The Impact of Hormonal Contraceptive Use on Serotonergic Neurotransmission and Antidepressant Treatment Response: Results From the NeuroPharm 1 Study.
Hormonal contraceptive (HC) use has been associated with an increased risk of developing a depressive episode. This might be related to HC's effect on the serotonergic brain system as suggested by recent cross-sectional data from our group, which show that healthy oral contraceptive (OC) users relative to non-users have lower cerebral serotonin 4 receptor (5-HT4R) levels. Here, we determine if cerebral 5-HT4R binding differs between HC non-users, OC users, and hormonal intrauterine device (HIUD) users among women with an untreated depressive episode. Also, we test if antidepressant drug treatment response and its association with pre-treatment 5-HT4R binding depends on HC status. [11C]-SB207145 Positron Emission Tomography imaging data from the NeuroPharm-NP1 Study (NCT02869035) were available from 59 depressed premenopausal women, of which 26 used OCs and 10 used HIUDs. The participants were treated with escitalopram. Treatment response was measured as the relative change in the Hamilton Depression Rating Scale 6 items (rΔHAMD6) from baseline to week eight. Latent variable models were used to evaluate the association between global 5-HT4R binding and OC and HIUD use as well as rΔHAMD6. We found no evidence of a difference in global 5-HT4R binding between depressed HC users and non-users (p≥0.51). A significant crossover interaction (p=0.02) was observed between non-users and OC users in the association between baseline global 5-HT4R binding and week eight rΔHAMD6; OC users had 3-4% lower binding compared to non-users for every 10% percent less improvement in HAMD6. Within the groups, we observed a trend towards a positive association in non-users (padj=0.10) and a negative association in OC users (padj=0.07). We found no strong evidence of a difference in treatment response between the groups (p=0.13). We found no difference in 5-HT4R binding between HC users vs. non-users in depressed women, however, it seemed that 5-HT4R settings differed qualitatively in their relation to antidepressant drug treatment response between OC users and non-users. From this we speculate that depressed OC users constitutes a special serotonin subtype of depression, which might have implications for antidepressant drug treatment response.


Aryl- and heteroaryl-substituted phenylalanines as AMPA receptor ligands.
A series of racemic unnatural amino acids was rationally designed on the basis of recently published X-ray structures of the GluA2 LBD with bound phenylalanine-based antagonists. Twelve new diaryl- or aryl/heteroaryl-substituted phenylalanine derivatives were synthesized and evaluated in vitro in radioligand binding assays at native rat ionotropic glutamate receptors. The most interesting compound in this series, (RS)-2-amino-3-(3'-hydroxy-5-(1H-pyrazol-4-yl)-[1,1'-biphenyl]-3-yl)propanoic acid 7e, showed the binding affinity of 4.6 μm for native AMPA receptors and over fourfold lower affinity for kainic acid receptors. Furthermore, 7e was evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. Recently reported X-ray structures 5CBR and 5CBS, representing two distinct antagonist binding modes, were used as templates for molecular docking of the synthesized series. Binding data supported with molecular modeling confirmed that aryl/heteroaryl-substituted phenylalanine analogues effectively bind to AMPA receptors with low micromolar affinity and high selectivity over native NMDA and kainate receptors. These properties make 7e a promising lead for the further development of new AMPA receptor ligands.


Adversarial Reinforced Instruction Attacker for Robust Vision-Language Navigation.
Language instruction plays an essential role in the natural language grounded navigation tasks. However, navigators trained with limited human-annotated instructions may have difficulties in accurately capturing key information from the complicated instruction at different timesteps, leading to poor navigation performance. In this paper, we exploit to train a more robust navigator which is capable of dynamically extracting crucial factors from the long instruction, by using an adversarial attacking paradigm. Specifically, we propose a Dynamic Reinforced Instruction Attacker (DR-Attacker), which learns to mislead the navigator to move to the wrong target by destroying the most instructive information in instructions at different timesteps. By formulating the perturbation generation as a Markov Decision Process, DR-Attacker is optimized by the reinforcement learning algorithm to generate perturbed instructions sequentially during the navigation, according to a learnable attack score. Then, the perturbed instructions, which serve as hard samples, are used for improving the robustness of the navigator with an effective adversarial training strategy and an auxiliary self-supervised reasoning task. Experimental results on both Vision-and-Language Navigation (VLN) and Navigation from Dialog History (NDH) tasks show the superiority of our proposed method over state-of-the-art methods. Moreover, the visualization analysis shows the effectiveness of the proposed DR-Attacker, which can successfully attack crucial information in the instructions at different timesteps. Code is available at https://github.com/expectorlin/DR-Attacker.


A salutogenic urban design framework: the case of UK local high streets and older people.
The article provides a novel look at the links between salutogenesis, health promotion, and urban design supported by the findings of recent research on local high streets and their benefits for the well-being of older people. Salutogenesis and the related explanatory concept of sense of coherence (SOC) have provided a theoretical framework for developing healthy settings interventions, shifting the focus from exploring barriers and deficits to assets and resources in promoting people's health and well-being. While these concepts have informed policies and programmes at the level of regions and cities, no attempt has been made to establish more direct links with the disciplines devoted to the organization and design of the built environment at the scale of public spaces and streets. This article advances the idea that the main categories of SOC-comprehensibility, manageability and meaningfulness-have found application in urban design theory. Linking these categories with urban design concepts in a comprehensive framework, it is possible to guide interventions aimed at strenghtening well-being resources available in the public realm. This is corroborated by the findings resulting from a study of the well-being experiences of older people (n = 84) across a range of local high streets in the city of Edinburgh (UK) applying an innovative multi-methods approach. The discussion establishes the links between well-being benefits, SOC constructs and urban design concepts, and underscores the potential of the proposed framework to guide a design-oriented salutogenic approach to the built environment.


Study on Tripping Risks in Fast Walking through Cadence-Controlled Gait Analysis.
Fast walking is a common exercise for most people to promote health. However, a higher cadence due to fast walking on ordinary or uneven ground raises the risk of tripping. To investigate the tripping issue, research to observe the gait in fast walking is needed. To explore the relationship between fast gait and the risk of tripping, a gait recording system with a specific synchronization mechanism was developed in this work. The system can acquire gait signals from wearable sensors and action cameras at different cadences. Meanwhile, algorithms for gait cycle segmentation and characteristic extraction were proposed for analyzing a fast gait. In the gait analysis, the correlations of low, moderate, and high cadence in cueing and no cueing gaits were computed, and two results were obtained. First, the higher the cadence is, the larger the motion strength in the terminal foot swing will be and the smaller the motion strength at the starting foot swing. Second, the decreased distance of foot clearance becomes more conspicuous as the cadence increased, especially if one is walking more than 120 beats. The results indicate that fast walking with bigger strides and lower cadence is the best way to maintain safety in moving over ordinary ground.


NeuPSIG guidelines on neuropathic pain assessment.
This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes. Measurement of trigeminal reflexes mediated by A-beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser-evoked potentials is useful for assessing function of the A-delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction. The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.


Glomerular basement membrane heparan sulfate in health and disease: A regulator of local complement activation.
The glomerular basement membrane (GBM) is an essential component of the glomerular filtration barrier. Heparan sulfate proteoglycans such as agrin are major components of the GBM, along with α345(IV) collagen, laminin-521 and nidogen. A loss of GBM heparan sulfate chains is associated with proteinuria in several glomerular diseases and may contribute to the underlying pathology. As the major determinants of the anionic charge of the GBM, heparan sulfate chains have been thought to impart charge selectivity to the glomerular filtration, a view challenged by the negligible albuminuria in mice that lack heparan sulfate in the GBM. Recent studies provide increasing evidence that heparan sulfate chains modulate local complement activation by recruiting complement regulatory protein factor H, the major inhibitor of the alternative pathway in plasma. Factor H selectively inactivates C3b bound to surfaces bearing host-specific polyanions such as heparan sulfate, thus limiting complement activation on self surfaces such as the GBM, which are not protected by cell-bound complement regulators. We discuss mechanisms whereby the acquired loss of GBM heparan sulfate can impair the local regulation of the alternative pathway, exacerbating complement activation and glomerular injury in immune-mediated kidney diseases such as membranous nephropathy and lupus nephritis.


Future relevance of genetic testing: a systematic horizon scanning analysis.
The aim of this study was to identify research and development on genetic testing to find out if research addresses important disease areas, how far it is from potential clinical use, and what consequences might arise for the prioritization of health technology assessment (HTA) activities. Also a horizon scanning methodology developed in Germany is demonstrated. A systematic search on genetic testing was conducted in an innovation database (ZIM database). Based on a daily monitoring of literature and Internet sources, reports from 2003 up to 2005 were classified related to the type of innovation, the addressed disease categories, and the developmental phase of the technology. More detailed analyses for the most frequently addressed groups of diseases were conducted. From 239 relevant reports, 41 percent referred to neoplasms; 10 percent to diseases of the cardiovascular system; 9 percent to diseases of the nervous system; 7 percent to mental and behavioral disorders; and 5 percent to endocrine, nutritional, and metabolic diseases. A total of 69 percent of research is situated in basic preclinical research, 22 percent in clinical/experimental research, and 6 percent are genetic tests being used. Diagnostic applications were most frequently reported (28 percent), followed by therapeutic prediction (22 percent), preventive prediction (18 percent), pharmacogenetics (16 percent), and screening (16 percent). Widespread diseases are frequently addressed in research. HTA on genetic testing might focus on innovations addressing neoplastic diseases (in particular breast, colon, and prostate cancers) and pharmacogenetic applications for therapeutic prediction. The horizon scanning approach seems useful in the early steps of HTA processes to identify emerging new technologies that might have significant impact on future health care.


