Reachability and the sense of embodiment in amputees using prostheses.
Amputated patients are hardly satisfied with upper limb prostheses, and tend to favour the use of their contralateral arm to partially compensate their disability. This may seem surprising in light of recent evidences that external objects (rubber hand or tool) can easily be embodied, namely incorporated in the body representation. We investigated both implicit body representations (by evaluating the peripersonal space using a reachability judgement task) and the quality of bodily integration of the patient's prosthesis (assessed via questionnaires). As expected, the patients estimated that they could reach further while wearing their prosthesis, showing an embodiment of their prosthesis in their judgement. Yet, the real reaching space was found to be smaller with their prosthesis than with their healthy limb, showing a large error between reachability judgement and actual capacity. An overestimation was also found on the healthy side (comparatively to healthy subjects) suggesting a bilateral modification of body representation in amputated patients. Finally, a correlation was found between the quality of integration of the prosthesis and the way the body representation changed. This study therefore illustrates the multifaceted nature of the phenomenon of prosthesis integration, which involves its incorporation as a tool, but also various specific subjective aspects.


Effect of a robotic seal on the motor activity and sleep patterns of older people with dementia, as measured by wearable technology: A cluster-randomised controlled trial.
The robotic seal, PARO, has been used as an alternative to animal-assisted therapies with residents with dementia in long-term care, yet understanding of its efficacy is limited by a paucity of research. We explored the effects of PARO on motor activity and sleep patterns, as measured by a wearable triaxial accelerometer. Cluster-randomised controlled trial, involving 28 facilities in Queensland, Australia. Nine facilities were randomised to the PARO group (individual, non-facilitated, 15-min sessions three afternoons per week for 10 weeks), 10 to a plush toy (PARO with robotic features disabled) and nine to usual care. Changes in day- and nighttime motor activity and sleep after the 10-week intervention, as measured by SenseWear® armbands, worn by participants continuously for 24 h at baseline, during two single intervention days in weeks 5 and 10 respectively, and post-intervention (week 15). Analyses followed intention-to-treat, using repeated-measures mixed-effects models. After 10 weeks, the PARO group showed a greater reduction in daytime step count than usual care (p = 0.023), and in nighttime step count (p = 0.028) and daytime physical activity (p = 0.026) compared with the plush toy group. At post-intervention, the PARO group showed a greater reduction in daytime step count than the plush toy group (p = 0.028), and at nighttime compared with both the plush toy group (p = 0.019) and the usual-care group (p = 0.046). The PARO group also had a greater reduction in nighttime physical activity than the usual-care group (p = 0.015). PARO may have some effect on motor activity of older people with dementia in long-term care, but not on sleep patterns. Australian New Zealand Clinical Trials Registry (ACTRN12614000508673).


Differences in prefrontal blood oxygenation during an acute multitasking stressor in ecstasy polydrug users.
Cognitive deficits are well documented in ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, with such deficits being taken as evidence of dysregulation of the serotonin (5-hydroxytryptamine; 5-HT) system. More recently neuroimaging has been used to corroborate these deficits. The present study aimed to assess multitasking performance in ecstasy polydrug users, polydrug users and drug-naive individuals. It was predicted that ecstasy polydrug users would perform worse than non-users on the behavioural measure and this would be supported by differences in cortical blood oxygenation. In the study, 20 ecstasy-polydrug users, 17 polydrug users and 19 drug-naive individuals took part. On day 1, drug use history was taken and questionnaire measures were completed. On day 2, participants completed a 20-min multitasking stressor while brain blood oxygenation was measured using functional near infrared spectroscopy (fNIRS). There were no significant differences between the three groups on the subscales of the multitasking stressor. In addition, there were no significant differences on self-report measures of perceived workload (NASA Task Load Index). In terms of mood, ecstasy users were significantly less calm and less relaxed compared with drug-naive controls. There were also significant differences at three voxels on the fNIRS, indicating decreased blood oxygenation in ecstasy users compared with drug-naive controls at voxel 2 (left dorsolateral prefrontal cortex), voxel 14 and voxel 16 (right dorsolateral prefrontal cortex), and compared with polydrug controls at V14. The results of the present study provide support for changes in brain activation during performance of demanding tasks in ecstasy polydrug users, which could be related to cerebral vasoconstriction.


Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen.
E-selectin and P-selectin on dermal postcapillary venules play critical roles in the migration of effector T cells into inflamed skin. P-selectin glycoprotein ligand-1 (PSGL-1) modified by alpha1,3-fucosyltransferase is the principal selectin ligand on skin-homing T cells and is required for effector T cell entry into inflamed skin. We have previously shown that a fluorinated analog of N-acetylglucosamine peracetylated-4-fluorinated-d-glucosamine (4-F-GlcNAc), inhibits selectin ligand expression on human T cell PSGL-1. To analyze 4-F-GlcNAc efficacy in dampening effector T cell migration to inflamed skin, we elicited allergic contact hypersensitivity (CHS) reactions in mice treated with 4-F-GlcNAc. We also investigated 4-F-GlcNAc efficacy on lymphocyte E-selectin ligand expression in LNs draining antigen-sensitized skin and on other immunological processes requisite for CHS responses. Our results showed that 4-F-GlcNAc treatment attenuated lymphocyte E-selectin ligand expression in skin-draining LNs and prevented CHS reactions. Significant reductions in inflammatory lymphocytic infiltrate were observed, while pathways related to antigenic processing and presentation and naive T cell recognition within skin-draining LNs were unaffected. These data indicate that 4-F-GlcNAc prevents CHS by inhibiting selectin ligand activity and the capacity of effector T cells to enter antigen-challenged skin without affecting the afferent phase of CHS.


Keratinocyte transglutaminase in human skin and oral mucosa: cytoplasmic localization and uncoupling of differentiation markers.
Expression of keratinocyte transglutaminase, a specific differentiation marker, has been examined by immunogold-silver cytochemistry in human epidermis and oral epithelium, and in oral mucosal hyperplasia and neoplasia. Two major findings have been obtained. First, considerable immunoreactivity was evident not only at the plasma membrane (the site of cross-linked envelope formation) but also in the cytoplasm of spinous cells, suggesting a cytoplasmic function for this transglutaminase. Staining at the cell border was seen principally in the granular layer of orthokeratinized epithelium (epidermis, hard palate), the outer spinous cells of ortho- and parakeratinized epithelium and in the suprabasal cells showing squamous differentiation in benign and malignant neoplasms. By contrast, diffuse cytoplasmic staining was observed in the upper spinous layer of the normal epithelium and benign lesions. The cytoplasmic immunoreactivity, which extended nearly to the basal layer in hyperkeratosis of the oral mucosa, was evident in two of three verrucous carcinomas examined. In keeping with their undifferentiated character, invasive nests of squamous cell carcinoma and basaloid epithelium in benign and neoplastic lesions were immunonegative for transglutaminase. The second major finding was that lesions of severe oral epithelial dysplasia, immunonegative for transglutaminase, were capable of expressing involucrin immunoreactivity, indicating an uncoupling of keratinocyte programming. These results suggest that immunogold-silver staining for transglutaminase may be useful in evaluating the degree of differentiation in benign and malignant oral epithelial proliferation.


The structure of childhood obsessions and compulsions: dimensions in an outpatient sample.
While obsessive-compulsive disorder (OCD) is defined as a unitary condition, prior research has identified meaningful and distinct symptom dimensions in adult samples. In contrast, there have been no investigations of symptom dimensions in samples of children diagnosed with OCD. The present study sought to address this gap. Children diagnosed with OCD (n = 137) were administered the Children's Yale-Brown Obsessive-Compulsive Scale symptom checklist and severity index. Symptoms were analyzed using principal components analysis. As with adult samples, four factors were identified from the checklist. However, these four factors (compulsions, sexual/aggressive obsessions, superstitions, and hoarding/ordering/somatic concerns) were different in content from adult studies. Further, several symptoms significantly contributed to more than one dimension. Each dimension was significantly correlated with scores from the severity index, with the exception of the obsession score with the hoarding/ordering/somatic concerns factor. Results suggest that there are distinct dimensions of symptoms in childhood OCD, but that these dimensions do not correspond to those identified in adults. Instead, it appears that some factors share variance, and the dimensions themselves are separated based upon developmental trajectories. The dimensions examined may be useful in future treatment studies using pharmacological and/or behavioral interventions.


Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog.
The mammalian Mcm-domain containing 2 (Mcmdc2) gene encodes a protein of unknown function that is homologous to the minichromosome maintenance family of DNA replication licensing and helicase factors. Drosophila melanogaster contains two separate genes, the Mei-MCMs, which appear to have arisen from a single ancestral Mcmdc2 gene. The Mei-MCMs are involved in promoting meiotic crossovers by blocking the anticrossover activity of BLM helicase, a function presumably performed by MSH4 and MSH5 in metazoans. Here, we report that MCMDC2-deficient mice of both sexes are viable but sterile. Males fail to produce spermatozoa, and formation of primordial follicles is disrupted in females. Histology and immunocytological analyses of mutant testes revealed that meiosis is arrested in prophase I, and is characterized by persistent meiotic double-stranded DNA breaks (DSBs), failure of homologous chromosome synapsis and XY body formation, and an absence of crossing over. These phenotypes resembled those of MSH4/5-deficient meiocytes. The data indicate that MCMDC2 is essential for invasion of homologous sequences by RAD51- and DMC1-coated single-stranded DNA filaments, or stabilization of recombination intermediates following strand invasion, both of which are needed to drive stable homolog pairing and DSB repair via recombination in mice.


