Stress tolerance and virulence of insect-pathogenic fungi are determined by environmental conditions during conidial formation.
The virulence to insects and tolerance to heat and UV-B radiation of conidia of entomopathogenic fungi are greatly influenced by physical, chemical, and nutritional conditions during mycelial growth. This is evidenced, for example, by the stress phenotypes of Metarhizium robertsii produced on various substrates. Conidia from minimal medium (Czapek's medium without sucrose), complex medium, and insect (Lepidoptera and Coleoptera) cadavers had high, moderate, and poor tolerance to UV-B radiation, respectively. Furthermore, conidia from minimal medium germinated faster and had increased heat tolerance and were more virulent to insects than those from complex medium. Low water-activity or alkaline culture conditions also resulted in production of conidia with high tolerance to heat or UV-B radiation. Conidia produced on complex media exhibited lower stress tolerance, whereas those from complex media supplemented with NaCl or KCl (to reduce water activity) were more tolerant to heat and UV-B than those from the unmodified complex medium. Osmotic and nutritive stresses resulted in production of conidia with a robust stress phenotype, but also were associated with low conidial yield. Physical conditions such as growth under illumination, hypoxic conditions, and heat shock before conidial production also induced both higher UV-B and heat tolerance; but conidial production was not decreased. In conclusion, physical and chemical parameters, as well as nutrition source, can induce great variability in conidial tolerance to stress for entomopathogenic fungi. Implications are discussed in relation to the ecology of entomopathogenic fungi in the field, and to their use for biological control. This review will cover recent technologies on improving stress tolerance of entomopathogenic fungi for biological control of insects.


Maximizing the effectiveness of national commitments to protected area expansion for conserving biodiversity and ecosystem carbon under climate change.
Global commitments to protected area expansion should prioritize opportunities to protect climate refugia and ecosystems which store high levels of irrecoverable carbon, as key components of an effective response to biodiversity loss and climate change. The United States and Canada are responsible for one-sixth of global greenhouse gas emissions but hold extensive natural ecosystems that store globally significant above- and below-ground carbon. Canada has initiated a process of protected area network expansion in concert with efforts at reconciliation with Indigenous Peoples, and acknowledged nature-based solutions as a key aspect of climate change mitigation. The US, although not a party to global biodiversity conventions, has recently committed to protecting 30% of its extent by 2030 and achieving the UNFCCC Paris Agreement's mitigation targets. The opportunities afforded by these dual biodiversity conservation and climate commitments require coordinated national and regional policies to ensure that new protected areas maximize biodiversity-focused adaptation and nature-based mitigation opportunities. We address how global commitments can best inform national policy initiatives which build on existing agency mandates for regional planning and species conservation. Previous analyses of global conservation priorities under climate change have been tenuously linked to policy contexts of individual nations and have lacked information on refugia due to limitations of globally available datasets. Comparison and synthesis of predictions from a range of recently developed refugia metrics allow such data to inform planning despite substantial uncertainty arising from contrasting model assumptions and inputs. A case study for endangered species planning for old-forest-associated species in the US Pacific Northwest demonstrates how regional planning can be nested hierarchically within national biodiversity-focused adaptation and nature-based mitigation strategies which integrate refugia, connectivity, and ecosystem carbon metrics to holistically evaluate the role of different land designations and where carbon mitigation and protection of biodiversity's resilience to climate change can be aligned.


A time-indexed reference standard of adverse drug reactions.
Undetected adverse drug reactions (ADRs) pose a major burden on the health system. Data mining methodologies designed to identify signals of novel ADRs are of deep importance for drug safety surveillance. The development and evaluation of these methodologies requires proper reference benchmarks. While progress has recently been made in developing such benchmarks, our understanding of the performance characteristics of the data mining methodologies is limited because existing benchmarks do not support prospective performance evaluations. We address this shortcoming by providing a reference standard to support prospective performance evaluations. The reference standard was systematically curated from drug labeling revisions, such as new warnings, which were issued and communicated by the US Food and Drug Administration in 2013. The reference standard includes 62 positive test cases and 75 negative controls, and covers 44 drugs and 38 events. We provide usage guidance and empirical support for the reference standard by applying it to analyze two data sources commonly mined for drug safety surveillance.


MDM2 mRNA expression is a favorable prognostic factor in non-small-cell lung cancer.
MDM2 is one of the downstream target genes for transcriptional activation by the product of the p53 tumor-suppressor gene. Transactivation of MDM2 gene expression is represented by the presence of a functional p53 protein. We hypothesized that MDM2 mRNA expression may be a more suitable prognostic factor than p53 or MDM2 protein expression and p53 gene mutations. In this study, expression of MDM2 mRNA, p53 protein, and MDM2 protein and mutations of the p53 gene were assessed in 81 lung tumor tissue specimens using RT-PCR, immunohistochemistry, and direct sequencing among exons 5-8, respectively. By immunohistochemistry, 33 and 42 of 81 patients with p53 (40.7%) and MDM2 (51.5%) protein expression were found in lung tumor specimens, respectively. The p53 direct sequencing data indicated that 13 of 81 patients (16.0%) had p53 mutations. However, Kaplan-Meier analysis showed that p53 protein and MDM2 protein expression and p53 mutation were not useful as prognostic factors. Interestingly, the survival of patients with MDM2 mRNA expression was longer than that of patients without MDM2 mRNA expression, though MDM2 mRNA expression was not associated with clinicopathological parameters, including tumor grade, tumor stage, tumor type, and TNM values. Moreover, Cox regression analysis showed that MDM2 mRNA expression was a significantly independent favorable prognostic factor in non-small-cell lung cancer (NSCLC) patients. Thus, measuring MDM2 mRNA expression using RT-PCR may be a simple, useful approach for predicting the survival of NSCLC patients.


The impact of perceived lack of support provided by health and social care services to caregivers of people with motor neuron disease.
Our objective was to investigate the relationship between support by health and social care services and caregiver well-being. A survey, including a generic health status measure (SF-12), a disease-specific measure for patients (ALSAQ-40), the Carer Strain Index (CSI) for caregivers and questions on experiences of health and social care services, was sent to patient members of the MND Association (UK) and their caregivers. A single 'problem score' was calculated from the experience questions and the relationship between the problem score with caregiver and patient well-being was analysed. Most caregivers reported at least one problem with support from services. The most common problems were services not valuing caregivers' experiences, and caregivers not feeling sufficiently involved in planning care. The problem score significantly increased with increasing caregiver strain and worsening mental health. The problem score was also increased as patient well-being decreased. The results suggest that caregiver strain was higher and mental health lower as the number of problems reported increased. A higher perceived lack of caregiver support was also related to a decrease in patient well-being, suggesting that caregivers' needs increase as the disease progresses. This emphasizes the importance of MND caregivers being appropriately supported by health and social care services in their caregiving role.


Chemical renal medullectomy; effect upon reversal of two-kidney, one-clip hypertension in the rat.
1. Chemical renal medullectomy was produced in rats by injection of 2-bromoethylamine hydrobromide. Plasma creatinine and blood pressure were unchanged although urine volume was increased fourfold. 2. Left renal artery constriction resulted in similar degrees of hypertension in both intact and medullectomized rats. This was associated with a significantly smaller rise in plasma renin concentration in the latter. 3. Blood pressure in conscious intact hypertensive rats became normal within 24 h of unclipping whereas blood pressure of medullectomized rats remained significantly elevated. 4. The presence of an intact renal medulla is essential to the complete reversal of two-kidney, one-clip hypertension in the rat. This may reflect the loss of a medullary vasodepressor system.


HDAC5-LSD1 axis regulates antineoplastic effect of natural HDAC inhibitor sulforaphane in human breast cancer cells.
Our recent studies have shown that cross-talk between histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) facilitates breast cancer progression. In this work, we demonstrated that regulatory activity at -356 to -100 bp promoter element plays a critical role in governing HDAC5 transcription. By using DNA affinity precipitation and mass spectrometry, we identified a group of factors that bind to this element. Among these factors, Upstream Transcription Factor 1 (USF1) was shown to play a critical role in controlling HDAC5 transcription. Through screening a panel of epigenetic modifying drugs, we showed that a natural bioactive HDAC inhibitor, sulforaphane, downregulated HDAC5 transcription by blocking USF1 activity. Sulforaphane facilitated LSD1 ubiquitination and degradation in an HDAC5-dependent manner. A comparative microarray analysis demonstrated a genome wide cooperative effect of HDAC5 and LSD1 on cancer-related gene expression. shRNA knockdown and sulforaphane inhibition of HDAC5/LSD1 exhibited similar effects on expression of HDAC5/LSD1 target genes. We also showed that coordinated cross-talk of HDAC5 and LSD1 is essential for the antitumor efficacy of sulforaphane. Combination treatment with sulforaphane and a potent LSD1 inhibitor resulted in synergistic growth inhibition in breast cancer cells, but not in normal breast epithelial cells. Furthermore, combined therapy with sulforaphane and LSD1 inhibitor exhibited superior inhibitory effect on MDA-MB-231 xenograft tumor growth. Taken together, our work demonstrates that HDAC5-LSD1 axis is an effective drug target for breast cancer. Inhibition of HDAC5-LSD1 axis with sulforaphane blocks breast cancer growth and combined treatment with LSD1 inhibitor improves the therapeutic efficacy of sulforaphane.