Insulin-induced phospho-oligosaccharide stimulates amino acid transport in isolated rat hepatocytes.
The ability of the insulin-induced phospho-oligosaccharide to stimulate amino acid transport was studied in isolated rat hepatocytes. At low alpha-aminoisobutyric acid concentrations (0.1 mM), both 100 nM-insulin and 10 microM-phospho-oligosaccharide doubled amino acid uptake after 2 h of incubation. This stimulation was prevented by 0.1 mM-cycloheximide or 5 micrograms of actinomycin D/ml, indicating that the phospho-oligosaccharide, like insulin, was acting via the synthesis of a high-affinity transport component. The effects of the phospho-oligosaccharide and of insulin were blocked by Ins2P (2.5 mM), but not by myo-inositol, inositol hexaphosphoric acid or several monosaccharides such as mannose, glucosamine and galactose. Both the temporal effect on amino acid entry and the extent of stimulation of this process by the phospho-oligosaccharide indicate that this molecule mimics, and may mediate, some of the long-term actions of insulin. However, the effects of phospho-oligosaccharide and insulin were not exactly the same, since the effect of insulin, but not of the phospho-oligosaccharide, was additive with that of glucagon.


Transgender and gender diverse adults' self-reported mental health diagnoses, engagement in mental health services, and perceptions of therapists.
Transgender and gender diverse (TGD) people face various challenges when seeking therapy. Given this, we wanted to understand more about TGD people's perceptions of providers and how these compare to researcher ratings of providers on metrics of affirming practice. The sample included 158 TGD adults (Mage = 33.06); 57.6% were in therapy. Participants completed measures about mental health, resilience, and therapy. We systematically coded provider websites and intake forms. Participants in therapy were older, had higher depression, and lower resilience than participants not in therapy. Non-binary/genderqueer participants rated providers as less knowledgeable compared to trans feminine participants. Overall, participants appeared satisfied (71.4% extremely satisfied) and viewed providers as at least moderately knowledgeable (89.1%). Provider coding revealed variation across the markers of affirmation; 66.04% identified a TGD-specialty and only 26.42% shared provider pronouns. Higher frequency of inclusivity (via coding) was related to higher ratings of provider knowledge and more of a focus on gender, however, there was not a significant association with satisfaction. Providers who engaged in more affirming practices were more knowledgeable compared to those who engaged in fewer affirming practices. This may influence the content of therapy and whether clients feel comfortable discussing gender.


[The oncologic patient and the gynecologist].
Affliction from cancer imposes heavy stress on the patient and her family, which raises important psychological problems. Adequate information, that is an adaptative strategy based on gradual explanation of the various steps of illness, can help the patient to accept it. Telling the simple truth is the best tool in the phase of prevention. In cancer management, too, information must respect the truth but it must also respect the patient's personality and the word "cancer" should be relieved of its terrible weight, leaving a window open to hope. The cancer patient must therefore be assisted by a team of experts in which the gynaecologist-oncologist has the fundamental role as coordinator.


Safety of early enrollment into outpatient cardiac rehabilitation after open heart surgery.
The safety of early enrollment (<2 weeks after hospital discharge) into cardiac rehabilitation (CR) after recent coronary artery bypass graft (CABG) surgery or heart valve surgery (HVS) has not previously been assessed and has important policy implications. Consequently, we performed a detailed review of all clinical adverse events within 6 months of hospital discharge. We compared early and late attendees for patients undergoing CABG surgery or HVS and included patients with myocardial infarction (MI) as an additional control group. We analyzed 112 patients undergoing CABG surgery, 69 patients undergoing HVS, and 59 patients with MI. Median time (interquartile range) from hospital discharge to CR enrollment was 10.5 (8 to 15), 12 (8.5 to 21), and 9 days (7 to 14), respectively. There was no difference in major event rates between early and late enrollees (17% vs 17%, respectively, log-rank p = 0.98) or by diagnosis (15%, 16%, and 22% for CABG surgery, HVS, and MI, respectively; log-rank p = 0.50). Sternal instability and wound infection rates were similar. CR-related adverse events trended toward increased event rates in surgical and early enrollees, but of 44 events, only 3 were exercise related, none resulted in permanent harm, and 41 (93%) were managed in CR without need for emergency services. In conclusion, it appears that a policy of encouraging early enrollment into CR in patients with a recent open heart surgery seems unlikely to harm patients when careful individualized assessment and exercise prescription take place within the bounds of an established CR program.


Histological characterization of bone marrow in ectopic bone, induced by devitalized Saos-2 human osteosarcoma cells.
Devitalized Saos-2, cultured human osteosarcoma cells, or guanidinium-hydrochloride (GuHCl) extracts of these cells, induce ectopic bone and marrow formation when implanted subcutaneously in Nu/Nu mice. The aim of the present study was to characterize the bone marrow induced by Saos-2 cell extracts, specifically to determine which of the four major hematopoietic cell lineages: erythropoietic, granulopoietic, lymphopoietic and megakaryocytic, are induced by Saos-2 cell derivatives. Immunohistochemical localization of specific antigens was used to determine the presence of each major cell type (glycophorin A for erythropoietic, neutrophil elastase for granulopoietic, factor-VIII related antigen for megakaryocytes, and CD79a for B lymphocytes). Standard H & E stains confirmed the presence of normally organized apparently complete bone marrow within all newly induced bone at 3 weeks post-implantation of devitalized Saos-2 cells. Immunohistochemistry confirmed the presence of erythropoietic cells, granulopoietic cells, megakaryocytes and B lymphocytes in the ectopic marrow. Saos-2 cells (freeze-dried) or their extracts, implanted subcutaneously into Nu/Nu mice, can induce normal marrow that is host-derived, and contains all major hematopoietic cell lineages. Saos-2 induced marrow could potentially restore deficient marrow and promote bone repair.


[Epidemiologic features of acute viral respiratory infections in familial foci].
A study was made of the epidemiological peculiarities of viral respiratory infections of various etiology in the familial foci with the use of a methodical approach permitting to detect the true spread of infection in the familial foci, with consideration to the subclinical forme fruste of the disease and "carrier state". It appeared that in the familial foci the infectiousness of the majority of respiratory viral infections was greater than in the closed collective bodies uniting persons of the same age. The age composition of the family influences the manifestness (particularly in parainfluenza infection) and the intensity of the epidemic process characterized by the coefficient of the secondary affections. The type of the apartment, the floor on which it is located, and the number of persons residing in it had no significant influence on the spread of the viral infections in the familial foci. A definite role in this process is played by the level of specific serum antibodies in the members of the family surrounding the patient. The association of morbidity level with the antibody level proved to be the most distinct in children with influenza and adenoviral infection; this association was less significant in adults.


Suppressed response to interferon inducation in mice infected with encephalomyocarditis virus, Semliki forest virus, influenza A2 virus, Herpesvirus hominis type 2, or murine cytomegalovirus.
Mice infected with encephalomyocarditis virus, Semliki Forest virus, influenza A2 virus, Herpesvirus hominis type 2, or murine cytomegalovirus developed a state of hyporeactivity to interferon induction. In general, the capacity of infected animals to produce interferon in response to inducers became progressively impaired during the course of infection. The severity and time of onset of hyporeactivity, however, were dependent upon the inducer and the nature of the viral infection. During viral infections associated with generalized hyporesponsiveness, a factor that could inhibit interferon production by murine cells in culture was identified in the serum. This serum hyporeactive factor may have mediated the development of hyporeactivity in vivo. Hyporeactivity of the host's interferon response was associated with progression of viral infection and may be partially responsible for the limited effectiveness of interferon inducers in the modification of viral infections, when administered after onset of symptoms.


Potential of active transport to improve health, reduce healthcare costs, and reduce greenhouse gas emissions: A modelling study.
Physical inactivity contributes substantively to disease burden, especially in highly car dependent countries such as New Zealand (NZ). We aimed to quantify the future health gain, health-sector cost-savings, and change in greenhouse gas emissions that could be achieved by switching short vehicle trips to walking and cycling in New Zealand. We used unit-level survey data to estimate changes in physical activity, distance travelled by mode, and air pollution for: (a) switching car trips under 1km to walking and (b) switching car trips under 5km to a mix of walking and cycling. We modelled uptake levels of 25%, 50%, and 100%, and assumed changes in transport behaviour were permanent. We then used multi-state life table modelling to quantify health impacts as quality adjusted life years (QALYs) gained and changes in health system costs over the rest of the life course of the NZ population alive in 2011 (n = 4.4 million), with 3% discounting. The modelled scenarios resulted in health gains between 1.61 (95% uncertainty interval (UI) 1.35 to 1.89) and 25.43 (UI 20.20 to 30.58) QALYs/1000 people, with total QALYs up to 112,020 (UI 88,969 to 134,725) over the remaining lifespan. Healthcare cost savings ranged between NZ$127million (UI $101m to 157m) and NZ$2.1billion (UI $1.6b to 2.6b). Greenhouse gas emissions were reduced by up to 194kgCO2e/year, though changes in emissions were not significant under the walking scenario. Substantial health gains and healthcare cost savings could be achieved by switching short car trips to walking and cycling. Implementing infrastructural improvements and interventions to encourage walking and cycling is likely to be a cost-effective way to improve population health, and may also reduce greenhouse gas emissions.


Green synthesis of biogenic selenium nanoparticles functionalized with ginger dietary extract targeting virulence factor and biofilm formation in Candida albicans.
To treat the systemic infections caused by Candida albicans (C. albicans), various drugs have been used, however, infections still persisted due to virulence factors and increasing antifungal resistance. As a solution to this problem, we synthesized selenium nanoparticles (SeNPs) by using Bacillus cereus bacteria. This is the first study to report a higher (70 %) reduction of selenite ions into SeNPs in under 6 h. The as-synthesized, biogenic SeNPs were used to deliver bioactive constituents of aqueous extract of ginger for inhibiting the growth and biofilm (virulence factors) in C. albicans. UV-visible spectroscopy revealed a characteristic absorption at 280 nm, and Raman spectroscopy showed a characteristic peak shift at 253 cm-1 for the biogenic SeNPs. The synthesized SeNPs are spherical with 240-250 nm in size as determined by electron microscopy. Fourier transform infrared spectroscopy confirmed the functionalization of antifungal constituents of ginger over the SeNPs (formation of Ginger@SeNPs nanoconjugates). In contrast to biogenic SeNPs, nanoconjugates were active against C. albicans for inhibiting growth and biofilm formation. In order to reveal antifungal mechanism of nanoconjugates', real-time polymerase chain reaction (RT-PCR) analysis was performed, according to RT-PCR analysis, the nanoconjugates target virulence genes involved in C. albicans hyphae and biofilm formation. Nanoconjugates inhibited 25 % growth of human embryonic kidney (HEK) 293 cell line, indicating moderate cytotoxicity of active nanoconjugates in an in-vitro cytotoxicity study. Therefore, biogenic SeNPs conjugated with ginger dietary extract may be a potential antifungal agent and drug carrier for inhibiting C. albicans growth and biofilm formation.