A neonatal oral Mycobacterium tuberculosis-SIV prime / intramuscular MVA-SIV boost combination vaccine induces both SIV and Mtb-specific immune responses in infant macaques.
Mother-to-child-transmission of HIV by breast-feeding remains a major obstacle in the eradication of HIV infection. Compared to adults, HIV-infected infants have more rapid disease and show higher susceptibility to co-infections like tuberculosis (TB). Although the Bacille Calmette-Guérin vaccine can be administered at birth to protect against TB, BCG can disseminate in HIV-infected infants and increase mortality. Thus, a pediatric combination vaccine to stop both HIV and TB infection in infants is urgently needed. Towards the goal of developing a pediatric combination HIV-TB vaccine to prevent both oral HIV acquisition by breast-feeding and TB infection, we tested and optimized an immunization regimen using a novel live attenuated Mycobacterium tuberculosis vaccine engineered to express simian immunodeficiency (SIV) antigens followed by heterologous MVA-SIV boosting in the infant macaque model. A single oral dose of the attenuated Mtb-SIV vaccine strain mc26435 during the first week of life was sufficient to induce persistent TB-specific immune responses. SIV-specific immunity was induced at low but comparable magnitudes after oral or intradermal priming, and was enhanced following MVA-SIV boosts. T cell responses were most pronounced in intestinal tissues and oral lymph nodes. Importantly, in addition to plasma SIV-specific IgG and IgA antibodies, infant macaques developed mucosal SIV-specific IgA in saliva and intestinal IgA and IgG. While future SIV and Mtb challenge studies will be needed to determine the protective efficacy of the Mtb-SIV / MVA-SIV vaccine, infants at high risk for oral HIV acquisition by breast-feeding and TB infection could profoundly benefit from an effective combination vaccine.


Targeting protein-protein interactions with trimeric ligands: high affinity inhibitors of the MAGUK protein family.
PDZ domains in general, and those of PSD-95 in particular, are emerging as promising drug targets for diseases such as ischemic stroke. We have previously shown that dimeric ligands that simultaneously target PDZ1 and PDZ2 of PSD-95 are highly potent inhibitors of PSD-95. However, PSD-95 and the related MAGUK proteins contain three consecutive PDZ domains, hence we envisioned that targeting all three PDZ domains simultaneously would lead to more potent and potentially more specific interactions with the MAGUK proteins. Here we describe the design, synthesis and characterization of a series of trimeric ligands targeting all three PDZ domains of PSD-95 and the related MAGUK proteins, PSD-93, SAP-97 and SAP-102. Using our dimeric ligands targeting the PDZ1-2 tandem as starting point, we designed novel trimeric ligands by introducing a PDZ3-binding peptide moiety via a cysteine-derivatized NPEG linker. The trimeric ligands generally displayed increased affinities compared to the dimeric ligands in fluorescence polarization binding experiments and optimized trimeric ligands showed low nanomolar inhibition towards the four MAGUK proteins, thus being the most potent inhibitors described. Kinetic experiments using stopped-flow spectrometry showed that the increase in affinity is caused by a decrease in the dissociation rate of the trimeric ligand as compared to the dimeric ligands, likely reflecting the lower probability of simultaneous dissociation of all three PDZ ligands. Thus, we have provided novel inhibitors of the MAGUK proteins with exceptionally high affinity, which can be used to further elucidate the therapeutic potential of these proteins.


Thyroid Cancer: Risk-Stratified Management and Individualized Therapy.
Thyroid cancer is the most common endocrine malignancy. Differentiated thyroid cancer (DTC) with the two subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most frequent subtype of thyroid cancer; more rare subtypes are medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC). The incidence of DTC has increased rapidly in recent years due to the more frequent use of imaging methods such as ultrasound of the neck and fine-needle aspiration (FNA) of thyroid nodules. After total thyroidectomy and radioiodine treatment, DTC remains an indolent and curable disease in most patients, whereas the cure rate in MTC is lower and depends on early diagnosis. Most ATCs are incurable. In recent years, there has been great progress in identifying genetic changes in thyroid cancer, and genetic testing of FNA samples or blood samples provides useful information for clinical decision making. Tumor staging, either postoperatively or by imaging, and measuring the tumor markers thyroglobulin for DTC and calcitonin for MTC, allow for dynamic risk-adapted stratification for follow-up procedures. In advanced metastatic thyroid cancer, molecular targeted therapy using tyrosine kinase receptor inhibitors, including sorafenib, lenvantinib, vandetanib, and cabozantinib, helps control tumor progression and prolongs progression-free survival. Using a dynamic risk-stratified approach to manage thyroid cancer, the outcomes for most thyroid cancer patients are excellent compared with those for other cancers. The major challenge in the future is to identify high-risk patients and to treat and monitor them appropriately. Clin Cancer Res; 22(20); 5012-21. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "ENDOCRINE CANCERS REVISING PARADIGMS".


Management of the stroke patient with patent foramen ovale: new insights and persistent questions in the wake of recent randomized trials.
Stroke without a known cause, or cryptogenic stroke, accounts for up to 30 % of all ischemic strokes. Paradoxical embolism through a patent foramen ovale (PFO) has been implicated as a potential cause of cryptogenic cerebral ischemia, particularly in young patients. Epidemiological studies have noted an association between PFO and cryptogenic stroke and observational studies have suggested the potential superiority of percutaneous PFO closure over medical therapy. However, until recently, there were no randomized data to test the hypothesis that PFO closure reduces the risk of recurrent cerebral ischemia. The publication of three such trials, all failing to demonstrate a therapeutic advantage for closure over medical therapy in intention-to-treat analyses, provides valuable new data in the field. We review epidemiological evidence linking PFO and stroke and recent observational and randomized trial data evaluating different treatment strategies.


Effective connectivity during working memory and resting states: A DCM study.
Although the relationship between resting-state functional connectivity and task-related activity has been addressed, the relationship between task and resting-state directed or effective connectivity - and its behavioral concomitants - remains elusive. We evaluated effective connectivity under an N-back working memory task in 24 participants using stochastic dynamic causal modelling (DCM) of 7 T fMRI data. We repeated the analysis using resting-state data, from the same subjects, to model connectivity among the same brain regions engaged by the N-back task. This allowed us to: (i) examine the relationship between intrinsic (task-independent) effective connectivity during resting (Arest) and task states (Atask), (ii) cluster phenotypes of task-related changes in effective connectivity (Btask) across participants, (iii) identify edges (Btask) showing high inter-individual effective connectivity differences and (iv) associate reaction times with the similarity between Btask and Arest in these edges. We found a strong correlation between Arest and Atask over subjects but a marked difference between Btask and Arest. We further observed a strong clustering of individuals in terms of Btask, which was not apparent in Arest. The task-related effective connectivity Btask varied highly in the edges from the parietal to the frontal lobes across individuals, so the three groups were clustered mainly by the effective connectivity within these networks. The similarity between Btask and Arest at the edges from the parietal to the frontal lobes was positively correlated with 2-back reaction times. This result implies that a greater change in context-sensitive coupling - from resting-state connectivity - is associated with faster reaction times. In summary, task-dependent connectivity endows resting-state connectivity with a context sensitivity, which predicts the speed of information processing during the N-back task.


Outcome of non-operative management of femoral shaft fractures in children.
Femoral shaft fractures are common injuries in childhood. There is paucity of information on their presentation and outcome of the available treatment methods in the African population. This study evaluated the outcome of non-operative methods of treatment of femoral shaft fractures in our centre. A retrospective review of the database of children aged 14 years and below with femoral shaft fractures treated non-operatively over a 10-year period. A total of 134 patients with 138 fractures met the study criteria. This consisted of 71 boys (mean age = 6.1 years ± SD) and 63 girls (mean age = 6.5 years ± SD). Pedestrian vehicular accident was the most common cause of femoral shaft fractures in the study population. The midshaft was the most common site of fractures. There were associated injuries to other parts of the body (especially head injury) in 34.3% of the patients. The commonest mode of treatment was skin traction only (87.7%). The mean time to fracture union was 4.9 weeks ± SD (range = 3-15 weeks). The mean length of hospitalisation was 6.7 weeks ± SD (range = 5 days-11 weeks). There was a fairly strong positive correlation between the length of hospitalisation and the presence of associated injuries, especially head injury, upper limb fractures and bilaterality of the fractures. The mean total cost of treatment was #7685 (Naira) or $51.2 (range = $14.2-$190). At the last follow up, 97.8% of the fractures united without significant angulation or shortening. The outcome of non-operative treatment of femoral shaft fractures in our setting is comparable to the results of other workers. Methods of treatment that shorten the length of hospitalisation without unduly increasing cost should be encouraged.


Solid phase nucleic acid extraction technique in a microfluidic chip using a novel non-chaotropic agent: dimethyl adipimidate.
Here, we present a silicon microfluidic system for the purification and extraction of nucleic acids from human body fluid samples utilizing a dimethyl adipimidate (DMA)-based solid-phase extraction method. We propose DMA, which has been used as an amino-reactive cross-linking agent within cells and proteins, as a non-chaotropic reagent for the capture of nucleic acids to overcome the limitations of existing chaotropic and non-chaotropic techniques such as low binding efficiency, PCR inhibition and so on. DMA contains bi-functional imidoesters that form reversible cross-linking structures with DNA therefore providing a high surface-area to volume ratio for capturing DNA without structurally modifying microfluidic channels. In this work, we have first demonstrated highly efficient capture and purification of genomic DNA (T24 cell line) with DMA using a label-free silicon microring resonator sensor device. In addition, we observed the improvement of the DNA amplification efficiency by using the proposed technique for both the genetic (HRAS) and epigenetic (RARβ) analysis of DNA biomarkers. Particularly, we confirmed that the DMA-based solid-phase extraction technique can be applied for the extraction of genomic DNA with higher purity (p < 0.001) using human body fluids (blood and urine) in silicon microfluidic devices compared to other chaotropic methods. Therefore, the proposed technique would be able to harmonize with a micro-total analysis system platform for the analysis of genetic and epigenetic DNA biomarkers related to human diseases in the field of point-of-care (POC) diagnostic applications.


An overview of surgery options for congenital coronary artery anomalies.
Congenital and acquired coronary artery anomalies are associated with significant morbidity and mortality and can be sudden in onset. The spectrum of congenital lesions include anomalous origin from the pulmonary artery, critical left main stenosis/atresia, coronary artery fistulas, anomalous aortic origin and intramyocardial courses. The spectrum of acquired lesions include Kawasaki disease, late postoperative obstructions in patients who had coronary artery surgical manipulations and iatrogenic injuries that can occur in the catheterization laboratory or the operating room. Surgical therapies for ischemic syndromes associated over the long term of these anomalies are presented herein.


