The effect of motion patterns on edge-loading of metal-on-metal hip resurfacing.
The occurrence of pseudotumours (soft tissue masses relating to the hip joint) following metal-on-metal hip resurfacing arthroplasty (MoMHRA) has been associated with high serum metal ion levels and consequently higher than normal bearing wear. We investigated the relationship between serum metal ion levels and contact stress on the acetabular component of MoMHRA patients for two functional activities; gait and stair descent. Four subjects with MoMHRA, who had their serum metal ion levels measured, underwent motion analysis followed by CT scanning. Their motion capture data was combined with published hip contact forces and finite element models representing 14% (peak force) and 60% (end of stance) of the gait cycle and 52% (peak force) of stair descent activity were created. The inclination angle of the acetabular component was increased by 10° in 1° intervals and the contact stresses were determined at each interval for each subject. When the inclination angle was altered in such a way as to cause the hip contact force to pass through the edge of the acetabular component edge-loading occurred. Edge-loading increased the contact stress by at least 50%; the maximum increase was 108%. Patients with low serum metal ion levels showed no increase in contact stress at peak force during gait or stair descent. Patients with high serum metal ion levels exhibited edge-loading with an increase to the inclination angle of their acetabular components. The increase in inclination angle that induced edge-loading for these subjects was less than the inter-subject variability in the angle of published hip contact forces. The results of this study suggest that high serum metal ion levels are the result of inclination angle influenced edge-loading but that edge-loading cannot be attributed to inclination angle alone and that an individual's activity patterns can reduce or even override the influence of a steep acetabular component and prevent edge-loading.


Does Nasal Septal Deviation Affect the Success of Tympanoplasty Surgery?
This paper deals with the investigation of the effects of nasal septal deviation evaluated by acoustic rhinometry (ARM) in the success of tympanoplasty surgery. All patients who underwent tympanoplasty surgery by the same surgeon were reviewed. The patients with nasopharyngeal or nasal masses, polyps, symptoms of allergic rhinitis or rhinosinusitis, or concha bullosa were excluded from the study. Forty patients who underwent tympanoplasty at least one year ago were included in the study. The patients were divided into two groups according to the graft success results. Acoustic rhinometry evaluations of the patients were performed. There were 25 and 15 cases in the intact graft (group A) and re-perforated group (group B), respectively. For the same side of the operated ear, ARM values of group A were 0.47 cm², at the first narrowest cross-sectional area (MCA 1), 0.43 cm² at the second narrowest cross-sectional area (MCA 2), 1.51 cm³ volume at the first 2 cm of the nasal cavity (Vol 1) and 3.33 cm³ volume between the second and fifth cm of the nasal cavity (Vol 2). Acoustic rhinometry values of group B were 0.50 cm², 0.47 cm², 1.60 cm³ and 3.19 cm³ for MCA 1, MCA 2, Vol 1 and Vol 2, respectively. The results of this study showed that nasal septal deviation may not affect the success of tympanoplasty surgery, and septoplasty may not be necessary before ear surgery.


A competency-based training program in early intervention.
This paper describes a federally funded training program developed to prepare entry-level occupational therapists to deliver early intervention services. The program had two phases. Phase I was designed to provide occupational therapy supervisors with advanced skills for supervising and teaching the students about the provision of early intervention services. These skills were specific supervisory strategies and learning techniques designed to facilitate optimal communication between the student, the supervisor, and the academic faculty members, as well as to facilitate consistency of information between workshops and practices in the clinic. Phase II involved a 12-week clinical fieldwork experience for the students in an early intervention program combined with didactic programs at the university. Both supervisors and students provided feed-back on the program. Supervisors reported that the training strengthened their supervisory skills and techniques. Students reported that the training helped them to clarify the role of occupational therapy in early intervention and that they had developed skills critical to providing family-centered early intervention. These skills included both providing direct treatment to children and working in partnership with families and caregivers.


Discovery of a HapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing.
Azole compounds are the primary therapy for patients with diseases caused by Aspergillus fumigatus. However, prolonged treatment may cause resistance to develop, which is associated with treatment failure. The azole target cyp51A is a hotspot for mutations that confer phenotypic resistance, but in an increasing number of resistant isolates the underlying mechanism remains unknown. Here, we report the discovery of a novel resistance mechanism, caused by a mutation in the CCAAT-binding transcription factor complex subunit HapE. From one patient, four A. fumigatus isolates were serially collected. The last two isolates developed an azole resistant phenotype during prolonged azole therapy. Because the resistant isolates contained a wild type cyp51A gene and the isolates were isogenic, the complete genomes of the last susceptible isolate and the first resistant isolate (taken 17 weeks apart) were sequenced using Illumina technology to identify the resistance conferring mutation. By comparing the genome sequences to each other as well as to two A. fumigatus reference genomes, several potential non-synonymous mutations in protein-coding regions were identified, six of which could be confirmed by PCR and Sanger sequencing. Subsequent sexual crossing experiments showed that resistant progeny always contained a P88L substitution in HapE, while the presence of the other five mutations did not correlate with resistance in the progeny. Cloning the mutated hapE gene into the azole susceptible akuB(KU80) strain showed that the HapE P88L mutation by itself could confer the resistant phenotype. This is the first time that whole genome sequencing and sexual crossing strategies have been used to find the genetic basis of a trait of interest in A. fumigatus. The discovery may help understand alternate pathways for azole resistance in A. fumigatus with implications for the molecular diagnosis of resistance and drug discovery.


SUPPORT Tools for evidence-informed health Policymaking (STP) 14: Organising and using policy dialogues to support evidence-informed policymaking.
This article is part of a series written for people responsible for making decisions about health policies and programmes and for those who support these decision makers. Policy dialogues allow research evidence to be considered together with the views, experiences and tacit knowledge of those who will be involved in, or affected by, future decisions about a high-priority issue. Increasing interest in the use of policy dialogues has been fuelled by a number of factors: 1. The recognition of the need for locally contextualised 'decision support' for policymakers and other stakeholders 2. The recognition that research evidence is only one input into the decision-making processes of policymakers and other stakeholders 3. The recognition that many stakeholders can add significant value to these processes, and 4. The recognition that many stakeholders can take action to address high-priority issues, and not just policymakers. In this article, we suggest questions to guide those organising and using policy dialogues to support evidence-informed policymaking. These are: 1. Does the dialogue address a high-priority issue? 2. Does the dialogue provide opportunities to discuss the problem, options to address the problem, and key implementation considerations? 3. Is the dialogue informed by a pre-circulated policy brief and by a discussion about the full range of factors that can influence the policymaking process? 4. Does the dialogue ensure fair representation among those who will be involved in, or affected by, future decisions related to the issue? 5. Does the dialogue engage a facilitator, follow a rule about not attributing comments to individuals, and not aim for consensus? 6. Are outputs produced and follow-up activities undertaken to support action?


A hydrogel pen for electrochemical reaction and its applications for 3D printing.
A hydrogel pen consisting of a microscopic pyramid containing an electrolyte offers a localized electroactive area on the nanometer scale via controlled contact of the apex with a working electrode. The hydrogel pen merges the fine control of atomic force microscopy with non-linear diffusion of an ultramicroelectrode, producing a faradaic current that depends on the small electroactive area. The theoretical and experimental investigations of the mass transport behavior within the hydrogel reveal that the steady-state current from the faradaic reaction is linearly proportional to the deformed length of the hydrogel pen by contact, i.e. signal transduction of deformation to an electrochemical signal, which enables the fine control of the electroactive area in the nanometer-scale regime. Combined with electrodeposition, localized electrochemistry of the hydrogel pen results in the ability to fabricate small sizes (110 nm in diameter), tall heights (up to 30 μm), and arbitrary structures, thereby indicating an additive process in 3 dimensions by localized electrodeposition.


HLA Antigen Profile Differences in Patients with SCC (Squamous Cell Carcinoma) In-Situ /Actinic Keratosis and Invasive SCC: Is There a Genetic Succeptibility for Invasive SCC Development?
Actinic keratoses (AK) are proliferation of neoplastic keratinocytes confined to the epidermis induced by damaging solar ultraviolet radiation (UVR). When the neoplastic keratinocytes extend in to papillary-reticular dermis, then the lesion termed as squamous cell carcinoma (SCC). We have compared HLA class I and II antigen profiles in three patient groups namely: AK (n: 31) (patients without past or present invasive SCC), invasive SCC (n: 38), and SCC derived from / inconjuction with AK (n: 11). Low-resolution typing for the HLA-A, B, C and HLA-DR/DQ was performed by means of the PCR-sequence specific primer (PCR-SSP) method using SSP HLA class I generic DNA Typing Tray. HLA results of these three groups were compared with the healthy control group (n: 100). There were not significant difference in HLA class I and II antigen profiles in AK group compared to the control. Whereas HLA-A2 allele (60.52%, p=0.016, OR=2.726, 95%CI=1.265-5.876), HLA-B60 (13.15%, p=0.025, OR=7.424, 95%CI=1.375-40.099) were higher in SCC group than the control. HLA-B51 allele (72.72%, p=0.008, OR=6.853, 95%CI=1.696-27.720) distribution were more common in SCC derived from AK than the control. Historically, AKs have been characterized as premalignant. It has, however, been considered that AK and SCC represent the same disease process at the different stages of evaluation. Clinically, and histopathologically it is difficult to determine where AK ends and invasive SCC begins. From dermatopathological point of view AK is clearly SCC in-situ, however although AK is a common lesion in Caucasians, not all AKs develop in to invasive SCC, at least not with the same biological pace. We concluded that genetic differences such as HLA class I and II distribution between AK and SCC may not seem to play susceptibility role for invasive SCC development.