Significance of malperfusion syndromes prior to contemporary surgical repair for acute type A dissection: outcomes and need for additional revascularizations.
The aim of this study was to assess the significance of malperfusion syndromes in patients with acute type A aortic dissection following a contemporary surgical management algorithm and the effects on morbidity, hospital mortality, and long-term survival. We believe that obliteration of the primary tear site with restoration of flow in the true aortic lumen results in decreased need for revascularization of malperfused organ systems. Our operative approach aims at replacing the entire ascending aorta, resuspension of the aortic valve with repair or replacement of the sinus segment, and routine open replacement of the arch under hypothermic circulatory arrest with retrograde cerebral perfusion with obliteration of false lumen at the distal arch/proximal descending thoracic aorta, thus reestablishing normal flow in the descending thoracic true lumen. From January 1993 to December 2004, 221 consecutive patients underwent repair of acute type A aortic dissection at our institution. Data were collected retrospectively and prospectively. Various types of malperfusion syndromes were present in 26.7% of patients. The organ systems with malperfusion were as follows: cardiac, 7.2%; cerebral, 7.2%; ileofemoral, 12.7%; renal, 4.1%; mesenteric, 1.4%; innominate, 5.4%; and spine, 2.2%. Coronary malperfusion required coronary revascularization in 62.5% of cases. Distal revascularization was needed in 42.9% of patients with ileofemoral malperfusion. Patients with malperfusion were more likely to suffer perioperative myocardial infarction (p<0.001), postoperative coma (p=0.012), delirium (p=0.011), sepsis (p=0.006), acute renal failure (p=0.017), dialysis (p=0.018), and acute limb ischemia (p<0.001). The in-hospital mortality was 30.5% in patients presenting with any malperfusion syndrome while only 6.2% in patients without malperfusion syndrome (p<0.001). Both cardiac (p=0.020) and cerebral malperfusions (p<0.001) were risk factors for in-hospital mortality. The actuarial long-term survival in patients with malperfusion syndrome was estimated by Kaplan-Meier methods to be 67.8%+/-6.1% at 1 year, 54.0%+/-7.0% at 5 years, and 43.1%+/-8.0% at 10 years and for patient without malperfusion 82.7%+/-3.0% at 1 year, 66.3%+/-3.9% at 5 years, and 46.1%+/-6.7% at 10 years (log rank 2.55, p=0.110). Cerebral malperfusion was a significant risk factor for decreased long-term survival (p=0.0002). The occurrence of malperfusion in patients with acute type A dissection is associated with significant increased risk of in-hospital mortality and complications. Additional revascularization is generally needed in patients with coronary malperfusion and ileofemoral malperfusion. Patients presenting with cardiac and cerebral malperfusions have a high hospital mortality and preoperative cerebral malperfusion is associated with dismal long-term survival.


Biogenesis of Marek's disease (type II leukosis) virus in vitro: electron microscopy and immunological study.
The kinetic events involved in Marek's disease herpesvirus infection of avian cell culture were investigated by assaying viral infectivity and antigenicity as well as by electron microscopy during the infectious cycle. The levels of viral infectivity and complement-fixing (CF) antigens revealed that the rates of appearance of infectious particles and CF antigens were not synchronous. Viral specific CF antigen could be detected 5 h after infection, whereas viral infectivity or the appearance of viral particles could be demonstrated only after 10 h of infection. High proportions of the recovered CF antigens during the various stages of the infectious cycle were found to be soluble and did not sediment with the virus particles. Cytological analysis of the developmental stages of the JM virus-infected cells by thin sectioning and electron microscopy revealed that at 8 h small particles approximately 35 nm in diameter appeared in the cell nuclei. The appearance of nucleocapsids occurred at 10 h, and these were of varying shapes; however, all were approximately 100 nm in diameter. At approximately 18 h postinfection, mature virus particles were observed. Viral maturation of the immature particles occurred by the acquisition of envelope from the inner leaflet of the nuclear membrane or from the cytoplasmic membrane of the cell.


Thermofluidic heat exchangers for actuation of transcription in artificial tissues.
Spatial patterns of gene expression in living organisms orchestrate cell decisions in development, homeostasis, and disease. However, most methods for reconstructing gene patterning in 3D cell culture and artificial tissues are restricted by patterning depth and scale. We introduce a depth- and scale-flexible method to direct volumetric gene expression patterning in 3D artificial tissues, which we call "heat exchangers for actuation of transcription" (HEAT). This approach leverages fluid-based heat transfer from printed networks in the tissues to activate heat-inducible transgenes expressed by embedded cells. We show that gene expression patterning can be tuned both spatially and dynamically by varying channel network architecture, fluid temperature, fluid flow direction, and stimulation timing in a user-defined manner and maintained in vivo. We apply this approach to activate the 3D positional expression of Wnt ligands and Wnt/β-catenin pathway regulators, which are major regulators of development, homeostasis, regeneration, and cancer throughout the animal kingdom.


miR‑183‑5p attenuates cerebral ischemia injury by negatively regulating PTEN.
Cerebral ischemia is a common cerebrovascular disease caused by the occlusion of a cerebral blood vessel. MicroRNAs (miRNAs/miRs) are emerging regulators of various human diseases, including cerebral ischemia. Upregulation of miR‑183‑5p has been reported to alleviate liver injury induced by ischemia‑reperfusion (I/R). However, the effect of miR‑183‑5p on cerebral ischemia injury remains unknown. The present study evaluated the effects of miR‑183‑5p on ischemia injury using ischemic models of mouse brains exposed to transient middle cerebral artery occlusion and Neuro‑2A (N2A) neuroblastoma cells exposed to oxygen‑glucose‑deprivation (OGD) and subsequently reoxygenated. Ischemia was evaluated in mice using neurological function scores, cerebral edema, 2,3,5‑triphenyltetrazoliumchloride, Nissl and Fluoro‑Jade B staining assays. In addition, miR‑183‑5p expression, N2A cell viability and the expression levels of apoptosis‑associated proteins were detected by quantitative PCR, Cell Counting Kit‑8 assay, flow cytometry and western blotting. The association between miR‑183‑5p and phosphatase and tensin homolog (PTEN) was also confirmed by a luciferase reporter assay. The results revealed that miR‑183‑5p expression was decreased and brain damage was increased in ischemic mice compared with the sham group. Additionally, miR‑183‑5p levels were reduced, and apoptosis was increased in N2A cells exposed to ischemia compared with the control group. Following transfection with agomiR‑183‑5p, cerebral ischemic injury and apoptosis levels were reduced in the in vivo I/R stroke model and OGD‑induced N2A cells. In addition, PTEN was determined to be a target of miR‑183‑5p following elucidation of a direct binding site. Overexpression of PTEN reversed the miR‑183‑5p‑induced N2A cell apoptosis inhibition and survival after OGD. The results of the present study suggested that miR‑183‑5p reduced ischemic injury by negatively regulating PTEN, which may aid the development of a novel therapeutic strategy for cerebral ischemia.


Blue-noise multitone dithering.
The introduction of the blue-noise spectra-high-frequency white noise with minimal energy at low frequencies-has had a profound impact on digital halftoning for binary display devices, such as inkjet printers, because it represents an optimal distribution of black and white pixels producing the illusion of a given shade of gray. The blue-noise model, however, does not directly translate to printing with multiple ink intensities. New multilevel printing and display technologies require the development of corresponding quantization algorithms for continuous tone images, namely multitoning. In order to define an optimal distribution of multitone pixels, this paper develops the theory and design of multitone, blue-noise dithering. Here, arbitrary multitone dot patterns are modeled as a layered superposition of stack-constrained binary patterns. Multitone blue-noise exhibits minimum energy at low frequencies and a staircase-like, ascending, spectral pattern at higher frequencies. The optimum spectral profile is described by a set of principal frequencies and amplitudes whose calculation requires the definition of a spectral coherence structure governing the interaction between patterns of dots of different intensities. Efficient algorithms for the generation of multitone, blue-noise dither patterns are also introduced.


Thera-Band application changes muscle activity and kyphosis and scapular winging during knee push-up plus in subjects with scapular winging: The cross-sectional study.
Scapular winging (SW) is defined as increased prominence of the whole medial border of the scapula. Many researchers recently recommended knee push-up plus (KPP) for enhancing serratus anterior (SA) activation. However, during push-up plus, thoracic kyphosis (TK) may usually occur as a compensatory movement. Thus, the purpose of this study was to investigate the effect of Thera-Band application during KPP on rectus abdominis (RA) activity, TK angle (TKA), SA activity, and amount of SW in subjects with SW.Fifteen subjects performed KPP with Thera-Band applied to different posterior body parts (no Thera-Band, in the occiput, and in the thoracic region). Electromyography was used to record the RA and SA activities. Image J software was used to calculate the compensatory TKA during KPP, and a scapulometer was used to measure SW in the quadruped position. One-way repeated-measures analysis of variance was used to test for significance.KPP with Thera-Band in the occiput showed significantly lower RA activity (P = .001) and TKA (P < .001) than KPP with no Thera-Band. SA activity (P = .020, P = .047) and SW (P < .001, P < .001) were significantly lower with Thera-Band applied to the occiput and thoracic regions than in KPP with no Thera-Band.Thera-Band applied to the occiput and thorax can be beneficial as it decreases RA and SA muscle activity and reduces TKA and SW during KPP in subjects with SW.