Nimesulide improves the disease modifying anti-rheumatic profile of methotrexate in mice with collagen-induced arthritis.
Methotrexate is a disease modifying anti-rheumatic drug that is widely used for the treatment of rheumatoid arthritis. Nimesulide is a non-steroidal anti-inflammatory drug which is frequently used as adjuvant therapy for symptomatic alleviation of rheumatoid arthritis. In this study, we have evaluated the potential influence of nimesulide on the disease modifying anti-rheumatic properties of methotrexate using the collagen-induced arthritis model. Mice were immunized with collagen type II for the induction of arthritis and treated with methotrexate (2.5mg/kg) twice a week, nimesulide (20mg/kg) every other day or a combination of both drugs. Treatment started one week after the onset of arthritis until day 40. An arthritic index was used to compare the severity of arthritis between different treatments. In addition, articular hyperalgesia, joint stiffness, radiological deterioration and intra-articular leucocytic infiltration were evaluated. Methotrexate alone showed modest but significant analgesic and anti-inflammatory effects, and the effects of nimesulide were comparable. On the other hand, nimesulide significantly improved the disease modifying anti-rheumatic profile of methotrexate in terms of arthritic index and joint mobility. Furthermore, although nimesulide failed to show any radiological evidence of articular protection, it significantly improved methotrexate-induced joint protection as judged by X-ray analysis.


Jaundice in typhoid patients: differentiation from other common causes of fever and jaundice in the tropics.
While typhoid fever is common in our environment, presentation with jaundice is unusual. The aim of this study has been to determine the clinical and laboratory features that allow early diagnosis of typhoid fever in patients that present with jaundice and differentiate it from other common causes of fever and jaundice in the tropics. This prospective study was conducted between May 1997 and October 1998 at Center Hopitalier Regional de Hombo Anjuoan, Comoros Islands. Patients with clinical and laboratory evidence of typhoid fever were included. Viral or toxic hepatitis, chronic liver disease, sickle cell disease and other causes of jaundice were excluded by clinical examination and appropriate investigations. Serial evaluation of liver function test and abdominal ultrasound were done. Patients were resuscitated with fluids and electrolytes and treated with appropriate antibiotics. Liver involvement was determined using clinical and laboratory parameters. Of the 254 patients with confirmed diagnosis of typhoid fever, 31 (12.2%) presented with jaundice. Their mean age was 24.6+/-9.2SD years. Fever preceded the appearance of jaundice by 8-27 days. In 27 (87.1%) patients, there was hepatosplenomegaly. Serum bilirubin ranged 38-165 micromol/l with mean of 117+/-14SD. Conjugated bilirubin ranged 31-150 micromol/l with mean of 95+/-8SD. Serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase were raised with mean values of 180, 105 and 136 IU, respectively. Six (19.4%) patients died compared to 12.1% of non-icteric patients. Typhoid patients may present with varying degrees of jaundice and fever that may be confused with viral, malarial or amebic hepatitis, diseases that are common in the tropics. Physical examination and simple biochemical tests would identify the typhoid patients who should be treated with appropriate antibiotics even before the results of blood culture are available.


Catalytic conversion of ethane to valuable products through non-oxidative dehydrogenation and dehydroaromatization.
Chemical utilization of ethane to produce valuable chemicals has become especially attractive since the expanded utilization of shale gas in the United States and associated petroleum gas in the Middle East. Catalytic conversion to ethylene and aromatic hydrocarbons through non-oxidative dehydrogenation and dehydroaromatization of ethane (EDH and EDA) are potentially beneficial technologies because of their high selectivity to products. The former represents an attractive alternative to conventional thermal cracking of ethane. The latter can produce valuable aromatic hydrocarbons from a cheap feedstock. Nevertheless, further progress in catalytic science and technology is indispensable to implement these processes beneficially. This review summarizes progress that has been achieved with non-oxidative EDH and EDA in terms of the nature of active sites and reaction mechanisms. Briefly, platinum-, chromium- and gallium-based catalysts have been introduced mainly for EDH, including effects of carbon dioxide co-feeding. Efforts to use EDA have emphasized zinc-modified MFI zeolite catalysts. Finally, some avenues for development of catalytic science and technology for ethane conversion are summarized.


Increased toxicity to invertebrates associated with a mixture of atrazine and organophosphate insecticides.
This study examined the joint toxicity of atrazine and three organophosphate (OP) insecticides (chlorpyrifos, methyl parathion, and diazinon) exposed to Hyalella azteca and Musca domestica. A factorial design was used to evaluate the toxicity of binary mixtures in which the lethal concentration/lethal dose (LC1/LD1, LC5/LD5, LC15/LD15, and LC50/LD50) of each OP was combined with atrazine concentrations of 0, 10, 40, 80, and 200 microg/L for H. azteca and 0, 200, and 2,000 ng/mg for M. domestica. Atrazine concentrations (> or = 40 microg/L) in combination with each OP caused a significant increase in toxicity to H. azteca compared with the OPs dosed individually. Acetylcholinesterase (AChE) activity also was examined for the individual OPs with and without atrazine treatment. Atrazine in combination with each of the OPs resulted in a significant decrease in AChE activity compared with the OPs dosed individually. In addition, H. azteca that were pretreated with atrazine (> or = 40 microg/L) were much more sensitive to the OP insecticides compared with H. azteca that were not pretreated with atrazine before being tested. Topical exposure to atrazine concentrations did not significantly increase OP toxicity to M. domestica. The results of this study indicate the potential for increased toxicity in organisms exposed to environmental mixtures.


Methodological aspects of clinical trials in tinnitus: a proposal for an international standard.
Chronic tinnitus is a common condition with a high burden of disease. While many different treatments are used in clinical practice, the evidence for the efficacy of these treatments is low and the variance of treatment response between individuals is high. This is most likely due to the great heterogeneity of tinnitus with respect to clinical features as well as underlying pathophysiological mechanisms. There is a clear need to find effective treatment options in tinnitus, however, clinical trials differ substantially with respect to methodological quality and design. Consequently, the conclusions that can be derived from these studies are limited and jeopardize comparison between studies. Here, we discuss our view of the most important aspects of trial design in clinical studies in tinnitus and make suggestions for an international methodological standard in tinnitus trials. We hope that the proposed methodological standard will stimulate scientific discussion and will help to improve the quality of trials in tinnitus.


Downregulation of matrix metalloproteinase-2 in corneal fibroblasts by interleukin-1 receptor antagonist released from corneal epithelial cells.
The authors previously showed that the expression of various junctional proteins in corneal epithelial cells or corneal fibroblasts (CFs) is regulated by the presence of the other cell type in a coculture system. In this study, the effect of corneal epithelial cells on the expression of matrix metalloproteinases (MMPs) in CFs was studied. Human CFs and simian virus 40-transformed human corneal epithelial (HCE) cells were cultured on opposite sides of a collagen vitrigel membrane. Expression of MMPs in CFs was examined by reverse transcription-polymerase chain reaction and immunoblot analyses. The amounts of MMP-2 mRNA and protein in CFs were decreased by the presence of HCE cells. HCE cells had no effect on the expression of MMP-1 in CFs. HCE cells released interleukin (IL)-1 receptor antagonist (IL-1RA) into the culture medium, and depletion of IL-1RA in HCE cells by RNA interference largely abolished the effect of these cells on MMP-2 expression in CFs. The downregulation of MMP-2 expression in CFs by HCE cells was blocked by an inhibitor of signaling by the mitogen-activated protein kinase (MAPK) ERK (PD98059) but was not affected by those of signaling by the MAPKs p38 (SB203580) or JNK (SP600125). Corneal epithelial cells downregulated expression of MMP-2 in CFs in a manner dependent at least in part on the release of IL-1RA from the former cells. This effect might contribute to the attenuation of corneal stromal remodeling by corneal epithelial cells.


Daily consumption of red grape cell powder in a dietary dose improves cardiovascular parameters: a double blind, placebo-controlled, randomized study.
Consumption of polyphenol-rich food and food ingredient such as grape and grape products improved various cardiovascular parameters. In this study, we investigate the effect of dietary daily consumption of red grape cell powder (RGC) on blood pressure (BP) and flow-mediated dilatation (FMD) as well as on oxidative stress in 50 subjects with prehypertension and mild hypertension. The subjects were randomized into groups that consumed 200, 400 mg RGC or placebo daily for 12 weeks. RGC consumption was associated with an improvement of FMD (p = 0.013). There was a significant decrease in lipid peroxidation (p = 0.013) after 12 weeks in a combined RGC-treated group. The diastolic BP decreased significantly in the 200 mg RGC group compared to the placebo group (p = 0.032). Our results indicate that a daily supplementation, of red grape cell powder, for 12 weeks affects endothelial function, diastolic BP and oxidative stress without any adverse effects.


Cancer prevention in the dental practice: oral cancer screening and tobacco cessation advice.
In this paper we describe the proportion of US adults who report receiving oral cancer screening and tobacco cessation counseling and assistance from dentists and other health professionals. Data from the 1992 National Health Interview Survey (NHIS) Cancer Control Supplement, a nationally representative sample of 12,035 adults 18 years of age and older, are analyzed. In 1992, less than 10 percent of adults reported oral cancer screening by a dentist or hygienist within the past three years. White adults (10.1%, 95% CI = 9.3, 10.9) reported an oral cancer screening three times more frequently than black (3.2%, 95% CI = 1.9, 4.5) or Hispanic (3.4%, 95% CI = 2.1, 4.7) adults. About half of adult current smokers had seen a dentist within 12 months, and of those only 24.1 percent (95% CI = 21.7, 26.5) had been advised to quit smoking. Heavy smokers (two or more packs a day) were more likely to have been advised to quit than light (pack or less per day) or occasional smokers. A similar proportion (24.3%, 95% CI = 17.6, 31.0) of white adult men who reported using smokeless tobacco products had been told by a dentist to quit using tobacco. Results from this population-based survey indicate that cancer screening and tobacco cessation advice are underutilized in the dental practice. Increased patient awareness and implementation of screening and tobacco cessation interventions could improve oral cancer incidence and mortality and have a public health benefit for other tobacco-related morbidity and mortality as well.