Resveratrol Prevents Acrylamide-Induced Mitochondrial Dysfunction and Inflammatory Responses via Targeting Circadian Regulator Bmal1 and Cry1 in Hepatocytes.
Acrylamide, mainly formed in Maillard browning reaction during food processing, causes defects in liver circadian clock and mitochondrial function by inducing oxidative stress. Resveratrol is a polyphenol that has powerful antioxidant and anti-inflammatory activity. However, the preventive effects of resveratrol on acrylamide-triggered oxidative damage and circadian rhythm disorders are unclear at the current stage. The present research revealed that resveratrol pretreatment prevented acrylamide-induced cell death, mitochondrial dysfunction, and inflammatory responses in HepG2 liver cells. Acrylamide significantly triggered disorders of circadian genes transcription and protein expressions including Bmal1 and Cry 1 in primary hepatocytes, which were prevented by resveratrol pretreatment. Moreover, we found that the beneficial effects of resveratrol on stimulating Nrf2/NQO-1 pathway and mitochondrial respiration complex expressions in acrylamide-treated cells were Bmal1-dependent. Similarly, the inhibitory effects of resveratrol on inflammation signaling NF-κB were Cry1-dependent. In conclusion, these results demonstrated resveratrol could be a promising compound in suppressing acrylamide-induced hepatotoxicity and balancing the circadian clock.


Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.
Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.


Diuretics as a basis of antihypertensive therapy. An overview.
Diuretics have been, except for during a few recent years, the most commonly used therapy for hypertension. Although use of these agents fell significantly in the early 1990s, since then it has begun to increase again. Their recent return to popularity reflects 3 major factors: (i) recognition of the effectiveness of much lower dosages than previously used, thereby providing good antihypertensive activity with fewer adverse effects; (ii) the excellent reductions in morbidity and mortality achieved by low dosage diuretic-based therapy in multiple randomised controlled trials in elderly patients with hypertension; and (iii) the increasing recognition that some diuretic-induced shrinkage of effective blood volume is essential for the adequate treatment of many, if not most, patients with hypertension. Therefore, diuretics will probably continue to be the basis for antihypertensive therapy, and the indapamide sustained release 1.5 mg formulation provides all the essential characteristics of diuretic therapy.


Transient brain networks underlying interpersonal strategies during synchronized action.
Interpersonal coordination is a core part of human interaction, and its underlying mechanisms have been extensively studied using social paradigms such as joint finger-tapping. Here, individual and dyadic differences have been found to yield a range of dyadic synchronization strategies, such as mutual adaptation, leading-leading, and leading-following behaviour, but the brain mechanisms that underlie these strategies remain poorly understood. To identify individual brain mechanisms underlying emergence of these minimal social interaction strategies, we contrasted EEG-recorded brain activity in two groups of musicians exhibiting the mutual adaptation and leading-leading strategies. We found that the individuals coordinating via mutual adaptation exhibited a more frequent occurrence of phase-locked activity within a transient action-perception-related brain network in the alpha range, as compared to the leading-leading group. Furthermore, we identified parietal and temporal brain regions that changed significantly in the directionality of their within-network information flow. Our results suggest that the stronger weight on extrinsic coupling observed in computational models of mutual adaptation as compared to leading-leading might be facilitated by a higher degree of action-perception network coupling in the brain.


The effect of grounding the human body on mood.
Earthing (grounding) refers to bringing the body in contact with the Earth. Health benefits were previously reported, but no study exists about mood. This study was conducted to assess if Earthing improves mood. 40 adult participants were either grounded or sham-grounded (no grounding) for 1 hr. while relaxing in a comfortable recliner chair equipped with a conductive pillow, mat, and patches connecting them to the ground. This pilot project was double-blinded and the Brief Mood Introspection Scale (comprising 4 mood scales) was used. Pleasant and positive moods statistically significantly improved among grounded-but not sham-grounded-participants. It is concluded that the 1-hr. contact with the Earth improved mood more than expected by relaxation alone. More extensive studies are, therefore, warranted.


Spontaneous brain activity as a source of ideal 1/f noise.
We study the electroencephalogram (EEG) of 30 closed-eye awake subjects with a technique of analysis recently proposed to detect punctual events signaling rapid transitions between different metastable states. After single-EEG-channel event detection, we study global properties of events simultaneously occurring among two or more electrodes termed coincidences. We convert the coincidences into a diffusion process with three distinct rules that can yield the same mu only in the case where the coincidences are driven by a renewal process. We establish that the time interval between two consecutive renewal events driving the coincidences has a waiting-time distribution with inverse power-law index mu approximately 2 corresponding to ideal 1/f noise. We argue that this discovery, shared by all subjects of our study, supports the conviction that 1/f noise is an optimal communication channel for complex networks as in art or language and may therefore be the channel through which the brain influences complex processes and is influenced by them.


Effect of macro-creatine kinase and increased creatine kinase BB on the rapid diagnosis of patients with suspected acute myocardial infarction in the emergency department.
Although there are more sensitive and earlier diagnostic markers for the diagnosis of acute myocardial infarction (AMI), measurement of creatine kinase (CK) MB isoenzyme (CKMB) using the immunoinhibition method is still widely used in stat laboratories. In this study, 3,290 patients with the prediagnosis of AMI underwent physical examinations, electrocardiography, and repetitive measurements of CK, CKMB activity, and CKMB mass, and 304 of them were diagnosed as having AMI. Electrophoresis of CK and CKMB mass was performed for the samples from 415 patients whose CKMB activity values were found to be increased and were not correlated with total CK levels. According to CKMB activity, CK electrophoresis, and CKMB index (100 x CKMB activity/CK) values, macro-CK (MCK) and/or increased CKBB levels were detected in 27 cases (MCK-I in 10 cases, MCK-II in 9, increased CKBB in 5, and both MCK-II and increased CKBB in 3). CKMB activity was found to be increased for all except one patient (96.3%), and the CKMB index was >25% in 25 (92.5%) of 27 cases. CKMB mass values were within the normal range in 25 of the cases with MCK. Two patients with MCK-I were diagnosed as having AMI because of increased CKMB mass and positive electrocardiography findings. The incidence of MCK and/or high CKBB levels (0.82%) in the whole group was similar to that reported for a normal population. MCK existence and increased CKBB levels may cause misleading diagnoses if CKMB mass measurements and/or CKMB index values are not used together for patients with suspected AMI.


Obese Adolescents with Type 2 Diabetes Mellitus Have Hippocampal and Frontal Lobe Volume Reductions.
The rates of type 2 diabetes (T2DM) continue to parallel the rising rates of obesity in the United States, increasingly affecting adolescents as well as adults. Hippocampal and frontal lobe reductions have been found in older adults with type 2 diabetes, and we sought to ascertain if these brain alterations were also present in obese adolescents with T2DM. In a cross-sectional study we compared MRI-based regional brain volumes of 18 obese adolescents with T2DM and 18 obese controls without evidence of marked insulin resistance. Groups were matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index, and waist circumference. Relative to obese controls, adolescents with T2DM had significantly reduced hippocampal and prefrontal volumes, and higher rates of global cerebral atrophy. Hemoglobin A1c, an index of long-term glycemic control, was inversely associated with prefrontal volume and positively associated with global cerebral atrophy (both p < 0.05). Brain integrity is negatively impacted by T2DM already during adolescence, long before the onset of overt macrovascular disease. Paralleling the findings of greater vascular and renal complications among obese adolescents with severe insulin resistance and T2DM relative to their age-matched peers with type 1 diabetes, we find clear evidence of possible brain complications. Our findings call for aggressive and early intervention to limit the negative impact of obesity-associated insulin resistance leading to T2DM on the developing brains of adolescents.


The effect of ocular aberrations on steady-state errors of accommodative response.
It is well accepted that the accommodation system is characterized by steady-state errors in focus. The purpose of this study was to correlate these errors with changes in ocular wavefront aberration and corresponding image quality when accommodating. A wavefront analyzing system, the Complete Ophthalmic Analysis System (COAS), was used in conjunction with a Badal optometer to allow continuous recording of the aberration structure of the eye for a range of accommodative demands (up to 8 D). Fifty consecutive recordings from seven subjects were taken. Monocular accommodative response was calculated as (i) the equivalent refraction minimizing wavefront error and (ii) the defocus needed to optimize the modulation transfer function at high spatial frequencies. Previously reported changes in ocular aberrations with accommodation (e.g., the shift of spherical aberration to negative values) were confirmed. Increased accommodation errors for near targets (lags) were evident for all subjects, although their magnitude showed a significant intersubject variability. It is concluded that the one-to-one stimulus/response slope in accommodation function should not always be considered as ideal, because higher order aberrations, especially changes of spherical aberration, may influence the actual accommodative demand. Fluctuations may serve to preserve image quality when errors of accommodation are moderate, by temporarily searching for the best focus.


Prevalence of depression and its relationship with work characteristics in a sample of public workers.
Occupation is a fundamental right, enabling social interaction and financial support for the individual. However, it is an undeniable source of stress, with consequences for physical and mental health. The prevalence of depression and somatic complaints were assessed in 1,013 public workers using the Beck Depression Inventory and a questionnaire investigating for the presence of somatic problems designed by the research team. The results were related to demographic characteristics, history of previous depressive episodes, work schedule (day work, night and day rotating shift work, day rotating shift work), and duration of current work schedule. There were more cases of moderate depression in the day rotating shift workers (84%) than in those working at night (83%). More women had mild or moderate depression than men (22% and 4% versus 10% and 3%, respectively). Severe depression was found only in men. Nearly 10% of depressed individuals reported previous depressive episodes. A link between depression and somatic complaints was also found. In particular, 59% of depressed subjects reported gastrointestinal complaints and 41% did not (P<0.001). In conclusion, the occurrence of depressive symptoms could be facilitated by occupation. A history of depressive symptoms should not be neglected, given the risk of recurrence. Somatic complaints could represent a "wake-up call" regarding depression. Global assessment and effective support are fundamental for promotion of a better quality of life in the at-risk category of workers.