Objective measures of activity level and mortality in older men.
To examine associations between objective measures of activity level and mortality risk in older men. Prospective cohort study. Six U.S. sites. Men aged 71 and older followed an average of 4.5 years (N = 2,918). Time awake spent in sedentary behavior (metabolic equivalent (MET) level ≤1.50), light activity (MET level 1.51-2.99), and at least moderate activity (MET level ≥3.00) measured using an activity monitor worn for 5 days or longer and expressed as quartiles. Deaths were confirmed with death certificates; cause of death was adjudicated by review of certificates and records. During follow-up, 409 (14%) men died. After multivariable adjustment, comparing Q4 with Q1, more time spent in sedentary behavior (Q4 vs Q1, hazard ratio (HR) = 1.51, 95% confidence interval (CI) = 1.10-2.08), less time spent in light activity (Q1 vs Q4, HR = 1.54, 95% CI = 1.06-2.24), and less time spent in at least moderate activity (Q1 vs Q4, HR = 1.56, 95% CI = 1.09-2.25) were similarly associated with greater mortality risk primarily due to higher risks of cardiovascular and noncardiovascular, noncancer death. The association between time spent in sedentary behavior and mortality varied according to time spent at higher activity level. More time spent in sedentary behavior was associated with greater risk of death in men spending 1.2 (median) h/d or more in at least moderate activity (Q4 vs Q1, HR = 2.09, 95% CI = 1.26-3.49) but not in those spending less time (Q4 vs Q1, HR = 1.02, 95% CI = 0.62-1.66) (P = .005 for interaction). In older men exceeding current guidelines on physical activity, more time spent in sedentary behavior is associated with greater mortality risk.


Insufficiency fractures of the calcaneus: a diagnostic pitfall for ankle arthritis.
To highlight the differential diagnosis between insufficiency fractures (IF) of the calcaneus and arthritis of the ankle. We retrospectively reviewed clinical charts and imaging findings for 6 patients with 7 IF of the calcaneus who were referred with the diagnosis of ankle arthritis. The main predisposing factors, clinical features, therapy, and outcome were recorded. IF was considered when occurring spontaneously or with minimal trauma. All patients were women, with a mean age of 73.8 +/- 6.3 years. The median delay to diagnosis was 6 weeks (25th, 75th percentiles: 1, 12). Two had previous IF at other locations. Three patients had a history of chronic inflammatory conditions while receiving longterm steroid therapy. All complained of moderate to severe pain that interfered with daily activities and was relieved with rest. Physical examination revealed ankle inflammation in all cases. Radiographs were normal in 5 patients. Magnetic resonance imaging (MRI) was diagnostic. All received conservative treatment with complete resolution of symptoms without sequelae. IF of the calcaneus are relatively rare but can be mistaken for ankle arthritis. MRI is recommended because this type of fracture is difficult to detect on plain films. Although IF have a good prognosis with conservative treatment, increased awareness is of importance for prompt diagnosis and proper management.


Topical capsaicin (high concentration) for chronic neuropathic pain in adults.
This review is an update of 'Topical capsaicin (high concentration) for chronic neuropathic pain in adults' last updated in Issue 2, 2013. Topical creams with capsaicin are used to treat peripheral neuropathic pain. Following application to the skin, capsaicin causes enhanced sensitivity, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitisation. High-concentration (8%) capsaicin patches were developed to increase the amount of capsaicin delivered; rapid delivery was thought to improve tolerability because cutaneous nociceptors are 'defunctionalised' quickly. The single application avoids noncompliance. Only the 8% patch formulation of capsaicin is available, with a capsaicin concentration about 100 times greater than conventional creams. High-concentration topical capsaicin is given as a single patch application to the affected part. It must be applied under highly controlled conditions, often following local anaesthetic, due to the initial intense burning sensation it causes. The benefits are expected to last for about 12 weeks, when another application might be made. To review the evidence from controlled trials on the efficacy and tolerability of topically applied, high-concentration (8%) capsaicin in chronic neuropathic pain in adults. For this update, we searched CENTRAL, MEDLINE, Embase, two clinical trials registries, and a pharmaceutical company's website to 10 June 2016. Randomised, double-blind, placebo-controlled studies of at least 6 weeks' duration, using high-concentration (5% or more) topical capsaicin to treat neuropathic pain. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and numbers needed to treat for one additional event, using standard methods.Efficacy outcomes reflecting long-duration pain relief after a single drug application were from the Patient Global Impression of Change (PGIC) at specific points, usually 8 and 12 weeks. We also assessed average pain scores over weeks 2 to 8 and 2 to 12 and the number of participants with pain intensity reduction of at least 30% or at least 50% over baseline, and information on adverse events and withdrawals.We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. We included eight studies, involving 2488 participants, two more studies and 415 more participants than the previous version of this review. Studies were of generally good methodological quality; we judged only one study at high risk of bias, due to small size. Two studies used a placebo control and six used 0.04% topical capsaicin as an 'active' placebo to help maintain blinding. Efficacy outcomes were inconsistently reported, resulting in analyses for most outcomes being based on less than complete data.For postherpetic neuralgia, we found four studies (1272 participants). At both 8 and 12 weeks about 10% more participants reported themselves much or very much improved with high-concentration capsaicin than with 'active' placebo, with point estimates of numbers needed to treat for an additional beneficial outcome (NNTs) of 8.8 (95% confidence interval (CI) 5.3 to 26) with high-concentration capsaicin and 7.0 (95% CI 4.6 to 15) with 'active' placebo (2 studies, 571 participants; moderate quality evidence). More participants (about 10%) had average 2 to 8-week and 2 to 12-week pain intensity reductions over baseline of at least 30% and at least 50% with capsaicin than control, with NNT values between 10 and 12 (2 to 4 studies, 571 to 1272 participants; very low quality evidence).For painful HIV-neuropathy, we found two studies (801 participants). One study reported the proportion of participants who were much or very much improved at 12 weeks (27% with high-concentration capsaicin and 10% with 'active' placebo). For both studies, more participants (about 10%) had average 2 to 12-week pain intensity reductions over baseline of at least 30% with capsaicin than control, with an NNT of 11 (very low quality evidence).For peripheral diabetic neuropathy, we found one study (369 participants). It reported about 10% more participants who were much or very much improved at 8 and 12 weeks. One small study of 46 participants with persistent pain following inguinal herniorrhaphy did not show a difference between capsaicin and placebo for pain reduction (very low quality evidence).We downgraded the quality of the evidence for efficacy outcomes by one to three levels due to sparse data, imprecision, possible effects of imputation methods, and susceptibility to publication bias.Local adverse events were common, but not consistently reported. Serious adverse events were no more common with active treatment (3.5%) than control (3.2%). Adverse event withdrawals did not differ between groups, but lack of efficacy withdrawals were somewhat more common with control than active treatment, based on small numbers of events (six to eight studies, 21 to 67 events; moderate quality evidence, downgraded due to few events). No deaths were judged to be related to study medication. High-concentration topical capsaicin used to treat postherpetic neuralgia, HIV-neuropathy, and painful diabetic neuropathy generated more participants with moderate or substantial levels of pain relief than control treatment using a much lower concentration of capsaicin. These results should be interpreted with caution as the quality of the evidence was moderate or very low. The additional proportion who benefited over control was not large, but for those who did obtain high levels of pain relief, there were usually additional improvements in sleep, fatigue, depression, and quality of life. High-concentration topical capsaicin is similar in its effects to other therapies for chronic pain.


Plasmalemmal vesicles and the effects of sterol-binding agents in rabbit aortic endothelium.
The rims of vesicle openings in capillary endothelium are reported to be highly sensitive to perturbation by the sterol probe filipin when this agent is administered by perfusion at 50 microM concentration in aldehyde fixative for 10 min. If, as supposed, this specific rim response reflects functionally significant aspects of membrane organization at the vesicle-plasmalemma boundary, then it would be expected to be a reproducible and universal feature of endothelial vesicles in general. In the present study, we have investigated in detail the response to filipin of rabbit and rat aortic endothelial plasmalemma. First, the effect of standard filipin treatment (150 microM, 3-20 h) was examined by freeze-fracture. The extensive generalized response observed, taken together with the effects of filipin seen by fluorescence microscopy of stripped aortic endothelial sheets, and the marked corrugation of the plasmalemma observed by freeze-fracture after tomatin treatment, indicate that substantial amounts of cholesterol are present in the membrane. Exposure of rabbit aortic endothelium to 50 microM filipin for 10, 20, 40 and 60 min enabled the progressive appearance of filipin deformations in the plasmalemma to be traced. Even at the very earliest stages of the response, there was no preferential association of filipin deformations with endothelial vesicle rims. Similar experiments in the rat gave the same result. Specific sensitivity of endothelial vesicle rims would, therefore, seem to be either non-universal in occurrence or non-reproducible, and so is unlikely to reflect any membrane property of fundamental significance to endothelial vesicle function.


Does early mentorship in child and adolescent psychiatry make a difference? The Klingenstein Third-Generation Foundation Medical Student Fellowship Program.
There is a critical shortage of child and adolescent psychiatrists in the United States. Increased exposure, through mentorship, clinical experiences, and research opportunities, may increase the number of medical students selecting child and adolescent psychiatry (CAP) as a career choice. Between 2008 and 2011, 241 first-year participants of a program to increase exposure to CAP, funded by the Klingenstein Third-Generation Foundation (KTGF) at 10 medical schools completed baseline surveys assessing their opinions of and experiences in CAP, and 115 second-year participants completed follow-up surveys to reflect 1 year of experience in the KTGF Program. Students reported significantly increased positive perception of mentorship for career and research guidance, along with perceived increased knowledge and understanding of CAP. Results suggest that the KTGF Program positively influenced participating medical students, although future studies are needed to determine whether these changes will translate into more medical students entering the field of CAP.


