Motility enhancement by tumor-derived mutant E-cadherin is sensitive to treatment with epidermal growth factor receptor and phosphatidylinositol 3-kinase inhibitors.
Diffuse-type gastric and lobular breast cancers are characterized by frequent mutations in the cell adhesion molecule E-cadherin. Here we report that tumor-associated mutations of E-cadherin enhanced random cell movement of transfected MDA-MB-435S mammary carcinoma cells as compared to wild-type (wt) E-cadherin-expressing cells. The mutations included in frame deletions of exons 8 or 9 and a point mutation in exon 8 which all affect putative calcium-binding sites within the linker region of the second and third extracellular domain. Motility enhancement by mutant E-cadherin was investigated by time-lapse laser scanning microscopy. Increased cell motility stimulated by mutant E-cadherin was influenced by cell-matrix interactions. The motility-increasing activity of mutant E-cadherin was blocked by application of pharmacological inhibitors of epidermal growth factor receptor and phosphatidylinositol (PI) 3-kinase. Investigation of the activation status of PI 3-kinase and the downstream signaling molecules Akt/protein kinase B and MAP kinase p44/42 showed that these kinases are not more strongly activated in mutant E-cadherin-expressing cells than in wt E-cadherin-expressing cells. Instead, the basal level of PI 3-kinase is necessary for mutant E-cadherin-enhanced cell motility. Our data suggest a critical role of E-cadherin mutations for the fine tuning of tumor cell motility.


Predicting attitude towards performance enhancing substance use: a comprehensive test of the Sport Drug Control Model with elite Australian athletes.
This study presents a comprehensive examination of the Sport Drug Control Model via survey data of elite Australian athletes. A cross-sectional nationwide mail survey. A mail survey of 1237 elite Australian athletes was conducted. Structural equation modelling was employed to test the model. Morality (personal moral stance on performance-enhancing substances use), reference group opinion (perceived moral stance of reference group on performance-enhancing substances use) and legitimacy (perceptions of the drug testing and appeals processes) evidenced significant relationships with attitude towards performance-enhancing substances use, which in turn was positively associated with doping behaviour. The model accounted for 81% and 13% of the variance in attitude towards performance-enhancing substances use and doping behaviour, respectively. These findings validate the usefulness of the Sport Drug Control Model for understanding influences on performance-enhancing substances use. Nevertheless, there is a need to survey athletes representing a broader range of competition levels and cross-cultural research to test the model's applicability to other populations of athletes.


Postpartum Care: An Approach to the Fourth Trimester.
The postpartum period, defined as the 12 weeks after delivery, is an important time for a new mother and her family and can be considered a fourth trimester. Outpatient postpartum care should be initiated within three weeks after delivery in person or by phone, and may require multiple contacts with the patient to fully address needs and concerns. A full assessment is recommended within 12 weeks. Care should initially focus on acute needs and risks for morbidity and mortality and then transition to care for chronic conditions and health maintenance. Complications of pregnancy, such as hypertensive disorders and gestational diabetes mellitus, affect a woman's long-term health and require specific attention. Women diagnosed with gestational diabetes should receive a 75-g two-hour fasting oral glucose tolerance test between four and 12 weeks postpartum. Patients with hypertensive disorders of pregnancy should have a blood pressure check performed within seven days of delivery. All women should have a biopsychosocial assessment (e.g., depression, intimate partner violence) screening in the postpartum period, and preventive counseling should be offered to women at high risk. Additional patient concerns may include urinary incontinence, constipation, breastfeeding, sexuality, and contraception. Treating these issues during the postpartum period is important to the new mother's immediate and long-term health.


The impact of an education program on hand hygiene compliance and nosocomial infection incidence in an urban neonatal intensive care unit: an intervention study with before and after comparison.
Nosocomial bloodstream infections are a major cause of morbidity and mortality in neonatal intensive care units. Appropriate hand hygiene is singled out as the most important measure in preventing these infections. However, hand hygiene compliance among healthcare professionals remains low despite the well-known effect on infection reduction. We studied the effectiveness of a hand hygiene education program on the incidence of nosocomial bloodstream infections. Observational study with two pretests and two posttest measurements and interrupted time series analysis. A 27 bed level IIID neonatal intensive care unit in a teaching hospital in the Netherlands. Healthcare professionals who had physical contact with very low birth weight (VLBW) infants. The study was conducted during a period of 4 years. Medical and nursing staff followed a problem-based education program on hand hygiene. Hand hygiene practices before and after the education program were compared by guided observations. The incidence of nosocomial infections in VLBW infants was compared. In addition, numbers of nosocomial bloodstream infections per day-at-risk in very low birth weight infants were analyzed by a segmented loglinear regression analysis. During 1201 observations hand hygiene compliance before patient contact increased from 65% to 88% (p<0.001). Median (interquartile range) drying time increased from 4s (4-10) to 10s (7-14) (p<0.001). The proportion of very low birth weight infants with one or more bloodstream infections and the infection rate per 1000 patient days (relative risk reduction) before and after the education program on hand hygiene intervention decreased from 44.5% to 36.1% (18.9%, p=0.03) and from 17.3% to 13.5% (22.0%, p=0.03), respectively. At the baseline the nosocomial bloodstream infections per day-at-risk decreased by +0.07% (95% CI -1.41 to +1.60) per month and decreased with -1.25% (95% CI -4.67 to +2.44) after the intervention (p=0.51). The level of instant change was -14.8% (p=0.48). The results are consistent with relevant improvement of hand hygiene practices among healthcare professionals due to an education program. Improved hand hygiene resulted in a reduction in nosocomial bloodstream infections.


Detection and characterisation of Lactobacillus spp. in the bovine uterus and their influence on bovine endometrial epithelial cells in vitro.
Bacterial infections and inflammation of the uterus are common in dairy cattle after parturition. In particular, pathogenic bacteria that cause endometritis have been the focus of research in cattle reproduction in the last ten years. The aim of the present study was to identify commensal lactobacilli in the bovine uterus and to examine their influence on the synthesis of pro-inflammatory factors in bovine endometrial epithelial cells in vitro. Lactobacillus species were isolated from healthy bovine uteri and further characterised. Bovine endometrial epithelial cells in the second passage (n = 5 animals) were co-cultured with the autochthonous isolates L. buchneri, L. ruminis and L. amylovorus as well as with a commercially available L. vaginalis in different multiplicities of infection (MOI = 1, 5 and 10, respectively). Endometrial epithelial cells cultured without bacteria served as controls. At distinct points in time (2, 4 and 6 h) total RNA was extracted from co-cultured epithelial cells and subjected to reverse transcription quantitative PCR of pro-inflammatory factors. Furthermore, the release of such factors by co-cultured epithelial cells was measured by ELISA or EIA after 24 and 48 h. L. ruminis and L. amylovorus induced increased interleukin (IL) IL1A, IL6, IL8 and prostaglandin-endoperoxide synthase 2 mRNA levels and the release of IL8 and prostaglandin F(2α) in endometrial epithelial cells compared with control cells. In contrast, L. buchneri did not significantly influence the expression and release of these factors. Toll-like receptors 2 and 6 transcripts were found unchanged in co-cultured and untreated epithelial cells in vitro. However, endometrial epithelial cells of each animal showed individual differences in the response to bacterial load. These results suggest that Lactobacillus species are present in the bovine uterus, revealing immunomodulatory properties.


Social reasoning in Tourette syndrome.
Tourette syndrome (TS) is thought to be associated with striatal dysfunction. Changes within frontostriatal pathways in TS could lead to changes in abilities reliant on the frontal cortex. Such abilities include executive functions and aspects of social reasoning. This study aimed to investigate executive functioning and Theory of Mind (ToM; the ability to reason about mental states, e.g., beliefs and emotions), in 18 patients with TS and 20 controls. A range of tasks involving ToM were used. These required participants to make judgements about mental states based on pictures of whole faces or the eyes alone, reason about humour in cartoons that featured sarcasm, irony or "slapstick" style humour, and make economic decisions. The executive measures assessed inhibition and verbal fluency. Patients with TS exhibited significantly poorer performance than controls on all four tasks involving ToM, even when patients with comorbid obsessive-compulsive disorder were excluded. These difficulties were despite no inhibitory deficits. Patients with TS exhibited impairment on the verbal fluency task but their performance on executive and ToM tasks was not related. We propose that TS is associated with changes in ToM. The observed deficits could reflect dysfunction in frontostriatal pathways involving ventromedial prefrontal cortex.


Effects and moderators of exercise on sleep in adults with cancer: Individual patient data and aggregated meta-analyses.
To evaluate the effects of exercise interventions on sleep disturbances and sleep quality in patients with mixed cancer diagnoses, and identify demographic, clinical, and intervention-related moderators of these effects. Individual patient data (IPD) and aggregated meta-analyses of randomized controlled trials (RCTs). Using data from the Predicting OptimaL cAncer RehabIlitation and Supportive care project, IPD of 2173 adults (mean age = 54.8) with cancer from 17 RCTs were analyzed. A complementary systematic search was conducted (until November 2018) to study the overall effects and test the representativeness of analyzed IPD. Effect sizes of exercise effects on self-reported sleep outcomes were calculated for all included RCTs. Linear mixed-effect models were used to evaluate the effects of exercise on post-intervention outcome values, adjusting for baseline values. Moderator effects were studied by testing interactions for demographic, clinical and intervention-related characteristics. For all 27 eligible RCTs from the updated search, exercise interventions significantly decreased sleep disturbances in adults with cancer (g = -0.09, 95% CI [-0.16; -0.02]). No significant effect was obtained for sleep quality. RCTs included in IPD analyses constituted a representative sample of the published literature. The intervention effects on sleep disturbances were not significantly moderated by any demographic, clinical, or intervention-related factor, nor by sleep disturbances. This meta-analysis provides some evidence that, compared to control conditions, exercise interventions may improve sleep disturbances, but not sleep quality, in cancer patients, although this effect is of a small magnitude. Among the investigated variables, none was found to significantly moderate the effect of exercise interventions on sleep disturbances.