Estimating diffusion propagator and its moments using directional radial basis functions.
The ensemble average diffusion propagator (EAP) obtained from diffusion MRI (dMRI) data captures important structural properties of the underlying tissue. As such, it is imperative to derive an accurate estimate of the EAP from the acquired diffusion data. In this work, we propose a novel method for estimating the EAP by representing the diffusion signal as a linear combination of directional radial basis functions scattered in q-space. In particular, we focus on a special case of anisotropic Gaussian basis functions and derive analytical expressions for the diffusion orientation distribution function (ODF), the return-to-origin probability (RTOP), and mean-squared-displacement (MSD). A significant advantage of the proposed method is that the second and the fourth order moment tensors of the EAP can be computed explicitly. This allows for computing several novel scalar indices (from the moment tensors) such as mean-fourth-order-displacement (MFD) and generalized kurtosis (GK)-which is a generalization of the mean kurtosis measure used in diffusion kurtosis imaging. Additionally, we also propose novel scalar indices computed from the signal in q-space, called the q-space mean-squared-displacement (QMSD) and the q-space mean-fourth-order-displacement (QMFD), which are sensitive to short diffusion time scales. We validate our method extensively on data obtained from a physical phantom with known crossing angle as well as on in-vivo human brain data. Our experiments demonstrate the robustness of our method for different combinations of b-values and number of gradient directions.


The possible role of endogenous digitalis-like substance in the causation of pre-eclampsia.
Digoxin levels have been reported in neonatal blood when neither the mother nor the baby had received digoxin. An endogenous digoxin-like substance (DLS) that may be causally related to hypertension has been described. Using a commercially available radioimmunoassay kit, we investigated the presence of an immunoreactive DLS in 21 pre-eclamptic mothers, 36 mothers with normal blood pressure (the control group) and their infants. We found mean DLS levels to be higher in cord blood from infants born to the pre-eclamptic mothers than in cord blood from those born to mothers in the control group. Levels were also higher in cord blood than in maternal blood in both the pre-eclamptic and the control groups. DLS seems to be associated with pre-eclampsia. Although further work is needed for verification, a hypothesis on the possible role of DLS in the causation of pre-eclampsia is presented.


Phenotypic biomonitoring using multivariate flow cytometric analysis of multi-stained microorganisms.
A new method for monitoring phenotypic profiles of pure cultures and complex microbial communities was evaluated. The approach was to stain microorganisms with a battery of fluorescent dyes prior to flow cytometry analysis (FCM) and to analyse the data using multivariate methods, including principal component analysis and partial least squares. The FCM method was quantitatively evaluated using different mixtures of pure cultures as well as microbial communities. The results showed that the method could quantitatively and reproducibly resolve both populations and communities of microorganisms with 5% abundance in a diverse microbial background. The feasibility of monitoring complex microbial communities over time during the biodegradation of naphthalene using the FCM method was demonstrated. The biodegradation of naphthalene occurred to differing extents in microcosms representing three different types of aromatic-contaminated groundwater and a sample of bio-basin water. The FCM method distinguished each of these four microbial communities. The phenotypic profiles were compared with genotypic profiles generated by random-amplified polymorphic DNA analysis. The genotypic profiles of the microbial communities described only the microbial composition, and not their functional change, whereas the phenotypic profiles seemed to contain information on both the composition and the functional change of the microorganisms. Furthermore, event analysis of the FCM data showed that microbial communities with initially differing compositions could converge towards a similar composition if they had a capacity for high levels of degradation, whereas microbial communities with similar initial compositions could diverge if they differed in biodegrading ability.


Multispectral UV imaging for fast and non-destructive quality control of chemical and physical tablet attributes.
Monitoring of tablet quality attributes in direct vicinity of the production process requires analytical techniques that allow fast, non-destructive, and accurate tablet characterization. The overall objective of this study was to investigate the applicability of multispectral UV imaging as a reliable, rapid technique for estimation of the tablet API content and tablet hardness, as well as determination of tablet intactness and the tablet surface density profile. One of the aims was to establish an image analysis approach based on multivariate image analysis and pattern recognition to evaluate the potential of UV imaging for automatized quality control of tablets with respect to their intactness and surface density profile. Various tablets of different composition and different quality regarding their API content, radial tensile strength, intactness, and surface density profile were prepared using an eccentric as well as a rotary tablet press at compression pressures from 20MPa up to 410MPa. It was found, that UV imaging can provide both, relevant information on chemical and physical tablet attributes. The tablet API content and radial tensile strength could be estimated by UV imaging combined with partial least squares analysis. Furthermore, an image analysis routine was developed and successfully applied to the UV images that provided qualitative information on physical tablet surface properties such as intactness and surface density profiles, as well as quantitative information on variations in the surface density. In conclusion, this study demonstrates that UV imaging combined with image analysis is an effective and non-destructive method to determine chemical and physical quality attributes of tablets and is a promising approach for (near) real-time monitoring of the tablet compaction process and formulation optimization purposes.


Myelodysplastic syndromes, version 2.2015.
The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care.


Testes size, testosterone production and reproductive behaviour in a natural mammalian mating system.
1. Testosterone (T) is a key mediator in the expression of numerous morphological and behavioural traits in mammals, but the factors underlying individual variation in circulating T levels are poorly understood. 2. The intimate structural integration of sperm and T production within the testes, alongside the dependency of sperm production on high levels of T, suggests that T requirements for spermatogenesis could be an important driver of individual differences in T. 3. To test this hypothesis, we examine how male capacity for sperm production (as indicated by their testes size) is associated with T levels in a feral population of Soay sheep, resident on St. Kilda, Scotland, during their rutting season. 4. We found a strong positive relationship between an individual's testes size (as measured before their seasonal enlargement) and the levels of circulating T during their rut, suggesting that T requirements for spermatogenesis has a prominent influence on the production of this androgen. 5. In contrast, body condition and competitive ability did not independently predict T levels, findings that are inconsistent with conventional 'condition-dependent' and 'challenge' hypotheses of T production. 6. This influence of male's capacity for sperm production on T appeared to be substantial enough to be biologically relevant, as testes size also predicted male aggression and mate-seeking behaviour. 7. Our results suggest that a male's inherent capacity for sperm and T production is tightly phenotypically integrated, with potential consequences for a wide range of other T-mediated reproductive traits.


Altered slow axonal transport and regeneration in a myelin-deficient mutant mouse: the trembler as an in vivo model for Schwann cell-axon interactions.
The thickness of the myelin sheath in normal myelinated nerve is proportional to the diameter of the axon. In the demyelinating mutant mouse, Trembler, not only is the thickness of the myelin sheath reduced, but the caliber of associated axons is smaller. This correlation suggests that the interaction between axons and Schwann cells may affect the shape and function of axons as well as properties of myelin. Since axonal diameter depends in part on the cytoskeleton and its movement with slow axonal transport, we have compared the properties of slow transport in the sciatic nerve of control and Trembler mice. Studies of the sciatic nerve of normal mice showed that the rates for proteins moving in slow component a (SCa) and slow component b (SCb) are similar to those previously measured in rat. In Trembler mice, tubulin was transported significantly faster than in control mice, with a rate of 1.73 mm/d for Trembler compared to 1.56 mm/d in the control. In contrast, the rate for neurofilament proteins was significantly slower in the Trembler (1.15 mm/d compared to 1.38 mm/d in the control). The majority of proteins in SCb were also transported slower in Trembler than control: actin and calmodulin were transported at 2.29 mm/d as compared to 2.73 mm/d in control, while spectrin and clathrin were transported at 2.01 and 2.43 mm/d, respectively, as compared to 2.54 mm/d in control. The importance of slow axonal transport in regeneration has been suggested by the clear correlation between the rates of regeneration and the rates of SCb. Therefore, we evaluated regeneration of motor axons in Trembler mice to determine whether the regenerative response was affected by deficient Schwann cells. A slower regeneration rate was found in the Trembler (1.7 mm/d) motor axon when compared to the control (2.29 mm/d), but elongation of fibers in regeneration began after a shorter delay in the Trembler (1.6 d) than in control (2.5 d). Thus, deficient Schwann cells and poor myelination appear to affect both quantitative and qualitative properties of slow axonal transport. These changes lead to alterations in the morphological and physiological properties of affected axons.


Mitotic inhibition of GRASP65 organelle tethering involves Polo-like kinase 1 (PLK1) phosphorylation proximate to an internal PDZ ligand.
GRASP65 links cis-Golgi cisternae via a homotypic, N-terminal PDZ interaction, and its mitotic phosphorylation disrupts this activity. Neither the identity of the PDZ ligand involved in the GRASP65 self-interaction nor the mechanism by which phosphorylation inhibits its interaction is known. Phospho-mimetic mutation of known cyclin-dependent kinase 1/cyclin B sites, all of which are in the C-terminal "regulatory domain" of the molecule, failed to block organelle tethering. However, we identified a site phosphorylated by Polo-like kinase 1 (PLK1) in the GRASP65 N-terminal domain for which mutation to aspartic acid blocked tethering and alanine substitution prevented mitotic Golgi unlinking. Further, using interaction assays, we discovered an internal PDZ ligand adjacent to the PLK phosphorylation site that was required for tethering. These results reveal the mechanism of phosphoinhibition as direct inhibition by PLK1 of the PDZ ligand underlying the GRASP65 self-interaction.


