the immune diversity of the host population, with potentially serious implications for vaccine design.


Application of the kurtosis statistic to the evaluation of the risk of hearing loss in workers exposed to high-level complex noise.
Develop dose-response relations for two groups of industrial workers exposed to Gaussian or non-Gaussian (complex) types of continuous noises and to investigate what role, if any, the kurtosis statistic can play in the evaluation of industrial noise-induced hearing loss (NIHL). Audiometric and noise exposure data were acquired on a population (N = 195) of screened workers from a textile manufacturing plant and a metal fabrication facility located in Henan province of China. Thirty-two of the subjects were exposed to non-Gaussian (non-G) noise and 163 were exposed to a Gaussian (G) continuous noise. Each subject was given a general physical and an otologic examination. Hearing threshold levels (0.5-8.0 kHz) were age adjusted (ISI-1999) and the prevalence of NIHL at 3, 4, or 6 kHz was determined. The kurtosis metric, which is sensitive to the peak and temporal characteristics of a noise, was introduced into the calculation of the cumulative noise exposure metric. Using the prevalence of hearing loss and the cumulative noise exposure metric, a dose-response relation for the G and non-G noise-exposed groups was constructed. An analysis of the noise environments in the two plants showed that the noise exposures in the textile plant were of a Gaussian type with an Leq(A)8hr that varied from 96 to 105 dB whereas the exposures in the metal fabrication facility with an Leq(A)8hr = 95 dB were of a non-G type containing high levels (up to 125 dB peak SPL) of impact noise. The kurtosis statistic was used to quantify the deviation of the non-G noise environment from the Gaussian. The dose-response relation for the non-G noise-exposed subjects showed a higher prevalence of hearing loss for a comparable cumulative noise exposure than did the G noise-exposed subjects. By introducing the kurtosis variable into the temporal component of the cumulative noise exposure calculation, the two dose-response curves could be made to overlap, essentially yielding an equivalent noise-induced effect for the two study groups. For the same exposure level, the prevalence of NIHL is greater in workers exposed to non-G noise environments than for workers exposed to G noise. The kurtosis metric may be a reasonable candidate for use in modifying exposure level calculations that are used to estimate the risk of NIHL from any type of noise exposure environment. However, studies involving a large number of workers with well-documented exposures are needed before a relation between a metric such as the kurtosis and the risk of hearing loss can be refined.


Mycolactone-mediated neurite degeneration and functional effects in cultured human and rat DRG neurons: Mechanisms underlying hypoalgesia in Buruli ulcer.
Mycolactone is a polyketide toxin secreted by the mycobacterium Mycobacterium ulcerans, responsible for the extensive hypoalgesic skin lesions characteristic of patients with Buruli ulcer. A recent pre-clinical study proposed that mycolactone may produce analgesia via activation of the angiotensin II type 2 receptor (AT2R). In contrast, AT2R antagonist EMA401 has shown analgesic efficacy in animal models and clinical trials for neuropathic pain. We therefore investigated the morphological and functional effects of mycolactone in cultured human and rat dorsal root ganglia (DRG) neurons and the role of AT2R using EMA401. Primary sensory neurons were prepared from avulsed cervical human DRG and rat DRG; 24 h after plating, neurons were incubated for 24 to 96 h with synthetic mycolactone A/B, followed by immunostaining with antibodies to PGP9.5, Gap43, β tubulin, or Mitotracker dye staining. Acute functional effects were examined by measuring capsaicin responses with calcium imaging in DRG neuronal cultures treated with mycolactone. Morphological effects: Mycolactone-treated cultures showed dramatically reduced numbers of surviving neurons and non-neuronal cells, reduced Gap43 and β tubulin expression, degenerating neurites and reduced cell body diameter, compared with controls. Dose-related reduction of neurite length was observed in mycolactone-treated cultures. Mitochondria were distributed throughout the length of neurites and soma of control neurons, but clustered in the neurites and soma of mycolactone-treated neurons. Functional effects: Mycolactone-treated human and rat DRG neurons showed dose-related inhibition of capsaicin responses, which were reversed by calcineurin inhibitor cyclosporine and phosphodiesterase inhibitor 3-isobutyl-1-Methylxanthine, indicating involvement of cAMP/ATP reduction. The morphological and functional effects of mycolactone were not altered by Angiotensin II or AT2R antagonist EMA401. Mycolactone induces toxic effects in DRG neurons, leading to impaired nociceptor function, neurite degeneration, and cell death, resembling the cutaneous hypoalgesia and nerve damage in individuals with M. Ulcerans infection.