Reopening of an obstructed third ventriculostomy: long-term success and factors affecting outcome in 215 infants.
The role of reopening an obstructed endoscopic third ventriculostomy (ETV) as treatment for ETV failure is not well defined. The authors studied 215 children with ETV closure who underwent successful repeat ETV to determine the indications, long-term success, and factors affecting outcome. The authors retrospectively reviewed the CURE Children's Hospital of Uganda database from August 2001 through December 2012, identifying 215 children with failed ETV (with or without prior choroid plexus cauterization [CPC]) who underwent reopening of an obstructed ETV stoma. Treatment survival according to sex, age at first and second operation, time to failure of first operation, etiology of hydrocephalus, prior CPC, and mode of ETV obstruction (simple stoma closure, second membrane, or cisternal obstruction from arachnoid scarring) were assessed using the Kaplan-Meier survival method. Survival differences among groups were assessed using log-rank and Wilcoxon methods and a Cox proportional hazards model. There were 125 boys and 90 girls with mean and median ages of 229 and 92 days, respectively, at the initial ETV. Mean and median ages at repeat ETV were 347 and 180 days, respectively. Postinfectious hydrocephalus (PIH) was the etiology in 126 patients, and nonpostinfectious hydrocephalus (NPIH) in 89. Overall estimated 7-year success for repeat ETV was 51%. Sex (p = 0.46, log-rank test; p = 0.54, Wilcoxon test), age (< vs > 6 months) at initial or repeat ETV (p = 0.08 initial, p = 0.13 repeat; log-rank test), and type of ETV obstruction (p = 0.61, log-rank test) did not affect outcome for repeat ETV (p values ≥ 0.05, Cox regression). Those with a longer time to failure of initial ETV (> 6 months 91%, 3-6 months 60%, < 3 months 42%, p < 0.01; log-rank test), postinfectious etiology (PIH 58% vs NPIH 42%, p = 0.02; log-rank and Wilcoxon tests) and prior CPC (p = 0.03, log-rank and Wilcoxon tests) had significantly better outcome. Repeat ETV was successful in half of the patients overall, and was more successful in association with later failures, prior CPC, and PIH. Obstruction of the original ETV by secondary arachnoid scarring was not a negative prognostic factor, and should not discourage the surgeon from proceeding. Repeat ETV may be a more durable solution to failed ETV/CPC than shunt placement in this context, especially for failures at more than 3 months after the initial ETV. Some ETV closures may result from an inflammatory response that is less robust at the second operation.


Radial glia phagocytose axonal debris from degenerating overextending axons in the developing olfactory bulb.
Axon targeting during the development of the olfactory system is not always accurate, and numerous axons overextend past the target layer into the deeper layers of the olfactory bulb. To date, the fate of the mis-targeted axons has not been determined. We hypothesized that following overextension, the axons degenerate, and cells within the deeper layers of the olfactory bulb phagocytose the axonal debris. We utilized a line of transgenic mice that expresses ZsGreen fluorescent protein in primary olfactory axons. We found that overextending axons closely followed the filaments of radial glia present in the olfactory bulb during embryonic development. Following overextension into deeper layers of the olfactory bulb, axons degenerated and radial glia responded by phagocytosing the resulting debris. We used in vitro analysis to confirm that the radial glia had phagocytosed debris from olfactory axons. We also investigated whether the fate of overextending axons was altered when the development of the olfactory bulb was perturbed. In mice that lacked Sox10, a transcription factor essential for normal olfactory bulb development, we observed a disruption to the morphology and positioning of radial glia and an accumulation of olfactory axon debris within the bulb. Our results demonstrate that during early development of the olfactory system, radial glia play an important role in removing overextended axons from the deeper layers of the olfactory bulb.


Beyond synexpression relationships: local clustering of time-shifted and inverted gene expression profiles identifies new, biologically relevant interactions.
The complexity of biological systems provides for a great diversity of relationships between genes. The current analysis of whole-genome expression data focuses on relationships based on global correlation over a whole time-course, identifying clusters of genes whose expression levels simultaneously rise and fall. There are, of course, other potential relationships between genes, which are missed by such global clustering. These include activation, where one expects a time-delay between related expression profiles, and inhibition, where one expects an inverted relationship. Here, we propose a new method, which we call local clustering, for identifying these time-delayed and inverted relationships. It is related to conventional gene-expression clustering in a fashion analogous to the way local sequence alignment (the Smith-Waterman algorithm) is derived from global alignment (Needleman-Wunsch). An integral part of our method is the use of random score distributions to assess the statistical significance of each cluster. We applied our method to the yeast cell-cycle expression dataset and were able to detect a considerable number of additional biological relationships between genes, beyond those resulting from conventional correlation. We related these new relationships between genes to their similarity in function (as determined from the MIPS scheme) or their having known protein-protein interactions (as determined from the large-scale two-hybrid experiment); we found that genes strongly related by local clustering were considerably more likely than random to have a known interaction or a similar cellular role. This suggests that local clustering may be useful in functional annotation of uncharacterized genes. We examined many of the new relationships in detail. Some of them were already well-documented examples of inhibition or activation, which provide corroboration for our results. For instance, we found an inverted expression profile relationship between genes YME1 and YNT20, where the latter has been experimentally documented as a bypass suppressor of the former. We also found new relationships involving uncharacterized yeast genes and were able to suggest functions for many of them. In particular, we found a time-delayed expression relationship between J0544 (which has not yet been functionally characterized) and four genes associated with the mitochondria. This suggests that J0544 may be involved in the control or activation of mitochondrial genes. We have also looked at other, less extensive datasets than the yeast cell-cycle and found further interesting relationships. Our clustering program and a detailed website of clustering results is available at http://www.bioinfo.mbb.yale.edu/expression/cluster (or http://www.genecensus.org/expression/cluster).


Snail/slug family of repressors: slowly going into the fast lane of development and cancer.
The existence of homologous genes in diverse species is intriguing. A detailed comparison of the structure and function of gene families may provide important insights into gene regulation and evolution. An unproven assumption is that homologous genes have a common ancestor. During evolution, the original function of the ancestral gene might be retained in the different species which evolved along separate courses. In addition, new functions could have developed as the sequence began to diverge. This may also explain partly the presence of multipurpose genes, which have multiple functions at different stages of development and in different tissues. The Drosophila gene snail is a multipurpose gene; it has been demonstrated that snail is critical for mesoderm formation, for CNS development, and for wing cell fate determination. The related vertebrate Snail and Slug genes have also been proposed to participate in mesoderm formation, neural crest cell migration, carcinogenesis, and apoptosis. In this review, we will discuss the Snail/Slug family of regulators in species ranging from insect to human. We will present the protein structures, expression patterns, and functions based on molecular genetic analyses. We will also include the studies that helped to elucidate the molecular mechanisms of repression and the relationship between the conserved and divergent functions of these genes. Moreover, the studies may enable us to trace the evolution of this gene family.


A physiologic role for serotonergic transmission in adult rat taste buds.
Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells) and was once thought to be essential to neurotransmission (now understood as purinergic). However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers and enhances the afferent signal. Serotonin may thus play a major modulatory role within peripheral taste in shaping the afferent taste signals prior to their transmission across gustatory nerves.


A prospective, randomized, multicenter trial comparing the efficacy and safety of the concurrent use of long-acting insulin with mitiglinide or voglibose in patients with type 2 diabetes.
This trial was conducted to compare the efficacy and safety of combination therapy with basal insulin glargine plus mitiglinide to that of basal insulin glargine plus voglibosein patients with type 2 diabetes. This was a 20-week, randomized, multicenter non-inferiority trial. Patients with HbA1c levels over 7.0% were randomly assigned to receive either mitiglinide (10 mg tid) or voglibose (0.2 mg tid) concurrent with insulin glargine for 16 weeks after a 4-week of basal insulin glargine monotherapy. The intention-to-treat population included 156 patients; 79 were placed in the mitiglinide group, and 77 were placed in the voglibose group. At 20 weeks, there was no significant difference between the mitiglinide group and the voglibose group in terms of the mean HbA1c level or the mean decrease of the HbAlc level from baseline (-0.9% [-7.5 mmol/mol] and -0.7%, [-5.3 mmol/mol] respectively). The mean fasting plasma glucose level and data of self-monitoring blood glucosewere significantly decreased from baseline to week 20 in both groups, but there was no significant difference between the two groups. The changes in the basal insulin requirements of each group were not significant. The prevalence of adverse events and the risk of hypoglycemia were similar for both groups. Combination therapy with mitiglinide plus basal insulin glargine was non-inferior to voglibose plus basal insulin glargine in terms of the effect on overall glycemic control.


KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer's disease-related pathology.
Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer's disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2-/- mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes.