Tumebacillus avium sp. nov., isolated from the gut of a cinereous vulture, Aegypius monachus.
A Gram-stain-positive, facultatively aerobic, spore-forming, oxidase-positive, catalase- and DNase-negative, rod-shaped and motile bacterial strain, AR23208T, was isolated from the gut of a cinereous vulture (Aegypius monachus), collected at Seoul Grand Park Zoo (Republic of Korea). Strain AR23208T grew optimally at 25-30 °C, at pH 7 and in the absence of NaCl. Phylogenetic analysis revealed that strain AR23208T shared 98.2 and 97.1 % 16S rRNA gene sequence similarity with Tumebacillus algifaecis THMBR28T and Tumebacilluslipolyticus NIO-S10T, respectively. The predominant fatty acids (>10 %) of strain AR23208T were iso-C15 : 0, summed feature 4 (anteiso-C17 : 1 B and/or iso-C17 : 1 I) and anteiso-C15 : 0 and the primary isoprenoid quinone was menaquinone-7. The polar lipids were phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylglycerol, six unidentified phospholipids, an unidentified aminophospholipid and ten unidentified lipids. The sugar components of the cell wall peptidoglycan were ribose and arabinose. The amino acids of the cell wall peptidoglycan were l-alanine, aspartic acid, meso-diaminopimelic acid, l-glutamic acid, glycine and l-lysine. The OrthoANI value based on the complete genome sequence of strain AR23208T and the closest related strain, T. algifaecis THMBR28T, was 80.4 %. The genomic DNA G+C content of strain AR23208T was 56.0 mol%. Based on the data presented in the current study, strain AR23208T is considered to represent a novel species of the genus Tumebacillus, for which the name Tumebacillus avium sp. nov. is proposed. The type strain is AR23208T (=KCTC 33929T=JCM 32188T).


Spinning the legs and blood: should intradialytic exercise be routinely offered during maintenance haemodialysis?
Patients with end-stage kidney disease on haemodialysis (HD) have an elevated risk of cardiovascular disease (CVD). These patients also experience high levels of physical deconditioning and programmes of rehabilitation have been tested in a variety of forms with variable success. It has been suggested that programmes of exercise rehabilitation have a role to play in improving the physical condition of patients on HD and in addressing the traditional and non-traditional risk factors that drive CVD for this population. Intradialytic exercise has often been suggested as a convenient way of delivering rehabilitation for patients on HD, as it makes use of otherwise dead time, but there are legitimate concerns about this group of at-risk patients undertaking exercise at a time when their myocardium is already vulnerable to the insults of demand ischaemia from the processes of dialysis and ultrafiltration. A study in this issue of Clinical Kidney Journal provides reassuring data, showing that cycling during dialysis potentially reduces evidence of demand ischaemia (episodes of myocardial stunning). Together with the safety and quality of life data, we expect from the multicentre PrEscription of Intra-Dialytic Exercise to Improve quAlity of Life in Patients With Chronic Kidney Disease study (the protocol for which is published concurrently), rehabilitation programmes that include intradialytic exercise are perhaps closer than ever for patients on HD.


Voltage-dependent enhancement of electrical coupling by a subthreshold sodium current.
Voltage-dependent changes in electrical coupling are often attributed to a direct effect on the properties of gap junction channels. Identifiable auditory afferents terminate as mixed (electrical and chemical) synapses on the distal portion of the lateral dendrite of the goldfish Mauthner cells, a pair of large reticulospinal neurons involved in the organization of sensory-evoked escape responses. At these afferents, the amplitude of the coupling potential produced by the retrograde spread of signals from the postsynaptic Mauthner cell is dramatically enhanced by depolarization of the presynaptic terminal. We demonstrate here that this voltage-dependent enhancement of electrical coupling does not represent a property of the junctions themselves but the activation of a subthreshold sodium current present at presynaptic terminals that acts to amplify the synaptic response. We also provide evidence that this amplification operates under physiological conditions, enhancing synaptic communication from the Mauthner cells to the auditory afferents where electrical and geometrical properties of the coupled cells are unfavorable for retrograde transmission. Retrograde electrical communication at these afferents may play an important functional role by promoting cooperativity between afferents and enhancing transmitter release. Thus, the efficacy of an electrical synapse can be dynamically modulated in a voltage-dependent manner by properties of the nonjunctional membrane. Finally, asymmetric amplification of electrical coupling by intrinsic membrane properties, as at the synapses between auditory afferents and the Mauthner cell, may ensure efficient communication between neuronal processes of dissimilar size and shape, promoting neuronal synchronization.


Toxicology of male reproduction in animals and humans.
Environmental contaminants can interfere with the male reproduction function. A review is presented of those pollutants with adverse effects on human reproduction. The possible effects of occupational and environmental exposure to various substances on male reproductive health are evaluated. This analysis considers studies showing damage of men exposed to halogenated hydrocarbons, other organic compounds, heavy metals and some physical agents, and some lifestyles, such as continuous stress, alcohol consumption, cigarette and marijuana smoking, and other addictions. Possible influences of these agents on the neuroendocrine system with the decrease of male fertility during the last decades are also discussed.


Low level viral persistence after infection with LCMV: a quantitative insight through numerical bifurcation analysis.
Many important viruses persist at very low levels in the body in the face of host immunity, and may influence the maintenance of this state of 'infection immunity'. To analyse low level viral persistence in quantitative terms, we use a mathematical model of antiviral cytotoxic T lymphocyte (CTL) response to lymphocytic choriomeningitis virus (LCMV). This model, described by a non-linear system of delay differential equations (DDEs), is studied using numerical bifurcation analysis techniques for DDEs. Domains where low level LCMV coexistence with CTL memory is possible, either as an equilibrium state or an oscillatory pattern, are identified in spaces of the model parameters characterising the interaction between virus and CTL populations. Our analysis suggests that the coexistence of replication competent virus below the conventional detection limit (of about 100 pfu per spleen) in the immune host as an equilibrium state requires the per day relative growth rate of the virus population to decrease at least 5-fold compared to the acute phase of infection. Oscillatory patterns in the dynamics of persisting LCMV and CTL memory, with virus population varying between 1 and 100 pfu per spleen, are possible within quite narrow intervals of the rates of virus growth and precursor CTL population death. Whereas the virus replication rate appears to determine the stability of the low level virus persistence, it does not affect the steady-state level of the viral population, except for very low values.


Non-invasive assessment of β-carotene levels in the skin of Colombian adults.
Carotenoid pigments have antioxidant properties beneficial for human health. Use of resonance Raman spectroscopy (RRS) as a reliable method for measuring carotenoid levels in tissues such as dermis has been suggested. However, data about the variability and reproducibility of this technique should be collected before it can be used. To assess reproducibility of RRS for detection of total β-carotene levels in the skin of Colombian adults. Forty-eight healthy men and 30 healthy women with various pigmentation levels were enrolled into the study. Measurements by RRS were performed in the palmar region and medial and lateral aspects of the arms. Odds ratio and 95% confidence intervals were calculated, adjusting for confounding factors: body mass index, waist circumference, percent body fat, age, race, smoking, and sex. Reproducibility of the technique was estimated using intraclass correlation coefficient (ICC). Mean β-carotene levels were 29.9 ± 11.9 in men and 30.6 ± 8.6 in women (P=.787). No differences or significant associations were found of β-carotene levels with confounding factors assessed by sex. ICCs were 0.89 in the palmar region, 0.85 in the medial aspect of arm, and 0.82 in the external aspect of arm. RRS spectroscopy is a reliable method for non-invasive measurement of β-carotene levels in skin, and may be used as an important biomarker of antioxidant status in nutritional and health studies in humans.


High-learners present larger mid-frontal theta power and connectivity in response to incorrect performance feedback.
A crucial aspect of cognitive control and learning is the ability to integrate feedback, that is, to evaluate action outcomes and their deviations from the intended goals and to adjust behavior accordingly. However, how high-learners differ from low-learners in relation to feedback processing has not been characterized. Further, little is known about the underlying brain connectivity patterns during feedback processing. This study aimed to fill these gaps by analyzing electrical brain responses from healthy adult human participants while they performed a time estimation task with correct and incorrect feedback. As compared with low-learners, high-learners presented larger mid-frontal theta (4-8 Hz) oscillations and lower sensorimotor beta (17-24 Hz) oscillations in response to incorrect feedback. Further, high-learners showed larger theta connectivity from left central, associated with motor activity, to mid-frontal, associated with performance monitoring, immediately after feedback (0-0.3 s), followed by (from 0.3 to 0.6 s after feedback) a flux from mid-frontal to prefrontal, associated with executive functioning. We suggest that these results reflect two cognitive processes related to successful feedback processing: first, the obtained feedback is compared with the expected one, and second, the feedback history is updated based on this information. Our results also indicate that high- and low-learners differ not only on how they react to incorrect feedback, but also in relation to how their distant brain areas interact while processing both correct and incorrect feedback. This study demonstrates the neural underpinnings of individual differences in goal-directed adaptive behavior.


3D Bioprinting Human Chondrocytes with Nanocellulose-Alginate Bioink for Cartilage Tissue Engineering Applications.
The introduction of 3D bioprinting is expected to revolutionize the field of tissue engineering and regenerative medicine. The 3D bioprinter is able to dispense materials while moving in X, Y, and Z directions, which enables the engineering of complex structures from the bottom up. In this study, a bioink that combines the outstanding shear thinning properties of nanofibrillated cellulose (NFC) with the fast cross-linking ability of alginate was formulated for the 3D bioprinting of living soft tissue with cells. Printability was evaluated with concern to printer parameters and shape fidelity. The shear thinning behavior of the tested bioinks enabled printing of both 2D gridlike structures as well as 3D constructs. Furthermore, anatomically shaped cartilage structures, such as a human ear and sheep meniscus, were 3D printed using MRI and CT images as blueprints. Human chondrocytes bioprinted in the noncytotoxic, nanocellulose-based bioink exhibited a cell viability of 73% and 86% after 1 and 7 days of 3D culture, respectively. On the basis of these results, we can conclude that the nanocellulose-based bioink is a suitable hydrogel for 3D bioprinting with living cells. This study demonstrates the potential use of nanocellulose for 3D bioprinting of living tissues and organs.