Extracorporeal shockwave treatment: A novel tool to improve Schwann cell isolation and culture.
As new approaches for peripheral nerve regeneration are sought, there is an increasing demand for native Schwann cells for in vitro testing and/or reimplantation. Extracorporeal shockwave treatment (ESWT) is an emergent technology in the field of regenerative medicine that has also recently been shown to improve peripheral nerve regeneration. In this study, we elucidate the effects of ESWT on Schwann cell isolation and culture. Rat sciatic nerves were dissected and treated with ESWT, and Schwann cells were isolated and cultured for 15 passages. Single treatment of the whole nerve ex vivo led to significantly increased extracellular adenosinetriphosphate as an immediate consequence, and subsequently a number of effects on the culture were observed, starting with a significantly increased Schwann cell yield after isolation. In the ESWT group, the quality of culture, reflected in consistently higher purity (S100b, morphology), proliferation rate (5-bromo-2-deoxyuridine, population doublings per passage) and expression of regenerative phenotype-associated markers (P75, glial fibrillary acidic protein, c-Jun), was significantly improved. In contrast, the control group exhibited progressively senescent behavior, reflected in a decrease of proliferation, loss of specific markers and increase in P16(INK4A) expression. ESWT has beneficial effects on Schwann cell isolation and culture.


Tedizolid phosphate for the treatment of acute bacterial skin and skin structure infections.
Acute bacterial skin and skin structure infections (ABSSSI) are associated with remarkable morbidity, and often require hospitalization. The cause of most ABSSSI is aerobic Gram-positive cocci, including Staphylococcus aureus, and β-hemolytic streptococci. Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety is tedizolid. It has shown potent in vitro activity against Gram-positive pathogens, encompassing methicillin-resistant S. aureus (MRSA) and strains resistant to vancomycin or linezolid. Animal studies suggested bactericidal activity in vivo. Pharmacokinetic studies demonstrated a good penetration into skin and soft tissues, and suitability for once-daily administration, either orally or intravenously at the same dosage. Pivotal phase III studies showed that tedizolid phosphate at 200 mg once daily for 6 days is noninferior to linezolid 600 mg twice daily for 10 days in ABSSSI patients, whereas gastrointestinal disorders were less frequent with tedizolid phosphate than linezolid. Tedizolid phosphate has been approved by the U.S. FDA, as Sivextro® to treat adult patients with ABSSSI.


Facilitated and Non-Gaussian Diffusion of Cholesterol in Liquid Ordered Phase Bilayers Depends on the Flip-Flop and Spatial Arrangement of Cholesterol.
The diffusion of cholesterol in biological membranes is critical to cellular processes such as the formation of cholesterol-enriched domains. The cholesterol diffusion may be complicated especially when cholesterol flip-flops and/or stays at the membrane center. Understanding the diffusion mechanism of cholesterol at a molecular level should be, therefore, a topic of interest. We perform molecular dynamics simulations up to 100 μs for lipid bilayers with various concentrations of cholesterol. We find that cholesterol diffusion in the liquid ordered phase depends on whether it is within leaflets or at the bilayer center, is non-Gaussian for several microseconds, and is enhanced significantly compared to that of lipids. Cholesterol at the bilayer center diffuses fast, while cholesterol in the hydrocarbon region with upright orientation diffuses relatively slowly. Such position-dependent dynamics of cholesterol leads to facilitated and non-Gaussian diffusion.


Sharper focus for a radially polarized light beam.
We experimentally demonstrate for the first time that a radially polarized field can be focused to a spot size significantly smaller [0.16(1)lambda(2)] than for linear polarization (0.26lambda(2)). The effect of the vector properties of light is shown by a comparison of the focal intensity distribution for radially and azimuthally polarized input fields. For strong focusing, a radially polarized field leads to a longitudinal electric field component at the focus which is sharp and centered at the optical axis. The relative contribution of this component is enhanced by using an annular aperture.


Mechanical Consequence of Induced Intervertebral Disc Degeneration in the SPARC-Null Mouse.
Intervertebral disc (IVD) degeneration is associated with low back pain (LBP) and accompanied by mechanical changes to the spine. Secreted protein acidic and rich in cysteine (SPARC) is a protein that contributes to the functioning and maintenance of the extracellular matrix. SPARC-null mice display accelerated IVD degeneration and pain-associated behaviors. This study examined if SPARC-null mice also display altered spine mechanics as compared to wild-type (WT) mice. Lumbar spines from SPARC-null (n = 36) and WT (n = 18) mice aged 14-25 months were subjected to cyclic axial tension and compression to determine neutral zone (NZ) length and stiffness. Three separate mechanical tests were completed for each spine to determine the effect of the number of IVDs tested in series (one versus two versus three IVDs). SPARC-null spine NZs were both stiffer (p < 0.001) and smaller in length (p < 0.001) than WT spines. There was an effect of the number of IVDs tested in series for NZ length but not NZ stiffness when collapsed across condition (SPARC-null and WT). Correlation analysis revealed a weak negative correlation (r = -0.24) between age and NZ length in SPARC-null mice and a weak positive correlation (r = 0.30) between age and NZ stiffness in WT mice. In conclusion, SPARC-null mice had stiffer and smaller NZs than WT mice, regardless of the number of IVDs in series being tested. The increased stiffness of these IVDs likely influences mobility at these spinal joints thereby potentially contributing to low back pain.


Phosphorus Stress-Induced Changes in Plant Root Exudation Could Potentially Facilitate Uranium Mobilization from Stable Mineral Forms.
Apparent deficiency of soil mineral nutrients often triggers specific physio-morphological changes in plants, and some of these changes could also inadvertently increase the ability of plants to mobilize radionuclides from stable mineral forms. This work, through a series of sand-culture, hydroponics, and batch-equilibration experiments, investigated the differential ability of root exudates of Andropogon virginicus grown under conditions with variable phosphorus (P) availability (KH2PO4, FePO4, Ca3(PO4)2, and no P) to solubilize uranium (U) from the uranyl phosphate mineral Chernikovite. The mineral form of P, and hence the bioavailability of P, affected the overall composition of the root exudates. The lower bioavailable forms of P (FePO4 and Ca3(PO4)2), but not the complete absence of P, resulted in a higher abundance of root metabolites with chelating capacity at 72 hrs after treatment application. In treatments with lower P-bioavailability, the physiological amino acid concentration inside of the roots increased, whereas the concentration of organic acids in the roots decreased due to the active exudation. In batch dissolution experiments, the organic acids, but not amino acids, increase the dissolution U from Chernikovite. The root exudate matrix of plants exposed to low available forms of P induced a >60% increase in U dissolution from Chernikovite due to 5-16 times greater abundance of organic acids in these treatments. However, this was ca. 70% of the theoretical dissolution achievable by this exudate matrix. These results highlight the potential of using active management of soil P as an effective tool to alter the plant-mediated mobilization of U in contaminated soil.


Using cultural-historical activity theory to study clinical reasoning in context.
The aim of this paper is to describe sources of conflict and congruence in critical areas of practice with caregivers of persons with dementia, using cultural-historical activity theory as an analytic framework. Findings are drawn from an ethnographic study that described the context of occupational therapists' (OTs') clinical reasoning in a funded, home-based environmental skill-building program designed to help caregivers manage the daily care of a family member with dementia. Data were gathered through observation of intervention sessions, debriefing sessions, semi-structured interviews with therapists, and review of intervention documentation. Primary sources of conflict and congruence within the identified practice context included conflicts between therapists and caregivers concerning which environmental strategies were best for addressing problems in caregiving and expectations regarding OT and caregiver roles. Areas of congruence included the fit between intervention protocols used to guide treatment and the approaches therapists developed to help caregivers modify care receivers' living environments. The study revealed the complexity of OT practice and demonstrated that practice contexts can be systematically analyzed using cultural-historical activity theory to determine key factors influencing clinical reasoning. The approach also presents an alternative perspective on clinical reasoning that more directly integrates clients/caregivers and therapists as co-constructors of OT intervention.


Pulmonary Imaging Biomarkers of Gas Trapping and Emphysema in COPD: (3)He MR Imaging and CT Parametric Response Maps.
To directly compare magnetic resonance (MR) imaging and computed tomography (CT) parametric response map (PRM) measurements of gas trapping and emphysema in ex-smokers both with and without chronic obstructive pulmonary disease (COPD). Participants provided written informed consent to a protocol that was approved by a local research ethics board and Health Canada and was compliant with the HIPAA (Institutional Review Board Reg. #00000940). The prospectively planned study was performed from March 2014 to December 2014 and included 58 ex-smokers (mean age, 73 years ± 9) with (n = 32; mean age, 74 years ± 7) and without (n = 26; mean age, 70 years ± 11) COPD. MR imaging (at functional residual capacity plus 1 L), CT (at full inspiration and expiration), and spirometry or plethysmography were performed during a 2-hour visit to generate ventilation defect percent (VDP), apparent diffusion coefficient (ADC), and PRM gas trapping and emphysema measurements. The relationships between pulmonary function and imaging measurements were determined with analysis of variance (ANOVA), Holm-Bonferroni corrected Pearson correlations, multivariate regression modeling, and the spatial overlap coefficient (SOC). VDP, ADC, and PRM gas trapping and emphysema (ANOVA, P < .001) measurements were significantly different in healthy ex-smokers than they were in ex-smokers with COPD. In all ex-smokers, VDP was correlated with PRM gas trapping (r = 0.58, P < .001) and with PRM emphysema (r = 0.68, P < .001). VDP was also significantly correlated with PRM in ex-smokers with COPD (gas trapping: r = 0.47 and P = .03; emphysema: r = 0.62 and P < .001) but not in healthy ex-smokers. In a multivariate model that predicted PRM gas trapping, the forced expiratory volume in 1 second normalized to the forced vital capacity (standardized coefficients [βS] = -0.69, P = .001) and airway wall area percent (βS = -0.22, P = .02) were significant predictors. PRM emphysema was predicted by the diffusing capacity for carbon monoxide (βS = -0.29, P = .03) and VDP (βS = 0.41, P = .001). Helium 3 ADC values were significantly elevated in PRM gas-trapping regions (P < .001). The spatial relationship for ventilation defects was significantly greater with PRM gas trapping than with PRM emphysema in patients with mild (for gas trapping, SOC = 36% ± 28; for emphysema, SOC = 1% ± 2; P = .001) and moderate (for gas trapping, SOC = 34% ± 28; for emphysema, SOC = 7% ± 15; P = .006) COPD. For severe COPD, the spatial relationship for ventilation defects with PRM emphysema (SOC = 64% ± 30) was significantly greater than that for PRM gas trapping (SOC = 36% ± 18; P = .01). In all ex-smokers, ADC values were significantly elevated in regions of PRM gas trapping, and VDP was quantitatively and spatially related to both PRM gas trapping and PRM emphysema. In patients with mild to moderate COPD, VDP was related to PRM gas trapping, whereas in patients with severe COPD, VDP correlated with both PRM gas trapping and PRM emphysema.