A balance between two nuclear localization sequences and a nuclear export sequence governs extradenticle subcellular localization.
During animal development, transcription factor activities are modulated by several means, including subcellular localization. The Hox cofactor Extradenticle (Exd) has a dynamic subcellular localization, such that Exd is cytoplasmic by default, but is nuclear when complexed with another homeodomain protein, Homothorax (Hth). These observations raise the question of whether dimerization with Hth simply induces Exd's nuclear localization or, alternatively, if Hth is also necessary for Exd activity. To address this question, we analyzed the nuclear transport signals in Exd, including a divergent nuclear export signal (NES) and two nuclear localization signals (NLSs). We show that, although these signals are weak compared to canonical signals, they balance each other in Exd. We also provide evidence that Exd contains an NLS mask that contributes to its cytoplasmic localization. With these signals characterized, we generated forms of Exd that are nuclear localized in the absence of Hth. Surprisingly, although these Exd forms are functional, they do not phenocopy Hth overexpression. These findings suggest that Hth is required for Exd activity, not simply for inducing its nuclear localization.


Teams with lower injury rates have greater success in the Currie Cup rugby union competition.
Professional football teams that rank high on the log at the end of the season generally have fewer injuries than teams that rank lower on the log. This highlights the importance of implementing injury prevention measures, not only to protect player welfare and ensure their longevity in the sport, but also to improve the performance of the team. The association between a low incidence of injury and superior performance during a season may be even more relevant in sports with a higher incidence of injury than football, such as rugby union. To examine this association in the South African Currie Cup rugby union competition, time-loss (≥ 1 day training/match play missed) injury data and final position in the competition was examined over five-seasons. Teams who ranked in 1st position had significantly lower average injury rates than teams who ranked in last position [48 injuries per 1 000 player hours (95% C.I 20 to 76) vs 130 injuries per 1 000 player hours (95% C.I 79 to 180)]. More specifically, the team with the lowest injury rate in each season ranked in 1st or 2nd position. This team performance aspect of injury prevention should be highlighted more. In particular, this should be used to assist with communicating the importance of injury prevention programmes to stakeholders directly involved with budgetary allocations in the team.


Wnt3a Expression Is Associated with Epithelial-Mesenchymal Transition and Impacts Prognosis of Lung Adenocarcinoma Patients.
Background: Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and migration during cancer metastasis. Wnt3a is one of the ligands in canonical Wnt/β-catenin signaling pathway, which contributes to the carcinogenesis and progression of lung cancer cell lines. The aim of this study was to evaluate the association between Wnt3a and EMT-related proteins (E-cadherin and N-cadherin), and to further investigate its impact on prognosis of lung adenocarcinoma patients. Methods: A total of 147 lung adenocarcinoma patients were included and their clinicopathological characteristics were collected in this retrospective study. The expression levels of Wnt3a, E-cadherin and N-cadherin in post-surgery cancerous and adjacent normal tissues were assessed by immunohistochemistry. The association between Wnt3a and EMT-related proteins and their prognostic values were systematically evaluated. HCC827 and PC9 cell lines were treated with Wnt3a to detect the expression of EMT-related and Wnt/β-catenin signaling-associated proteins, as well as the in vitro migration and invasion abilities. Results: High Wnt3a expression level was significantly associated with low E-cadherin (P<0.001) and high N-cadherin (P<0.001) expression levels in lung adenocarcinoma tissues. Besides, high Wnt3a level predicted poorer lung adenocarcinoma survival by univariate Cox analysis (P=0.001), while the multivariate result was not significant (P=0.355). Subgroup analysis suggested that the prognostic value of Wnt3a expression level was significant in stage T1-T2 (log rank P=0.003) and stage N0 (log rank P=0.031) patients. The multivariate Cox analysis suggested N-cadherin was an independent prognostic factor for lung adenocarcinoma patients (P=0.012). After including these markers into a nomogram, the Harrell's C-index of the nomogram was 0.755. The decision-curve analysis of our nomogram performed net benefit at the threshold probability from 21.6% to 82.0%, and the current model had a better prognostic value than TNM-classification with a lower Akaike information criterion (AIC) value of 166.54. In vitro experiments suggested that Wnt3a could regulate EMT-related proteins and promotes in vitro invasion and migration abilities. Conclusions: Wnt3a could regulate EMT-related proteins and promote the migration and invasion process of lung adenocarcinoma. Although its value as an independent prognostic factor was limited, the combined model suggested good prognostic performance for lung adenocarcinoma patients.


Paeoniflorin inhibits IL-1β-induced MMP secretion via the NF-κB pathway in chondrocytes.
Paeoniflorin serves important cellular roles, exerting anti-cancer, anti-inflammatory and anti-pulmonary fibrosis effects and possesses immune-modulatory properties. However, the exact role of paeoniflorin in the pathogenesis of osteoarthritis (OA) remains unclear. The aim of the present study was to investigate the effects of paeoniflorin on articular surfaces in vitro. Rat chondrocytes were cultured in vitro and an MTT assay was performed to assess chondrocyte survival. Following treatment with interleukin (IL)-1β and paeoniflorin, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) was examined using reverse transcription-quantitative polymerase chain reaction and western blotting. The interleukin (IL)-1β-induced nuclear factor (NF)-κB pathway activation was also investigated. The results demonstrated that paeoniflorin was able to downregulate the expression of MMP and increase the expression of TIMP-1ntmRNA and protein in IL-1β-induced rat chondrocytes. Furthermore, treating chondrocytes with paeoniflorin blocked the activation of NF-κB. These results suggest that paeoniflorin may serve am anti-catabolic role in the progression of OA and may be an effective preventative treatment for OA.


Towards the Automatic Classification of Avian Flight Calls for Bioacoustic Monitoring.
Automatic classification of animal vocalizations has great potential to enhance the monitoring of species movements and behaviors. This is particularly true for monitoring nocturnal bird migration, where automated classification of migrants' flight calls could yield new biological insights and conservation applications for birds that vocalize during migration. In this paper we investigate the automatic classification of bird species from flight calls, and in particular the relationship between two different problem formulations commonly found in the literature: classifying a short clip containing one of a fixed set of known species (N-class problem) and the continuous monitoring problem, the latter of which is relevant to migration monitoring. We implemented a state-of-the-art audio classification model based on unsupervised feature learning and evaluated it on three novel datasets, one for studying the N-class problem including over 5000 flight calls from 43 different species, and two realistic datasets for studying the monitoring scenario comprising hundreds of thousands of audio clips that were compiled by means of remote acoustic sensors deployed in the field during two migration seasons. We show that the model achieves high accuracy when classifying a clip to one of N known species, even for a large number of species. In contrast, the model does not perform as well in the continuous monitoring case. Through a detailed error analysis (that included full expert review of false positives and negatives) we show the model is confounded by varying background noise conditions and previously unseen vocalizations. We also show that the model needs to be parameterized and benchmarked differently for the continuous monitoring scenario. Finally, we show that despite the reduced performance, given the right conditions the model can still characterize the migration pattern of a specific species. The paper concludes with directions for future research.


Factors affecting flavor perception in space: Does the spacecraft environment influence food intake by astronauts?
The intention to send a crewed mission to Mars involves a huge amount of planning to ensure a safe and successful mission. Providing adequate amounts of food for the crew is a major task, but 20 years of feeding astronauts on the International Space Station (ISS) have resulted in a good knowledge base. A crucial observation from the ISS is that astronauts typically consume only 80% of their daily calorie requirements when in space. This is despite daily exercise regimes that keep energy usage at very similar levels to those found on Earth. This calorie deficit seems to have little effect on astronauts who spend up to 12 months on the ISS, but given that a mission to Mars would take 30 to 36 months to complete, there is concern that a calorie deficit over this period may lead to adverse effects in crew members. The key question is why astronauts undereat when they have a supply of food designed to fully deliver their nutritional needs. This review focuses on evidence from astronauts that foods taste different in space, compared to on Earth. The underlying hypothesis is that conditions in space may change the perceived flavor of the food, and this flavor change may, in turn, lead to underconsumption by astronauts. The key areas investigated in this review for their potential impact on food intake are the effects of food shelf life, physiological changes, noise, air and water quality on the perception of food flavor, as well as the link between food flavor and food intake.


Preimplantation Exposure to Bisphenol A and Triclosan May Lead to Implantation Failure in Humans.
Endocrine disrupting chemicals (EDCs) are chemicals that have the capacity to interfere with normal endocrine systems. Two EDCs, bisphenol A (BPA) and triclosan (TCS), are mass-produced and widespread. They both have estrogenic properties and similar chemical structures and pharmacokinetic features and have been detected in human fluids and tissues. Clinical evidence has suggested a positive association between BPA exposure and implantation failure in IVF patients. Studies in mouse models have suggested that preimplantation exposure to BPA and TCS can lead to implantation failure. This paper reviews the relationship between preimplantation exposure to BPA and TCS and implantation failure and discusses the remaining problems and possible solutions.