The use of botanicals during pregnancy and lactation.
Women are the largest consumers of healthcare, and this extends to their utilization of complementary and alternative medicine (CAM). Researchers have attempted to uncover the reasons why women turn to CAM in general and to botanical medicine in particular. Desire to have personal control over their health has been cited as the strongest motive for women to use herbal medicine. Second was dissatisfaction with conventional treatment and its disregard for a holistic approach, as well as concerns about the side effects of medications.' These concerns may explain, in part, the fact that many women use herbal remedies during pregnancy. A survey of 578 pregnant women in the eastern United States reported that 45% of respondents had used herbal medicines, and a survey of 588 women in Australia revealed that 36% had used at least 1 herbal product during pregnancy. Women probably feel comfortable using herbal remedies because of their perceived safety, easy access, and the widespread availability of information about them (ie, Internet, magazines, books). While it is true that many botanicals are mild in both treatment effects and side effects, the data regarding safety during pregnancy are very limited. Given the small sample sizes in clinical trials studying botanicals in pregnant women, only large differences in measures of pregnancy outcomes would likely be detected. For example, if an herb were thought to increase the rate of spontaneous abortion from 6% to 7%, a sample size of more than 19000 women would be needed. It is highly unlikely that there will be any studies of a botanical (or drug) with this large a sample size. So when addressing the safety of an herb during pregnancy, we must look at the totality of the evidence, which includes traditional and contemporary use, animal studies, pharmacological studies, and clinical trial data, when available. Survey data tell us that women often do not share their use of herbal remedies with their healthcare providers due to fear of offending providers or to the belief that clinicians will be ignorant about their use. Practitioners should maintain an open and respectful demeanor when counseling pregnant and nursing women about the use of botanical medicines, and they should know how to access unbiased and authoritative information sources, so they may reliably answer questions on inadvertent exposures and provide guidance on herbal products that might be beneficial.


Automatic segmentation of the solid core and enclosed vessels in subsolid pulmonary nodules.
Subsolid pulmonary nodules are commonly encountered in lung cancer screening and clinical routine. Compared to other nodule types, subsolid nodules are associated with a higher malignancy probability for which the size and mass of the nodule and solid core are important indicators. However, reliably measuring these characteristics on computed tomography (CT) can be hampered by the presence of vessels encompassed by the nodule, since vessels have similar CT attenuation as solid cores. This can affect treatment decisions and patient management. We present a method based on voxel classification to automatically identify vessels and solid cores in given subsolid nodules on CT. Three experts validated our method on 170 screen-detected subsolid nodules from the Multicentric Italian Lung Disease trial. The agreement between the proposed method and the observers was substantial for vessel detection and moderate for solid core detection, which was similar to the inter-observer agreement. We found a relatively high variability in the inter-observer agreement and low method-observer agreements for delineating the borders of vessels and solid cores, illustrating the difficulty of this task. However, 92.4% of the proposed vessel and 80.6% of the proposed solid core segmentations were labeled as usable in clinical practice by the majority of experts.


Depth Estimation and Semantic Segmentation from a Single RGB Image Using a Hybrid Convolutional Neural Network.
Semantic segmentation and depth estimation are two important tasks in computer vision, and many methods have been developed to tackle them. Commonly these two tasks are addressed independently, but recently the idea of merging these two problems into a sole framework has been studied under the assumption that integrating two highly correlated tasks may benefit each other to improve the estimation accuracy. In this paper, depth estimation and semantic segmentation are jointly addressed using a single RGB input image under a unified convolutional neural network. We analyze two different architectures to evaluate which features are more relevant when shared by the two tasks and which features should be kept separated to achieve a mutual improvement. Likewise, our approaches are evaluated under two different scenarios designed to review our results versus single-task and multi-task methods. Qualitative and quantitative experiments demonstrate that the performance of our methodology outperforms the state of the art on single-task approaches, while obtaining competitive results compared with other multi-task methods.


Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy.
Cytogenetic clonal evolution (CE) is a known poor prognostic factor in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph-positive CML). However, its prognostic relevance in the era of imatinib therapy is unknown. We investigated the independent prognostic relevance of CE in 498 patients with Ph-positive CML treated with imatinib for chronic or accelerated phases. One hundred twenty-one patients had CE alone (n = 70) or with other accelerated phase criteria (n = 51). Patients were compared in 4 categories: chronic phase (n = 295), CE only (n = 70), accelerated phase without CE (n = 82), and accelerated phase with CE (n = 51). Statistical methods used established methodologies for univariate and multivariate analyses. In chronic and accelerated phases of CML, CE was not associated with significant differences in major or complete cytogenetic response rates, but it was an independent poor prognostic factor for survival by multivariate analyses in both chronic (P =.005) and accelerated phase (P =.03). Multivariate analyses conducted at the 3-month landmark (including the 3-month cytogenetic response) identified the lack of cytogenetic response at 3 months to be a stronger independent poor prognostic factor for survival than CE for both chronic (major cytogenetic response versus other) and accelerated phase (any cytogenetic response versus other). We conclude that cytogenetic CE is not an important factor for achieving major or complete cytogenetic response with imatinib mesylate therapy, but it is an independent poor prognostic factor for survival in both chronic and accelerated phases of CML. The 3-month cytogenetic response to imatinib mesylate refined the prognostic relevance of such studies in patients on imatinib mesylate therapy.


Programmed death-ligand 1 expression is associated with fibrosarcomatous transformation of dermatofibrosarcoma protuberans.
Dermatofibrosarcoma protuberans (DFSP) is a locally invading tumor, characterized by the presence of the collagen type I α 1 (COL1A1)-platelet-derived growth factor (PDGF) β fusion gene. We herein report the case of a 31-year-old man with a history of resection of an abdominal wall DFSP. The patient presented with chest pain and a computed tomography scan revealed a large mass in the posterior mediastinum and another mass in the right lung. The mediastinal mass was a sarcomatous lesion expressing the COL1A1-PDGFβ fusion gene, suggesting that it represented a metastasis of the DFSP following fibrosarcomatous (FS) transformation. Following resection of the mediastinal metastasis and subsequent radiotherapy, the mass in the right lung was also resected. Due to the emergence of pleural and pancreatic tail metastases, the patient was treated with a combination therapy of adriamycin and ifosfamide. After five courses, the disease progressed and the patient was subsequently treated with pazopanib for ~2 months until further progression. Three years after the diagnosis of the mediastinal metastasis of DFSP, the patient was referred to another hospital for palliative care. The expression of programmed cell death 1 ligand (PD-L1) in the primary and metastatic tumors was investigated: PD-L1 expression was detected in the metastasis but not in the primary tumor. Given that the metastatic tumor exhibited FS transformation (DFSP-FS), PD-L1 expression may be induced by FS transformation, contributing to the metastasis through escape from immune surveillance. Further investigation of the PD-L1 pathway in DFSP and DFSP-FS in primary as well as metastatic sites is required to evaluate the clinical efficacy of therapies targeting the PD-L1 signaling cascade.


Probing molecular choreography through single-molecule biochemistry.
Single-molecule approaches are having a dramatic impact on views of how proteins work. The ability to observe molecular properties at the single-molecule level allows characterization of subpopulations and acquisition of detailed kinetic information that would otherwise be hidden in the averaging over an ensemble of molecules. In this Perspective, we discuss how such approaches have successfully been applied to in vitro-reconstituted systems of increasing complexity.


Human F(ab')2-containing immune complexes together with anti-hinge natural antibodies stimulate complement amplification in vitro and in vivo.
The systemic inflammatory response syndrome (SIRS) is triggered by C5a generation following an excessive complement amplification, but it has remained unclear how complement amplification is stimulated. It is known that neutrophilic elastase can cleave IgG to F(ab')(2) and that F(ab')(2)-containing immune complexes (F(ab')(2)-IC) stimulate complement amplification together with an unidentified plasma factor. We show that absorption of plasma on F(ab')(2) from human IgG removed this factor and prevented F(ab')(2)-IC from stimulating complement amplification. The required factor was purified from pooled whole human IgG (IVIG) as those naturally occurring antibodies (NAbs) that bind to F(ab')(2), but not to intact IgG. These "anti-hinge NAbs" restored complement amplification by F(ab')(2)-IC in absorbed plasma. Anti-hinge NAbs must have formed secondary, rigidified IC from F(ab')(2)-IC, because the F(ab')(2) fragments evidently captured dimeric C3b, known as a potent C3 convertase precursor. This process may also stimulate complement amplification in vivo, because plasma from septic patients at the onset of SIRS indeed contained F(ab')(2) fragments. The concentrations of F(ab')(2) and that of factor Bb, an unbiased measure of complement amplification, correlated linearly with that of released elastase. Moreover, the F(ab')(2) fragments migrated on gelfiltration columns together with anti-hinge NAbs as ICs with MW of up to approximately 750kDa, as verified on plasma of each of the nine patients studied. These findings provide for the first time a plausible mechanism of how F(ab')(2)-containing immune complexes stimulate complement amplification together with anti-hinge NAbs. The same mechanism may contribute to complement overreaction at the onset of SIRS.


Effect of dietary fat saturation on plasma lipoproteins and high density lipoprotein metabolism of the rhesus monkey.
Rhesus monkeys were fed corn or coconut oil-based diets for 3-6 mo to determine effects on the composition of all lipoprotein classes and on the metabolism of high density lipoproteins (HDL). Major findings included the following. Coconut oil feeding increased concentrations of all classes of plasma lipoproteins without altering lipoprotein size, suggesting an increase in particle number. The percentage of saturated fatty acids in the cholesteryl esters (CE) of low density lipoproteins (LDL) and HDL reached 40% with coconut oil feeding. This value probably constitutes a minimum estimate of the CE which were of intracellular rather than intraplasmic origin. The CE in LDL and HDL were nearly identical suggesting virtually complete equilibration by the core lipid transfer reaction. The CE in very low density lipoproteins, in contrast, were significantly more saturated than those in LDL and HDL irrespective of diet. Lower HDL levels on the corn oil diet were associated with higher fractional catabolic rates for both apolipoprotein A-I (0.42 vs. 0.31 d-1) and apolipoprotein A-II (0.45 vs. 0.30 d-1).