Applying the International Classification of Headache Disorders to the emergency department: an assessment of reproducibility and the frequency with which a unique diagnosis can be assigned to every acute headache presentation.
Although almost 2 decades have passed since the International Headache Society first introduced its International Classification of Headache Disorders (ICHD), the applicability of this classification scheme in the emergency department (ED) has not been assessed. As a first step toward identifying the role the ICHD should play in the ED, we address 2 questions: Can a structured interview and adherence to the ICHD allow ED headache patients to be classified in a reproducible manner? With the ICHD, how often can one specific diagnosis be assigned to each ED headache presentation? This was a structured interview and medical record review of patients with nontraumatic headache, performed in an urban ED from March 2004 through August 2005. Using the data from the interview and the subject's ED record, 2 emergency medicine investigators independently classified each of the headaches twice: first, to determine presence or absence of a primary headache disorder, and then to determine presence or absence of a secondary headache disorder. If a primary headache was present, it was further classified as migraine, tension-type headache, trigeminal autonomic cephalalgia, chronic daily headache, or primary headache unclassifiable. Interobserver discordance was adjudicated by an experienced headache specialist. Four hundred eighty patients were enrolled in the study. The emergency medicine investigators had a high level of interobserver agreement on secondary headaches (agreement 94% [95% confidence interval (CI) 92% to 96%]) and primary headaches (agreement 91% [95% CI 88% to 93%]). Among the 480 subjects, 122 (25%) had a secondary headache disorder, 309 (64%) had a primary headache disorder, 49 (10%) had a coexisting primary and secondary headache, and for 95 (20%) subjects, neither a primary nor a secondary headache could be diagnosed. Of 309 subjects with a primary headache, 186 (60%) had migraine, 34 (11%) had tension-type headache, 2 (1%) had trigeminal autonomic cephalalgia, and 77 (26%) had an unclassifiable primary headache. Overall, a specific ICHD headache diagnosis could not be assigned to 36% of subjects either because a specific primary headache disorder could not be identified or because neither a primary nor a secondary headache disorder could be diagnosed. Although a detailed structured interview in the ED and adherence to the ICHD resulted in reproducible classification of headache patients, more than one third of acute headache patients could not readily be given a specific ICHD diagnosis in the ED.


Thermo-alkaline Treatment as a Practical Degradation Strategy To Reduce Indospicine Contamination in Camel Meat.
Ingestion of indospicine-contaminated camel and horse meat has caused fatal liver injury to dogs in Australia, and it is currently not known if such contaminated meat may pose a human health risk upon dietary exposure. To date, indospicine-related research has tended to focus on analytical aspects, with little information on post-harvest management of indospicine-contaminated meat. In this study, indospicine degradation was investigated in both aqueous solution and also contaminated meat, under a range of conditions. Aqueous solutions of indospicine and indospicine-contaminated camel meat were microwaved (180 °C) or autoclaved (121 °C) with the addition of food-grade additives [0.05% (v/v) acetic acid or 0.05% (w/v) sodium bicarbonate] for 0, 15, 30, and 60 min. An aqueous sodium bicarbonate solution demonstrated the greatest efficacy in degrading indospicine, with complete degradation after 15 min of heating in a microwave or autoclave; concomitant formation of indospicine degradation products, namely, 2-aminopimelamic and 2-aminopimelic acids, was observed. Similar treatment of indospicine-contaminated camel meat with aqueous sodium bicarbonate resulted in 50% degradation after 15 min of heating in an autoclave and 100% degradation after 15 min of heating in a microwave. The results suggest that thermo-alkaline aqueous treatment has potential as a pragmatic post-harvest handling technique in reducing indospicine levels in indospicine-contaminated meat.


Ocean acidification increases fatty acids levels of larval fish.
Rising levels of anthropogenic carbon dioxide in the atmosphere are acidifying the oceans and producing diverse and important effects on marine ecosystems, including the production of fatty acids (FAs) by primary producers and their transfer through food webs. FAs, particularly essential FAs, are necessary for normal structure and function in animals and influence composition and trophic structure of marine food webs. To test the effect of ocean acidification (OA) on the FA composition of fish, we conducted a replicated experiment in which larvae of the marine fish red drum (Sciaenops ocellatus) were reared under a climate change scenario of elevated CO2 levels (2100 µatm) and under current control levels (400 µatm). We found significantly higher whole-body levels of FAs, including nine of the 11 essential FAs, and altered relative proportions of FAs in the larvae reared under higher levels of CO2. Consequences of this effect of OA could include alterations in performance and survival of fish larvae and transfer of FAs through food webs.


Larval habitats and seasonal abundance of Culicoides biting midges found in association with sheep in northern Sardinia, Italy.
Between January 2005 and December 2006, the larval habitats and seasonal abundances of 21 species of Culicoides (Diptera: Ceratopogonidae) found in association with livestock on a farm in northern Sardinia were studied. Culicoides were collected using two light traps (one placed in a sheep shed and the other near water ponds) and reared from mud collected in and along the margins of a small and a large water pond. The mammalophilic Culicoides imicola Kieffer and Culicoides newsteadi Austen were the most prevalent (>95%) of 20 species in the sheep shed, whereas the ornithophilic Culicoides univittatus Vimmer, Culicoides sahariensis Kieffer, Culicoides festivipennis Kieffer, Culicoides circumscriptus Kieffer and Culicoides cataneii Clastrier were most abundant in the traps set at the ponds (73%) and in 16 species of Culicoides reared from laboratory-maintained mud samples retrieved from three microhabitats (a non-vegetated pond shoreline, 20 cm above a pond shoreline, the shoreline of a secondary, permanently inundated, grass-covered pool). The species reared most abundantly from along the pond shoreline were C. festivipennis, C. circumscriptus and C. sahariensis, whereas those most prevalent at the grassed pool were C. cataneii and C. festivipennis. C. imicola was found to breed preferentially in mud 20 cm above the pond shoreline, whereas C. newsteadi was restricted almost entirely to the grassed pool, which had a high organic matter content. Using the light trap and adult emergence data, the seasonal abundance patterns of the eight species of Culicoides were determined. In general, there was good correspondence between light trap catches and emergence trends. Well-defined emergence peaks indicate four or five generations for C. festivipennis and C. circumscriptus and three generations for C. cataneii, C. newsteadi and Culicoides jumineri Callot & Kremer. The emergence trends for C. imicola and C. sahariensis were unimodal, but, because they stretched over several months, indicated that a number of overlapping generations had occurred. Adults of C. imicola were reared and captured only sporadically in the first half of the year, gradually building to a peak in autumn. Conversely, C. newsteadi was reared throughout the year and displayed three clearly defined peaks (in winter, spring and autumn); captures of C. newsteadi in the light traps peaked in May-June and again to a lesser extent in autumn. In Sardinia the late seasonal peak in the abundance of C. imicola occurs in synchrony with outbreaks of bluetongue (BT) in sheep, which is consistent with earlier findings elsewhere in the Mediterranean basin and in Africa that it is the principal vector of bluetongue virus (BTV). Although the status of C. newsteadi as a vector of BTV is not known, its low-level presence in winter and heightened abundances in spring may provide a pathway along which the virus can overwinter.


High-sensitivity C-reactive protein and exercise-induced changes in subjects suspected of coronary artery disease.
Inflammation plays a major role in the development of atherosclerosis. We wanted to investigate the effects of exercise on high-sensitivity (hs) C-reactive protein (CRP) in subjects who were suspected of having coronary artery disease (CAD). Blood samples were obtained before, 5 minutes after, and 20 hours after an exercise test in 155 subjects who were suspected of CAD. Coronary anatomy was evaluated by computed tomography coronary angiography and/or coronary angiography. Median baseline hs-CRP was higher in subjects with ≥50% coronary artery lumen diameter stenosis (n=41), compared with non-CAD-subjects (n=114), 2.93 mg/L (interquartile range 1.03-5.06 mg/L) and 1.30 mg/L (interquartile range 0.76-2.74 mg/L), respectively, P=0.007. In multivariate analyses testing conventional risk factors, hs-CRP proved borderline significant, odds ratio =2.32, P=0.065. Adding baseline hs-CRP to the results of the exercise test did not improve the diagnostic evaluation. Baseline natural logarithm (Ln) hs-CRP was positively associated with body mass index and baseline Ln-transformed hs troponin T levels, and negatively associated with the daily life activity level. An increase in hs-CRP of 0.13 mg/L (interquartile range 0.05-0.24 mg/L) from baseline to 5 minutes after peak exercise was found (P<0.0001), but the increase was not associated with presence of CAD. From baseline to 20 hours after exercise, no increase in hs-CRP was found. In conclusion, hs-CRP was not independently associated with CAD. Hs-CRP increased immediately as a response to the exercise, and the increase was modest and not associated with CAD. The results indicate that exercise has potential to cause unwanted variations in hs-CRP and that exercise prior to hs-CRP measurements in subjects included in epidemiological studies, therefore, should be avoided.