Psychiatric Disease and Post-Acute Traumatic Brain Injury.
Psychiatric disorders are common following traumatic brain injury (TBI) and can include depression, anxiety, and psychosis, as well as other maladaptive behaviors and personality changes. The epidemiologic data of psychiatric disorders post-TBI vary widely, although the incidence and prevalence rates typically are higher than in the general population. Although the experience of psychiatric symptoms may be temporary and may resolve in the acute period, many patients with TBI can experience psychopathology that is persistent or that develops in the post-acute period. Long-term psychiatric disorder, along with cognitive and physical sequelae and greater risk for substance use disorders, can pose a number of life-long challenges for patients and their caregivers, as they can interfere with participation in rehabilitation as well as limit functional independence in the community. The current review of the literature considers the common psychiatric problems affecting individuals with TBI in the post-acute period, including personality changes, psychosis, executive dysfunction, depression, anxiety, and substance misuse. Although treatment considerations (pharmacological and nonpharmacological) are referred to, an extensive description of such protocols is beyond the scope of the current review. The impact of persistent psychiatric symptoms on perceived caregiver burden and distress is also discussed.


IART: intraoperative avidination for radionuclide treatment. A new way of partial breast irradiation.
A new procedure, known as Intraoperative Avidination for Radionuclide Therapy (IART), is described in breast cancer patients. In this paper, we provide proof of the principle that intraoperative injection of avidin in the tumour bed after quadrantectomy allows homing in of intravenously (IV) administered radioactive biotin to the target site. This approach of targeted therapy consists of two steps: (i) "avidination" of the anatomical area of the tumour with avidin injected by the surgeon, into and around the tumour bed; (ii) targeting the anatomical area of the tumour by IV injection of radiolabelled biotin. The scintigraphic images demonstrated fast and stable uptake of labelled biotin at the site of operated breast. The radiation dose released to the index quadrant was more than 5 Gy/GBq, consistent with a boost of 20 Gy for an activity of 3.7 GBq 90Y-biotin (100mCi). A further large clinical trial facing IART in combination with reduced external-beam radiotherapy is, in our opinion, fully justified.


Asbestos is still with us: repeat call for a universal ban.
All forms of asbestos are proven human carcinogens. All forms of asbestos cause malignant mesothelioma, lung, laryngeal, and ovarian cancers, and may cause gastrointestinal and other cancers. No exposure to asbestos is without risk. Asbestos cancer victims die painful lingering deaths. These deaths are almost entirely preventable. When evidence of the carcinogenicity of asbestos became incontrovertible, concerned parties, including the Collegium Ramazzini, called for a universal ban on the mining, manufacture, and use of asbestos in all countries around the world (J Occup Environ Med. 1999;41:830-832). Asbestos is now banned in 52 countries, and safer products have replaced many materials that once were made with asbestos. Nonetheless, a large number of countries still use, import, and export asbestos and asbestos-containing products. And in many countries that have banned other forms of asbestos, the so-called "controlled use" of chrysotile asbestos is exempted from the ban, an exemption that has no basis in medical science but rather reflects the political and economic influence of the asbestos mining and manufacturing industry. All countries of the world have an obligation to their citizens to join in the international endeavor to ban all forms of asbestos. An international ban on asbestos is urgently needed.


Klinefelter syndrome and cancer: from childhood to adulthood.
The classic clinical manifestations of Klinefelter syndrome (KS) are expressions of the primary hypogonadism that causes severe alterations of the reproductive and endocrine functions of the testis. It is a syndrome that causes infertility, and in addition leads to multiple disorders that involve a variety of tissues and organs. Important medical conditions associated with KS are categorized as: 1) motor, cognitive, and behavioral dysfunction; 2) tumors; 3) vascular disease and 4) endocrine/ metabolic and autoimmune diseases. The overall incidence of cancer in men with this syndrome is similar to that of the general population, but some malignancies show a significantly higher prevalence in these patients. It is possible that the increased risk of developing certain cancers can be attributed to a direct effect of the chromosomal abnormality (the supernumerary X chromosome), or the combined action of the abnormal chromosomes and hormonal imbalances. Although data in the literature on cancer and KS are abundant, most of them are individual case reports. Only three epidemiological studies with relatively large cohorts provide data with greater reliability, although each has inherent imitations related to study design. This review paper summarizes the current knowledge about cancer risk from childhood to adulthood in patients with KS.


Modeling HER2 effects on cell behavior from mass spectrometry phosphotyrosine data.
Cellular behavior in response to stimulatory cues is governed by information encoded within a complex intracellular signaling network. An understanding of how phenotype is determined requires the distributed characterization of signaling processes (e.g., phosphorylation states and kinase activities) in parallel with measures of resulting cell function. We previously applied quantitative mass spectrometry methods to characterize the dynamics of tyrosine phosphorylation in human mammary epithelial cells with varying human epidermal growth factor receptor 2 (HER2) expression levels after treatment with epidermal growth factor (EGF) or heregulin (HRG). We sought to identify potential mechanisms by which changes in tyrosine phosphorylation govern changes in cell migration or proliferation, two behaviors that we measured in the same cell system. Here, we describe the use of a computational linear mapping technique, partial least squares regression (PLSR), to detail and characterize signaling mechanisms responsible for HER2-mediated effects on migration and proliferation. PLSR model analysis via principal component inner products identified phosphotyrosine signals most strongly associated with control of migration and proliferation, as HER2 expression or ligand treatment were individually varied. Inspection of these signals revealed both previously identified and novel pathways that correlate with cell behavior. Furthermore, we isolated elements of the signaling network that differentially give rise to migration and proliferation. Finally, model analysis identified nine especially informative phosphorylation sites on six proteins that recapitulated the predictive capability of the full model. A model based on these nine sites and trained solely on data from a low HER2-expressing cell line a priori predicted migration and proliferation in a HER2-overexpressing cell line. We identify the nine signals as a "network gauge," meaning that when interrogated together and integrated according to the quantitative rules of the model, these signals capture information content in the network sufficiently to predict cell migration and proliferation under diverse ligand treatments and receptor expression levels. Examination of the network gauge in the context of previous literature indicates that endocytosis and activation of phosphoinositide 3-kinase (PI3K)-mediated pathways together represent particularly strong loci for the integration of the multiple pathways mediating HER2's control of mammary epithelial cell proliferation and migration. Thus, a PLSR modeling approach reveals critical signaling processes regulating HER2-mediated cell behavior.


Automatic front-crawl temporal phase detection using adaptive filtering of inertial signals.
This study introduces a novel approach for automatic temporal phase detection and inter-arm coordination estimation in front-crawl swimming using inertial measurement units (IMUs). We examined the validity of our method by comparison against a video-based system. Three waterproofed IMUs (composed of 3D accelerometer, 3D gyroscope) were placed on both forearms and the sacrum of the swimmer. We used two underwater video cameras in side and frontal views as our reference system. Two independent operators performed the video analysis. To test our methodology, seven well-trained swimmers performed three 300 m trials in a 50 m indoor pool. Each trial was in a different coordination mode quantified by the index of coordination. We detected different phases of the arm stroke by employing orientation estimation techniques and a new adaptive change detection algorithm on inertial signals. The difference of 0.2 ± 3.9% between our estimation and video-based system in assessment of the index of coordination was comparable to experienced operators' difference (1.1 ± 3.6%). The 95% limits of agreement of the difference between the two systems in estimation of the temporal phases were always less than 7.9% of the cycle duration. The inertial system offers an automatic easy-to-use system with timely feedback for the study of swimming.


Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways.
Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, PI3 kinase, MAP kinase, NF-kappaB and Wnt/beta-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGFbeta was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent beta-catenin was monitored in response to the inhibition of GSK3beta. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGFbeta-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach.


Serum matrix metalloproteinase 3 levels during treatment with sulfasalazine or combination of methotrexate and sulfasalazine in patients with early rheumatoid arthritis.
To determine the effects of treatment with sulfasalazine (SSZ) or the combination of methotrexate (MTX) and SSZ on serum matrix metalloproteinase 3 (MMP-3) levels in patients with early rheumatoid arthritis (RA). Eighty-two patients with early RA (symptoms < 1 year and DMARD-naive at presentation) were selected who had been treated with SSZ (2000 mg/day) or with the combination of MTX (7.5-15 mg/week) and SSZ. Serum MMP-3 levels, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), swollen joint count (SJC), tender joint count (TJC), Ritchie articular index (RAI), and the Disease Activity Score (DAS) were determined at 4 week intervals during a followup of 28 weeks for each treatment group. Response was based on clinical grounds and CRP at 12, 20, and 28 weeks. SSZ responders (n = 52) had lower baseline values of serum MMP-3, CRP, and ESR, compared to partial/nonresponders (n = 30), but did not differ in joint scores and DAS. In the SSZ responder group all variables decreased. In the SSZ partial/nonresponders, CRP, ESR, and SJC decreased in contrast to serum MMP-3, TJC. RAI, and DAS-3. After addition of MTX all variables decreased in 24 of the 30 patients who had shown a partial or no response taking SSZ. In the SSZ responders there was a delayed decrease in serum MMP-3 compared to CRP. Serum MMP-3 levels decrease in patients with early RA who respond to SSZ or to the combination of MTX and SSZ. In patients who respond to SSZ the changes in serum MMP-3 levels indicate a delayed response compared to CRP.


DNA sequence divergence and functional conservation at the STB locus of yeast 2 microns circle variants.
2 microns DNA isolated from industrial Saccharomyces cerevisiae yeasts exhibited extensive restriction fragment length polymorphisms. At least five 2 microns species were identified from eleven [cir+] strains. Southern hybridization mapped restriction fragment length polymorphisms at STB, a cis-acting locus essential for plasmid partitioning. Some 2 microns variants (e.g., 4110-2 microns and 4108-2 microns) had an altered number of 125-bp consensus repeats at STB. However, the corresponding region of 7754-2 microns has only approximately 70% nucleotide sequence homology with the 125-bp STB consensus repeat. YRp plasmids containing 7754-2 microns STB behave as YEp plasmids in laboratory yeasts, thereby indicating STB sequence divergence coupled to conservation of function.