Voluntary Running Attenuates Memory Loss, Decreases Neuropathological Changes and Induces Neurogenesis in a Mouse Model of Alzheimer's Disease.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by loss of memory and cognitive abilities, and the appearance of amyloid plaques composed of the amyloid-β peptide (Aβ) and neurofibrillary tangles formed of tau protein. It has been suggested that exercise might ameliorate the disease; here, we evaluated the effect of voluntary running on several aspects of AD including amyloid deposition, tau phosphorylation, inflammatory reaction, neurogenesis and spatial memory in the double transgenic APPswe/PS1ΔE9 mouse model of AD. We report that voluntary wheel running for 10 weeks decreased Aβ burden, Thioflavin-S-positive plaques and Aβ oligomers in the hippocampus. In addition, runner APPswe/PS1ΔE9 mice showed fewer phosphorylated tau protein and decreased astrogliosis evidenced by lower staining of GFAP. Further, runner APPswe/PS1ΔE9 mice showed increased number of neurons in the hippocampus and exhibited increased cell proliferation and generation of cells positive for the immature neuronal protein doublecortin, indicating that running increased neurogenesis. Finally, runner APPswe/PS1ΔE9 mice showed improved spatial memory performance in the Morris water maze. Altogether, our findings indicate that in APPswe/PS1ΔE9 mice, voluntary running reduced all the neuropathological hallmarks of AD studied, reduced neuronal loss, increased hippocampal neurogenesis and reduced spatial memory loss. These findings support that voluntary exercise might have therapeutic value on AD.


Nanopatterning reveals an ECM area threshold for focal adhesion assembly and force transmission that is regulated by integrin activation and cytoskeleton tension.
Integrin-based focal adhesions (FA) transmit anchorage and traction forces between the cell and the extracellular matrix (ECM). To gain further insight into the physical parameters of the ECM that control FA assembly and force transduction in non-migrating cells, we used fibronectin (FN) nanopatterning within a cell adhesion-resistant background to establish the threshold area of ECM ligand required for stable FA assembly and force transduction. Integrin-FN clustering and adhesive force were strongly modulated by the geometry of the nanoscale adhesive area. Individual nanoisland area, not the number of nanoislands or total adhesive area, controlled integrin-FN clustering and adhesion strength. Importantly, below an area threshold (0.11 µm(2)), very few integrin-FN clusters and negligible adhesive forces were generated. We then asked whether this adhesive area threshold could be modulated by intracellular pathways known to influence either adhesive force, cytoskeletal tension, or the structural link between the two. Expression of talin- or vinculin-head domains that increase integrin activation or clustering overcame this nanolimit for stable integrin-FN clustering and increased adhesive force. Inhibition of myosin contractility in cells expressing a vinculin mutant that enhances cytoskeleton-integrin coupling also restored integrin-FN clustering below the nanolimit. We conclude that the minimum area of integrin-FN clusters required for stable assembly of nanoscale FA and adhesive force transduction is not a constant; rather it has a dynamic threshold that results from an equilibrium between pathways controlling adhesive force, cytoskeletal tension, and the structural linkage that transmits these forces, allowing the balance to be tipped by factors that regulate these mechanical parameters.


Climate change impact on atmospheric nitrogen deposition in northwestern Europe: a model study.
A high-resolution chemical transport model, driven by meteorology representing current and future climate, was used to investigate the effects of possible future changes in climate on nitrogen deposition in northwestern Europe. The model system was able to resolve the climatology of precipitation and chemical properties observed in northern Europe during the 1980s, albeit with some underestimation of the temporal and spatial variability of meteorological parameters and chemical components. The results point toward a substantial increase (30% or more) in nitrogen deposition over western Norway as a consequence of increasing precipitation but more moderate changes for other areas. Deposition of oxidized nitrogen will increase more than the deposition of reduced nitrogen. Over Sweden, oxidized nitrogen will increase only marginally and reduced nitrogen will decrease, although annual precipitation is expected to increase here as well. This is probably because more reduced nitrogen will be removed further west in Scandinavia because of the strong increase in precipitation along the Norwegian coast. The total deposition of oxidized nitrogen over Norway is expected to increase from 96 Gg N y(-1) during the current climate to 107 Gg N y(-1) by 2100 due only to changes in climate. The corresponding values for Sweden are more modest, from 137 Gg N y(-1) to 139 Gg N y(-1).


Decreased Interleukin-1β and Elastase in the Gingival Crevicular Fluid of Individuals Undergoing Anti-Inflammatory Treatment for Rheumatoid Arthritis.
The primary aim of this study was to compare the inflammatory activity in the gingival crevicular fluid (GCF) in a group of patients with rheumatoid arthritis (RA) and a group of matched controls. Secondarily, we aimed to evaluate the effect of rheumatologic treatment on periodontal inflammation. Seventeen individuals with RA with a mean duration of disease of 12.1 (± 9.9) years and the same number of systemically healthy individuals matched for age, gender, periodontal status, and tobacco use were selected. Medication data were registered, and GCF was collected by means of an intracrevicular washing method. Besides clinical registrations, periodontal inflammation was assessed by analysis of the cytokines interleukin (IL)-1β and -18 and of elastase activity. Amounts of IL-1β and total elastase were significantly lower in the patient group. IL-1β and total elastase had a significant and strong correlation in the RA group (rs = 0.883). This correlation was not observed in the control group. The anti-inflammatory treatment taken by RA patients might influence the periodontal inflammation status represented by IL-1β and elastase in the GCF.


How we diagnose and treat iron deficiency anemia.
It is estimated that one-third of the world's population is anemic, the majority being due to iron deficiency (ID). In adults, ID is associated with fatigue in the absence of anemia, restless legs syndrome, pica and, in neonates, delayed growth and development. In adolescents, ID is associated with decrements in learning and behavioral abnormalities. In the absence of a clear cause, search for a source of bleeding is indicated. No single test is diagnostic of ID unless the serum ferritin is low or the percent transferrin saturation is low with an elevated total iron binding capacity. Oral iron is considered front line therapy except for conditions such as gastric bypass, heavy uterine bleeding, inflammatory bowel disease, and hereditary hemorrhagic telangiectasia. Oral iron has many unpleasant side effects, resulting in low patient adherence. For patients intolerant of, or unresponsive to, oral iron, intravenous (IV) administration is the preferred route. While early formulations were associated with a high incidence of serious adverse events (SAEs), newer formulations are much safer with SAEs occurring very infrequently. Full replacement doses can be administered in a matter of minutes to a few hours. Nevertheless, there remains a reluctance to use IV iron due to a misunderstanding of the safety of the available formulations. IV iron is safe and effective in all clinical circumstances including pregnancy. The preponderance of published evidence suggests IV iron therapy is underutilized and we believe that IV iron should be moved forward in the treatment of ID and iron deficiency anemia (IDA).


HAMAP in 2015: updates to the protein family classification and annotation system.
HAMAP (High-quality Automated and Manual Annotation of Proteins--available at http://hamap.expasy.org/) is a system for the automatic classification and annotation of protein sequences. HAMAP provides annotation of the same quality and detail as UniProtKB/Swiss-Prot, using manually curated profiles for protein sequence family classification and expert curated rules for functional annotation of family members. HAMAP data and tools are made available through our website and as part of the UniRule pipeline of UniProt, providing annotation for millions of unreviewed sequences of UniProtKB/TrEMBL. Here we report on the growth of HAMAP and updates to the HAMAP system since our last report in the NAR Database Issue of 2013. We continue to augment HAMAP with new family profiles and annotation rules as new protein families are characterized and annotated in UniProtKB/Swiss-Prot; the latest version of HAMAP (as of 3 September 2014) contains 1983 family classification profiles and 1998 annotation rules (up from 1780 and 1720). We demonstrate how the complex logic of HAMAP rules allows for precise annotation of individual functional variants within large homologous protein families. We also describe improvements to our web-based tool HAMAP-Scan which simplify the classification and annotation of sequences, and the incorporation of an improved sequence-profile search algorithm.


Validation of a standard field test method in four countries to assess the toxicity of residues in dung of cattle treated with veterinary medical products.
Registration of veterinary medical products includes the provision that field tests may be required to assess potential nontarget effects associated with the excretion of product residues in dung of treated livestock (phase II, tier B testing). However, regulatory agencies provide no guidance on the format of these tests. In the present study, the authors report on the development of a standardized field test method designed to serve as a tier B test. Dung was collected from cattle before and up to 2 mo after treatment with a topical application of a test compound (ivermectin). Pats formed of dung from the different treatments were placed concurrently in the field to be colonized by insects. The abundance, richness, and diversity of insects developing from egg to adult in these pats were compared across treatments using analysis of variance tests. Regression analyses were used to regress abundance, richness, and diversity against residue concentrations in each treatment. Results of the regression were used to estimate mean lethal concentration (LC50) values. The robustness of the method and the repeatability of its findings were assessed concurrently in 4 countries (Canada, France, Switzerland, and The Netherlands) in climatically diverse ecoregions. Results were generally consistent across countries, and support the method's formal adoption by the European Union to assess the effects of veterinary medical product residues on the composition and diversity of insects in dung of treated livestock. Environ Toxicol Chem 2016;35:1934-1946. © 2015 Crown in the right of Canada. Published by Wiley Periodicals Inc., on behalf of SETAC.