Using dynamic N-mixture models to test cavity limitation on northern flying squirrel demographic parameters using experimental nest box supplementation.
Dynamic N-mixture models have been recently developed to estimate demographic parameters of unmarked individuals while accounting for imperfect detection. We propose an application of the Dail and Madsen (2011: Biometrics, 67, 577-587) dynamic N-mixture model in a manipulative experiment using a before-after control-impact design (BACI). Specifically, we tested the hypothesis of cavity limitation of a cavity specialist species, the northern flying squirrel, using nest box supplementation on half of 56 trapping sites. Our main purpose was to evaluate the impact of an increase in cavity availability on flying squirrel population dynamics in deciduous stands in northwestern Québec with the dynamic N-mixture model. We compared abundance estimates from this recent approach with those from classic capture-mark-recapture models and generalized linear models. We compared apparent survival estimates with those from Cormack-Jolly-Seber (CJS) models. Average recruitment rate was 6 individuals per site after 4 years. Nevertheless, we found no effect of cavity supplementation on apparent survival and recruitment rates of flying squirrels. Contrary to our expectations, initial abundance was not affected by conifer basal area (food availability) and was negatively affected by snag basal area (cavity availability). Northern flying squirrel population dynamics are not influenced by cavity availability at our deciduous sites. Consequently, we suggest that this species should not be considered an indicator of old forest attributes in our study area, especially in view of apparent wide population fluctuations across years. Abundance estimates from N-mixture models were similar to those from capture-mark-recapture models, although the latter had greater precision. Generalized linear mixed models produced lower abundance estimates, but revealed the same relationship between abundance and snag basal area. Apparent survival estimates from N-mixture models were higher and less precise than those from CJS models. However, N-mixture models can be particularly useful to evaluate management effects on animal populations, especially for species that are difficult to detect in situations where individuals cannot be uniquely identified. They also allow investigating the effects of covariates at the site level, when low recapture rates would require restricting classic CMR analyses to a subset of sites with the most captures.


Quality of care. Development of a patient-centred questionnaire based on a grounded theory model.
In a previous study (Wilde et al. 1993), we developed a model of quality of care from a patient perspective using a grounded theory approach. The aim of the present study was to derive an instrument from this model. A questionnaire, Quality from Patients' Perspective (QPP), was developed which consisted of 56 items. Each item was evaluated in two ways by the respondent; assessment of perceived reality and evaluation of subjective importance (Likert scales). A personal quality of care index was computed on the basis of the relationship between these two scores. The QPP was tested on two samples, patients with infectious diseases (n = 147, mean age: 60 years) and nursing students (n = 103, mean age: 27 years). Patient's scores were factor analysed (principal factoring with oblique rotation) and 17 factors were extracted. Subgroups of patients were compared and correlations were computed between factor scores and self-rated health and well-being. Students also responded to a short form of the QPP (41 items) and personality scales. Correlations between these sets of variables were computed. The QPP was discussed in relation to existing scales.


Dealing with dilemmas in health campaigning.
Campaigners on public health issues face a number of dilemmas when tactical choices in public debating involve uncomfortable mixtures of benefits and costs. Key dilemmas for campaigners are whether to acknowledge weaknesses in their own position, whether to advocate research to address claims by opponents, whether to acknowledge vested interests on their own side, whether to debate with opponents, whether to launch attacks on opposition individuals and groups and whether to criticize extreme behaviour by those on their own side. Drawing on the literature on scientific controversies, these dilemmas are outlined, with illustrations from the Australian vaccination debate. Dilemmas in health campaigning warrant attention because choices made can affect both the success of policy initiatives and the image of professions, sometimes with trade-offs between these. However, dilemmas have been neglected because most studies of health controversies give little attention to campaigning tactics. Campaigners can choose options that seem to maximize the likelihood of winning in the short term. However, options for short-term advantage may establish a precedent for approaches to campaigning that undermine commitment to free and open debate to possible long-term disadvantage.


CROI 2019: advances in antiretroviral therapy.
The 2019 Conference on Retroviruses and Opportunistic Infections included many exciting advances in antiretroviral therapy (ART). Investigators presented a case report of a second patient possibly cured of HIV through an allogeneic hematopoietic stem cell transplant from a CC chemokine receptor 5-delta 32 donor. Two clinical trials of long-acting injectable cabotegravir and rilpivirine showed promising safety, efficacy, and tolerability as maintenance ART. Test-and-treat and rapid-ART-start strategies show promise in advancing progress toward the HIV care cascade 90-90-90 Joint United Nations Programme on HIV/AIDS/World Health Organization targets. However, late diagnosis and mortality after ART initiation remain high, even in the context of HIV service scale-up, and mortality from unintentional opioid overdose in people living with HIV in the United States is on the rise. In vitro studies were presented that identified and evaluated the effect of resistance-associated mutations on ART susceptibility and elucidated mechanisms of resistance. Epidemiologic data were reported on the prevalence, impact, regional variation, and changes over time of resistance-associated mutations. Decreasing regional and national rates of resistance may be a benefit of increasing use of integrase strand transfer inhibitors (InSTIs). New findings were presented on maternal and fetal health outcomes in women of reproductive potential, drug-drug interactions between hormonal contraception and ART, and further exploration of the association between InSTIs and birth defects.


Common and metal-specific proteomic responses to cadmium and zinc in the metal tolerant ericoid mycorrhizal fungus Oidiodendron maius Zn.
Although adaptive metal tolerance may arise in fungal populations in polluted soils, the mechanisms underlying metal-specific tolerance are poorly understood. Comparative proteomics is a powerful tool to identify variation in protein profiles caused by changing environmental conditions, and was used to investigate protein accumulation in a metal tolerant isolate of the ericoid mycorrhizal fungus Oidiodendron maius exposed to zinc and cadmium. Two-dimensional gel electrophoresis and shotgun proteomics followed by mass spectrometry lead to the identification of common and metal-specific proteins and pathways. Proteins selectively induced by cadmium exposure were molecular chaperons of the Hsp90 family, cytoskeletal proteins and components of the translation machinery. Zinc significantly up-regulated metabolic pathways related to energy production and carbohydrates metabolism, likely mirroring zinc adaptation of this fungal isolate. Common proteins induced by the two metal ions were the antioxidant enzyme Cu/Zn superoxide dismutase and ubiquitin. In mycelia exposed to zinc and cadmium, both proteomic techniques also identified agmatinase, an enzyme involved in polyamine biosynthesis. This novel finding suggests that, like plants, polyamines may have important functions in response to abiotic environmental stress in fungi. Genetic evidence also suggests that the biosynthesis of polyamines via an alternative metabolic pathway may be widespread in fungi.


Uranium immobilization by sulfate-reducing biofilms.
Hexavalent uranium [U(VI)] was immobilized using biofilms of the sulfate-reducing bacterium (SRB) Desulfovibrio desulfuricans G20. The biofilms were grown in flat-plate continuous-flow reactors using lactate as the electron donor and sulfate as the electron acceptor. U(VI)was continuously fed into the reactor for 32 weeks at a concentration of 126 microM. During this time, the soluble U(VI) was removed (between 88 and 96% of feed) from solution and immobilized in the biofilms. The dynamics of U immobilization in the sulfate-reducing biofilms were quantified by estimating: (1) microbial activity in the SRB biofilm, defined as the hydrogen sulfide (H2S) production rate and estimated from the H2S concentration profiles measured using microelectrodes across the biofilms; (2) concentration of dissolved U in the solution; and (3) the mass of U precipitated in the biofilm. Results suggest that U was immobilized in the biofilms as a result of two processes: (1) enzymatically and (2) chemically, by reacting with microbially generated H2S. Visual inspection showed that the dissolved sulfide species reacted with U(VI) to produce a black precipitate. Synchrotron-based U L3-edge X-ray absorption near edge structure (XANES) spectroscopy analysis of U precipitated abiotically by sodium sulfide indicated that U(VI) had been reduced to U(IV). Selected-area electron diffraction pattern and crystallographic analysis of transmission electron microscope lattice-fringe images confirmed the structure of precipitated U as being that of uraninite.


Genomic regions associated with muscularity in beef cattle differ in five contrasting cattle breeds.
Linear type traits, which reflect the muscular characteristics of an animal, could provide insight into how, in some cases, morphologically very different animals can yield the same carcass weight. Such variability may contribute to differences in the overall value of the carcass since primal cuts vary greatly in price; such variability may also hinder successful genome-based association studies. Therefore, the objective of our study was to identify genomic regions that are associated with five muscularity linear type traits and to determine if these significant regions are common across five different breeds. Analyses were carried out using linear mixed models on imputed whole-genome sequence data in each of the five breeds, separately. Then, the results of the within-breed analyses were used to conduct an across-breed meta-analysis per trait. We identified many quantitative trait loci (QTL) that are located across the whole genome and associated with each trait in each breed. The only commonality among the breeds and traits was a large-effect pleiotropic QTL on BTA2 that contained the MSTN gene, which was associated with all traits in the Charolais and Limousin breeds. Other plausible candidate genes were identified for muscularity traits including PDE1A, PPP1R1C and multiple collagen and HOXD genes. In addition, associated (gene ontology) GO terms and KEGG pathways tended to differ between breeds and between traits especially in the numerically smaller populations of Angus, Hereford, and Simmental breeds. Most of the SNPs that were associated with any of the traits were intergenic or intronic SNPs located within regulatory regions of the genome. The commonality between the Charolais and Limousin breeds indicates that the genetic architecture of the muscularity traits may be similar in these breeds due to their similar origins. Conversely, there were vast differences in the QTL associated with muscularity in Angus, Hereford, and Simmental. Knowledge of these differences in genetic architecture between breeds is useful to develop accurate genomic prediction equations that can operate effectively across breeds. Overall, the associated QTL differed according to trait, which suggests that breeding for a morphologically different (e.g. longer and wider versus shorter and smaller) more efficient animal may become possible in the future.


Forecasting the risk of harmful algal blooms.
The "Applied Simulations and Integrated Modelling for the Understanding of Harmful Algal Blooms" (Asimuth) project sought to develop a harmful algal bloom (HAB) alert system for Atlantic Europe. This was approached by combining, at a national or regional level, regulatory monitoring phytoplankton and biotoxin data with satellite remote sensing and other information on current marine conditions, coupled with regional scale models that included a representation of HAB transport. Synthesis of these products was achieved by expert interpretation within HAB risk alert bulletins that were prepared on a regular basis (typically weekly) for use by the aquaculture industry. In this preface to the Asimuth Special Issue we outline the main HAB species of concern in the region and the strengths and limitations of different methodologies to provide early warning of their blooms.