Molecular systematics of Blepharida beetles (Chrysomelidae: Alticinae) and relatives.
I investigated the phylogenetic relationships within the New World Blepharida and among related genera, using sequences of the Internal Transcriber Spacer 2 (ITS2) of nuclear ribosomal DNA and sequences of the COI and COII genes of the mitochondrial genome. Cladistic analyses were performed using parsimony, maximum likelihood, and Bayesian methods. These methods generated almost identical topologies using the combined data sets. The analyses suggest that Blepharida rhois, the type species, should be separated from the New World Blepharida and that the New World Blepharida might be congeneric with closely related Notozona. Also, according to this phylogeny, all of the New World Blepharida species that feed on Bursera (Burseraceae) form a single monophyletic clade, with the Afrotropical species forming its sister clade. The analyses also identified four main groups of species within the New World Blepharida.


FISH analysis of 15 chromosomes in human day 4 and 5 preimplantation embryos: the added value of extended aneuploidy detection.
Screening for an increased number of chromosomes may improve the detection of abnormal embryos and thus contribute to the capability of preimplantation genetic screening (PGS) to detect the embryo(s) for transfer in IVF with the best chance for a healthy child. Good-quality day 4 and 5 embryos were analyzed after cryopreservation for the nine chromosomes mostly recommended for screening (13, 14, 15, 16, 18, 21, 22, X and Y), next to six additional chromosomes which are less well studied in this context (1, 2, 7, 6, 10 and 17). The copy numbers of 15 chromosomes were investigated by fluorescence in situ hybridization (FISH) in three consecutive rounds. The proportion of aneuploid and mosaic embryos was determined and compared in retrospect to results in case only the recommended probe set had been analyzed. A total of 52 embryos from 29 infertile women were analyzed. Screening the embryos for six additional chromosomes increased the proportion of abnormal embryos from 67 to 81% (P = 0.03), owing to an increase in mosaic embryos. All but one of the meiotic aneuploidies found in this study would have been detected by the probe set most frequently used in PGS clinics. However, aneuploid cell lines originating from mitotic errors could be detected for almost all chromosomes, so screening of six additional chromosomes mainly increased the proportion of mosaic embryos. The added value of screening for six additional chromosomes in PGS for clinical practice will remain undetermined as long as the fate of mosaic embryos after transfer is unclear.


Exploring researchers' experiences of working with people with acquired brain injury.
This study aimed to investigate the challenges and positive experiences of researchers who work with people who have experienced an acquired brain injury and their families. People who were currently or had previously worked as a researcher in the field of acquired brain injury (using either quantitative or qualitative methods) were invited to participate in a focus group or individual interview about their experiences. An expert reference group meeting was held to discuss strategies that could be implemented to enhance the researcher experience based on the interview data. A total of 19 researchers who worked across four different research teams took part in the study. Six inter-connected themes were identified: researcher motivation, meaning and fulfillment; human connection; knowing and understanding the role; complexity of brain injury in the research context; the research process; and state of the researcher. A number of recommendations for supporting researchers more effectively were identified. Researchers described a number of positive aspects as well as tensions they encountered in their role. The findings highlight the need to ensure researchers are supported effectively to ensure the quality of research studies in the field of brain injury.


Maximum acceleration performance of professional soccer players in linear sprints: Is there a direct connection with change-of-direction ability?
The purpose of this study was to examine the selective influences of the maximum acceleration capability on change of direction (COD) speed, COD deficit, linear sprint speed, sprint momentum, and loaded and unloaded vertical jump performances in forty-nine male professional soccer players (24.3 ± 4.2 years; 75.4 ± 5.4 kg; 177.9 ± 6.4 cm). Soccer players performed the assessments in the following order: 1) squat and countermovement jumps; 2) 20-m sprinting speed test; 3) Zigzag COD ability test; and 4) bar-power outputs in the jump squat exercise. Athletes were divided, using a median split analysis, into two different groups according to their maximum acceleration rates from zero to 5-m (e.g., higher and lower ACC 0-5-m). Magnitude-based inference was used to compare the differences in the physical test results between "higher" and "lower" acceleration groups. A selective influence of the maximum acceleration ability on speed-power tests was observed, as the higher acceleration group demonstrated likely to almost certain higher performances than the lower acceleration group in all measurements (effect sizes varying from 0.66 [for sprint momentum in 20-m] to 2.39 [for sprint velocity in 5-m]). Conversely, the higher acceleration group demonstrated a higher COD deficit when compared to the lower acceleration group (ES = 0.55). This indicates compromised efficiency to perform COD maneuvers in this group of players. In summary, it was observed that soccer players with higher maximum acceleration rates are equally able to jump higher, sprint faster (over short distances), and achieve higher COD velocities than their slower counterparts. However, they appear to be less efficient at changing direction, which may be related to their reduced ability to deal with greater entry and exit velocities, or counterbalance the associated mechanical consequences (i.e., greater inertia) of being faster and more powerful.


Bracing of the trunk and neck has a differential effect on head control during gait.
During gait, the trunk and neck are believed to play an important role in dissipating the transmission of forces from the ground to the head. This attenuation process is important to ensure head control is maintained. The aim of the present study was to assess the impact of externally restricting the motion of the trunk and/or neck segments on acceleration patterns of the upper body and head and related trunk muscle activity. Twelve healthy adults performed three walking trials on a flat, straight 65-m walkway, under four different bracing conditions: 1) control-no brace; 2) neck-braced; 3) trunk-braced; and 4) neck-trunk braced. Three-dimensional acceleration from the head, neck (C7) and lower trunk (L3) were collected, as was muscle activity from trunk. Results revealed that, when the neck and/or trunk were singularly braced, an overall decrease in the ability of the trunk to attenuate gait-related oscillations was observed, which led to increases in the amplitude of vertical acceleration for all segments. However, when the trunk and neck were braced together, acceleration amplitude across all segments decreased in line with increased attenuation from the neck to the head. Bracing was also reflected by increased activity in erector spinae, decreased abdominal muscle activity and lower trunk muscle coactivation. Overall, it would appear that the neuromuscular system of young, healthy individuals was able to maintain a consistent pattern of head acceleration, irrespective of the level of bracing, and that priority was placed over the control of vertical head accelerations during these gait tasks.


Meteorological influence on the occurrence of gastric dilatation-volvulus in military working dogs in Texas.
Gastric dilatation-volvulus (GDV) is a life-threatening condition in dogs and other species in which the stomach dilates and rotates on itself. The etiology of the disease is multi-factorial, but explicit precipitating causes are unknown. This study sought to determine if there was a significant association between changes in hourly-measured temperature and/or atmospheric pressure and the occurrence of GDV in the population of high-risk working dogs in Texas. The odds of a day being a GDV day, given certain temperature and atmospheric pressure conditions for that day or the day before, was estimated using logistic regression models. There were 57 days in which GDV(s) occurred, representing 2.60% of the days in the 6-year study period. The months of November, December, and January collectively accounted for almost half (47%) of all cases. Disease risk was negatively associated with daily maximum temperature. An increased risk of GDV was weakly associated with the occurrence of large hourly drops in temperature that day and of higher minimum barometric pressure that day and the day before GDV occurrence, but extreme changes were not predictive of the disease.


What is the place of internal urethrotomy in the treatment of urethral stricture disease?
As a treatment for male urethral stricture, internal urethrotomy (IU) has the advantages of ease, simplicity, speed and short convalescence. Various modifications of the single cold-knife incision in the 12 o'clock position have been proposed, but there are no prospective, randomized studies to prove their claims of greater efficacy. IU can be performed as an outpatient procedure using local anesthesia, with an indwelling silicone catheter for 3 days after the procedure. Complications of IU are usually minor, including infection and hemorrhage. The reported success rate of IU varies, mainly because of differences in the definition of success and the duration of follow-up. Strictures can recur, usually within 3-12 months of IU. There are several known risk factors for recurrence: a previous IU, penile and membranous strictures, long (>2 cm) and multiple strictures, untreated perioperative urinary infection and extensive periurethral spongiofibrosis. Repeated IU might be useful in patients who have a stricture recurrence more than 6 months after the initial procedure, but repeat IU offers no long-term cure after a third IU, or if a stricture recurs within 3 months of the first IU. Such patients should be offered urethroplasty. Repeated IU followed by long-term self-dilation is an alternative option for men with severe comorbidity and limited life expectancy, or those who have failed previous urethroplasty. Overall, IU has a lower success rate (+/-60%) than urethroplasty (+/-80-90%), but if used for selected strictures, the success rate of IU could approach that of urethroplasty.


Comprehensive Performance Nutrition for Special Operations Forces.
Special Operations Forces (SOF) training, combat, and contingency operations are unique and demanding. Performance nutrition within the Department of Defense has emphasized that nutrition is relative to factors related to the desired outcome, which includes successful performance of mentally and physically demanding operations and missions of tactical and strategic importance, as well as nonoperational assignments. Discussed are operational, nonoperational, and patient categories that require different nutrition strategies to facilitate category-specific performance outcomes. Also presented are 10 major guidelines for a SOF comprehensive performance nutrition program, practical nutrition recommendations for Special Operators and medical providers, as well as resources for dietary supplement evaluation. Foundational health concepts, medical treatment, and task-specific performance factors should be considered when developing and systematically implementing a comprehensive SOF performance nutrition program. When tailored to organizational requirements, SOF unit- and culture-specific nutrition education and services can optimize individual Special Operator performance, overall unit readiness, and ultimately, mission success.