Hyperthyroid cats have altered pulmonary arterial hemodynamics but rarely have intermediate or high probability of pulmonary hypertension.
Apply the 3-site echocardiographic metrics utilized to assess pulmonary hypertension (PH) probability in dogs and humans to feline echocardiographic examinations to investigate the translatability of this scheme and subsequent enhancement of detection of PH in cats. 27 client-owned cats (euthyroid [n = 11] and hyperthyroid [16]). This was a single-center, prospective, observational case-control study. Demographic, physical examination, and echocardiographic data from hyperthyroid and euthyroid cats were compared via Fisher exact test and Kruskal-Wallis test. Hyperthyroid versus euthyroid cats had significantly greater right atrial area index values and were more likely to have late-peaking main pulmonary artery pulsed-wave flow profiles. Two hyperthyroid cats had measurable tricuspid regurgitation tracings (one with a high probability of PH and another with a low probability of PH). Hyperthyroid cats demonstrated altered pulmonary arterial hemodynamics and lacked consistent intermediate or high probability of PH. The 3-site echocardiographic metrics scheme is applicable for the evaluation of right-sided cardiac and pulmonary arterial hemodynamics in cats. Further research is needed to determine reference ranges in larger populations of healthy cats and those with high clinical suspicion for PH.


Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial.
To assess the outcome of elderly patients with primary CNS lymphoma (PCNSL) treated within the G-PCNSL-SG-1 trial. We reviewed response, toxicity, and survival of patients with PCNSL aged 70 or more enrolled in the G-PCNSL-SG-1 trial. A total of 126 of the 526 eligible patients (24%) and 66 of 318 patients (21%) in the per protocol population were aged 70 or more. Among all eligible patients, the rate of complete and partial responses (CR+PR) to HD-MTX-based chemotherapy was 44% in the elderly vs 57% in the younger patients (p = 0.016). Toxicity was age-independent except for a higher rate of grade III/IV leukopenia in the elderly (34% vs 21%, p = 0.007). Death on therapy was more frequent (18% vs 11%; p = 0.027), and progression-free survival (PFS) (4.0 vs 7.7 months, p = 0.014) and overall survival (12.5 vs 26.2 months, p < 0.001) inferior, in the elderly. A striking difference between younger and elderly patients was the PFS of CR patients of 35.0 in the younger vs 16.1 in the elderly patients (p = 0.024). Elderly patients were treated less often and less aggressively at salvage. However, age was not associated with survival from salvage whole brain radiotherapy in patients progressing during primary HD-MTX-based chemotherapy (p = 0.633). Lower response rate and higher mortality on HD-MTX-based chemotherapy as well as lower PFS of CR patients and less salvage therapy contribute to the poor prognosis of elderly patients with PCNSL.


Heat shock protein 27 phosphorylation state is associated with cancer progression.
Understanding the mechanisms that control stress-induced survival is critical to explain how tumors frequently resist to treatment and to improve current anti-cancer therapies. Cancer cells are able to cope with stress and escape drug toxicity by regulating heat shock proteins (Hsps) expression and function. Hsp27 (HSPB1), a member of the small Hsp family, represents one of the key players of many signaling pathways contributing to tumorigenicity, treatment resistance, and apoptosis inhibition. Hsp27 is overexpressed in many types of cancer and its functions are regulated by post-translational modifications, such as phosphorylation. Protein phosphorylation is the most widespread signaling mechanism in eukaryotic cells, and it is involved in all fundamental cellular processes. Aberrant phosphorylation of Hsp27 has been associated with cancer but the molecular mechanisms by which it is implicated in cancer development and progression remain undefined. This mini-review focuses on the role of phosphorylation in Hsp27 functions in cancer cells and its potential usefulness as therapeutic target in cancer.


Physician associates working in secondary care teams in England: Interprofessional implications from a national survey.
Physician associates (PAs) are a new type of healthcare professional to the United Kingdom; however, they are well established in the United States (where they are known as physician assistants). PAs are viewed as one potential solution to the current medical workforce doctor shortage. This study investigated the deployment of PAs within secondary care teams in England, through the use of a cross-sectional electronic, self-report survey. The findings from 14 questions are presented. Sixty-three PAs working in a range of specialties responded. A variety of work settings were reported, most frequently inpatient wards, with work generally taking place during weekdays. Both direct and non-direct patient care activities were reported, with the type of work undertaken varying at times, depending on the presence or absence of other healthcare professionals. PAs reported working within a variety of secondary care team staffing permutations, with the majority of these being interprofessional. Line management was largely provided by consultants; however day-to-day supervision varied, often relating to different work settings. A wide variation in ongoing supervision was also reported. Further research is required to understand the nature of PAs' contribution to collaborative care within secondary care teams in England.


Mineral vs. Organic Amendments: Microbial Community Structure, Activity and Abundance of Agriculturally Relevant Microbes Are Driven by Long-Term Fertilization Strategies.
Soil management is fundamental to all agricultural systems and fertilization practices have contributed substantially to the impressive increases in food production. Despite the pivotal role of soil microorganisms in agro-ecosystems, we still have a limited understanding of the complex response of the soil microbiota to organic and mineral fertilization in the very long-term. Here, we report the effects of different fertilization regimes (mineral, organic and combined mineral and organic fertilization), carried out for more than a century, on the structure and activity of the soil microbiome. Organic matter content, nutrient concentrations, and microbial biomass carbon were significantly increased by mineral, and even more strongly by organic fertilization. Pyrosequencing revealed significant differences between the structures of bacterial and fungal soil communities associated to each fertilization regime. Organic fertilization increased bacterial diversity, and stimulated microbial groups (Firmicutes, Proteobacteria, and Zygomycota) that are known to prefer nutrient-rich environments, and that are involved in the degradation of complex organic compounds. In contrast, soils not receiving manure harbored distinct microbial communities enriched in oligotrophic organisms adapted to nutrient-limited environments, as Acidobacteria. The fertilization regime also affected the relative abundances of plant beneficial and detrimental microbial taxa, which may influence productivity and stability of the agroecosystem. As expected, the activity of microbial exoenzymes involved in carbon, nitrogen, and phosphorous mineralization were enhanced by both types of fertilization. However, in contrast to comparable studies, the highest chitinase and phosphatase activities were observed in the solely mineral fertilized soil. Interestingly, these two enzymes showed also a particular high biomass-specific activities and a strong negative relation with soil pH. As many soil parameters are known to change slowly, the particularity of unchanged fertilization treatments since 1902 allows a profound assessment of linkages between management and abiotic as well as biotic soil parameters. Our study revealed that pH and TOC were the majors, while nitrogen and phosphorous pools were minors, drivers for structure and activity of the soil microbial community. Due to the long-term treatments studied, our findings likely represent permanent and stable, rather than transient, responses of soil microbial communities to fertilization.


Increased platelet membrane [3H]-LSD binding in patients on chronic neuroleptic treatment.
Using a [3H]-lysergic acid diethylamide [( 3H]-LSD) binding technique, platelet 5-hydroxytryptamine (5-HT) receptor number and affinity were compared in schizophrenics treated with depot thioxanthenes and phenothiazines and controls. There was an approximately 30% increase in platelet receptor number (Bmax) in the patient group. There was a decrease in affinity (increase in Kd) of about 30% in the patient group. This was probably due to the persistence of the neuroleptic in the platelet membrane preparation. There was a weak positive correlation between receptor number and total neuroleptic dosage. The increased number of 5-HT receptors is consistent with the previously reported enhancement of 5-HT-induced platelet aggregation in patients treated with long-term phenothiazines and thioxanthenes. Our findings are compatible with 5-HT up-regulation in human platelets produced by depot neuroleptic therapy. It is not known whether parallel changes may be occurring in brain 5-HT receptors.


Aging alters surround modulation of perceived contrast.
It is well established that many visual functions deteriorate with age. Perhaps counter-intuitively, a recent study revealed that older people actually require less time to discriminate the direction of motion of large, high contrast moving stimuli than young adults (L. R. Betts, C. P. Taylor, A. B. Sekuler, & P. J. Bennett, 2005). L. R. Betts et al. (2005) proposed their finding as evidence for a reduction of cortical inhibitory function within the aging visual system. There is some neurophysiological support for this suggestion, as broadening of visual cortical neural tuning consistent with reduced inhibitory function has been observed in older animals. Here we explore the perceptual consequences of center-surround suppression within the healthy aging human visual system and report data from a center-surround contrast discrimination task (the Chubb contrast illusion). We predicted that older observers would demonstrate less center-surround suppression than younger subjects (consistent with reduced inhibition). Our data does not support this prediction as perceived contrast was altered more by surround modulation in the older than younger group (t(33) = 2.53, p = 0.02). A possible explanation for our findings is a decrease in perceptual brightness induction in the elderly group. Brightness induction relies on neural synchronization which might be disrupted by aging.


Role of electrodiagnosis in nerve transfers for focal neuropathies and brachial plexopathies.
Over the past 2 decades, the surgical treatment of brachial plexus and peripheral nerve injuries has advanced considerably. Nerve transfers have become an important surgical tool in addition to nerve repair and grafting. Electrodiagnosis has traditionally played a role in the diagnosis and localization of peripheral nervous system injuries, but a different approach is needed for surgical decision-making and monitoring recovery. When patients have complete or severe injuries they should be referred to surgical colleagues early after injury, as outcomes are best when nerve transfers are performed within the first 3 to 6 mo after onset. Patients with minimal recovery of voluntary activity are particularly challenging, and the presence of a few motor unit action potentials in these individuals should be interpreted on the basis of timing and evidence of ongoing reinnervation. Evaluation of potential recipient and donor muscles, as well as redundant muscles, for nerve transfers requires an individualized approach to optimize the chances of a successful surgical intervention. Anomalous innervation takes on new importance in these patients. Communication between surgeons and electrodiagnostic medicine specialists (EMSs) is best facilitated by a joint collaborative clinic. Ongoing monitoring of recovery post-operatively is critical to allow for decision making for continued surgical and rehabilitation treatments. Different electrodiagnostic findings are expected with resolution of neurapraxia, distal axon sprouting, and axonal regrowth. As new surgical techniques become available, EMSs will play an important role in the assessment and treatment of these patients with severe nerve injuries.