Fibrillogenesis from nanosurfaces: multiphoton imaging and stereological analysis of collagen 3D self-assembly dynamics.
The assembly of proteins into fibrillar structures is an important process that concerns different biological contexts, including molecular medicine and functional biomaterials. Engineering of hybrid biomaterials can advantageously provide synergetic interactions of the biopolymers with an inorganic component to ensure specific supramolecular organization and dynamics. To this aim, we designed hybrid systems associating collagen and surface-functionalized silica particles and we built a new strategy to investigate fibrillogenesis processes in such multicomponents systems, working at the crossroads of chemistry, physics and mathematics. The self-assembly process was investigated by bimodal multiphoton imaging coupling second harmonic generation (SHG) and 2 photon excited fluorescence (2PEF). The in-depth spatial characterization of the system was further achieved using the three-dimensional analysis of the SHG/2PEF data via mathematical morphology processing. Quantitation of collagen distribution around particles offers strong evidence that the chemically induced confinement of the protein on the silica nanosurfaces has a key influence on the spatial extension of fibrillogenesis. This new approach is unique in the information it can provide on 3D dynamic hybrid systems and may be extended to other associations of fibrillar molecules with optically responsive nano-objects.


The origin of the Debye relaxation in liquid water and fitting the high frequency excess response.
We critically review the literature on the Debye absorption peak of liquid water and the excess response found on the high frequency side of the Debye peak. We find a lack of agreement on the microscopic phenomena underlying both of these features. To better understand the molecular origin of Debye peak we ran large scale molecular dynamics simulations and performed several different distance-dependent decompositions of the low frequency dielectric spectra, finding that it involves processes that take place on scales of 1.5-2.0 nm. We also calculated the k-dependence of the Debye relaxation, finding it to be highly dispersive. These findings are inconsistent with models that relate Debye relaxation to local processes such as the rotation/translation of molecules after H-bond breaking. We introduce the spectrumfitter Python package for fitting dielectric spectra and analyze different ways of fitting the high frequency excess, such as including one or two additional Debye peaks. We propose using the generalized Lydanne-Sachs-Teller (gLST) equation as a way of testing the physicality of model dielectric functions. Our attempts at fitting the experimental spectrum using the gLST relation as a constraint indicate that the traditional way of fitting the excess response with secondary and tertiary Debye relaxations is problematic. All of our work is consistent with the recent theory of Popov et al. (2016) that Debye relaxation is due to the migration of Bjerrum-like defects in the hydrogen bond network. Under this theory, the mechanism of Debye relaxation in liquid water is similar to the mechanism in ice, but the heterogeneity and power-law dynamics of the H-bond network in water results in excess response on the high frequency side of the peak.


Left-right asymmetry is required for the habenulae to respond to both visual and olfactory stimuli.
Left-right asymmetries are most likely a universal feature of bilaterian nervous systems and may serve to increase neural capacity by specializing equivalent structures on left and right sides for distinct roles. However, little is known about how asymmetries are encoded within vertebrate neural circuits and how lateralization influences processing of information in the brain. Consequently, it remains unclear the extent to which lateralization of the nervous system is important for normal cognitive and other brain functions and whether defects in lateralization contribute to neurological deficits. Here we show that sensory responses to light and odor are lateralized in larval zebrafish habenulae and that loss of brain asymmetry leads to concomitant loss of responsiveness to either visual or olfactory stimuli. We find that in wild-type zebrafish, most habenular neurons responding to light are present on the left, whereas neurons responding to odor are more frequent on the right. Manipulations that reverse the direction of brain asymmetry reverse the functional properties of habenular neurons, whereas manipulations that generate either double-left- or double-right-sided brains lead to loss of habenular responsiveness to either odor or light, respectively. Our results indicate that loss of brain lateralization has significant consequences upon sensory processing and circuit function.


Targeting metabolism and AMP-activated kinase with metformin to sensitize non-small cell lung cancer (NSCLC) to cytotoxic therapy: translational biology and rationale for current clinical trials.
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress. Metformin, a well-tolerated anti-diabetic agent, which blocks mitochondria oxidative phosphorylation complex I, became the poster child agent to elicit AMPK activity and tumor suppression. Metformin sensitizes NSCLC models to chemotherapy and radiation. Here, we discuss the rationale for targeting metabolism, the evidence supporting metformin as an anti-tumor agent and adjunct to cytotoxic therapy in NSCLC and we review retrospective evidence and on-going clinical trials addressing this concept.


Bacterial contamination and health risks of drinking water from the municipal non-government managed water treatment plants.
Water quality and bacterial contamination from 18 drinking water municipal plants in three locations at Giza governorate were investigated. The average total count of bacteria detected after four stages of treatments in the investigated plants was 32 CFU/1 mL compared to 2330 cfu/mL for raw water, with a reduction percentage of 98.6. Although there is a relatively high removal percent of bacterial contamination from the water sources, however, several bacterial pathogens were identified in the produced water prepared for drinking including Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Shigella spp. After 3 days of water incubation at 30 °C, the amount of bacterial endotoxins ranged from 77 to 137 ng/mL in the water produced from the municipal plants compared to 621-1260 ng/mL for untreated water. The main diseases reported from patients attending different clinics and hospitals during summer 2014 at the surveyed locations and assuredly due to drinking water from these plants indicated that diarrheas and gastroenteritis due to E. coli and Campylobacter jejuni constituted 65.7% of the total patients followed by bacillary dysentery or shigellosis due to Shigella spp. (7.9%) and cholera due to Vibrio cholera (7.2%). There was an increase in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) as well as urea and creatinine values of guinea pigs consuming water produced from the non-governmental plants for 6 months indicating remarkable liver and kidney damages. Histological sections of liver and kidney from the tested animal revealed liver having ballooning degeneration of hepatocytes and distortion and fragmentation of the nuclei, while the section of the kidney showed irregularly distributed wrinkled cells, degenerated Bowman's capsule, congested blood vessels, and inflammatory cells.


Developmental paediatrics in primary care: what should we teach?
There is little agreement about what constitutes good developmental paediatric practice at the level of primary care. Many of the available screening tests are intrinsically unsatisfactory or badly performed, but screening is only a small part of developmental paediatrics. Every primary care doctor should be familiar with the scientific basis of the subject even if a decision is made not to embark on a formal screening programme.


Varying fitness functions in genetic algorithm constrained optimization: the cutting stock and unit commitment problems.
We present a specific varying fitness function technique in genetic algorithm (GA) constrained optimization. This technique incorporates the problem's constraints into the fitness function in a dynamic way. It consists of forming a fitness function with varying penalty terms. The resulting varying fitness function facilitates the GA search. The performance of the technique is tested on two optimization problems: the cutting stock, and the unit commitment problems. Also, new domain-specific operators are introduced. Solutions obtained by means of the varying and the conventional (nonvarying) fitness function techniques are compared. The results show the superiority of the proposed technique.


VMP1 Establishes ER-Microdomains that Regulate Membrane Contact Sites and Autophagy.
The endoplasmic reticulum (ER) regulates organelle dynamics through the formation of membrane contact sites (MCS). Here we describe that VMP1, a multispanning ER-resident protein involved in autophagy, is enriched in ER micro-domains that are in close proximity to diverse organelles in HeLa and Cos-7 cells. These VMP1 puncta are highly dynamic, moving in concert with lipid droplets, mitochondria and endosomes. Some of these micro-domains are associated with ER sliding events and also with fission events of mitochondria and endosomes. VMP1-depleted cells display increased ER-mitochondria MCS and altered mitochondria morphology demonstrating a role in the regulation of MCS. Additional defects in ER structure and lipid droplets size and distribution are consistent with a more general function of VMP1 in membrane remodeling and organelle function. We hypothesize that in autophagy VMP1 is required for the correct morphogenesis of the omegasome by regulating MCS at the site of autophagosome formation.


Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis.
Chronic inflammation, a hallmark of obliterative bronchiolitis, is known to induce lymphangiogenesis. We therefore studied the role of lymphangiogenic vascular endothelial growth factor C (VEGF-C), its receptor VEGFR-3, and lymphangiogenesis during development of experimental obliterative bronchiolitis [ie, obliterative airway disease (OAD)] in rat tracheal allografts. The functional importance of VEGF-C was investigated by adenovirus-mediated overexpression of VEGF-C (AdVEGF-C), and by inhibition of VEGF-C activity with VEGFR-3-Ig (AdVEGFR-3-Ig). Analyses included histology, immunohistochemistry, and real-time RT-PCR 10 and 30 days after transplantation. In the course of OAD development, lymphangiogenesis was induced in the airway wall during the alloimmune response, which was reversed by cyclosporine A in a dose-dependent fashion. VEGF-C overexpression in tracheal allografts induced epithelial activation, neutrophil chemotaxis, and a shift toward a Th17 adaptive immune response, followed by enhanced lymphangiogenesis and the development of OAD. In contrast, inhibition of VEGF-C activity with VEGFR-3-Ig inhibited lymphangiogenesis and angiogenesis and reduced infiltration of CD4(+) T cells and the development of OAD. Lymphangiogenesis was linked to T-cell responses during the development of OAD, and VEGF-C/VEGFR-3 signaling modulated innate and adaptive immune responses in the development of OAD in rat tracheal allografts. Our results thus suggest VEGFR-3-signaling as a novel strategy to regulate T-cell responses in the development of obliterative bronchiolitis after lung transplantation.