Transition from paediatric to adult care of adolescents living with HIV in sub-Saharan Africa: challenges, youth-friendly models, and outcomes.
The number of adolescents with perinatally or behaviourally acquired HIV is increasing in low-income countries, and especially in sub-Saharan Africa where HIV prevalence and incidence are the highest. As they survive into adulthood in the era of antiretroviral therapy, there is a pressing need to transfer them from paediatric to adult care, known as the transition of care. We conducted a narrative review of recent evidence on their transition outcomes in Africa, highlighting the specific needs and challenges in these populations and settings, and the different models of care for transition. We searched PubMed bibliographic database, HIV conference content, and grey literature from January 2000 to August 2016 with the following keywords: HIV infections AND (adolescents or youth) AND transition AND Africa. All qualitative and quantitative, experimental and observational studies including HIV-infected patients aged 10-24 years with information on transition were eligible. Few data on transition outcomes for HIV-infected adolescents are available from Africa settings. Studies mainly from Southern and East Africa reported on the barriers to successful transition, highlighting several gaps. These included lack of adequate infrastructure, staff training and communication between paediatric and adult clinicians as well as the fear of stigma of adolescents and youth living with HIV. Most countries have no specific national guidelines on when to disclose HIV status or when and how to transition to adult care. Several models of care adapted to the adolescent transition question have been implemented in specific settings. These models include teen clinics, peer educators or the use of social media. However, regardless of the model, services are increasingly overburdened and have insufficient human resources. Furthermore, very high attrition has been observed among adolescents and youth compared to younger children or older adults. There is a need to identify sub-groups at higher risk of loss to follow-up for targeted care and peer support. Although the available HIV-related data on adolescent transition outcomes are limited, there is evidence of their increased vulnerability during this period. Standardized data gathering, analysis, and reporting systems specific to adolescent transition are essential to improve understanding and adolescent outcomes in Africa.


Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.
Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10(-5)) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value <10(-5) in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10(-6), OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10(-12)). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.


Are large wattles related to particular MHC genotypes in the male pheasant?
In sexually dimorphic species, partners can assess heritable mate quality by analyzing costly sexual ornaments in terms of their dimension and possibly of their symmetry. In vertebrates an important aspect of genetic quality is the efficiency of the immune system, and in particular the Major Histocompatibility Complex (MHC). If ornaments are honest advertisements of pathogen resistance (good genes), in line with the Hamilton-Zuk hypothesis, a correlation between ornament expression and MHC profiles should exist. We tested this hypothesis in the common pheasant Phasianus colchicus by comparing male ornament characteristics (wattle and spur size, and wattle fluctuating asymmetry) with a portion of exon 2 of the class IIB MHC genes containing 19 putative antigen recognition sites. A total of 8 new alleles was observed in the MHCPhco exon IIB. We found significant differences in the occurrence of MHC genotypes between males carrying large or small wattles. Homozygous genotypes predicted large wattle males more correctly than small wattle males. The association between the dimension of the spur and the occurrence of MHC genotypes was marginally significant, however, we did not find any significant association between MHC genotypes and asymmetry. Our results suggest that female pheasants may use the ornament size as a cue to evaluate male quality and thus choose males carrying particular MHC profiles.


Perceived facial adiposity conveys information about women's health.
Although several prominent theories of human facial attractiveness propose that some facial characteristics convey information about people's health, empirical evidence for this claim is somewhat mixed. While most previous research into this issue has focused on facial characteristics such as symmetry, averageness, and sexual dimorphism, a recent study reported that ratings of facial adiposity (i.e., perceptions of fatness in the face) were positively correlated with indices of poor physical condition in a sample of young adults (i.e., reported past health problems and measures of cardiovascular fitness). These findings are noteworthy, since they suggest that perceived adiposity is a potentially important facial cue of health that has been overlooked by much of the previous work in this area. Here, we show that ratings of young adult women's facial adiposity are (1) better predicted by their body weight than by their body shape (Studies 1 and 2), (2) correlated with a composite measure of their physical and psychological condition (Study 2), and (3) negatively correlated with their trait (i.e., average) salivary progesterone levels (Study 3). Together, these findings present further evidence that perceived facial adiposity, or a correlate thereof, conveys potentially important information about women's actual health.


Resveratrol treatment delays growth plate fusion and improves bone growth in female rabbits.
Trans-resveratrol (RES), naturally produced by many plants, has a structure similar to synthetic estrogen diethylstilbestrol, but any effect on bone growth has not yet been clarified. Pre-pubertal ovary-intact New Zealand white rabbits received daily oral administration of either vehicle (control) or RES (200 mg/kg) until growth plate fusion occurred. Bone growth and growth plate size were longitudinally monitored by X-ray imaging, while at the endpoint, bone length was assessed by a digital caliper. In addition, pubertal ovariectomized (OVX) rabbits were treated with vehicle, RES or estradiol cypionate (positive control) for 7 or 10 weeks and fetal rat metatarsal bones were cultured in vitro with RES (0.03 µM-50 µM) and followed for up to 19 days. In ovary-intact rabbits, sixteen-week treatment with RES increased tibiae and vertebrae bone growth and subsequently improved final length. In OVX rabbits, RES delayed fusion of the distal tibia, distal femur and proximal tibia epiphyses and femur length and vertebral bone growth increased when compared with controls. Histomorphometrical analysis showed that RES-treated OVX rabbits had a wider distal femur growth plate, enlarged resting zone, increased number/size of hypertrophic chondrocytes, increased height of the hypertrophic zone, and suppressed chondrocyte expression of VEGF and laminin. In cultured fetal rat metatarsal bones, RES stimulated growth at 0.3 µM while at higher concentrations (10 μM and 50 μM) growth was inhibited. We conclude that RES has the potential to improve longitudinal bone growth. The effect was associated with a delay of growth plate fusion resulting in increased final length. These effects were accompanied by a profound suppression of VEGF and laminin expression suggesting that impairment of growth plate vascularization might be an underlying mechanism.


Distinguishing reference intervals and clinical decision limits - A review by the IFCC Committee on Reference Intervals and Decision Limits.
Reference Intervals (RIs) and clinical decision limits (CDLs) are a vital part of the information supplied by laboratories to support the interpretation of numerical clinical pathology results. RIs describe the typical distribution of results seen in a healthy reference population while CDLs are associated with a significantly higher risk of adverse clinical outcomes or are diagnostic for the presence of a specific disease. However, as the two concepts are sometimes confused, there is a need to clarify the differences between these terms and to ensure they are easily distinguished, especially because CDLs have a clinical association with specific diseases and risks, thereby implying that effective clinical interventions are available. It is important to note that, because population-based RIs are derived from the range of values expected in a typical community population, laboratory results that fall outside a RI do not necessarily indicate a disease but rather that additional medical follow-up and/or treatment may be warranted. In contrast, CDLs are associated with a risk of specific adverse outcomes, and are commonly used to interpret laboratory test results, including lipid parameters, glucose, hemoglobin A1c (HbA1c), and tumor markers, to determine risk of disease, to diagnose or to treat. In recent years, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) has focused primarily on RIs and has performed multicenter studies to obtain common RIs. However, the broader responsibility of the Committee, from its name, includes "decision limits". C-RIDL now aims to emphasize the importance of the correct use of both RIs and CDLs and to encourage laboratories to specify the appropriate information to clinicians as needed. This review discusses RIs and CDLs in detail, describes the similarities and the differences between these two important tools in laboratory medicine, and clearly explains the processes used to define them. C-RIDL encourages the involvement of laboratory professionals in the establishment of both RIs and CDLs.


Representation of stimulus azimuth by low-frequency neurons in inferior colliculus of the cat.
The responses to changes in stimulus azimuth of 204 neurons in the inferior colliculus of the cat with best frequencies of less than 3 kHz were studied. Three main unit classes were identified: omnidirectional units uninfluenced by speaker azimuth (39%); multipeaked units with several azimuthal regions at which peak firing occurred (9%); and azimuth-selective units that showed clear preferences for a discrete range of sound-source azimuths (52%). Alterations in stimulus intensity produced little change in the shapes of profiles relating firing rate to stimulus azimuth (azimuth functions), but the peaks of these functions could shift by up to 20 degrees. Similar observations were made for a small sample of units, each of which was examined with a variety of stimulus frequencies. The pinnae were removed bilaterally in 11 cats, and azimuth functions for 35 units were measured both binaurally and with the ipsilateral or contralateral ear occluded. Evidence was found for facilitative or suppressive interactions, as a function of stimulus azimuth, between monaural inputs. The sharpness of an azimuth function was expressed by the half-width of the function, i.e., the number of degrees of azimuth between the peak of the function and the point at which 50% of maximum firing occurred on the medial side of the peak. When half-widths were plotted as a function of best frequency, it was found that the sharpest azimuth functions occurred for units with best frequencies between 1.1 and 1.5 kHz. Most units in the lowest two octaves (0.1-0.4 kHz) or having best frequencies between 2 and 3 kHz were omnidirectional. The relationship between half-width and the azimuth at which peak firing occurred (best azimuth) revealed that a range of best azimuths between 10 and 40 degrees contralateral contained the sharpest azimuth functions. When best frequency was plotted against best azimuth, it was observed that the majority of units (93%) had best azimuths in the contralateral hemifield. For frequencies between 0.7 and 1.7 kHz, best azimuths occurred relatively evenly between 10 and 60 degrees contralateral. These data suggested that for frequencies between 1.2 and 1.4 kHz, at least, the best azimuths of different units with the same best frequency collectively provide information about stimulus location across much of the contralateral hemifield.(ABSTRACT TRUNCATED AT 400 WORDS)


FANCD2-FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair.
Vertebrate DNA crosslink repair excises toxic replication-blocking DNA crosslinks. Numerous factors involved in crosslink repair have been identified, and mutations in their corresponding genes cause Fanconi anemia (FA). A key step in crosslink repair is monoubiquitination of the FANCD2-FANCI heterodimer, which then recruits nucleases to remove the DNA lesion. Here, we use cryo-EM to determine the structures of recombinant chicken FANCD2 and FANCI complexes. FANCD2-FANCI adopts a closed conformation when the FANCD2 subunit is monoubiquitinated, creating a channel that encloses double-stranded DNA (dsDNA). Ubiquitin is positioned at the interface of FANCD2 and FANCI, where it acts as a covalent molecular pin to trap the complex on DNA. In contrast, isolated FANCD2 is a homodimer that is unable to bind DNA, suggestive of an autoinhibitory mechanism that prevents premature activation. Together, our work suggests that FANCD2-FANCI is a clamp that is locked onto DNA by ubiquitin, with distinct interfaces that may recruit other DNA repair factors.