Nicking of the tryptophan synthase beta 2-subunit at Glu-296 prevents the conformational change undergone on binding the alpha-subunit.
Using a monoclonal antibody as conformational probe it has been shown that the weakly active nicked-beta 2 dimer of tryptophan synthase generated by proteolytic cleavage at Glu-296, does not undergo on association with alpha subunit a conformational change known to occur in intact beta 2 subunit. This alpha induced conformational change is also prevented in intact beta 2 by the coenzyme pyridoxal-5'-phosphate when the substrate L-serine is absent.


A study of suicide in farmers in England and Wales.
The proportional mortality ratio for suicide is higher in farmers than in the general population. The reasons for this are likely to be complex, but may include easy availability of firearms, stress related to work, financial difficulties, and family problems. A psychological autopsy study of suicide in 84 farmers who died between 1991-1994 is presented and some preliminary findings are discussed.


Nasal carriage in Vietnamese children of Streptococcus pneumoniae resistant to multiple antimicrobial agents.
Resistance to antimicrobial agents in Streptococcus pneumoniae is increasing rapidly in many Asian countries. There is little recent information concerning resistance levels in Vietnam. A prospective study of pneumococcal carriage in 911 urban and rural Vietnamese children, of whom 44% were nasal carriers, was performed. Carriage was more common in children <5 years old than in those >/=5 years old (192 of 389 [49.4%] versus 212 of 522 [40.6%]; P, 0.01). A total of 136 of 399 isolates (34%) had intermediate susceptibility to penicillin (MIC, 0.1 to 1 mg/liter), and 76 of 399 isolates (19%) showed resistance (MIC, >1.0 mg/liter). A total of 54 of 399 isolates (13%) had intermediate susceptibility to ceftriaxone, and 3 of 399 isolates (1%) were resistant. Penicillin resistance was 21.7 (95% confidence interval, 7.0 to 67.6) times more common in urban than in rural children (35 versus 2%; P, <0.001). More than 40% of isolates from urban children were also resistant to erythromycin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline. Penicillin resistance was independently associated with an urban location when the age of the child was controlled for. Multidrug resistance (resistance to three or more antimicrobial agent groups) was present in 32% of isolates overall but in 39% of isolates with intermediate susceptibility to penicillin and 86% of isolates with penicillin resistance. The predominant serotypes of the S. pneumoniae isolates were 19, 23, 14, 6, and 18. Almost half of the penicillin-resistant isolates serotyped were serotype 23, and these isolates were often multidrug resistant. This study suggests that resistance to penicillin and other antimicrobial agents is common in carriage isolates of S. pneumoniae from children in Vietnam.


Understanding barriers to fruit and vegetable intake in the Australian Longitudinal Study of Indigenous Children: a mixed-methods approach.
To identify barriers to fruit and vegetable intake for Indigenous Australian children and quantify factors related to these barriers, to help understand why children do not meet recommendations for fruit and vegetable intake. We examined factors related to carer-reported barriers using multilevel Poisson models (robust variance); a key informant focus group guided our interpretation of findings. Eleven diverse sites across Australia. Australian Indigenous children and their carers (N 1230) participating in the Longitudinal Study of Indigenous Children. Almost half (45 %; n 555/1230) of carers reported barriers to their children's fruit and vegetable intake. Dislike of fruit and vegetables was the most common barrier, reported by 32·9 % of carers; however, we identified few factors associated with dislike. Carers were more than ten times less likely to report barriers to accessing fruit and vegetables if they lived large cities v. very remote areas. Within urban and inner regional areas, child and carer well-being, financial security, suitable housing and community cohesion promoted access to fruit and vegetables. In this national Indigenous Australian sample, almost half of carers faced barriers to providing their children with a healthy diet. Both remote/outer regional carers and disadvantaged urban/inner regional carers faced problems accessing fruit and vegetables for their children. Where vegetables were accessible, children's dislike was a substantial barrier. Nutrition promotion must address the broader family, community, environmental and cultural contexts that impact nutrition, and should draw on the strengths of Indigenous families and communities.


Dielectric dispersion studies of some potentised homeopathic medicines reveal structured vehicle.
Avogadro's Number gives 12c as the limit beyond which no original substance can be present in a highly diluted and succcussed (potentised) homeopathic medicine, implying that chemically such dilutions consist of nothing but the vehicle. But there is evidence that living systems react to homeopathic medicines diluted even above 12c. To explain how such medicines differ from another I hypothesise that altered structure may cause the difference, such as that between diamond and amorphous carbon. Some scientists have argued that dilution followed by succussion may lead to altered structural arrangement of water molecules. This concept may be termed 'Induced Molecular Structure'. Dielectric dispersion studies were conducted in a broad range with potencies below and above the Avogadro limit by taking 6c and 30c potencies of Graphites and Cuprum Metallicum in liquid form. Measurements were made with an Anomalous Dielectric Dispersion Detector (A3D), an instrument developed by the author. Experiments were carried out in a frequency range of 100 kHz to 50 MHz. Shifting of resonance frequencies as a function of medicine and potency, with potencies below and above the Avogadro limit, was observed. The range of resonance frequencies suggest that the phenomenon might originate from oscillation of dipoles caused by electric field in variously structured and polarised water. Also, there is reasonable evidence that frequencies change with materials and potency.


Cost-effectiveness analysis of systematic fast-track transition from oncological treatment to specialised palliative care at home for patients and their caregivers: the DOMUS trial.
While hospitals remain the most common place of death in many western countries, specialised palliative care (SPC) at home is an alternative to improve the quality of life for patients with incurable cancer. We evaluated the cost-effectiveness of a systematic fast-track transition process from oncological treatment to SPC enriched with a psychological intervention at home for patients with incurable cancer and their caregivers. A full economic evaluation with a time horizon of six months was performed from a societal perspective within a randomised controlled trial, the DOMUS trial ( Clinicaltrials.gov : NCT01885637). The primary outcome of the health economic analysis was a incremental cost-effectiveness ratio (ICER), which is obtained by comparing costs required per gain in Quality-Adjusted Life Years (QALY). The costs included primary and secondary healthcare costs, cost of intervention and informal care from caregivers. Public transfers were analysed in seperate analysis. QALYs were measured using EORTC QLQ-C30 for patients and SF-36 for caregivers. Bootstrap simulations were performed to obtain the ICER estimate. In total, 321 patients (162 in intervention group, 159 in control group) and 235 caregivers (126 in intervention group, 109 in control group) completed the study. The intervention resulted in significantly higher QALYs for patients when compared to usual care (p-value = 0.026), while being more expensive as well. In the 6 months observation period, the average incremental cost of intervention compared to usual care was €2015 per patient (p value < 0.000). The mean incremental gain was 0.01678 QALY (p-value = 0.026). Thereby, the ICER was €118,292/QALY when adjusting for baseline costs and quality of life. For the caregivers, we found no significant differences in QALYs between the intervention and control group (p-value = 0.630). At a willingness to pay of €80,000 per QALY, the probability that the intervention is cost-effective lies at 15% in the base case scenario. This model of fast-track SPC enriched with a psychological intervention yields better QALYs than usual care with a large increase in costs. The trial was prospectively registered 25.6.2013. Clinicaltrials.gov Identifier: NCT01885637 .


Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.
Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell-specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mouse. An Ang1 relative, termed angiopoietin-2 (Ang2), was identified by homology screening and shown to be a naturally occurring antagonist for Ang1 and Tie2. Transgenic overexpression of Ang2 disrupts blood vessel formation in the mouse embryo. In adult mice and humans, Ang2 is expressed only at sites of vascular remodeling. Natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.


Oxidative damage and amyloid-β metabolism in brain regions of the longest-lived rodents.
Naked mole rats (NMRs) are the longest-lived rodents, with young individuals having high levels of Aβ in their brains. The purpose of this study was twofold: to assess the distribution of Aβ in key regions of NMR brains (cortex, hippocampus, cerebellum) and to understand whether the accumulation of Aβ is due to enhanced production or decreased degradation. Recent evidence indicates that lipid peroxides directly participate in induction of cytoprotective proteins, such as heat shock proteins (Hsps), which play a central role in the cellular mechanisms of stress tolerance. Amyloid precursor protein processing, lipid peroxidation, Hsps, redox status, and protein degradation processes were therefore assessed in key NMR brain regions. NMR brains had high levels of lipid peroxidation compared with mice, and the NMR hippocampus had the highest levels of the most toxic moiety of Aβ (soluble Aβ1 - 42 ). This was due not to increased Aβ production but rather to low antioxidant potential, which was associated with low induction of Hsp70 and heme oxygenase-1 as well as low ubiquitin-proteasome activity. NMRs may therefore serve as natural models for understanding the relationship between oxidative stress and Aβ levels and its effects on the brain.


Isolation and characterization of a scFv antibody specific for tumor endothelial marker 1 (TEM1), a new reagent for targeted tumor therapy.
Tumor endothelial marker 1 (TEM1) is a protein predominantly expressed on the cell surface of endothelial cells in newly developing blood vessels and on tumor cells. It is therefore ideally suited as a target for anti-angiogenic tumor therapy. Using phage display technology a single chain antibody fragment (scFv-CM6) was isolated that specifically binds to the extracellular part of TEM1. Antibody specificity was determined in ELISA, by Western analysis, fluorescence microscopy and flow cytometry performed with TEM1-expressing cells. ScFv-CM6 was further functionalized and coupled to liposomes. Such immunoliposomes loaded with the cytotoxic drug N4-octadecyl-1-beta-D-arabinofuranosylcytosine-(5'-5')-3'-C-ethinylcytidine showed increased binding affinity and up to 80% higher cytotoxic activity towards TEM1-expressing IMR-32 tumor cells compared with control liposomes.