Porphyromonas spp., Fusobacterium spp., and Bacteroides spp. dominate microbiota in the course of macropod progressive periodontal disease.
Macropod progressive periodontal disease (MPPD) is a necrotizing, polymicrobial, inflammatory disease commonly diagnosed in captive macropods. MPPD is characterized by gingivitis associated with dental plaque formation, which progresses to periodontitis and then to osteomyelitis of the mandible or maxilla. However, the underlying microbial causes of this disease remain poorly understood. In this study, we collected 27 oral plaque samples and associated clinical records from 22 captive Macropodidae and Potoroidae individuals that were undergoing clinical examination at Adelaide and Monarto Zoos in South Australia (15 healthy, 7 gingivitis and 5 periodontitis-osteomyelitis samples). The V3-V4 region of the 16S ribosomal RNA gene was sequenced using an Illumina Miseq to explore links between MPPD and oral bacteria in these animals. Compositional differences were detected between the microbiota of periodontitis-osteomyelitis cases compared to healthy samples (p-value with Bonferroni correction < 0.01), as well as gingivitis cases compared to healthy samples (p-value with Bonferroni correction < 0.05) using Permutational Multivariate Analysis of Variance (PERMANOVA). An overabundance of Porphyromonas, Fusobacterium, and Bacteroides taxa was also identified in animals with MPPD compared to healthy individuals using linear discriminant analysis effect size (LEfSe; p = < 0.05). An increased abundance of Desulfomicrobium also was detected in MPPD samples (LEfSe; p < 0.05), which could potentially reflect differences in disease progression. This is the first microbiota analysis of MPPD in captive macropods, and these results support a polymicrobial pathogenesis of MPPD, suggesting that the microbial interactions underpinning MPPD may be more complex than previously documented.


Comparison of risk and protective factors associated with smartphone addiction and Internet addiction.
Smartphone addiction is a recent concern that has resulted from the dramatic increase in worldwide smartphone use. This study assessed the risk and protective factors associated with smartphone addiction in college students and compared these factors to those linked to Internet addiction. College students (N = 448) in South Korea completed the Smartphone Addiction Scale, the Young's Internet Addiction Test, the Alcohol Use Disorders Identification Test, the Beck Depression Inventory I, the State-Trait Anxiety Inventory (Trait Version), the Character Strengths Test, and the Connor-Davidson Resilience Scale. The data were analyzed using multiple linear regression analyses. The risk factors for smartphone addiction were female gender, Internet use, alcohol use, and anxiety, while the protective factors were depression and temperance. In contrast, the risk factors for Internet addiction were male gender, smartphone use, anxiety, and wisdom/knowledge, while the protective factor was courage. Discussion These differences may result from unique features of smartphones, such as high availability and primary use as a tool for interpersonal relationships. Our findings will aid clinicians in distinguishing between predictive factors for smartphone and Internet addiction and can consequently be utilized in the prevention and treatment of smartphone addiction.


Ten-year trends, predictors and outcomes of mechanical circulatory support in percutaneous coronary intervention for acute myocardial infarction with cardiogenic shock.
There are limited data on the trends and outcomes of mechanical circulatory support (MCS)-assisted early percutaneous coronary intervention (PCI) in acute myocardial infarction with cardiogenic shock (AMI-CS). In this study, we sought to assess the use, temporal trends, and outcomes of percutaneous MCS-assisted early PCI in AMI-CS. Using the National Inpatient Sample database from 2005-2014, a retrospective cohort of AMI-CS admissions receiving early PCI (hospital day zero) was identified. MCS use was defined as intra-aortic balloon pump (IABP), percutaneous left ventricular assist device (pLVAD) and extracorporeal membrane oxygenation (ECMO) support. Outcomes of interest included in-hospital mortality, resource utilisation, trends and predictors of MCS-assisted PCI. Of the 110,452 admissions, MCS assistance was used in 55%. IABP, pLVAD and ECMO were used in 94.8%, 4.2% and 1%, respectively. During 2009-2014, there was a decrease in MCS-assisted PCI due to a decrease in IABP, despite an increase in pLVAD and ECMO. Younger age, male sex, lower comorbidity, and cardiac arrest independently predicted MCS use. MCS-assisted PCI was predictive of higher in-hospital mortality (31% vs 26%, adjusted odds ratio 1.23 [1.19-1.27]; p<0.001) and greater resource utilisation. IABP-assisted PCI had lower in-hospital mortality and lesser resource utilisation compared to pLVAD/ECMO. MCS-assisted PCI identified a sicker AMI-CS cohort. There was a decrease in IABP and an increase in pLVAD/ECMO.


Impact of the visceral leishmaniasis elimination initiative on Leishmania donovani transmission in Nepal: a 10-year repeat survey.
Nepal launched a visceral leishmaniasis (also known as kala-azar) elimination initiative in 2005. We primarily aimed to assess whether transmission of Leishmania donovani had decreased since the launch of the initiative. We also assessed the validity of the direct agglutination test (DAT) as a marker of infection, in view of future surveillance systems. We did a repeat survey in a population aged 2 years and older for whom baseline serological data were available from 2006. Data were from three districts in the eastern region of Nepal. The primary outcome of interest was prevalent infection with L donovani as measured with DAT (cutoff value ≥1:3200). We compared age group-specific and cluster-specific seroprevalences in 2016 with those in 2006, using χ2 tests, with a specific focus on the comparison of seroprevalences in children born between 1996 and 2005, and those born between 2006 and 2015. To estimate the overall adjusted risk ratio for being seropositive in 2016 compared with 2006, we fitted a Poisson model controlling for age, sex, and cluster. Between Oct 17, 2016, and Dec 26, 2016, we assessed 6609 individuals. DAT prevalence in children younger than 10 years was 4·1% (95% CI 3·2-5·4) in 2006 versus 0·5% (0·1-1·7) in 2016 (p<0·0001). Seroprevalence was lower in 2016 than in 2006 in all age groups and in all repeated clusters. The overall adjusted risk ratio of being seropositive was 0·44 (95% CI 0·37-0·52) for 2016 compared with 2006, and 0·04 (0·01-0·16) in children younger than 10 years. Our findings show that transmission of L donovani in Nepal has decreased significantly between 2006 and 2016, coinciding with the elimination programme. DAT seems useful for monitoring of L donovani transmission. The Directorate-General for Development Cooperation of Belgium.


Bifocals and Down's syndrome: correction or treatment?
Accommodation is reduced in approximately 75% of children with Down's syndrome (DS). Bifocals have been shown to be beneficial and they are currently prescribed regularly. Clinical observations suggest the likelihood of improving accommodative ability after bifocal wear. The aim of the study is to evaluate the potential use of bifocals as a treatment for the reduced accommodation. Clinical records of 40 children from the Cardiff Down's Syndrome Vision Research Unit, who were prescribed bifocals, were reviewed. Accommodation was noted before wearing the bifocals and during either their latest visit or when the children stopped using bifocals. Accommodation was reassessed during a follow up visit for the children who stopped wearing bifocals. Development of accommodation before bifocal commencement, age at bifocal prescription, gender, type of refractive error, visual acuity and the presence of strabismus were examined to evaluate their contribution to accommodation improvement. The accommodative ability of 65% (n = 26) of the children improved (through the distance part of the lens) after using the bifocals. More than half of those developed accurate accommodation without the use of bifocals (n = 14). Accommodative responses did not show any improvement with age before the children began wearing bifocals. Accurate accommodation was sustained after returning to single vision lenses in all examined children. The age distribution of the children on bifocal commencement was diverse. Presence of strabismus, refractive error type, visual acuity and gender did not have any effect on gaining improvement. Bifocals are an effective correction for the reduced accommodation in children with DS and also act to improve accommodation with a success rate of 65%. Bifocal wear can therefore be temporary, i.e. a 'treatment' for the deficit, in at least one third of children.


Overexpressed gene signature of EPH receptor A/B family in cancer patients-comprehensive analyses from the public high-throughput database.
Although a previous study suggested that erythropoietin-producing hepatoma (EPH) receptors play important roles in tumor progression and the overexpression of EPHs in cancer patients is related to poor prognoses, high-throughput gene expression profiling of EPH family members in different types and subtypes of cancers has so far not been conducted. We herein carried out a series of bioinformatic analyses on expressive profiles of every EPH member across 21 different types of clinical cancers versus matched normal tissues gathered from the Oncomine platform. We validated these results by protein expression study of all EPHs family members by The Human Protein Atlas repository. Our results uncovered the overexpression of most EPH subunits in numerous cancer types, especially the dramatic overexpression of six EPHs members, namely EPHA1, EPHA2, EPHA3, EPHA4 and EPHB1, EPHB2, EPHB3, EPHB4 in bladder, colorectal, esophageal, gastric, and prostate cancers. Furthermore, EPHB2 was specifically highly expressed in cervical cancer, EPHA3 in liver cancer, and EPHB1 in uterine cancer. Collectively, expressive profiles of these EPHs were confirmed and correlated with different cancer subtypes as potential biomarkers. This study provides useful information for further studies on cancer development and clinical treatments.


Educational priorities and current involvement in genetic practice: a survey of midwives in the Netherlands, UK and Sweden.
to investigate whether practising midwives are adequately prepared to integrate genetic information into their practice. a cross-sectional, postal, structured questionnaire survey was sent to practising midwives. practising midwives from the Netherlands (NL), Sweden (SE) and the United Kingdom (UK). 1021 replies were received, achieving a response rate of 62%. 79% (799/1015) of midwives reported attending courses with some 'genetic content' during their initial training. Sixty-eight per cent (533/784) judged this to have been useful for clinical practice. Variation was seen between countries in the amount of genetic content in post-registration training (SE 87%, NL 44%, UK 17%) and most was considered useful. Questions assessing clinical activity identified a current need for genetic knowledge. Midwives described low levels of self-reported confidence both in overtly genetic procedures and in everyday tasks that were underpinned by genetic knowledge. For eight of the 12 procedures, fewer than 20% of midwives considered themselves to be confident. Differences were apparent between countries. Midwives identified psychosocial, screening and risk assessment aspects of genetic education as being important to them, rather than technical aspects or genetic science. given the low reported confidence with genetic issues in clinical practice, it is essential that this is addressed in terms of the amount, content and targeting of genetic education. This is especially important to ensure the success of national antenatal and baby screening programmes. The results of this study suggest that midwives would welcome further training in genetics, addressing genetic topics most relevant to their clinical practice.