Long Non-coding MIR205HG Depletes Hsa-miR-590-3p Leading to Unrestrained Proliferation in Head and Neck Squamous Cell Carcinoma.
Over 70% of head & neck squamous cell carcinoma (HNSCC) patients carry TP53 oncogenic mutations. Here we studied the role of specific tumor-derived mutant p53 proteins in the aberrant transcription of long non-coding (lnc) MIR205HG gene in head and neck cancer cells. Methods: To understand the role of lncMIR205HG, that we showed to be transcriptionally regulated by mutant p53 in HNSCC, we have employed siRNA and shRNA in CAL27 and FaDu HNSCC cell lines to suppress p53 gene expression in ChIP assays and RT-qPCR. We validated our findings in a cohort of 522 HNSCC patients from The Cancer Genome Atlas Data Portal (TCGA). We further evaluated our results in 63 HNSCC tumor samples collected at our institute, 32 of which were characterized by mutated TP53 (missense mutations) while 31 were characterized by wild-type TP53. Results: Maturation of pre-MIR205HG transcript produces two non-coding RNAs, lncMIR205HG and hsa-miR-205-5p. Down-regulation of lncMIR205HG expression significantly reduced cell proliferation, cell migration and clonogenic activity of head and neck cancer cells. Expression of MIR205HG was significantly increased in HNSCC with mutated TP53 when compared with matched non-tumoral tissues. Furthermore, MIR205HG expression levels were significantly higher in tumoral samples with mutant p53 than in tumoral tissues expressing wild-type p53. Mechanistically, MIR205HG depletes endogenous miR-590-3p leading to increased cyclin B, cdk1, and YAP protein expression. Conclusions: Taken together, these findings identify a transcriptional and post-transcriptional molecular network that includes mutant p53 protein, lncMIR205HG, YAP, and other proliferation-related genes, which are enriched in HNSCC patients with poor prognosis.


A novel isolator-based system promotes viability of human embryos during laboratory processing.
In vitro fertilisation (IVF) and related technologies are arguably the most challenging of all cell culture applications. The starting material is a single cell from which one aims to produce an embryo capable of establishing a pregnancy eventually leading to a live birth. Laboratory processing during IVF treatment requires open manipulations of gametes and embryos, which typically involves exposure to ambient conditions. To reduce the risk of cellular stress, we have developed a totally enclosed system of interlinked isolator-based workstations designed to maintain oocytes and embryos in a physiological environment throughout the IVF process. Comparison of clinical and laboratory data before and after the introduction of the new system revealed that significantly more embryos developed to the blastocyst stage in the enclosed isolator-based system compared with conventional open-fronted laminar flow hoods. Moreover, blastocysts produced in the isolator-based system contained significantly more cells and their development was accelerated. Consistent with this, the introduction of the enclosed system was accompanied by a significant increase in the clinical pregnancy rate and in the proportion of embryos implanting following transfer to the uterus. The data indicate that protection from ambient conditions promotes improved development of human embryos. Importantly, we found that it was entirely feasible to conduct all IVF-related procedures in the isolator-based workstations.


The genetics and genomics of Syngnathidae: pipefishes, seahorses and seadragons.
The goal of this review was to provide a historical overview of how molecular techniques have increased the understanding of the ecology and evolution of the family Syngnathidae (pipefishes, seahorses and seadragons). Molecular studies based primarily on mitochondrial DNA markers have proved their worth by elucidating complex phylogenetic relationships within the family. Phylogeographic studies, which have revealed how life-history traits and past climatic events shape geographic distributions and patterns of genetic variation within syngnathid species, also provide interesting case studies for the conservation and management of threatened species. The application of microsatellite DNA markers has opened a floodgate of studies concerned with the breeding biology of these fishes, which are interesting due to their unique reproductive mode of male pregnancy. Research in this area has contributed significantly to the understanding of mating patterns and sexual selection. Molecular markers may also be employed in studies of demography, migration and local breeding population sizes. Genomic studies have identified genes that are probably involved in male pregnancy and promise additional insights into various aspects of syngnathid biology at the level of the gene. Despite these advances, much more remains to be explored. Goals for future research should include: (1) a more inclusive phylogeny to resolve outstanding issues concerning the relationships within the family and higher order taxa, (2) a broader use of molecular studies to aid management and conservation efforts, (3) the inclusion of more genera in comparative behavioural studies and (4) the continued development of genomic resources for syngnathids to facilitate comparative genomic work.


[Focal therapy-a new era in the treatment of prostate cancer].
Treatment options for prostate cancer are currently widely discussed in the media and by urologic associations. International studies showed that current treatment options may significantly affect the quality of life (including incontinence and erectile dysfunction) while only offering marginal survival benefits. Low to medium risk patients in particular don't seem to be ideal candidates for radical treatment by surgery of radio therapy. For this large group of patients focal therapy offers additional valuable treatment option. Malignant prostate tissue can be specifically ablated by High-Intensity Focused Ultrasound (HIFU). Thus, the cancer can be controlled without removing the whole prostate and with minimal side effects. Multimodal magnetic resonance tomography, specific biopsies and monitoring contribute to the safety of this new treatment strategy.


Management and retrospective analysis of pelvic ramus tumors and tumor-like lesions: Evaluation with 31 cases.
This study aims to investigate the characterization, treatment approaches, and follow-up results of tumors and tumor-like lesions located in the pelvic ramus. Thirty-one patients (9 males, 22 females; mean age 48.9 years; range, 7 to 79 years) with benign and malignant tumors or tumor-like lesions in the pelvic ramus region treated and followed-up in our clinic between January 2005 and January 2019 were evaluated retrospectively. Surgical procedures were performed with anterior approach or inner-thigh approach. Twelve patients were diagnosed with malignant tumors, 12 patients with benign tumors, and seven patients with tumor-like lesions. Seventeen patients who underwent surgical treatment were followed-up for a mean period of 61.7 months. The diameters of benign and malignant tumors were similar (p=0.425). Of all lesions, 64.5% were located in the pubis. Ischium location was significantly higher in patients with malignant lesions than tumor-like lesions. The most common complication was diffuse subcutaneous edema in the inguinal region and thigh (8.3%). There are many different tumoral lesions in the pelvic ramus. Pelvic ramus tumors tend to settle more frequently in pubic ramus, whereas ramus ischium tumors are more likely to be malignant. In addition, the diagnosis of insufficiency fracture should be considered primarily in pathologic fractures of pubic ramus in females over 50 years of age. In the postoperative follow-up of pelvic ramus tumors, diffuse edema may occur even if there is no intraoperative vascular damage.


Candidate luminal B breast cancer genes identified by genome, gene expression and DNA methylation profiling.
Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.


On Time Domain Analysis of Photoplethysmogram Signals for Monitoring Heat Stress.
There are a limited number of studies on heat stress dynamics during exercise using the photoplethysmogram (PPG) and its second derivative (APG). However, we investigate the most suitable index from short PPG signal recordings for heat stress assessment. The APG waveform consists of a, b, c and d waves in systole and an e wave in diastole. Our preliminary results indicate that the use of the energy of aa area, derived from PPG signals measured from emergency responders in tropical conditions, is promising in determining the heat stress level using 20-s recordings. After examining 14 time domain features using leave-one-out cross-validation, we found that the aa energy extracted from PPG signals is the most informative feature for classifying heat-stressed subjects, with an overall accuracy of 79%. Moreover, the combination of the aa energy with the traditional Sensors 2015, 15 24717 heart rate variability index of heat stress (i.e., the square root of the mean of the squares of the successive aa intervals) improved the heat stress detection to an overall accuracy of 83%.


RNF115 plays dual roles in innate antiviral responses by catalyzing distinct ubiquitination of MAVS and MITA.
MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115-/- organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115-/- cells compared to the wild-type counterparts. Consequently, the Rnf115-/- mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.