Sexual reproduction in Aspergillus flavus sclerotia naturally produced in corn.
Aspergillus flavus is the major producer of carcinogenic aflatoxins worldwide in crops. Populations of A. flavus are characterized by high genetic variation and the source of this variation is likely sexual reproduction. The fungus is heterothallic and laboratory crosses produce ascospore-bearing ascocarps embedded within sclerotia. However, the capacity for sexual reproduction in sclerotia naturally formed in crops has not been examined. Corn was grown for 3 years under different levels of drought stress at Shellman, GA, and sclerotia were recovered from 146 ears (0.6% of ears). Sclerotia of A. flavus L strain were dominant in 2010 and 2011 and sclerotia of A. flavus S strain were dominant in 2012. The incidence of S strain sclerotia in corn ears increased with decreasing water availability. Ascocarps were not detected in sclerotia at harvest but incubation of sclerotia on the surface of nonsterile soil in the laboratory resulted in the formation of viable ascospores in A. flavus L and S strains and in homothallic A. alliaceus. Ascospores were produced by section Flavi species in 6.1% of the 6,022 sclerotia (18 of 84 ears) in 2010, 0.1% of the 2,846 sclerotia (3 of 36 ears) in 2011, and 0.5% of the 3,106 sclerotia (5 of 26 ears) in 2012. For sexual reproduction to occur under field conditions, sclerotia may require an additional incubation period on soil following dispersal at crop harvest.


Tyrosine phosphorylation in early embryonic growth cones.
A large and growing body of evidence suggests that the regulation of tyrosine phosphorylation is important in the induction of axon growth. We have examined the subcellular distribution of enzymes regulating tyrosine phosphorylation in early embryonic brain, employing a preparation of isolated growth cone particles (GCPs). Because of the early developmental age and well-characterized nature of our tissue source, our GCP preparation offers some advantages over those described previously. As was found with other GCPs, our GCPs had relatively high levels of both the growth-associated protein GAP-43 and the intracellular tyrosine kinase pp60c-arc. In addition, we found that both total tyrosine kinase activity and total tyrosine phosphatase activity were concentrated two- to threefold in the GCPs relative to a neuronal membrane fraction. Two other nonreceptor tyrosine kinases, YES and FYN, were concentrated in the GCPs to a similar degree as that seen for SRC. In addition, we examined the developmental expression in brain of the three tyrosine kinases, using both a quantitative ELISA and Western blot analysis. Our results show that FYN, like SRC, reaches a peak of expression early in development, and declines thereafter. In contrast, expression of YES peaks later, and remains high in the adult brain. Immunofluorescence staining suggests that FYN is expressed both by neurons and by glia, and possibly by neuronal precursor cells. Our results implicate multiple tyrosine kinases as well as tyrosine phosphatases in growth cone function. In addition, the concentration of FYN in early embryonic growth cones combined with its early peak of expression suggests an important role for FYN in early neuronal development.


Insecticidal activity of the medicinal plant, Alstonia boonei De Wild, against Sesamia calamistis Hampson.
The bioactivity of the aqueous extracts of the leaf and stem bark of the medicinal plant, Alstonia boonei De Wild (Apocyanaceae), against the pink stalk borer, Sesamia calamistis Hampson (Lepidoptera: Noctuidae) was studied in a laboratory bioassay. The extracts were incorporated into artificial diet at a rate of 0.0% (control), 1.0%, 2.5%, 5.0%, and 10.0% (w/w). Both extracts significantly (P<0.01) reduced larval survival and weight in a dose dependent manner. The concentrations that killed 50% of the larvae (LC(50)) for the stem bark extract were 2.8% and 2.1% at 10 and 20 DAI (days after introduction), respectively, while those for the leaves extract were 5.6% and 3.5%. The weights of the larvae also varied significantly (P<0.05) between the treatments in a dose dependent manner. We conclude that both leaf and stem bark extracts of A. boonei are toxic, used as growth inhibitors to S. calamistis larvae, and hold good promise for use as alternative crop protectants against S. calamistis.


So glad you came! Harm reduction therapy in community settings.
Harm reduction therapy was originally developed as a nonabstinence-based method of treating people with drug and alcohol problems. In this article, we describe and apply the principles and practices of harm reduction therapy in community settings, places where people congregate for nontherapeutic reasons-street corners, community drop-in centers, needle exchanges, and primary care clinics. Low-threshold welcome and flexible session arrangements are defining characteristics of this community-based approach. We have been instrumental in developing several programs, three of which are described here. These programs work with more than 1,000 clients per year, with varying levels of intensity. The programs offer drop-in or sidewalk sessions, drop-in support groups, regular therapy appointments, and psychiatric medications. Many impressive outcomes, such as reduction of harmful drug use, stabilization of psychiatric problems, and permanent housing, are found each year.


Dominant inheritance of retinal ganglion cell resistance to optic nerve crush in mice.
Several neurodegenerative diseases are influenced by complex genetics that affect an individual's susceptibility, disease severity, and rate of progression. One such disease is glaucoma, a chronic neurodegenerative condition of the eye that targets and stimulates apoptosis of CNS neurons called retinal ganglion cells. Since ganglion cell death is intrinsic, it is reasonable that the genes that control this process may contribute to the complex genetics that affect ganglion cell susceptibility to disease. To determine if genetic background influences susceptibility to optic nerve damage, leading to ganglion cell death, we performed optic nerve crush on 15 different inbred lines of mice and measured ganglion cell loss. Resistant and susceptible strains were used in a reciprocal breeding strategy to examine the inheritance pattern of the resistance phenotype. Because earlier studies had implicated Bax as a susceptibility allele for ganglion cell death in the chronic neurodegenerative disease glaucoma, we conducted allelic segregation analysis and mRNA quantification to assess this gene as a candidate for the cell death phenotype. Inbred lines showed varying levels of susceptibility to optic nerve crush. DBA/2J mice were most resistant and BALB/cByJ mice were most susceptible. F1 mice from these lines inherited the DBA/2J phenotype, while N2 backcross mice exhibited the BALB/cByJ phenotype. F2 mice exhibited an intermediate phenotype. A Wright Formula calculation suggested as few as 2 dominant loci were linked to the resistance phenotype, which was corroborated by a Punnett Square analysis of the distribution of the mean phenotype in each cross. The levels of latent Bax mRNA were the same in both lines, and Bax alleles did not segregate with phenotype in N2 and F2 mice. Inbred mice show different levels of resistance to optic nerve crush. The resistance phenotype is heritable in a dominant fashion involving relatively few loci. Bax was excluded as a candidate gene for this phenotype.


Simpson's paradox in a synthetic microbial system.
The maintenance of "public" or "common good" producers is a major question in the evolution of cooperation. Because nonproducers benefit from the shared resource without bearing its cost of production, they may proliferate faster than producers. We established a synthetic microbial system consisting of two Escherichia coli strains of common-good producers and nonproducers. Depending on the population structure, which was varied by forming groups with different initial compositions, an apparently paradoxical situation could be attained in which nonproducers grew faster within each group, yet producers increased overall. We show that a simple way to generate the variance required for this effect is through stochastic fluctuations via population bottlenecks. The synthetic approach described here thus provides a way to study generic mechanisms of natural selection.


Nitrate ammonification in mangrove soils: a hidden source of nitrite?
Nitrate reduction is considered to be a minor microbial pathway in the oxidation of mangrove-derived organic matter due to a limited supply of nitrate in mangrove soils. At a limited availability of this electron acceptor compared to the supply of degradable carbon, nitrate ammonification is thought to be the preferential pathway of nitrate reduction. Mangrove forest mutually differ in their productivity, which may lead to different available carbon to nitrate ratios in their soil. Hence, nitrate ammonification is expected to be of more importance in high- compared to low-productive forests. The hypothesis was tested in flow-through reactors that contain undisturbed mangrove soils from high-productive Avicennia germinans and Rhizophora mangle forests in Florida and low-productive Avicennia marina forests in Saudi Arabia. Nitrate was undetectable in the soils from both regions. It was assumed that a legacy of nitrate ammonification would be reflected by a higher ammonium production from these soils upon the addition of nitrate. Unexpectedly, the soils from the low-productive forests in Saudi Arabia produced considerably more ammonium than the soils from the high-productive forests in Florida. Hence, other environmental factors than productivity must govern the selection of nitrate ammonification or denitrification. A rather intriguing observation was the 1:1 production of nitrite and ammonium during the consumption of nitrate, more or less independent from sampling region, location, sampling depth, mangrove species and from the absence or presence of additional degradable carbon. This 1:1 ratio points to a coupled production of ammonium and nitrite by one group of nitrate-reducing microorganisms. Such a production of nitrite will be hidden by the presence of active nitrite-reducing microorganisms under the nitrate-limited conditions of most mangrove forest soils.


The magnitude and duration of Late Ordovician-Early Silurian glaciation.
Understanding ancient climate changes is hampered by the inability to disentangle trends in ocean temperature from trends in continental ice volume. We used carbonate "clumped" isotope paleothermometry to constrain ocean temperatures, and thereby estimate ice volumes, through the Late Ordovician-Early Silurian glaciation. We find tropical ocean temperatures of 32° to 37°C except for short-lived cooling by ~5°C during the final Ordovician stage. Evidence for ice sheets spans much of the study interval, but the cooling pulse coincided with a glacial maximum during which ice volumes likely equaled or exceeded those of the last (Pleistocene) glacial maximum. This cooling also coincided with a large perturbation of the carbon cycle and the Late Ordovician mass extinction.