Moonlighting microtubule-associated proteins: regulatory functions by day and pathological functions at night.
The sensing, integrating, and coordinating features of the eukaryotic cells are achieved by the complex ultrastructural arrays and multifarious functions of the cytoskeletal network. Cytoskeleton comprises fibrous protein networks of microtubules, actin, and intermediate filaments. These filamentous polymer structures are highly dynamic and undergo constant and rapid reorganization during cellular processes. The microtubular system plays a crucial role in the brain, as it is involved in an enormous number of cellular events including cell differentiation and pathological inclusion formation. These multifarious functions of microtubules can be achieved by their decoration with proteins/enzymes that exert specific effects on the dynamics and organization of the cytoskeleton and mediate distinct functions due to their moonlighting features. This mini-review focuses on two aspects of the microtubule cytoskeleton. On the one hand, we describe the heteroassociation of tubulin/microtubules with metabolic enzymes, which in addition to their catalytic activities stabilize microtubule structures via their cross-linking functions. On the other hand, we focus on the recently identified moonlighting tubulin polymerization promoting protein, TPPP/p25. TPPP/p25 is a microtubule-associated protein and it displays distinct physiological or pathological (aberrant) functions; thus it is a prototype of Neomorphic Moonlighting Proteins. The expression of TPPP/p25 is finely controlled in the human brain; this protein is indispensable for the development of projections of oligodendrocytes that are responsible for the ensheathment of axons. The nonphysiological, higher or lower TPPP/p25 level leads to distinct CNS diseases. Mechanisms contributing to the control of microtubule stability and dynamics by metabolic enzymes and TPPP/p25 will be discussed.


Man-made electromagnetic noises causing difficulty in geomagnetic and geoelectric observations in city area.
In city area, there are several types of electromagnetic noises originated in daily activities of human beings. The noises possibly cause difficulty to detect geomagnetic and geoelectric signatures. It is important for investigators who are studying geomagnetic effects for biology, medicine and so on to be aware that such noises are present in city area. Among these noises, the one due to electric railways driven by direct-current electric power supply might give the largest influence because this type of noise continues almost all the time and have complex wave forms. The characteristics of the noises are briefly introduced by showing a theoretical background and some experimental studies.


The internal methionine codons of human T-cell leukemia virus type II rex gene are not required for p24rex production or virus replication and transformation.
Human T-cell leukemia virus types I (HTLV-I) and II (HTLV-II) have two nonstructural trans-acting regulatory genes, tax and rex, located in the 3' region of the viral genome. The tax gene product (HTLV-I p40tax and HTLV-II p37tax) is the transcriptional activator of the viral long terminal repeat. The rex gene encodes two protein products, p27rex/p21rex and p26rex/p24rex in HTLV-I and HTLV-II, respectively. Rex acts posttranscriptionally to facilitate accumulation of full-length gag/pol and singly spliced env mRNA in the cytoplasm of HTLV-infected cells. Previous studies showed that the first ATG of the rex gene is critical for Rex production and function. The importance of the internal ATGs to Rex function is not known. However, in vitro mutagenesis of the HTLV-I rex gene has provided indirect evidence which suggests that p21rex, and by analogy HTLV-II p24rex, results from initiation at an internal AUG of the tax/rex mRNA. By using an infectious molecular clone of HTLV-II, we investigated the importance of the internal ATGs of the rex gene on Rex protein production and function. Our results indicate that p24rex of HTLV-II is not initiated at an internal AUG and that the internal methionine codons are not crucial to the function of the rex gene and, ultimately, the transforming properties of the virus.


Fungal infections of dialysis fistulae.
Bacterial infections of dialysis access fistulae are well known in patients with end-stage renal disease, but fungal infections of these prostheses have not been reported. Two patients who presented with recurrent infections and thromboses of their grafts grew Staphylococcus aureus and Cephalosporium species. This new entity suggests a different approach to the management of clotted grafts in patients with end-stage renal disease. If fungus is isolated from the graft, extirpation of the graft and amphotericin B therapy are suggested. We review here the mycology of Cephalosporium species, in-vitro sensitivity studies, and previous reports of infection with this fungus.


Sex-related differences in sudomotor function in healthy early twenties focused on activated sweat gland density.
The purpose of this study was to quantitatively assess the difference in sudomotor function between healthy males and females in their early twenties by measuring skin surface area and activated sweat gland density (ASGD). The quantitative sudomotor axon reflex test (QSART), a method for evaluating autonomic nervous system activity, was used for quantification. In QSART, the sweat glands are activated directly or indirectly by the subcutaneous application of neurotransmitters, such as acetylcholine, through iontophoresis. This series of mechanisms is called the sudomotor axon reflex. After recording age, height, weight, and several measurements of the forearm, QSART was performed on 101 healthy controls aged 21-26 years to measure ASGD. The mean temperature and humidity on the measurement days were 11.4°C and 58.1% on May 3, 2018, and 14.7°C and 70.3% on May 10, 2018. The result of independent sample t-test showed higher ASGD in women (P < 0.05). The body surface area and the surface area of the forearms were higher in men (P < 0.001), but the number of activated sweat glands was not significantly different according to sex. The activated sweat gland counts of the body and forearms were analyzed through linear regression by age for males and females. Except for the activated sweat gland count of the male body, the analysis showed a tendency to decrease with increasing age but was not statistically significant in any case (P > 0.05). Showing insufficient coefficient of determination (R2), multiple regression analyses with sex and ages did not correct this insignificance between age and activated sweat gland count.


Depression in Lesbian, Gay, and Bisexual Members of the Canadian Armed Forces.
Lesbians, gay men, and bisexuals have been shown to have different risks for mood and anxiety disorders than heterosexuals in population studies, but there is a paucity of research in this area in military populations. This study examined the relationship between sexual orientation and depression in the Canadian Armed Forces (CAF). Data were drawn from the Canadian Forces Mental Health Survey 2013 (n = 8165), a representative sample of Regular and Reserve members of the Canadian military. Binomial logistic regression was used to predict 12-month and lifetime odds ratios for major depressive episode (MDE) stratified by sexual orientation and sex. Gay male members had higher risk (AOR = 3.80, 95% CI 1.60-9.05) for lifetime MDE, but not for past 12-month MDE compared to heterosexual males. There was no significant difference in risk for lesbians or bisexuals compared to heterosexuals. The results suggest that gay male members of the CAF are at higher risk for a history of MDE, but not current MDE. This may be a result of ongoing discrimination and stigma faced by gay men in the military or may reflect MDE that occurred before military service. The lack of difference in MDE risk for lesbian and bisexual members compared to heterosexual members is an important positive finding.


Detection and determination of theobromine and caffeine in urine after administration of chocolate-coated peanuts to horses.
The objective of this study was to determine the urinary excretion of methylxanthines in horses following ingestion of chocolate over eight days. The study was performed in response to gas chromatography-mass spectrometry (GC-MS) confirmation of the presence of caffeine in a positive urine test in a racehorse. The trainer of the horse alleged that he often administered chocolate-coated peanuts as treats to his horses, and he believed that the ingestion of chocolate was responsible for the positive urine test. The urinary excretion of theobromine and caffeine after the ingestion of chocolate-coated peanuts was investigated in three horses. Enzyme-linked immunoassay (ELISA), high-performance liquid chromatography (HPLC), and GC-MS assays were performed on all urine specimens. Theobromine (HPLC) was detected for 72 h and caffeine (GC-MS) for 48 h after chronic ingestion of chocolate-coated peanuts. Methylxanthines were detected by ELISA for 120 h after administration of chocolate.


Effect of 2-bromostearate on glucose-phosphorylating activities and the dynamics of insulin secretion in islets of Langerhans during fasting.
Glucose-phosphorylating activity and insulin secretion were measured in homogenates of isolated rat islets and of perfused rat pancreas, respectively. Fasting for 96 h produced a significant decrease of both low-and high-Km glucose-phosphorylating activities and blocked the insulin secretory response to glucose. In the presence of glucose, 0.25 mM 2-bromostearate, a known inhibitor of fatty acid oxidation, partially restored the insulin response to glucose that was lost during fasting. This effect paralleled the restoration of glucose-phosphorylation activities (primarily the high-Km component) seen when islets isolated from 96-h-fasted rats were preincubated with 0.25 mM 2-bromostearate. It is concluded that fasting-induced adaptations of glucose-phosphorylating enzymes could account, at least in part, for the reduced insulin secretory response to glucose. 2-Bromostearate, an inhibitor of fatty acid oxidation, is able to restore both insulin secretory response and glucose-phosphorylating activities, suggesting possible interrelations among the correlated impairment in insulin secretion, islet glucose-phosphorylating activity, islet glucose metabolism, and the oxidation of fatty acids in the B-cell during fasting.