Measurements of the noise spectral power density of photosensitive materials at high spatial frequencies.
A new method of measuring the scattered light to determine the noise spectral power density is described The technique is shown to be useful at the high spatial frequencies used in holography, beyond the range of the former methods of noise power measurement. Measurements of the grain noise of several photographic emulsions used for holography are presented; they are consistent with a model of emulsions characterized by a transmission correlation length. The measured correlation length of several of the emulsions fit experimentally observed spatial frequency responses. Data on noise power of several other photosensitive materials suitable for holography are also presented.


Resilience actions to counteract the effects of climate change and health emergencies in cities: the role of artificial neural networks.
Both the World Health Organization (WHO) with its 2015 "Climate and Health Country Profile Project" and the Istituto Superiore di Sanità (ISS) with its 2018 "Health and Climate Change", agree on the emergency generated by the climate change and concerning health problems. The mitigation strategy suggested by the Intergovernmental Panel On Climate Change (IPCC) against greenhouse gas emissions and their effects on climate change, has not yet yielded the desired results. It is therefore necessary to focus on adaptation strategies, to immediately counter the effects of climate change (CC) on most vulnerable people and environments, by increasing their resilience through local interventions and targeted resilience actions. Coordinated resilience actions are necessary to combat the effects of CC especially in urban areas. Useful tools to manage and optimize resilience actions are artificial neural networks (ANN) in complex and dynamic domains as cities are. The case of ANN applied to a city is presented as an example to increase the climate resilience of health local systems. In the current state of knowledge, ANN prove to be the most advanced and global solution to coordinate and manage a set of resilience actions in urban areas.


Combination scaffolds of salmon fibrin, hyaluronic acid, and laminin for human neural stem cell and vascular tissue engineering.
Human neural stem/progenitor cells (hNSPCs) are good candidates for treating central nervous system (CNS) trauma since they secrete beneficial trophic factors and differentiate into mature CNS cells; however, many cells die after transplantation. This cell death can be ameliorated by inclusion of a biomaterial scaffold, making identification of optimal scaffolds for hNSPCs a critical research focus. We investigated the properties of fibrin-based scaffolds and their effects on hNSPCs and found that fibrin generated from salmon fibrinogen and thrombin stimulates greater hNSPC proliferation than mammalian fibrin. Fibrin scaffolds degrade over the course of a few days in vivo, so we sought to develop a novel scaffold that would retain the beneficial properties of fibrin but degrade more slowly to provide longer support for hNSPCs. We found combination scaffolds of salmon fibrin with interpenetrating networks (IPNs) of hyaluronic acid (HA) with and without laminin polymerize more effectively than fibrin alone and generate compliant hydrogels matching the physical properties of brain tissue. Furthermore, combination scaffolds support hNSPC proliferation and differentiation while significantly attenuating the cell-mediated degradation seen with fibrin alone. HNSPCs express two fibrinogen-binding integrins, αVβ1 and α5β1, and several laminin binding integrins (α7β1, α6β1, α3β1) that can mediate interaction with the scaffold. Lastly, to test the ability of scaffolds to support vascularization, we analyzed human cord blood-derived endothelial cells alone and in co-culture with hNSPCs and found enhanced vessel formation and complexity in co-cultures within combination scaffolds. Overall, combination scaffolds of fibrin, HA, and laminin are excellent biomaterials for hNSPCs. Interest has increased recently in the development of biomaterials as neural stem cell transplantation scaffolds to treat central nervous system (CNS) injury since scaffolds improve survival and integration of transplanted cells. We report here on a novel combination scaffold composed of fibrin, hyaluronic acid, and laminin to support human neural stem/progenitor cell (hNSPC) function. This combined biomaterial scaffold has appropriate physical properties for hNSPCs and the CNS, supports hNSPC proliferation and differentiation, and attenuates rapid cell-mediated scaffold degradation. The hNSPCs and scaffold components synergistically encourage new vessel formation from human endothelial cells. This work marks the first report of a combination scaffold supporting human neural and vascular cells to encourage vasculogenesis, and sets a benchmark for biomaterials to treat CNS injury.


Amebic colitis in asymptomatic subjects with positive fecal occult blood test results: clinical features different from symptomatic cases.
Amebiasis is a common parasitic infectious disease in developing countries. In developed countries, it is occasionally encountered in travelers to the tropics and in homosexual males. During the past eight years, we detected four cases of amebic colitis among 5,193 subjects who underwent colonoscopy because of positive fecal occult blood test results in a mass screening. All four cases did not have any abdominal symptoms. Ulcerative lesions were observed only in the cecum and ascending colon; another portion of the colon and rectum appeared normal. We may encounter amebic colitis during colonoscopic examination even in subjects who are asymptomatic.


2N+4-rule and an atlas of bulk optical resonances of zigzag graphene nanoribbons.
Development of on-chip integrated carbon-based optoelectronic nanocircuits requires fast and non-invasive structural characterization of their building blocks. Recent advances in synthesis of single wall carbon nanotubes and graphene nanoribbons allow for their use as atomically precise building blocks. However, while cataloged experimental data are available for the structural characterization of carbon nanotubes, such an atlas is absent for graphene nanoribbons. Here we theoretically investigate the optical absorption resonances of armchair carbon nanotubes and zigzag graphene nanoribbons continuously spanning the tube (ribbon) transverse sizes from 0.5(0.4) nm to 8.1(12.8) nm. We show that the linear mapping is guaranteed between the tube and ribbon bulk resonance when the number of atoms in the tube unit cell is [Formula: see text], where [Formula: see text] is the number of atoms in the ribbon unit cell. Thus, an atlas of carbon nanotubes optical transitions can be mapped to an atlas of zigzag graphene nanoribbons.


Increased Risk for Meningococcal Disease Among Men Who Have Sex With Men in the United States, 2012-2015.
Several clusters of serogroup C meningococcal disease among men who have sex with men (MSM) have been reported in the United States in recent years. The epidemiology and risk of meningococcal disease among MSM is not well described. All meningococcal disease cases among men aged 18-64 years reported to the National Notifiable Disease Surveillance System between January 2012 and June 2015 were reviewed. Characteristics of meningococcal disease cases among MSM and men not known to be MSM (non-MSM) were described. Annualized incidence rates among MSM and non-MSM were compared through calculation of the relative risk and 95% confidence intervals. Isolates from meningococcal disease cases among MSM were characterized using standard microbiological methods and whole-genome sequencing. Seventy-four cases of meningococcal disease were reported among MSM and 453 among non-MSM. Annualized incidence of meningococcal disease among MSM was 0.56 cases per 100000 population, compared to 0.14 among non-MSM, for a relative risk of 4.0 (95% confidence interval [CI], 3.1-5.1). Among the 64 MSM with known status, 38 (59%) were infected with human immunodeficiency virus (HIV). HIV-infected MSM had 10.1 times (95% CI, 6.1-16.6) the risk of HIV-uninfected MSM. All isolates from cluster-associated cases were serogroup C sequence type 11. MSM are at increased risk for meningococcal disease, although the incidence of disease remains low. HIV infection may be an important factor for this increased risk. Routine vaccination of HIV-infected persons with a quadrivalent meningococcal conjugate vaccine in accordance with Advisory Committee on Immunization Practices recommendations should be encouraged.


Gallium-68 DOTATATE PET in the Evaluation of Intracranial Meningiomas.
Meningiomas are the most common primary intracranial tumors, typically treated with surgery and adjuvant radiation in cases of subtotal resection and/or higher histopathologic grade. Contrast-enhanced magnetic resonance imaging (MRI) is the gold standard for postoperative assessment and adjuvant treatment planning. However, MRI can have limited accuracy particularly in the presence of posttreatment change. [68Ga]-DOTATATE is a Positron Emission Tomography (PET) radiotracer targeting somatostatin receptor 2A (SSTR2A). SSTR2A is a reliable biomarker of meningiomas. We report a consecutive case series of 20 patients evaluated with [68Ga]-DOTATATE PET/MRI, propose a novel approach to quantitative analysis, and discuss clinical implications. We present a consecutive case series of 20 patients with clinically suspected or pathology-proven meningioma evaluated between July 2018 and February 2019. [68Ga]-DOTATATE PET/MRI was obtained in order to confirm the diagnosis or determine tumor recurrence/progression to help guide surgical and/or radiation therapy management in cases in which MRI findings were indeterminate or equivocal. Seventeen (85%) patients had undergone prior surgery and 11 (55%) underwent adjuvant radiation therapy. In 17 patients [68Ga]-DOTATATE confirmed the presence of recurrent meningioma. A total of 49 meningiomas were identified (median: 2 meningiomas/patient, range 0-14). There was excellent differentiation between meningioma and posttreatment change based on our approach of target lesion/superior sagittal sinus maximum standardized uptake values ratio (16.6 vs. 1.6, P < .0001). [68Ga]-DOTATATE PET/MRI is a promising tool in the assessment of both treatment naïve and resected/irradiated meningiomas, allowing improved diagnosis and extent of disease evaluation. Future prospective studies are needed to determine utility of [68Ga]-DOTATATE PET/MRI in treatment response assessment.


Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation.
Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such "oncogenic" kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene. Just like the well-known tumor suppressor gene Phosphatase and Tensin Homolog (PTEN) it hydrolyses phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P3). However, unlike PTEN, the reaction product is PI(3,4)P2, which is required for full activation of the downstream protein kinase B (PKB/Akt), suggesting that SHIP2, in contrast to PTEN, could have a tumor initiating role through PKB activation. In this work, we investigated the role of SHIP2 in colorectal cancer. We found that SHIP2 and INPPL1 expression is increased in colorectal cancer tissue in comparison to adjacent normal tissue, and this is correlated with decreased patient survival. Moreover, SHIP2 is more active in colorectal cancer tissue, suggesting that SHIP2 can induce oncogenesis in colonic epithelial cells. Furthermore, in vitro experiments performed on colorectal cancer cell lines shows an oncogenic role for SHIP2, by enhancing chemoresistance, cell migration, and cell invasion. Together, these data indicate that SHIP2 expression contributes to the malignant potential of colorectal cancer, providing a possible target in the fight against this devastating disease.


Preventing collisions involving surface mining equipment: a GPS-based approach.
An average of three workers a year are killed in surface mining operations when a piece of haulage equipment collides with another smaller vehicle or a worker on foot. Another three workers are killed each year when haulage equipment backs over the edge of a dump point or stockpile. Devices to monitor the blind areas of mining equipment are needed to provide a warning to operators when a vehicle, person, or change in terrain is near the equipment. A proximity warning system (PWS) based on the global positioning system (GPS) and peer-to-peer communication has been developed to prevent collisions between mining equipment, small vehicles, and stationary structures. A final system was demonstrated using one off-highway haul truck, three smaller vehicles, and various stationary structures at a surface mining operation. The system successfully displayed the location of nearby vehicles and stationary structures and provided visual and audible warnings to the equipment operator when they were within a preset distance. Many surface mining operations already use GPS technology on their mobile equipment for tracking and dispatch. Our tests have shown that it is feasible to add proximity warning to these existing systems as a safety feature. Larger scale and long-term tests are needed to prove the technology adequately. A PWSs that incorporates a combination of technologies could significantly reduce accidents that involve collisions or driving over an edge at surface mining operations.


Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.
We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors. Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.


Effects of excess glucose on mammalian post-implantation embryos.
Studies on the effects of excess glucose on mammalian post-implantation embryos grown in culture are reviewed and selected examples of these studies are discussed to demonstrate the value, and the limitations, of the embryo-culture system. By use of culture techniques the precise concentrations of exogenous glucose causing morphological and biochemical changes are defined for a range of developmental stages in both rat and mouse embryos. The critical window of exposure is known and the morphological, cellular and biochemical changes associated with hyperglycemic culture are described. The effects of hyperglycemic serum are briefly compared with those of serum prepared from diabetic rats and the contribution of the high glucose concentrations to the embryopathic effects of the "diabetic" serum is assessed. The advantages and the limitations of the culture system are discussed.


A novel gain-of-function mutant of the cyclic GMP-dependent protein kinase egl-4 affects multiple physiological processes in Caenorhabditis elegans.
cGMP-dependent protein kinases are key intracellular transducers of cell signaling. We identified a novel dominant mutation in the C. elegans egl-4 cGMP-dependent protein kinase (PKG) and show that this mutation causes increased normal gene activity although it is associated with a reduced EGL-4 protein level. Prior phenotypic analyses of this gain-of-function mutant demonstrated a reduced longevity and a reduced feeding behavior when the animals were left unperturbed. We characterize several additional phenotypes caused by increased gene activity of egl-4. These phenotypes include a small body size, reduced locomotion in the presence of food, a pale intestine, increased intestinal fat storage, and a decreased propensity to form dauer larvae. The multiple phenotypes of egl-4 dominant mutants are consistent with an instructive signaling role of PKG to control many aspects of animal physiology. This is among the first reported gain-of-function mutations in this enzyme of central physiological importance. In a genetic screen we have identified extragenic suppressors of this gain-of-function mutant. Thus, this mutant promises to be a useful tool for identifying downstream targets of PKG.


The antidepressant clomipramine regulates cortisol intracellular concentrations and glucocorticoid receptor expression in fibroblasts and rat primary neurones.
Incubation of LMCAT fibroblasts cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of cortisol, but not of corticosterone. We have suggested that antidepressants do so by inhibiting the LMCAT cells membrane steroid transporter and thus by increasing cortisol intracellular concentrations. We now confirm and extend this model to primary neuronal cultures. Clomipramine, a tricyclic antidepressant, increased the intracellular accumulation of 3H-cortisol, but not 3H-corticosterone, in LMCAT cells (+80%) and primary rat neurones (+20%). The latter finding is the first demonstration that a membrane steroid transporter is present in neurones. Moreover, verapamil, a membrane steroid transporter inhibitor, reduced the effects of clomipramine on the intracellular accumulation of 3H-cortisol in LMCAT cells. Finally, clomipramine also decreased GR expression (whole-cell Western blot) in LMCAT cells (50% reduction) and primary rat neurones (80% reduction). This GR downregulation can explain the reduced GR-mediated gene transcription previously described under experimental conditions that do not elicit the effects on the LMCAT cells steroid transporter. This work further supports the hypothesis that membrane steroid transporters regulating the access of glucocorticoids to the brain in vivo are a fundamental target for antidepressant action.


The 5th Conference on Asian Trends in Prostate Cancer Hormone Therapy.
The Conference on Asian Trends in Prostate Cancer Hormone Therapy is an annual forum for Asian urologists now in its 5th year. The 2006 conference, held in Bali, Indonesia, was attended by 27 leading urologic oncologists from China, Indonesia, Japan, Korea, Singapore, and Taiwan and featured a packed program of presentations and discussions on a wide range of topics such as relationships among clinicians and the newly opened Asia Regional Office for Cancer Control of the International Union Against Cancer (UICC), detection rates of prostate cancer by biopsy in each of the 6 Asian countries, and favored treatment modalities for hormone-refractory prostate cancer (HRPC) in each country. The first session of the conference kicked off with a keynote lecture entitled "Activities of the UICC ARO". UICC's new office will be the nerve center for its activities in the Asia region. Along with the Asian Pacific Organization for Cancer Prevention (APOCP), UICC aims to shift the focus of attention to cancer control. As such APOCP's long-running publication the APJCP is to be re-launched as the Asian Pacific Journal of Cancer Control. Although UICC is primarily concerned with cancer, several risk factors for cancer are common also to other non-communicable diseases such as diabetes and heart disease, and an important strategy is to implement measures to control these various pathologic conditions as a whole. Apart from contributing to an Asian prostate cancer registry the UICC-ARO will provide training courses, working groups, and assistance in collecting and processing data. The keynote lecture was followed by a roundtable discussion on possible ways in which clinicians from each Asian country can work with UICC. A number of suggestions were put forth including better registration, epidemiology research, possible implementation of UICC prostate cancer guidelines, early detection and screening, and roles of diet and phytotherapy. The underlying reasons for the large but dwindling difference in incidence rates of prostate cancer in various regions of Asia should be studied while the opportunity lasts. Session 2 was devoted to 6 presentations on detection rates by biopsy in each country. Although biopsy is the gold standard for detecting prostate cancer in most areas, indications for conducting biopsy are different in each country. For example, in Indonesia doctors may use PSAD 0.15 as the cutoff level. TRUS-guided biopsy is most widely used in Asian countries. Traditional sextant biopsy is often performed, although multiple-core biopsy is commonly available and associated with better detection rates, especially in men with large prostate volume. Positive DRE, high PSA, and older age were identified as factors associated with high biopsy detection rate, although elevated PSA has limited specificity. First biopsy in men with elevated PSA had a positive detection rate of approximately 30% in all countries. Community-based screening in some countries has an overall detection rate of approximately 1%. The favorable treatment modality for HRPC was the subject of the final session. First priority for doctors in all 6 countries is to maintain serum testosterone at castration level. Many therapeutic options are available, from cytotoxic drugs to traditional herbal medicines Chemotherapeutic agents such as estramustine, docetaxel, cyclophosphamide, and mitoxantrone are often given to patients with HRPC although not all are available in every country. Prednisone and dexamethasone are used for secondary hormonal therapy. External beam radiotherapy, radioisotopic drugs such as strontium 89, and bisphosphonates are common choices to control bone pain.


Cortical diffusivity investigation in posterior cortical atrophy and typical Alzheimer's disease.
To investigate the global cortical and regional quantitative features of cortical neural architecture in the brains of patients with posterior cortical atrophy (PCA) and typical Alzheimer's disease (tAD) compared with elderly healthy controls (HC). A novel diffusion MRI method, that has been shown to correlate with minicolumnar organization changes in the cerebral cortex, was used as a surrogate of neuropathological changes in dementia. A cohort of 15 PCA patients, 23 tAD and 22 healthy elderly controls (HC) were enrolled to investigate the changes in cortical diffusivity among groups. For each subject, 3 T MRI T1-weighted images and diffusion tensor imaging (DTI) scans were analysed to extract novel cortical DTI derived measures (AngleR, PerpPD and ParlPD). Receiver operating characteristics (ROC) curve analysis and the area under the curve (AUC) were used to assess the group discrimination capability of the method. The results showed that the global cortical DTI derived measures were able to detect differences, in both PCA and tAD patients compared to healthy controls. The AngleR was the best measure to discriminate HC from tAD (AUC = 0.922), while PerpPD was the best measure to discriminate HC from PCA (AUC = 0.961). Finally, the best global measure to differentiate the two patient groups was ParlPD (AUC = 0.771). The comparison between PCA and tAD patients revealed a different pattern of damage within the AD spectrum and the regional comparisons identified significant differences in key regions including parietal and temporal lobe cortical areas. The best AUCs were shown by PerpPD right lingual cortex (AUC = 0.856), PerpPD right superior parietal cortex (AUC = 0.842) and ParlPD right lateral occipital cortex (AUC = 0.826). Diagnostic group differences were found, suggesting that the new cortical DTI analysis method may be useful to investigate cortical changes in dementia, providing better characterization of neurodegeneration, and potentially aiding differential diagnosis and prognostic accuracy.