Multiple I-Type Lysozymes in the Hydrothermal Vent Mussel Bathymodiolus azoricus and Their Role in Symbiotic Plasticity.
The aim of this study was first to identify lysozymes paralogs in the deep sea mussel Bathymodiolus azoricus then to measure their relative expression or activity in different tissue or conditions. B. azoricus is a bivalve that lives close to hydrothermal chimney in the Mid-Atlantic Ridge (MAR). They harbour in specialized gill cells two types of endosymbiont (gram-bacteria): sulphide oxidizing bacteria (SOX) and methanotrophic bacteria (MOX). This association is thought to be ruled by specific mechanism or actors of regulation to deal with the presence of symbiont but these mechanisms are still poorly understood. Here, we focused on the implication of lysozyme, a bactericidal enzyme, in this endosymbiosis. The relative expression of Ba-lysozymes paralogs and the global anti-microbial activity, were measured in natural population (Lucky Strike--1700 m, Mid-Atlantic Ridge), and in in situ experimental conditions. B. azoricus individuals were moved away from the hydrothermal fluid to induce a loss of symbiont. Then after 6 days some mussels were brought back to the mussel bed to induce a re-acquisition of symbiotic bacteria. Results show the presence of 6 paralogs in B. azoricus. In absence of symbionts, 3 paralogs are up-regulated while others are not differentially expressed. Moreover the global activity of lysozyme is increasing with the loss of symbiont. All together these results suggest that lysozyme may play a crucial role in symbiont regulation.


Structural switch from a multistranded G-quadruplex to single strands as a consequence of point mutation in the promoter of the human GRIN1 gene.
A huge number of G-rich sequences forming quadruplexes are found in the human genome, especially in telomeric regions, UTRs, and the promoter regions of a number of genes. One such gene is GRIN1 encoding the NR1 subunit of the N-methyl-d-aspartate receptor (NMDA). Several lines of reports have implicated that attenuated function of NMDA results in schizophrenia, a genetic disorder characterized by hallucinations, delusions, and psychosis. Involvement of the GRIN1 gene in the pathogenesis of schizophrenia has been extensively analysed. Recent reports have demonstrated that polymorphism in the promoter region of GRIN1 at position -855 (G/C) has a possible association with schizophrenia. The binding site for the NF-κB transcription factor gets altered due to this mutation, resulting in reduced gene expression as well as NMDA activity. By combining gel electrophoresis (PAGE), circular dichroism (CD) and CD melting techniques, the G → C single nucleotide polymorphism (SNP) at the G-rich sequence (d-CTTAGCCCGAGGAG[combining low line]GGGGGTCCCAAGT; GRIN1) was investigated. We report that the GRIN1 sequence can form an octameric/multistranded quadruplex structure with parallel conformation in the presence of K+ as well as Na+. CD and gel studies are in good correlation in order to detect molecularity and strand conformation. The parallel G-quadruplex species was hypothesized to be octameric in K+/Na+ salts. The mutated sequence (d-CTTAGCCCGAGGAC[combining low line]GGGGGTCCCAAGT; GRIN1M) remained single stranded under physiological conditions. CD melting studies support the formation of an interstranded G-quadruplex structure by the GRIN1 sequence. Two structural models are propounded for a multistranded parallel G-quadruplex conformation which might be responsible for regulating the gene expression normally underlying memory and learning.


Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studies.
To examine and quantify the potential dose-response relation between intake of total, animal, and plant protein and the risk of mortality from all causes, cardiovascular disease, and cancer. Systematic review and meta-analysis of prospective cohort studies. PubMed, Scopus, and ISI Web of Science until December 2019, and references of retrieved relevant articles. Prospective cohort studies that reported the risk estimates for all cause, cardiovascular, and cancer mortality in adults aged 18 or older. Random effects models were used to calculate pooled effect sizes and 95% confidence intervals for the highest versus lowest categories of protein intake and to incorporate variation between studies. Linear and non-linear dose-response analyses were done to evaluate the dose-response relations between protein intake and mortality. 32 prospective cohort studies were included in the systematic review and 31 in the meta-analysis. During the follow-up period of 3.5 to 32 years, 113 039 deaths (16 429 from cardiovascular disease and 22 303 from cancer) occurred among 715 128 participants. Intake of total protein was associated with a lower risk of all cause mortality (pooled effect size 0.94, 95% confidence interval 0.89 to 0.99, I2=58.4%, P<0.001). Intake of plant protein was significantly associated with a lower risk of all cause mortality (pooled effect size 0.92, 95% confidence interval 0.87 to 0.97, I2=57.5%, P=0.003) and cardiovascular disease mortality (pooled hazard ratio 0.88, 95% confidence interval 0.80 to 0.96, I2=63.7%, P=0.001), but not with cancer mortality. Intake of total and animal protein was not significantly associated with risk of cardiovascular disease and cancer mortality. A dose-response analysis showed a significant inverse dose-response association between intake of plant protein and all cause mortality (P=0.05 for non-linearity). An additional 3% energy from plant proteins a day was associated with a 5% lower risk of death from all causes. Higher intake of total protein was associated with a lower risk of all cause mortality, and intake of plant protein was associated with a lower risk of all cause and cardiovascular disease mortality. Replacement of foods high in animal protein with plant protein sources could be associated with longevity.


Rare LPL gene variants attenuate triglyceride reduction and HDL cholesterol increase in response to fenofibric acid therapy in individuals with mixed dyslipidemia.
Individuals with mixed dyslipidemia have elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and increased risk for coronary disease. Fibrate therapy is commonly used to lower TG and increase HDL-C. Common genetic variants are known to affect the response to fibrate therapy. We sought to identify rare genetic variants (frequency ≤ 1%) in genes involved in TG and HDL-C metabolism that affect the response to fenofibric acid (FA) therapy. Four genes with a major role in HDL-C and TG metabolism APOA1, APOC2, APOC-III and LPL were sequenced in 2385 participants with mixed dyslipidemia in a randomized, double-blind, active-controlled study comparing therapy with FA alone, in combination with statins, or statin alone. Rare variants collapsing or SKAT methods were used for the analysis. Synonymous rare variants in the LPL gene were significantly associated with absolute HDL-C change (P = 9 × 10(-4)) and TG percent change (P = 6.76 × 10(-4)) in those treated with FA only. Participants with these rare variants had a 2 mg/dL increase in HDL-C and 39 mg/dL decrease in TG as compared to 6.2 mg/dL increase in HDL-C and 100 mg/dL decrease in TG in those without these variants. Rare variants in the APOC-III gene were associated with a modest 3 mg/dL less reduction in APOB (P = 8.72 × 10(-4)) in those receiving FA and statin. In individuals with mixed dyslipidemia rare synonymous variants within LPL gene were associated with attenuated response to FA therapy while APOCIII rare variants were associated with a modest effect on APOB response to FA-statin therapy. These results should be replicated in a similar clinical trial for further confirmation.


Asking New Questions with Old Data: The Centralized Open-Access Rehabilitation Database for Stroke.
This paper introduces a tool for streamlining data integration in rehabilitation science, the Centralized Open-Access Rehabilitation database for Stroke (SCOAR), which allows researchers to quickly visualize relationships among variables, efficiently share data, generate hypotheses, and enhance clinical trial design. Bibliographic databases were searched according to inclusion criteria leaving 2,892 titles that were further screened to 514 manuscripts to be screened by full text, leaving 215 randomized controlled trials (RCTs) in the database (489 independent groups representing 12,847 patients). Demographic, methodological, and statistical data were extracted by independent coders and entered into SCOAR. Trial data came from 114 locations in 27 different countries and represented patients with a wide range of ages, 62 year [41; 85] [shown as median (range)] and at various stages of recovery following their stroke, 141 days [1; 3372]. There was considerable variation in the dose of therapy that patients received, 20 h [0; 221], over interventions of different durations, 28 days [10; 365]. There was also a lack of common data elements (CDEs) across trials, but this lack of CDEs was most pronounced for baseline assessments of patient impairment and severity of stroke. Data integration across hundreds of RCTs allows clinicians and researchers to quickly visualize data from the history of the field and lays the foundation for making SCOAR a living database to which researchers can upload new data as trial results are published. SCOAR is a useful tool for clinicians and researchers that will facilitate data visualization, data sharing, the finding of relevant past studies, and the design of clinical trials by enabling more accurate and comprehensive power analyses. Furthermore, these data speak to the need for CDEs specific to stroke rehabilitation in randomized controlled trials. CRD42014009010.


Endoscopic resection of submucosal tumor of the esophagus: results in 62 patients.
Although most submucosal tumors of the esophagus are benign, reliable exclusion of leiomyosarcoma requires histological analysis. However, this is rarely possible with an endoscopic forceps biopsy. In an attempt to establish the diagnosis, and as an alternative to surgery, we present here our experience with the endoscopic removal of submucosal tumors of the esophagus using two different techniques. Sixty-two patients (38 men, 24 women, mean age 47) with submucosal tumors of the esophagus were treated endoscopically. If the tumor was less than 2 cm in diameter, polypoid, or showed a round protrusion with at least moderate elevation at endoscopy, a conventional snare polypectomy was performed. If the tumor was larger than 2 cm in diameter or only mildly elevated, the technique of modified endoscopic incisional enucleation was carried out, consisting of complete stripping of the overlying tissue followed by tumor enucleation using an electrocautery snare and a coagulation electrode. Based on these criteria, 36 patients underwent conventional snare polypectomy, and 25 received endoscopic incisional enucleation; complete resection of the tumor was possible in these 61 cases. In one patient, only partial removal was possible, due to firm and wide adhesions to the surrounding tissue. The tumor diameters ranged from 0.6 cm to 7.5 cm, with a mean value of 1.9 cm; 14 tumors measured more than 3 cm. At histopathology, the resected specimens were found to be 56 leiomyomas, four granular cell tumors, one neurogenic tumor, and one cyst. No serious complications such as perforation or massive bleeding occurred, and oozing bleeding, which was encountered in three patients, was easily managed by endoscopic electrocoagulation. During the follow-up period (mean 38.4 months, range 3-107 months) no recurrence was observed in any of the 61 patients who received complete resections. This method of endoscopic removal of submucosal tumors of the esophagus appears to be safe and effective in experienced hands. It allows complete histopathological workup, and at the same time complete removal of the tumor. The method can be considered as an alternative to surgery in symptomatic cases.