Tetrameric Orai1 is a teardrop-shaped molecule with a long, tapered cytoplasmic domain.
The Ca(2+) release-activated Ca(2+) channel is a principal regulator of intracellular Ca(2+) rise, which conducts various biological functions, including immune responses. This channel, involved in store-operated Ca(2+) influx, is believed to be composed of at least two major components. Orai1 has a putative channel pore and locates in the plasma membrane, and STIM1 is a sensor for luminal Ca(2+) store depletion in the endoplasmic reticulum membrane. Here we have purified the FLAG-fused Orai1 protein, determined its tetrameric stoichiometry, and reconstructed its three-dimensional structure at 21-A resolution from 3681 automatically selected particle images, taken with an electron microscope. This first structural depiction of a member of the Orai family shows an elongated teardrop-shape 150A in height and 95A in width. Antibody decoration and volume estimation from the amino acid sequence indicate that the widest transmembrane domain is located between the round extracellular domain and the tapered cytoplasmic domain. The cytoplasmic length of 100A is sufficient for direct association with STIM1. Orifices close to the extracellular and intracellular membrane surfaces of Orai1 seem to connect outside the molecule to large internal cavities.


Brief report: Use of the mini-clinical evaluation exercise in internal medicine core clerkships.
Direct observation of medical students' clinical skills is important, but occurs infrequently. The mini-clinical evaluation exercise (mCEX) is a tool developed for use with internal medicine (IM) residents that can be used to promote direct observation of medical students' clinical skills. It is unknown how many IM core clerkships in the United States use the mCEX or how it has been implemented. Questions about use of the mCEX were incorporated into an online annual survey distributed to the 114 IM clerkships belonging to Clerkship Directors in Internal Medicine, a national organization of individuals responsible for teaching IM to medical students. The survey response rate was 83%. Twenty-eight percent (N=27) of respondents use the mCEX in their clerkship. The mean number of required mCEX encounters is 2.3 (SD 1.6). The mCEX is used for formative assessment (68%) more than summative assessment (11%). Ward attendings are the most common mCEX evaluators (72%). The mCEX is being used to promote direct observation of medical students' clinical skills in a significant minority of IM core clerkships. The mCEX is 1 tool for facilitating feedback from both faculty and residents on trainees' developing skills.


Detection of focal source and arrhythmogenic substrate from body surface potentials to guide atrial fibrillation ablation.
Focal sources (FS) are believed to be important triggers and a perpetuation mechanism for paroxysmal atrial fibrillation (AF). Detecting FS and determining AF sustainability in atrial tissue can help guide ablation targeting. We hypothesized that sustained rotors during FS-driven episodes indicate an arrhythmogenic substrate for sustained AF, and that non-invasive electrical recordings, like electrocardiograms (ECGs) or body surface potential maps (BSPMs), could be used to detect FS and AF sustainability. Computer simulations were performed on five bi-atrial geometries. FS were induced by pacing at cycle lengths of 120-270 ms from 32 atrial sites and four pulmonary veins. Self-sustained reentrant activities were also initiated around the same 32 atrial sites with inexcitable cores of radii of 0, 0.5 and 1 cm. FS fired for two seconds and then AF inducibility was tested by whether activation was sustained for another second. ECGs and BSPMs were simulated. Equivalent atrial sources were extracted using second-order blind source separation, and their cycle length, periodicity and contribution, were used as features for random forest classifiers. Longer rotor duration during FS-driven episodes indicates higher AF inducibility (area under ROC curve = 0.83). Our method had accuracy of 90.6±1.0% and 90.6±0.6% in detecting FS presence, and 93.1±0.6% and 94.2±1.2% in identifying AF sustainability, and 80.0±6.6% and 61.0±5.2% in determining the atrium of the focal site, from BSPMs and ECGs of five atria. The detection of FS presence and AF sustainability were insensitive to vest placement (±9.6%). On pre-operative BSPMs of 52 paroxysmal AF patients, patients classified with initiator-type FS on a single atrium resulted in improved two-to-three-year AF-free likelihoods (p-value < 0.01, logrank tests). Detection of FS and arrhythmogenic substrate can be performed from ECGs and BSPMs, enabling non-invasive mapping towards mechanism-targeted AF treatment, and malignant ectopic beat detection with likely AF progression.


Clinical and genetic analysis of Korean patients with facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominantly inherited muscular disorder, which is characterized by weakness of facial, shoulder and hip girdle, humeral, and anterior distal leg muscles. The FSHD gene has been mapped to 4q35 and a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4 was known to be the genetic background of the disorder. Although FSHD is the second most common muscular dystrophy in adulthood, there were few reports on the genetically confirmed patients in Korea. Recently, we experienced four Korean patients with clinical features resembling FSHD. In order to confirm the diagnosis, conventional Southern blot (SB) analysis by using double digestion with EcoRI and BlnI and hybridization with p13E-11 probe was performed in three patients and newly developed long polymerase chain reaction (PCR) method was used for one patient because genomic DNA was not enough for conventional SB for this patient. All patients were demonstrated to have shortened D4Z4 repeats that were consistent with FSHD. Therefore, we could confirm the diagnosis of FSHD in four Korean patients and appropriate genetic counseling was done for the patients and their families. It is of note that long-PCR method could be a good alternative for conventional SB when D4Z4 repeats were less than 5.


Big Data, Internet of Things and Cloud Convergence--An Architecture for Secure E-Health Applications.
Big data storage and processing are considered as one of the main applications for cloud computing systems. Furthermore, the development of the Internet of Things (IoT) paradigm has advanced the research on Machine to Machine (M2M) communications and enabled novel tele-monitoring architectures for E-Health applications. However, there is a need for converging current decentralized cloud systems, general software for processing big data and IoT systems. The purpose of this paper is to analyze existing components and methods of securely integrating big data processing with cloud M2M systems based on Remote Telemetry Units (RTUs) and to propose a converged E-Health architecture built on Exalead CloudView, a search based application. Finally, we discuss the main findings of the proposed implementation and future directions.


Ultrasound-guided direct basilic-axillary approach in preoperative venography for hemodialysis access.
Hemodialysis patients with suspected central vein stenosis or occlusion require venographic assessment before access surgery. Conventional venography may be unsatisfactory because of the limited ability to image central veins via peripheral arm veins that are inadequate or that have been damaged by multiple cannulations. Imaging of the central veins requires high flow contrast injection, which may be unattainable through small peripheral veins. We suggest a simple technique to improve central vein imaging by ultrasound-guided direct puncture of the basilic vein at its entry to the axilla. We studied 20 patients in whom upper limb venography via peripheral veins was inadequate for the satisfactory demonstration of central vein anatomy and they underwent direct basilic-axillary vein puncture with Doppler ultrasound guidance. A 4Fr micropuncture catheter was used for manual injection of the contrast agent to image the central veins. All patients had inadequate upper limb venography via peripheral vein cannulation, and stenosis could not be ruled out due to poor visualization of the central veins. In all cases, venography by Doppler ultrasound-guided direct basilic-axillary vein puncture was very easy for both the radiologist and the patient, consistently providing high quality imaging without the need for repeated attempts at cannulation and without the need for infusion pumps. No complications were noted during or after the procedure. Venography by Doppler ultrasound-guided direct basilic-axillary vein puncture is a simple and rapidly performed technique that improves the visualization of the central veins.


Environmental and socioeconomic factors contributing to elevated blood lead levels in children from an industrial area of Upper Silesia.
The present study concentrated on a cross-sectional analysis of recent exposure to lead (Pb) and the socioeconomic factors behind increased Pb exposure in Polish children. Lead is one of the most widespread toxic heavy metals in the industrial region of Upper Silesia (Poland). Elevated blood Pb levels in children continue to be a matter of serious concern. The present study involved 4882 children from the Upper Silesia region, aged from 3 yr to 18 yr, over the calendar years 1999 to 2013. The concentration of Pb in blood was determined in each child. The children's parents were asked to answer survey questions about the child's environmental exposure to Pb as well as the socioeconomic condition of the family. Factors that correspond with increased exposure to Pb included: lower level of education of parents, unemployment, parents' occupational Pb exposure, poor socioeconomic status of the family, smoking at home, living on the ground floor of buildings, consumption of locally grown vegetables and fruits, longer outdoor playing periods in a polluted environment, and male gender. Environmental exposure to Pb is the most important factor behind chronic poisoning of children in Upper Silesia. The most important socioeconomic factor associated with concentrations of Pb in children's blood is a lower level of education of a child's mother and father. Environ Toxicol Chem 2016;35:2597-2603. © 2016 SETAC.


Hydrogen peroxide induces spawning in mollusks, with activation of prostaglandin endoperoxide synthetase.
Addition of hydrogen peroxide to seawater causes synchronous spawning in gravid male and female abalones, and certain other mollusks as well. This effect is blocked by exposure of the animals to aspirin, an inhibitor of the enzyme catalyzing oxidative synthesis of prostaglandin endoperoxide. Hydrogen peroxide activates this enzymatic reaction in cell-free extracts prepared from abalone eggs (a very rich source of the prostaglandin endoperoxide synthetase); this effect appears to reveal a fundamental property of prostaglandin endoperoxide synthesis. Applicability of these findings to both mariculture and medical purposes is suggested.


Role of oxygen in arteriolar functional vasodilation in hamster striated muscle.
Small isolated groups of striated muscle cells were stimulated in the hamster cremaster muscle. During and after stimulation, oxygen microelectrodes were employed to determine the relationships among arteriolar vasodilation, tissue Po2, and periarteriolar Po2. Localized contraction produced a biphasic arteriolar vasodilation without associated alteration of Po2 on the surface of the arterioles (vascular smooth muscle Po2). In contrast, muscle contraction produced a decline in muscle tissue Po2 that was proportional to the contraction frequency over the range of 1--4 contractions per second. An increase in contraction frequency also produced a graded increase in arteriolar diameter, the magnitude of which was statistically correlated with the steady-state change in tissue Po2. However, arteriolar diameter changes preceded tissue Po2 changes, both with the initiation of functional dilation and during the recovery period. Tissue Po2 was manipulated at rest and during contraction by increasing the Po2 of the superfusion solution. Increasing the tissue Po2 caused a decrease in vascular diameter under both conditions and a reduction in the magnitude of the arteriolar vasodilation during contraction. Restoration of tissue Po2 to resting levels during muscle contraction produced only partial restoration of vascular diameters. The results are consistent with the hypothesis that at least three components are involved in the vascular control process during muscular activity: an early component independent of tissue oxygen levels, a late component independent of oxygen, and a late component associated with a decrease in muscle Po2, without an effect on vascular smooth muscle Po2. The evidence indicated that Po2 of the smooth muscle of the arterioles had no role in the dilation observed.