Cocaine-induced Psychosis and Brain-derived Neurothrophic Factor in Patients with Cocaine Dependence: Report of Two Cases.
Brain-derived neurotrophic factor (BDNF) is linked to numerous brain functions. In addition, BDNF alterations contribute to neurological, mental, and addictive disorders. Cocaine dependence has received much attention recently due to its prevalence and psychological effects. Symptoms of psychosis are one of the most serious adverse events precipitated by cocaine use. It is particularly important to identify patients at risk of developing cocaine-induced psychosis (CIP). We described two cases of patients with cocaine dependence who presented with CIP and had changes in their BDNF levels during the psychotic episode. BDNF levels were initially low in both patients, and then decreased by more than 50% in association with CIP. The relationship between BDNF and psychosis is described in the literature. These cases revealed that BDNF levels decreased during a CIP episode and, thus, it is necessary to investigate BDNF and its relationship with CIP further.


Maturation of early endosomes and vesicular traffic to lysosomes in relation to membrane recycling.
The controversy whether endocytic processing occurs by organellar maturation or by vesicular traffic has not been resolved. It is also not clear whether maturation continues to the stage of lysosomes, to what extent it involves a decrease in organellar fusogenicity, and how it relates to membrane recycling. Maturation and vesicular traffic imply distinct kinetics for the intermingling of endocytic markers after sequential endocytic uptake. We have studied the kinetics of intermingling of fluid-phase markers (fluorescein-labelled dextran and horseradish peroxidase) and cell surface-derived membrane (labelled by galactosylation) in organelles at early and late stages of the endocytic pathway in macrophage-like P388D1 cells. Intermingling declined by sigmoid kinetics, indicating that endosomes matured within about 3 minutes to become non-fusogenic towards early endosomes. During maturation about 60% of internalized membrane was recycled with T1/2 approximately 2 minutes. Whereas matured endosomes were non-fusogenic towards early endosomes and towards each other, a second phase of intermingling was observed upon delivery to lysosomes. This intermingling occurred by a first-order process (T1/2 approximately 4 minutes), concurrent with recycling of the remaining 40% of internalized membrane marker. These kinetic observations suggest a model for endocytic processing which reconciles maturation of early endosomes with the known function of carrier vesicles: Endocytic carrier vesicles do not bud off from permanent early endosomes as proposed for vesicular traffic, but are derived, together with recycling vesicles, from the maturation of early endosomes which are consumed by this process; these carrier vesicles subsequently mediate delivery to lysosomes by vesicular traffic during which the remaining surface-derived membrane is recycled.


[Detecting poliovirus in wastewater from Armenia, Colombia].
Implementing environmental surveillance for poliovirus circulating from wastewater. Six wastewater samples were collected from each final site within a wastewater collection system in Armenia, Quindío. Virus was extracted and concentrated by a method using polyethylenglycol and sodium chloride as concentrating agent. Polioviruses were identified by polymerase chain reaction assay with group-specific, serotype-specific and Sabin vaccine-specific primers. It was confirmed that the viral detection method is highly efficient. Poliovirus was detected in 5 of 6 (83%) samples collected. Serotype-specific identification revealed the presence of type 1 and type 3 polioviruses in the samples. All of them were of the vaccine type, which provided evidence regarding the non-circulation of wild poliovirus in the country. Wastewater surveillance can be a sensitive tool for detecting poliovirus circulation.


Advances in antiretroviral therapy.
The 14th Conference on Retroviruses and Opportunistic Infections provided a forum for presentation of state-of-the-art research on antiretroviral therapy. This year's conference marked the first public presentation of phase III trials of the lead compounds in 2 new drug classes: maraviroc (a CCR5 inhibitor) and raltegravir (an HIV-1 integrase inhibitor). These agents are likely to be approved by the US Food and Drug Administration this year and should provide major new options for treatment-experienced patients with multidrug resistant virus. Other dominant themes of the conference were the impressive number of presentations describing outcomes of antiretroviral therapy programs in resource-limited settings and new information on mechanisms of drug resistance. Among the latter, the importance of drug resistance mutations occurring in the RNase H and connection domains of the HIV-1 reverse transcriptase was of special note. In addition, substantial new information was presented on other new antiretroviral agents, studies in treatment-naive patients, antiretroviral therapy strategies, prevention of mother-to-child transmission, predictors of clinical response to therapy, and antiretroviral pharmacokinetics. Research in antiretroviral therapy remains dynamic and advances in the field continue to improve our ability to maintain long-term control of HIV-1 replication in infected persons.


Review of Low-Cost 3D Bioprinters: State of the Market and Observed Future Trends.
Three-dimensional (3D) bioprinting has become mainstream for precise and repeatable high-throughput fabrication of complex cell cultures and tissue constructs in drug testing and regenerative medicine, food products, dental and medical implants, biosensors, and so forth. Due to this tremendous growth in demand, an overwhelming amount of hardware manufacturers have recently flooded the market with different types of low-cost bioprinter models-a price segment that is most affordable to typical-sized laboratories. These machines range in sophistication, type of the underlying printing technology, and possible add-ons/features, which makes the selection process rather daunting (especially for a nonexpert customer). Yet, the review articles available in the literature mostly focus on the technical aspects of the printer technologies under development, as opposed to explaining the differences in what is already on the market. In contrast, this paper provides a snapshot of the fast-evolving low-cost bioprinter niche, as well as reputation profiles (relevant to delivery time, part quality, adherence to specifications, warranty, maintenance, etc.) of the companies selling these machines. Specifically, models spanning three dominant technologies-microextrusion, droplet-based/inkjet, and light-based/crosslinking-are reviewed. Additionally, representative examples of high-end competitors (including up-and-coming microfluidics-based bioprinters) are discussed to highlight their major differences and advantages relative to the low-cost models. Finally, forecasts are made based on the trends observed during this survey, as to the anticipated trickling down of the high-end technologies to the low-cost printers. Overall, this paper provides insight for guiding buyers on a limited budget toward making informed purchasing decisions in this fast-paced market.


Enhancing the effectiveness of media messages promoting regular breast self-examination: messages based on innovation adoption principles.
As public health departments have come to rely more and more on the mass media for the promotion of healthful behavior, it has become increasingly desirable to determine the motivating capability of the messages used in this promotion. A fact that is well understood is that many times any message at all is better than none. However, the effectiveness of various media health messages has not been well researched.A study was therefore undertaken of the comparative effectiveness of two different messages describing how to do a breast self-examination. An "experimental message" for the study was designed by applying the principles that facilitate innovation adoption to the message's format and presentation. This message's impact was then compared with that of the American Cancer Society's pamphlet "How To Examine Your Breasts." This pamphlet had been mailed to a sample of women similar to those receiving the experimental message, but who lived in a different geographic area. The use in each area of control groups who had received no messages afforded an opportunity to study maturation effects (other factors than the mailings that might have influenced study results).The experimental message proved more successful in persuading women to adopt breast self-examination than the comparison message. The women who reported a change in breast self-examination practice following the mailing could be characterized as having a more extensive social support system to promote breast examinations and as having a pre-experiment perception that breast self-examination was a complex practice to perform repeatedly at regular intervals.


Intercontinental dispersal of bacteria and archaea by transpacific winds.
Microorganisms are abundant in the upper atmosphere, particularly downwind of arid regions, where winds can mobilize large amounts of topsoil and dust. However, the challenge of collecting samples from the upper atmosphere and reliance upon culture-based characterization methods have prevented a comprehensive understanding of globally dispersed airborne microbes. In spring 2011 at the Mt. Bachelor Observatory in North America (2.8 km above sea level), we captured enough microbial biomass in two transpacific air plumes to permit a microarray analysis using 16S rRNA genes. Thousands of distinct bacterial taxa spanning a wide range of phyla and surface environments were detected before, during, and after each Asian long-range transport event. Interestingly, the transpacific plumes delivered higher concentrations of taxa already in the background air (particularly Proteobacteria, Actinobacteria, and Firmicutes). While some bacterial families and a few marine archaea appeared for the first and only time during the plumes, the microbial community compositions were similar, despite the unique transport histories of the air masses. It seems plausible, when coupled with atmospheric modeling and chemical analysis, that microbial biogeography can be used to pinpoint the source of intercontinental dust plumes. Given the degree of richness measured in our study, the overall contribution of Asian aerosols to microbial species in North American air warrants additional investigation.