Randomised controlled trial of two sequential artemisinin-based combination therapy regimens to treat uncomplicated falciparum malaria in African children: a protocol to investigate safety, efficacy and adherence.
Management of uncomplicated Plasmodium falciparum malaria relies on artemisinin-based combination therapies (ACTs). These highly effective regimens have contributed to reductions in malaria morbidity and mortality. However, artemisinin resistance in Asia and changing parasite susceptibility to ACT in Africa have now been well documented. Strategies that retain current ACT as efficacious treatments are urgently needed. We present an open-label, randomised three-arm clinical trial protocol in three African settings representative of varying malaria epidemiology to investigate whether prolonged ACT-based regimens using currently available formulations can eliminate potentially resistant parasites. The protocol investigates whether a sequential course of two licensed ACT in 1080 children aged 6-120 months exhibits superior efficacy against acute P. falciparum malaria and non-inferior safety compared with standard single-course ACT given to 540 children. The primary endpoint is PCR-corrected clinical and parasitological response at day 42 or day 63 of follow-up. Persistence of PCR-detectable parasitaemia at day 3 is analysed as a key covariate. Secondary endpoints include gametocytaemia, occurrence of treatment-related adverse events in the double-ACT versus single-ACT arms, carriage of molecular markers of drug resistance, drug kinetics and patient adherence to treatment. This protocol addresses efficacy and safety of sequential ACT regimens in P. falciparum malaria in Africa. The approach is designed to extend the useful life of this class of antimalarials with maximal impact and minimal delay, by deploying licensed medicines that could be swiftly implemented as sequential double ACT by National Malaria Control Programmes, before emerging drug resistance in Africa becomes a major threat to public health.


Influence of dietary fat, caloric restriction, and voluntary exercise on N-nitrosomethylurea-induced mammary tumorigenesis in rats.
The effect of dietary fat, energy restriction, and exercise on N-nitrosomethylurea (NMU:CAS:684-93-5)-induced mammary tumorigenesis in female F344 rats was investigated. Rats were fed the NIH-07 diet until N-nitrosomethylurea administration on Day 50 of age, when they were transferred to six treatment groups. Three sedentary groups were fed either high-fat (20%, w/w), medium-fat (10%), or low-fat (5%) diets ad libitum (HFAL, MFAL, LFAL, respectively); two sedentary groups were fed high fat and medium fat diets restricted to 75% of the food consumed by their ad libitum counterparts (HFR, MFR), and one group was fed a HFAL diet but allowed free access to an activity wheel (HFEX). Tumor yields among the three ad libitum sedentary groups were significantly greater in the HFAL and MFAL groups when compared to the LFAL group. Dietary restriction reduced tumor yields by more than 90% of ad libitum controls regardless of fat intake. Voluntary exercise reduced tumor yields and delayed time of tumor appearance in HFEX animals to levels similar to those found in LFAL animals. Animals with voluntary access to exercise wheels averaged between 1.03 and 2.85 miles/day, consumed more food (+18%), and exhibited greater weight gain (+13%) than their sedentary counterparts. Restricted animals exhibited significantly decreased body weight gains (-15%) compared to their ad libitum counterparts, but no differences in weight gains were detected among the HFAL, MFAL, and LFAL groups, despite widely varying amounts of fat intake. Body composition studies indicated that body fat content was not influenced by the quantity of fat consumed in the diet, but was significantly reduced by caloric restriction (-20 to 26%) and exercise (-20%). While the precise mechanisms underlying the tumor-promoting effects of HFAL diets and the antipromoting effects of energy restriction and exercise remain to be elucidated, available evidence suggests that these effects are not due to alterations in energy homeostasis per se, but may instead be exerted indirectly, and perhaps independently via endocrine, paracrine, or neurohormonal mechanisms.


Dose response curves for microwave ablation in the cardioplegia-arrested porcine heart.
Microwave ablation has been used clinically for the surgical treatment of atrial fibrillation, particularly during valve procedures. However, dose- response curves have not been established for this surgical environment. The purpose of this study was to examine dosimetry curves for the Flex 4 and Flex 10 microwave devices in an acute cardioplegia-arrested porcine model. Twelve domestic pigs (40-45 kg) were acutely subjected to Flex 4 (n = 6) and Flex 10 (n = 6) ablations. On a cardioplegically arrested heart maintained at 10-15(o)C, six endocardial atrial and seven epicardial ventricular lesions were created in each animal. Ablations were performed for 15 s, 30 s, 45 s, 60 s, 90 s, 120 s, and 150 s (65 W, 2.45 GHz). The tissue was stained with 2,3,5-triphenyl-tetrazolium chloride and lesions were sectioned at 5 mm intervals. Lesion depth and width were determined from digital photomicrographs of each lesion (resolution +/- .03 mm). Average atrial thickness was 2.88 +/- .4 mm (range 1.0 to 8.0 mm). 94% of ablated atrial sections created by the FLEX 4 (n = 16) and the FLEX 10 (n = 16) were transmural at 45 seconds. 100% of atrial sections were transmural at 90 seconds with the FLEX 10 (n = 14) and at 60 seconds with the Flex 4 device (n = 15). Lesion width and depth increased with duration of application. Both devices were capable of producing transmural lesions on the cardioplegically arrested heart at 65 W. These curves will allow surgeons to ensure transmural ablation by tailoring energy delivery to the specific atrial geometry.


Role of Cx36 gap junction modulation in general anaesthetic anticonvulsant action.
Many GABAergic anaesthetics reduce gap junction coupling but it is currently unknown whether this effect contributes to anaesthetic anticonvulsant action. In this study we examined the possible role of connexin36 gap junctions in the anticonvulsant action of isoflurane and compared this to etomidate, an anaesthetic known for having proconvulsant effects. We compared the effect of anaesthetic concentrations of isoflurane (1 MAC) and etomidate (16 microM) on low-magnesium-induced interictal-like activity in isolated neocortical slices. The effect of connexin36 gap junction blockade was explored by comparing effects in slices from wild-type mice and from a transgenic mouse strain lacking the gene for connexin36. In slices from wild-type mice, both isoflurane (1 MAC) and etomidate (16 microM) reduced interictal-like event frequency; mean(S.D.) reduction of 44(13)% (P<0.0001) and 25(24)% (P<0.0001), respectively. The reduction in event frequency was greater for isoflurane (P<0.005). Isoflurane had no effect on the amplitude of interictal-like events, but event amplitude was enhanced by etomidate (18(28)% increase, P<0.005). The capacity for isoflurane to reduce event frequency was significantly reduced, but not eliminated in slices from connexin36 knock-out mice (33(15)% reduction, P<0.05 for the difference with wild-type), while that of etomidate remained unchanged (23(39)% reduction). The etomidate-mediated increase in event amplitude was eliminated in connexin36 knock-out slices. The results from this study support the hypothesis that the anticonvulsant effect of isoflurane is in part mediated by gap junction blockade. The role of gap junction modulation by etomidate is more complicated and may be important in the mechanism of action of etomidate's proconvulsant effects.


Treatment of severe COVID-19 with convalescent plasma in Bronx, NYC.
Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as a treatment for coronavirus disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who received 200 mL of CCP with a spike protein IgG titer ≥ 1:2430 (median 1:47,385) within 72 hours of admission with propensity score-matched controls cared for at a medical center in the Bronx, between April 13 and May 4, 2020. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroid use, and anticoagulation use. There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared with matched controls, CCP recipients less than 65 years had 4-fold lower risk of mortality and 4-fold lower risk of deterioration in oxygenation or mortality at day 28. For CCP recipients, pretransfusion spike protein IgG, IgM, and IgA titers were associated with mortality at day 28 in univariate analyses. No adverse effects of CCP were observed. Our results suggest CCP may be beneficial for hospitalized patients less than 65 years, but data from controlled trials are needed to validate this finding and establish the effect of aging on CCP efficacy.


Agonist-sensitive calcium stores in arteries from steroid hypertensive rats.
The present study characterizes cellular calcium stores that are sensitive to norepinephrine and caffeine in arteries from deoxycorticosterone acetate hypertensive rats. Mesenteric arteries from normotensive and hypertensive rats were excised and cut into helical strips for isometric force recording. In calcium-free solution, phasic contractile responses to norepinephrine (5.9 x 10(-9) to 5.9 x 10(-6) M), but not caffeine (0.3-30 mM), were greater in hypertensive arteries. D-600, a calcium channel blocker, or removal of the endothelium did not alter phasic contractions to norepinephrine or caffeine. In contrast, contractions to both norepinephrine and caffeine were inhibited by ryanodine, a drug that depletes calcium from intracellular stores. An inhibitor of phospholipase C (2-nitro-4-carboxyphenyl N,N-diphenylcarbamate) attenuated contractions to norepinephrine but not those to caffeine. The augmented response to norepinephrine in hypertensive rats did not occur early after implantation of the mineralocorticoid, suggesting that this vascular change may not play a role in the development of high blood pressure in this experimental model. The augmented response to norepinephrine was reduced in mineralocorticoid-treated rats maintained on a low sodium diet, and these rats had blood pressures in the normotensive range. Because contractile responses to caffeine were not enhanced in arteries from hypertensive rats, we conclude that the cellular store for calcium is not enlarged compared with that in normotensive arteries. In contrast, the mobilization of calcium from cellular stores by norepinephrine is augmented in mineralocorticoid hypertension. This augmented response may be linked to altered phospholipase C activity and thus to an augmented action of inositol trisphosphate that releases calcium from intracellular sites.