The treatment of retained gallstones.
Various techniques are available to evaluate patients suspected of having common duct stones before an operation on the biliary tract. In patients without jaundice, intravenous cholangiography with tomography may provide satisfactory visualization of the biliary system and its contents. Sonography and computerized axial tomography are useful noninvasive methods. Endoscopic retrograde and transhepatic cholangiography are invasive techniques; but, when successful, they provide the most precise preoperative information obtainable about the presence or absence of stones in the biliary system. The most appropriate diagnostic procedures must be carefully selected for each patient. Each year in 3,000 to 4,000 cases, stones are found remaining in the bile ducts after common duct exploration for the removal of stones. Retained stones can be treated by nonoperative extraction, by irrigation techniques and by surgical removal. Extraction methods probably deserve first consideration, if experienced personnel are available. The technique of irrigation of the common bile duct with cholic acid or other solutions, although limited in success, may also be tried; if these procedures fail, then reoperation is indicated.


Vildagliptin added to metformin on β-cell function after a euglycemic hyperinsulinemic and hyperglycemic clamp in type 2 diabetes patients.
This study evaluated the effect of vildagliptin + metformin on glycemic control and β-cell function in type 2 diabetes patients. One hundred seventy-one type 2 diabetes patients, naive to antidiabetes therapy and with poor glycemic control, were instructed to take metformin for 8±2 months up to a mean dosage of 2,500±500 mg/day; then they were randomly assigned to add vildaglipin 50 mg twice a day or placebo for 12 months. We evaluated at 3, 6, 9, and 12 months: body mass index, glycemic control, fasting plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment β-cell function index (HOMA-β), fasting plasma proinsulin, proinsulin/fasting plasma insulin ratio, C-peptide, glucagon, adiponectin, and high-sensitivity C-reactive protein. Before and at 12 months after the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation, to assess insulin sensitivity and insulin secretion. After 12 months of treatment, vildagliptin + metformin gave a better decrease of body weight, glycemic control, HOMA-IR, and glucagon and a better increase of HOMA-β compared with placebo + metformin. Regarding the measures of β-cell function, treatment-induced changes in M-value, first- and second-phase C-peptide response to glucose, and C-peptide response to arginine were significantly higher in the vildagliptin + metformin group compared with the placebo + metformin group. The addition of vildagliptin to metformin gave a better improvement of glycemic control, insulin resistance, and β-cell function compared with metformin alone.


Interruption of Aspergillus niger spore germination by the bacterially produced secondary metabolite collimomycin.
Collimonas fungivorans Ter331 (CfTer331) is a soil bacterium that produces collimomycin, a secondary metabolite that inhibits the vegetative growth of fungi. Here we show that CfTer331 can also interfere with fungal spore germination and that collimomycin biosynthesis is required for this activity. More specifically, in co-cultures of Aspergillus niger N402 (AnN402) co-nidiospores with CfTer331, the rate of transition from the isotropic to polarized stage of the germination process was reduced and the relatively few AnN402 conidiospores that completed the germination process were less likely to survive than those that were arrested in the isotropic phase. By contrast, a collimomycin-deficient mutant of CfTer331 had no effect on germination: in its presence, as in the absence or delayed presence of CfTer331, unhindered germination of conidiospores allowed rapid establishment of AnN402 mycelium and the subsequent acidification of the culture medium to the detriment of any bacteria present. However, when challenged early enough with CfTer331, the collimomycin-dependent arrest of the AnN402 germination process enabled CfTer331 to prevent AnN402 from forming mycelia and to gain dominance in the culture. We propose that the collimomycin-dependent arrest of spore germination represents an early intervention strategy used by CfTer331 to mitigate niche construction by fungi in nature.


Solexa sequencing identification of conserved and novel microRNAs in backfat of Large White and Chinese Meishan pigs.
The domestic pig (Sus scrofa), an important species in animal production industry, is a right model for studying adipogenesis and fat deposition. In order to expand the repertoire of porcine miRNAs and further explore potential regulatory miRNAs which have influence on adipogenesis, high-throughput Solexa sequencing approach was adopted to identify miRNAs in backfat of Large White (lean type pig) and Meishan pigs (Chinese indigenous fatty pig). We identified 215 unique miRNAs comprising 75 known pre-miRNAs, of which 49 miRNA*s were first identified in our study, 73 miRNAs were overlapped in both libraries, and 140 were novelly predicted miRNAs, and 215 unique miRNAs were collectively corresponding to 235 independent genomic loci. Furthermore, we analyzed the sequence variations, seed edits and phylogenetic development of the miRNAs. 17 miRNAs were widely conserved from vertebrates to invertebrates, suggesting that these miRNAs may serve as potential evolutional biomarkers. 9 conserved miRNAs with significantly differential expressions were determined. The expression of miR-215, miR-135, miR-224 and miR-146b was higher in Large White pigs, opposite to the patterns shown by miR-1a, miR-133a, miR-122, miR-204 and miR-183. Almost all novel miRNAs could be considered pig-specific except ssc-miR-1343, miR-2320, miR-2326, miR-2411 and miR-2483 which had homologs in Bos taurus, among which ssc-miR-1343, miR-2320, miR-2411 and miR-2483 were validated in backfat tissue by stem-loop qPCR. Our results displayed a high level of concordance between the qPCR and Solexa sequencing method in 9 of 10 miRNAs comparisons except for miR-1a. Moreover, we found 2 miRNAs, miR-135 and miR-183, may exert impacts on porcine backfat development through WNT signaling pathway. In conclusion, our research develops porcine miRNAs and should be beneficial to study the adipogenesis and fat deposition of different pig breeds based on miRNAs.


Hormones, nutrition, and cancer.
The effects of obesity on steroid metabolism in women with breast and uterine cancer have been considered. Obesity may increase plasma estrone by two mechanisms, a higher rate of secretion of the estrone precursor, androstenedione, and a higher rate of conversion of androstenedione to estrone. Obesity may alter routes of metabolism of androgens and estrogens. The excretion of specific urinary metabolites can therefore be altered by obesity alone. Thus, steroid indices of relative cancer risk or responsiveness must be constructed with due attention to obesity, one of many important variables.


Monitoring Crimean-Congo haemorrhagic fever virus RNA shedding in body secretions and serological status in hospitalised patients, Turkey, 2015.
IntroductionCrimean-Congo haemorrhagic fever (CCHF) is a tick-borne disease in Africa, Asia, the Balkan peninsula, the south-east of Europe and the Middle East, with mortality rates of 3-30%. Transmission can also occur through contact with infected animals or humans.AimThis observational, prospective case series aimed to investigate detectable viral genomic RNA in whole-body fluids and antibody dynamics in consecutive daily samples of patients diagnosed with CCHF until discharge from hospital.MethodsWe tested 18 patients and 824 swabs and sera with RT-PCR and 125 serum samples serologically.ResultsThe longest duration until clearance of viral RNA was 18 days from serum collection and 18, 15, 13, 19 and 17 days, respectively, from nasal, oral, genital (urethral or vaginal) and faecal swab, and urine. In seven patients, viral load decreased in serum at the same time as it increased in urine or persisted at the same logarithmic values. Despite clearance in serum, viral RNA was detected in faeces and genital swabs in two and three patients, respectively. Viral clearance from body fluids occurred earlier than from serum in eight patients on ribavirin treatment. The shortest seroconversion time was 3 days after symptom onset for IgM and IgG. Seroconversion of IgG occurred until Day 14 of symptoms.ConclusionWe report persistence of viral RNA in urine, faeces and genital swabs despite serum clearance. This may indicate a need for extending isolation precautions, re-evaluating discharge criteria and transmission risk after discharge, and considering oral swabs as a less invasive diagnostic alternative.


Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma.
Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6-10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m(2) on days 1-5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials.


Mammalian and Invertebrate Models as Complementary Tools for Gaining Mechanistic Insight on Muscle Responses to Spaceflight.
Bioinformatics approaches have proven useful in understanding biological responses to spaceflight. Spaceflight experiments remain resource intensive and rare. One outstanding issue is how to maximize scientific output from a limited number of omics datasets from traditional animal models including nematodes, fruitfly, and rodents. The utility of omics data from invertebrate models in anticipating mammalian responses to spaceflight has not been fully explored. Hence, we performed comparative analyses of transcriptomes of soleus and extensor digitorum longus (EDL) in mice that underwent 37 days of spaceflight. Results indicate shared stress responses and altered circadian rhythm. EDL showed more robust growth signals and Pde2a downregulation, possibly underlying its resistance to atrophy versus soleus. Spaceflight and hindlimb unloading mice shared differential regulation of proliferation, circadian, and neuronal signaling. Shared gene regulation in muscles of humans on bedrest and space flown rodents suggest targets for mitigating muscle atrophy in space and on Earth. Spaceflight responses of C. elegans were more similar to EDL. Discrete life stages of D. melanogaster have distinct utility in anticipating EDL and soleus responses. In summary, spaceflight leads to shared and discrete molecular responses between muscle types and invertebrate models may augment mechanistic knowledge gained from rodent spaceflight and ground-based studies.


Perturbed breakup of gas bubbles in water: memory, gas flow, and coalescence.
The pinch-off of an air bubble from an underwater nozzle ends in a singularity with a remarkable sensitivity to a variety of perturbations. I report on experiments that break both the axial (i.e., vertical) and azimuthal symmetry of the singularity formation. The density of the inner gas influences the axial asymmetry of the neck near pinch-off. For denser gases, flow through the neck late in collapse changes the pinch-off dynamics. Gas density is also implicated in the formation of satellite bubbles. The azimuthal shape oscillations described by Schmidt et al. can be initiated by anisotropic boundary conditions in the liquid as well as with an asymmetric nozzle shape. I measure the n=3 oscillatory mode and observe the nonlinear, highly three-dimensional outcomes of pinch-off with large azimuthal perturbations. These are consistent with prior theory.