Volume-localized measurement of oxygen extraction fraction in the brain using MRI.
T2 -relaxation-under-spin-tagging (TRUST) is an MR technique for the non-invasive assessment of whole-brain cerebral oxygen extraction fraction (OEF), through measurement of the venous blood T2 relaxation time in the sagittal sinus. A key limitation of TRUST, however, is the lack of spatial specificity of the measurement. We sought to develop a modified TRUST sequence, selective localized TRUST (SL-TRUST), having sensitivity to venous blood T2 within a targeted brain region, and therefore achieving spatially localized measurements of cerebral tissue OEF, while still retaining acquisition in the sagittal sinus. A method for selective localization of TRUST sequence was developed, and the reproducibility of the technique was evaluated in healthy participants. Regional measurements were achieved for a single hemisphere and for a 3D-localized 70 × 70 × 80 mm3 tissue region using SL-TRUST and compared to a global TRUST measure. An additional measure of venous blood T1 in the sagittal sinus was used to estimate subject-specific hematocrit. Six subjects were scanned over 4 sessions, including intra-session repeat measurements. The average T2 in the sagittal sinus was found to be 60.8 ± 8.9, 62.7 ± 7.9, 64.6 ± 8.4, and 66.3 ± 10.3 ms (mean ± SD) for conventional TRUST, global SL-TRUST, hemispheric SL-TRUST, and 3D-localized SL-TRUST, respectively. Intra-, inter-session, and inter-subject coefficients of variation for OEF using SL-TRUST were found to be comparable and in some cases superior to those obtained using TRUST. OEF comparison of 2 contralateral regions was achievable in under 5 min suggesting SL-TRUST offers potential for quantifying regional OEF differences in both healthy and clinical populations.


Perceived strategies to reduce traumatic childbirth amongst Iranian childbearing women: a qualitative study.
Psychological birth trauma (PBT), mainly due to overlooking maternal mental health, is a common and high prevalence public health problem in low-resource settings. Preventing PBT is a good indicator of the realization of human rights in healthcare. This work reports the results of a qualitative study that aimed to identify perceived strategies of PBT prevention among childbearing women in Iran. We conducted semi-structured in-depth interviews with 22 mothers with history of traumatic childbirth, two mothers with positive childbirth experience, two spouses, and eight health professionals between April and June 2017. We used purposive sampling method to recruit traumatized mothers, while health experts were selected based on their relevant expertise and experience. Our initial literature review identified eight categories, using which we developed our interview guide and conducted the content analysis approach. With the maximum possible purification, we reached 50 thematic codes. The strategies to prevent PBT are generally summarized in four major themes and 13 categories: 1) skill-builder knowledge [Birth preparedness, Mothers' empowerment in maintaining mental health, Understanding the importance of mental care in maternity services], 2) responsible caregiving [Support loop, Good behavior of the caregivers, Deepening trust, Struggle with medicalization of childbirth, Labour pain relief, Special services for maternal mental health], 3) the alliance of prenatal and antenatal care [Continuity of care, Coordination of prenatal and antenatal caregivers], and 4) reconstruction of the structures [Efficient management, Rebuilding physical structures]. This is a comprehensive approach towards PBT prevention, which can guide future efforts to reduce PBT at the clinical level and open further avenues for future studies. We recommend policy makers to consider the integration of multilevel and multidimensional PBT prevention interventions, simultaneously within maternity care services packages for promotion of mental health.