The role of point-of-care blood testing for ketones in the diagnosis of diabetic ketoacidosis.
Urine dipstick testing for ketones is widely used when diabetic ketoacidosis (DKA) is suspected in patients with hyperglycaemia. If urinary ketones are positive, patients are referred for further management--often inappropriately, as the test is a poor surrogate for plasma ketones. Plasma beta-hydroxybutyrate (β-OHB) levels>3 mmol/L are diagnostic of DKA, while levels<1 mmol/L are insignificant. To evaluate a hand-held electrochemical (point-of-care testing; POCT) ketone monitor and compare it with the gold-standard manual enzymatic method (MEM) for detection of plasma ketones. In a prospective and comparative study, we evaluated the measurement of β-OHB by means of POCT and the MEM in 61 consecutive samples from patients with suspected DKA at Tygerberg and Karl Bremer hospitals, Cape Town, South Africa. Capillary (for POCT) and plasma samples (for the MEM) were obtained simultaneously and compared for accuracy. Precision was assessed with control samples. The POCT method was precise (coefficient of variation <4.5%), and there was a good correlation between the two methods (r=0.95). Regression analysis showed a proportional bias, with POCT reading higher than the MEM. However, when assessed at the relevant medical decision limits (β-OHB>3 mmol/L and <1 mmol/L), the total allowable error (bias+imprecision) was not exceeded. Patients will therefore still be classified correctly. The POCT method had a sensitivity of 100% and specificity of 89% for DKA (β-OHB>3 mmol/L), while at levels<1 mmol/L sensitivity was 100% and specificity 87.5%. The POCT device provides an accurate and precise result and can be used as an alternative to the MEM in the diagnosis of DKA.


Comparison of conventional color Doppler imaging and power doppler imaging for the diagnosis of ovarian cancer: results of a European study.
The purpose of this prospective study was to compare the diagnostic accuracy of conventional color Doppler (CCD) imaging and power Doppler (PD) imaging in the diagnosis of ovarian cancer. Six hundred fifty-six consecutive women with adnexal masses scheduled for surgery in two European university departments of obstetrics and gynecology underwent preoperative transvaginal ultrasound. The scanning procedure was the same in the two institutions: after B-mode sonography, a CCD/PD imaging scan was performed before pulsed Doppler evaluation. Using both modalities of color Doppler, malignancy was suspected when arterial flow was visualized in an echogenic portion defined as malignant by B-mode. To avoid the risk of bias due to the absence of blindness of the examiner after the first Doppler evaluation, at one institution 328 consecutive women with an adnexal mass were evaluated using only CCD imaging, whereas at the second institution the ultrasonographic evaluation of the same number of masses was performed using PD imaging, and the results were compared prospectively. The age, the rate of postmenopausal women, and the rate of ovarian cancer were similar in the two institutions. The false-positive rate of B-mode imaging was similar in the two institutions (17 versus 18%), while the false-positive rates of CCD and PD imaging were 4.6 and 7.4%, respectively. Although the overall diagnostic accuracy of two techniques seems comparable, with a similar value of K (0.81 versus 0.84), a significantly lower sensitivity in differentiation of benign from malignant ovarian lesions was found using CCD (87 versus 100%). At least one of the two Doppler techniques should be used in conjunction with B-mode imaging in order to decrease the false-positive rate of B-mode used alone but CCD imaging showed a higher false-negative rate.


Granular flow down an inclined plane: Bagnold scaling and rheology.
We have performed a systematic, large-scale simulation study of granular media in two and three dimensions, investigating the rheology of cohesionless granular particles in inclined plane geometries, i.e., chute flows. We find that over a wide range of parameter space of interaction coefficients and inclination angles, a steady-state flow regime exists in which the energy input from gravity balances that dissipated from friction and inelastic collisions. In this regime, the bulk packing fraction (away from the top free surface and the bottom plate boundary) remains constant as a function of depth z, of the pile. The velocity profile in the direction of flow vx(z) scales with height of the pile H, according to vx(z) proportional to H(alpha), with alpha=1.52+/-0.05. However, the behavior of the normal stresses indicates that existing simple theories of granular flow do not capture all of the features evidenced in the simulations.


All-ceramic single-tooth implant reconstructions using modified zirconia abutments: a prospective randomized controlled clinical trial of the effect of pink veneering ceramic on the esthetic outcomes.
The aim of this study was to test whether veneering of the submucosal part of zirconia abutments using pink veneering ceramic positively influences the color of the peri-implant mucosa. Single-tooth implants were restored with either white zirconia abutments (control group) or pink-veneered zirconia abutments and all-ceramic crowns. Esthetic outcome measurements included a spectrophotometric evaluation of the peri-implant mucosal color. Test and control groups induced a visible discoloration of the peri-implant mucosa after the insertion of the abutments and following cementation of the crowns compared to natural teeth. The calculated color differences were above the clinically visible threshold value and were more favorable for the control group, although not statistically significant. It is concluded that veneering of zirconia abutments with pink veneering ceramic failed to positively influence the esthetic outcome, mostly due to a decrease of the brightness compared with the control group.


Biological actions and metabolism of currently used pharmacological agents for the treatment of congestive heart failure.
Congestive heart failure (CHF), a complex clinical syndrome with impaired cardiac pump function, occurs as a consequence of mechanical deformities (pressure and volume overload), myocardial abnormalities (neurohormonal disorders, myocarditis, cardiomyopathies, inflammation and loss of cardiomyocytes) and rhythmic defects (conduction disturbances, fibrillation and tachycardia). Several studies have demonstrated that chronic activation of sympathetic and renin-angiotensin systems, alteration in myocardial substrate utilization, increase in intracellular Ca(2+) concentration, development of oxidative stress, release of pro-inflammatory cytokines and increased production of endothelin are responsible for the maladaptive cardiac and subcellular remodeling depending upon the type and stage of heart failure. A variety of pharmacological agents have been used to prevent the development and progression of CHF under different experimental and clinical settings. Although these drugs belong to specific classes, depending on their mechanism of action, individual drug biotransformation into different metabolites makes them distinct chemical moieties. Thorough understanding of biological effects of these pharmacological agents and metabolism is necessary to establish the basis for their preeminent use in clinical settings. The purpose of this review is to present a mechanistic understanding for the biological activities of different drugs used to treat CHF and to provide an insight of different metabolites formed after biotransformation of these chemical entities. Since development of CHF is a multifactorial and heterogeneous process, induction of combination regimens and improvement in patient compliance are the major challenges for future drug development.


Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia.
Fibromyalgia (FM) is a complex, multi-symptom condition that predominantly affects women. The majority of those affected are unlikely to gain significant symptomatic control from the few treatments that are approved for FM. In this 10-week, single-blind, crossover trial we tested the immune effects of eight weeks of oral administration of low-dose naltrexone (LDN). We enrolled eight women with an average age of 46 years, symptom severity of 62 out of 100, and symptom duration of 14 years. We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF). We also found a 15% reduction of FM-associated pain and an 18% reduction in overall symptoms. The findings of this pilot trial suggest that LDN treatment in fibromyalgia is associated with a reduction of several key pro-inflammatory cytokines and symptoms. The potential role of LDN as an atypical anti-inflammatory medication should be explored further.


Protein kinase D1 (PKD1) activation mediates a compensatory protective response during early stages of oxidative stress-induced neuronal degeneration.
Oxidative stress is a key pathophysiological mechanism contributing to degenerative processes in many neurodegenerative diseases and therefore, unraveling molecular mechanisms underlying various stages of oxidative neuronal damage is critical to better understanding the diseases and developing new treatment modalities. We previously showed that protein kinase C delta (PKCδ) proteolytic activation during the late stages of oxidative stress is a key proapoptotic signaling mechanism that contributes to oxidative damage in Parkinson's disease (PD) models. The time course studies revealed that PKCδ activation precedes apoptotic cell death and that cells resisted early insults of oxidative damage, suggesting that some intrinsic compensatory response protects neurons from early oxidative insult. Therefore, the purpose of the present study was to characterize protective signaling pathways in dopaminergic neurons during early stages of oxidative stress. Herein, we identify that protein kinase D1 (PKD1) functions as a key anti-apoptotic kinase to protect neuronal cells against early stages of oxidative stress. Exposure of dopaminergic neuronal cells to H2O2 or 6-OHDA induced PKD1 activation loop (PKD1S744/748) phosphorylation long before induction of neuronal cell death. Blockade of PKCδ cleavage, PKCδ knockdown or overexpression of a cleavage-resistant PKCδ mutant effectively attenuated PKD1 activation, indicating that PKCδ proteolytic activation regulates PKD1 phosphorylation. Furthermore, the PKCδ catalytic fragment, but not the regulatory fragment, increased PKD1 activation, confirming PKCδ activity modulates PKD1 activation. We also identified that phosphorylation of S916 at the C-terminal is a preceding event required for PKD1 activation loop phosphorylation. Importantly, negative modulation of PKD1 by the RNAi knockdown or overexpression of PKD1S916A phospho-defective mutants augmented oxidative stress-induced apoptosis, while positive modulation of PKD1 by the overexpression of full length PKD1 or constitutively active PKD1 plasmids attenuated oxidative stress-induced apoptosis, suggesting an anti-apoptotic role for PKD1 during oxidative neuronal injury. Collectively, our results demonstrate that PKCδ-dependent activation of PKD1 represents a novel intrinsic protective response in counteracting early stage oxidative damage in neuronal cells. Our results suggest that positive modulation of the PKD1-mediated compensatory protective mechanism against oxidative damage in dopaminergic neurons may provide novel neuroprotective strategies for treatment of PD.