Representations of autism: implications for community healthcare practice.
The work presented in this paper is part of a larger project in which online asynchronous discussion groups were employed to examine how a range of contributors--including people with autism, parents of people with autism, and professionals working within the field of autism--view and understand autism. In this paper, we focus on the voices of people with autism. The terminology used in the paper takes its lead from the writings of people with autism, who frequently use the term 'AS' to refer to autistic spectrum and Asperger syndrome and 'NT', which refers to neurologically typical people without autism. We examine a key theme identified in the online discussion groups--the representation of individuals with autism as occupying a separate world of autism. In doing so, we question an apparent goal of therapeutic interventions--to bring people with autism out of their 'separate world' and integrate them into a more typically 'social world'. We present an alternative understanding of autism that argues for valuing diversity and viewing autism as a difference rather than a deficit. We will discuss some of the implications that this may have for working with people with autism in health and social care practice.


Bat wing sensors support flight control.
Bats are the only mammals capable of powered flight, and they perform impressive aerial maneuvers like tight turns, hovering, and perching upside down. The bat wing contains five digits, and its specialized membrane is covered with stiff, microscopically small, domed hairs. We provide here unique empirical evidence that the tactile receptors associated with these hairs are involved in sensorimotor flight control by providing aerodynamic feedback. We found that neurons in bat primary somatosensory cortex respond with directional sensitivity to stimulation of the wing hairs with low-speed airflow. Wing hairs mostly preferred reversed airflow, which occurs under flight conditions when the airflow separates and vortices form. This finding suggests that the hairs act as an array of sensors to monitor flight speed and/or airflow conditions that indicate stall. Depilation of different functional regions of the bats' wing membrane altered the flight behavior in obstacle avoidance tasks by reducing aerial maneuverability, as indicated by decreased turning angles and increased flight speed.


Brain basis of communicative actions in language.
Although language is a key tool for communication in social interaction, most studies in the neuroscience of language have focused on language structures such as words and sentences. Here, the neural correlates of speech acts, that is, the actions performed by using language, were investigated with functional magnetic resonance imaging (fMRI). Participants were shown videos, in which the same critical utterances were used in different communicative contexts, to Name objects, or to Request them from communication partners. Understanding of critical utterances as Requests was accompanied by activation in bilateral premotor, left inferior frontal and temporo-parietal cortical areas known to support action-related and social interactive knowledge. Naming, however, activated the left angular gyrus implicated in linking information about word forms and related reference objects mentioned in critical utterances. These findings show that understanding of utterances as different communicative actions is reflected in distinct brain activation patterns, and thus suggest different neural substrates for different speech act types.


Outcomes of the Bridle Procedure for the Treatment of Foot Drop.
The purpose of this study was to determine the clinical outcomes and objective measures of function that can be expected for patients following the Bridle procedure (modification of the posterior tibial tendon transfer) for the treatment of foot drop. Nineteen patients treated with a Bridle procedure and 10 matched controls were evaluated. The Bridle group had preoperative and 2-year postoperative radiographic foot alignment measurements and completion of the Foot and Ankle Ability Measure. At follow-up, both groups were tested for standing balance (star excursion test) and for ankle plantarflexion and dorsiflexion isokinetic strength, and the American Orthopaedic Foot & Ankle Society and Stanmore outcome measures were collected only on the Bridle patients. There was no change in radiographic foot alignment from pre- to postoperative measurement. Foot and Ankle Ability Measure subscales of activities of daily living and sport, American Orthopaedic Foot & Ankle Society, and Stanmore scores were all reduced in Bridle patients as compared with controls. Single-limb standing-balance reaching distance in the anterolateral and posterolateral directions were reduced in Bridle participants as compared with controls (P < .03). Isokinetic ankle dorsiflexion and plantarflexion strength was lower in Bridle participants (2 ± 4 ft·lb, 44 ± 16 ft·lb) as compared with controls (18 ± 13 ft·lb, 65 ± 27 ft·lb, P < .02, respectively). All Bridle participants reported excellent to good outcomes and would repeat the operation. No patient wore an ankle-foot orthosis for everyday activities. The Bridle procedure was a successful surgery that did not restore normal strength and balance to the foot and ankle but allowed individuals with foot drop and a functional tibialis posterior muscle to have significantly improved outcomes and discontinue the use of an ankle-foot orthosis. In addition, there was no indication that loss of the normal function of the tibialis posterior muscle resulted in change in foot alignment 2 years after surgery. Level III, retrospective comparative series.


Increased mortality in COPD among construction workers exposed to inorganic dust.
The aim of this study was to find out if occupational exposure to dust, fumes or gases, especially among never-smokers, increased the mortality from chronic obstructive pulmonary disease (COPD). A cohort of 317,629 Swedish male construction workers was followed from 1971 to 1999. Exposure to inorganic dust (asbestos, man-made mineral fibres, dust from cement, concrete and quartz), gases and irritants (epoxy resins, isocyanates and organic solvents), fumes (asphalt fumes, diesel exhaust and metal fumes), and wood dust was based on a job-exposure matrix. An internal control group with "unexposed" construction workers was used, and the analyses were adjusted for age and smoking. When all subjects were analysed, there was an increased mortality from COPD among those with any airborne exposure (relative risk 1.12 (95% confidence interval (CI) 1.03-1.22)). In a Poisson regression model, including smoking, age and the major exposure groups, exposure to inorganic dust was associated with an increased risk (hazard ratio (HR) 1.10 (95% CI 1.06-1.14)), especially among never-smokers (HR 2.30 (95% CI 1.07-4.96)). The fraction of COPD among the exposed attributable to any airborne exposure was estimated as 10.7% overall and 52.6% among never-smokers. In conclusion, occupational exposure among construction workers increases mortality due to chronic obstructive pulmonary disease, even among never-smokers.


Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice.
The development of small animal models that elicit human immune responses to dengue virus (DENV) is important since prior immunity is a major risk factor for developing severe dengue disease. This study evaluated anti-DENV human antibody (hAb) responses generated from immortalized B cells after DENV-2 infection in NOD-scid IL2rγ(null) mice that were co-transplanted with human fetal thymus and liver tissues (BLT-NSG mice). DENV-specific human antibodies predominantly of the IgM isotype were isolated during acute infection and in convalescence. We found that while a few hAbs recognized the envelope protein produced as a soluble recombinant, a number of hAbs only recognized epitopes on intact virions. The majority of the hAbs isolated during acute infection and in immune mice were serotype-cross-reactive and poorly neutralizing. Viral titers in immune BLT-NSG mice were significantly decreased after challenge with a clinical strain of dengue. DENV-specific hAbs generated in BLT-NSG mice share some of the characteristics of Abs isolated in humans with natural infection. Humanized BLT-NSG mice provide an attractive preclinical platform to assess the immunogenicity of candidate dengue vaccines.


Pediatric allergy and immunology in Italy.
In Italy, according to the International Study on Asthma and Allergies in Childhood study, the prevalence of current asthma, allergic rhinoconjunctivitis, and atopic eczema in 2006 was 7.9%, 6.5%, and 10.1% among children aged 6-7 and 8.4%, 15.5%, and 7.75% among children aged 13-14 yr. University education in this field is provided by the Postgraduate Schools of Pediatrics and those of Allergology and Clinical Immunology, as well as several annual Master courses. The Italian Society of Pediatric Allergology and Immunology (SIAIP) was founded in 1996 and counts about 1000 members. SIAIP promotes evidence-based management of allergic children and disseminates information to patients and their families through a quite innovative website and the National Journal 'Rivista Italiana di Allergologia Pediatrica'. In the last decade, four major regional, inter-regional, and national web-based networks have been created to link pediatric allergy centers and to share their clinical protocols and epidemiologic data. In addition, National Registers of Primary Immune-deficiencies and on Pediatric HIV link all clinical excellence centers. Research projects in the field of pediatric allergy and immunology are founded by the Italian Ministry of Education, University and Research (MIUR) and by the National Research Council (CNR), but the overall investments in this research area are quite low. Only a handful Italian excellence centers participate in European Projects on Pediatric Allergy and Immunology within the 7th Framework Program. The European Academy of Allergy and Clinical Immunology currently hosts two Italians in its Executive Committee (EC) and one in the EC of the Pediatric Section; moreover, major European Academy of Allergy and Clinical Immunology meetings and courses in the area of pediatrics (e.g., PAAM, Venice, 2009) have been held in Italy in the last 3 yr. Italian hallmarks in the management of allergic diseases in childhood are a quite alive and spread interest in Molecular Allergology and a remarkable predominance of sublingual (SLIT) compared to the subcutaneous (SCIT) immunotherapy.