Correlates of Self-Estimated Intelligence.
This paper reports two studies examining correlates of self-estimated intelligence (SEI). In the first, 517 participants completed a measure of SEI as well as self-estimated emotional intelligence (SEEQ), physical attractiveness, health, and other ratings. Males rated their IQ higher (74.12 vs. 71.55) but EQ lower (68.22 vs. 71.81) than females but there were no differences in their ratings of physical health in Study 1. Correlations showed for all participants that the higher they rated their IQ, the higher their ratings of EQ, attractiveness, and health. A regression of self-estimated intelligence onto three demographic, three self-ratings and three beliefs factors accounted for 30% of the variance. Religious, educated males who did not believe in alternative medicine gave higher SEI scores. The second study partly replicated the first, with an N = 475. Again, males rated their IQ higher (106.88 vs. 100.71) than females, but no difference was found for EQ (103.16 vs. 103.74). Males rated both their attractiveness (54.79 vs. 49.81) and health (61.24 vs. 55.49) higher than females. An objective test-based cognitive ability and SEI were correlated r = 0.30. Correlations showed, as in Study 1, positive relationships between all self-ratings. A regression showed the strongest correlates of SEI were IQ, sex and positive self-ratings. Implications and limitations are noted.


A fast identification algorithm for Box-Cox transformation based radial basis function neural network.
In this letter, a Box-Cox transformation-based radial basis function (RBF) neural network is introduced using the RBF neural network to represent the transformed system output. Initially a fixed and moderate sized RBF model base is derived based on a rank revealing orthogonal matrix triangularization (QR decomposition). Then a new fast identification algorithm is introduced using Gauss-Newton algorithm to derive the required Box-Cox transformation, based on a maximum likelihood estimator. The main contribution of this letter is to explore the special structure of the proposed RBF neural network for computational efficiency by utilizing the inverse of matrix block decomposition lemma. Finally, the Box-Cox transformation-based RBF neural network, with good generalization and sparsity, is identified based on the derived optimal Box-Cox transformation and a D-optimality-based orthogonal forward regression algorithm. The proposed algorithm and its efficacy are demonstrated with an illustrative example in comparison with support vector machine regression.


COLLABORATING WITH THE COMMUNITY: THE EXTRA-TERRITORIAL TRANSLATIONAL RESEARCH TEAM.
The purpose of the present study is to suggest a revision of the team science concept to the more inclusive extra-territorial research team (ETRT). Translational thinking is largely marked by the perception of the team as a thing-like structure at the center of the scientific activity. Collaboration accordingly involves bringing external others (e.g., scientists, community members, and clinicians) into the team through limited or dependent participation. We suggest that a promising and innovative way to see the team is as an idea: a schema for assembling and managing relationships among otherwise disparate individuals with vested interests in the problem at hand. Thus, the ETRT can be seen as a process as well as an object. We provide a case study derived from a qualitative analysis of the impact of the logic of translational science on a team assessment of environmental health following an off-coast oil disaster. The ETRT in question displayed the following principles of constructive relationship management: a high sense of adventure given the quick pace and timeliness given the relevance of the oil spill to all team members; regular meetings in the community to avoid the appearance of academic hegemony; open access by lay as well as institutional scientists; integration of emergency management coordinators into the group; and the languages of public health, environmental pharmacology/toxicology and coastal culture seamlessly interwoven in discussion. The ETRT model is an appropriate strategy for mobilizing and integrating the knowledge and skills needed for comprehensive science and service responses, especially during crisis.


Three-dimensional structure of cholera toxin penetrating a lipid membrane.
Two-dimensional crystals of cholera toxin bound to receptors in a lipid membrane give diffraction extending to 15 A resolution. Three-dimensional structure determination reveals a ring of five B subunits on the membrane surface, with one-third of the A subunit occupying the center of the ring. The remaining mass of the A subunit appears to penetrate the hydrophobic interior of the membrane. Cleavage of a disulfide bond in the A subunit, which activates the toxin, causes a major conformational change, with the A subunit mostly exiting from the B ring.


Is poker a game of skill or chance? A quasi-experimental study.
Due to intensive marketing and the rapid growth of online gambling, poker currently enjoys great popularity among large sections of the population. Although poker is legally a game of chance in most countries, some (particularly operators of private poker web sites) argue that it should be regarded as a game of skill or sport because the outcome of the game primarily depends on individual aptitude and skill. The available findings indicate that skill plays a meaningful role; however, serious methodological weaknesses and the absence of reliable information regarding the relative importance of chance and skill considerably limit the validity of extant research. Adopting a quasi-experimental approach, the present study examined the extent to which the influence of poker playing skill was more important than card distribution. Three average players and three experts sat down at a six-player table and played 60 computer-based hands of the poker variant "Texas Hold'em" for money. In each hand, one of the average players and one expert received (a) better-than-average cards (winner's box), (b) average cards (neutral box) and (c) worse-than-average cards (loser's box). The standardized manipulation of the card distribution controlled the factor of chance to determine differences in performance between the average and expert groups. Overall, 150 individuals participated in a "fixed-limit" game variant, and 150 individuals participated in a "no-limit" game variant. ANOVA results showed that experts did not outperform average players in terms of final cash balance. Rather, card distribution was the decisive factor for successful poker playing. However, expert players were better able to minimize losses when confronted with disadvantageous conditions (i.e., worse-than-average cards). No significant differences were observed between the game variants. Furthermore, supplementary analyses confirm differential game-related actions dependent on the card distribution, player status, and game variant. In conclusion, the study findings indicate that poker should be regarded as a game of chance, at least under certain basic conditions, and suggest new directions for further research.


Home chemotherapy for children with cancer: perspectives from health care professionals.
The goal of this study was to determine the perspectives of healthcare professionals (HPs) from community and hospital settings involved in a paediatric home chemotherapy programme. Using a prospective descriptive study design, HPs including paediatricians, community nurses, hospital clinic nurses, administrators and pharmacists were interviewed using a moderately structured open-ended approach. Through inductive content analysis, data were categorised under three themes reflecting HPs' perspectives on the programme: (1) perceived family benefits, (2) human resources and service delivery considerations and (3) impact on the role of the HP. All HPs reported that home chemotherapy helped reduce both disruption to family life and psychological stress. Community-based HPs reported increased job satisfaction, increased workload and increased frustration related to scheduling challenges. Hospital-based HPs reported decreased patient interaction and discrepancies in workload changes. Both groups emphasised the need for consistency in care and for specific chemotherapy training. Service delivery issues included the need for more clarity in the programme process, improved eligibility criteria, a focus on community laboratory coordination and development of centralised communications.


Evidence of exposure to zoonotic flaviviruses in zoo mammals in Spain and their potential role as sentinel species.
A serosurvey was carried out to assess emerging flavivirus exposure in zoo mammals in Spain and to determine the dynamics of seropositivity in species that were longitudinally sampled during the study period. Sera from 570 zoo animals belonging to 120 mammal species were collected at ten zoos (A-J) in Spain between 2002 and 2019. Twenty-one of these animals, belonging to ten different species, were sampled longitudinally at four of the zoos during the study period. Antigenically-related flavivirus antibodies were detected in 19 (3.3 %; 95 %CI: 2.0-5.2) of the 570 animals analyzed using bELISA. Seropositivity was observed in ten (8.3 %) of the 120 species tested. Five (23.8 %) of the 21 animals sampled more than once presented seropositivity in all samplings whereas seroconversion was only observed in one white rhinoceros (Ceratotherium simum). Flavivirus antibodies were found at six of the ten sampled zoos and in consecutive years between 2008 and 2018. Virus neutralization tests confirmed West Nile virus (WNV), Usutu virus (USUV) and tick-borne encephalitis virus (TBEV) infection in ten (1.8 %; 95 %CI: 0.7-2.8), five (0.9 %; 95 %CI: 0.1-1.6) and one (0.2 %; 95 %CI: 0.0-0.5) animal, respectively. Antibodies against Meaban virus (0 %; 95 %CI: 0.0-0.7 %) were not found in the tested sera. The results demonstrate WNV, USUV and TBEV exposure in zoo mammals, which may be of public health and conservation concern. Seropositivity to WNV and USUV was detected in regions where these viruses have not been reported previously. Anti-WNV antibodies found in zoo animals sampled in 2009 point to WNV circulation at least one year before the first outbreaks were reported in horses and humans in Spain. Our results indicate that zoo mammals could be useful sentinel species for monitoring emerging flavivirus activity in urban areas.


Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis.
Protein tyrosine kinases activate the STAT (signal transducer and activator of transcription) signaling pathway, which can play essential roles in cell differentiation, cell cycle control, and development. However, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon (IFN-gamma) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells. EGF receptor autophosphorylation and mitogen-activated protein kinase activation in response to EGF were similar in both cell lines. The breast cancer cell line MDA-MB-468 exhibited a similar response to A431 cells, i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-gamma treatment. In addition, in a mutant A431 cell line in which STAT activation was abolished, no apoptosis was induced by either EGF or IFN-gamma. We further demonstrated that both EGF and IFN-gamma induced caspase 1 (interleukin-1beta converting enzyme [ICE]) gene expression in a STAT-dependent manner. IFN-gamma was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-gamma in U3A cells into which STAT1 had been reintroduced. Moreover, both EGF-induced apoptosis and IFN-gamma-induced apoptosis were effectively blocked by Z-Val-Ala-Asp-fluoromethylketone (ZVAD) in all the cells tested, and studies from ICE-deficient cells indicated that ICE gene expression was necessary for IFN-gamma-induced apoptosis. We conclude that activation of the STAT signaling pathway can induce apoptosis through the induction of ICE gene expression.