Neuroprotective and neuroregenerative effects of low-intensity aerobic exercise on sciatic nerve crush injury in mice.
Here, we established a program of low-intensity aerobic exercise and compared the effects of exercise preoperative, postoperative, and a combination of both pre- and postoperative protocols on recovery from sciatic nerve crush injury in mice using behavioral, biochemical, and morphological assays. Sciatic nerve crush was performed in adult male mice. The animals were submitted to preoperative (for 2 weeks), postoperative (for 2 weeks), and a combination of preoperative-postoperative (for 4 weeks) training protocols. During the training period, functional recovery was monitored using the Sciatic Functional Index, the Sciatic Static Index, and mechanical and cold hypersensitivity analyses. Morphological and biochemical alterations were analyzed on the 14th day post-crushing. The functional recovery values of all of the exercised groups were significantly better than the nonexercised group. Biochemically, all of the exercise groups showed a reduction in the increase of interleukin-1β (IL-1β) in the sciatic nerve and in the IL-1β and interleukin-6 receptor (IL-6R) levels in the spinal cord. However, the levels of tumor necrosis factor alpha (TNF-α) decreased only in the postoperative group and in the combination exercise protocols. In the morphological analysis, the combination exercise subjects presented an increase in fiber and axon diameter, in the myelination degree and in the number of myelinated fibers. The present study showed that pre- and postoperative exercise achieved values for functional and morphological sciatic nerve regeneration that were significantly better than either the preoperative or postoperative protocols. This experimental study suggests that physical exercise can restore motor and nerve function to a substantial degree when performed using a prophylactic and therapeutic approach.


Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice.
Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. We show here that dietary supplementation with physiologically relevant levels of copper (Cu) reverses preestablished hypertrophic cardiomyopathy caused by pressure overload induced by ascending aortic constriction in a mouse model. The reversal occurs in the continued presence of pressure overload. Sustained pressure overload leads to decreases in cardiac Cu and vascular endothelial growth factor (VEGF) levels along with suppression of myocardial angiogenesis. Cu supplementation replenishes cardiac Cu, increases VEGF, and promotes angiogenesis. Systemic administration of anti-VEGF antibody blunts Cu regression of hypertrophic cardiomyopathy. In cultured human cardiomyocytes, Cu chelation blocks insulin-like growth factor (IGF)-1- or Cu-stimulated VEGF expression, which is relieved by addition of excess Cu. Both IGF-1 and Cu activate hypoxia-inducible factor (HIF)-1alpha and HIF-1alpha gene silencing blocks IGF-1- or Cu-stimulated VEGF expression. HIF-1alpha coimmunoprecipitates with a Cu chaperone for superoxide dismutase-1 (CCS), and gene silencing of CCS, but not superoxide dismutase-1, prevents IGF-1- or Cu-induced HIF-1alpha activation and VEGF expression. Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy at least in part through CCS-mediated HIF-1alpha activation of VEGF expression and angiogenesis.


[Cerebral vasculitis, a diagnostic labyrinth].
- A diagnosis of cerebral vasculitis is frequently considered in patients with new or progressive neurological symptoms for which there is no other explanation.- A clinician considering a diagnosis of cerebral vasculitis should be well aware of alternative diagnoses, since these are generally more common.- Several consecutive examinations are required for diagnosing cerebral vasculitis, because there is no diagnostic procedure that is highly sensitive as well as highly specific.- The added value of the different procedures may depend on the type of blood vessels involved.- Standard MRI examinations are sensitive but not specific.- Special MRI techniques now make it also possible to make images of the vessel wall itself.- Catheter angiography remains important, especially when non-invasive angiographic techniques do not reveal any abnormalities.- Brain biopsy can provide proof of cerebral vasculitis and also serves to exclude mimicking conditions.


The Utility of Measuring Intentions to Use Best Practices: A Longitudinal Study Among Teachers Supporting Students With Autism.
School-based interventions can result in profound social, behavioral, and academic improvement for students with autism, but teachers rarely implement them. It is important to understand why this occurs and use this information to increase the use of evidence-based practices. Toward this goal, 2 proof-of-construct studies demonstrate the theoretical and methodological advantages of measuring behavioral intentions to use specific practices. Two observational studies enrolled public school teachers who work with students with autism. The studies measure the strength of teachers' intentions to use each of 4 different evidence-based practices, assess variability in intentions, and test whether intentions predict future teacher behavior. In adjusted analyses, intentions to use a specific evidence-based practice were strongly associated with subsequent use (adjusted odds ratio = 5.2). The proportion of teachers who reported strong intentions varied from a low of 33% to a high of 66%, depending on the practice. The findings illustrate that the strength of intentions, which varies depending on the specific practice, can predict implementation. More generally, the studies demonstrate how measures of intention can aid efforts to identify implementation barriers. The approach taken can be applied to study implementation of any practices designed to improve student health.


Information-rich localization microscopy through machine learning.
Recent years have witnessed the development of single-molecule localization microscopy as a generic tool for sampling diverse biologically relevant information at the super-resolution level. While current approaches often rely on the target-specific alteration of the point spread function to encode the multidimensional contents of single fluorophores, the details of the point spread function in an unmodified microscope already contain rich information. Here we introduce a data-driven approach in which artificial neural networks are trained to make a direct link between an experimental point spread function image and its underlying, multidimensional parameters, and compare results with alternative approaches based on maximum likelihood estimation. To demonstrate this concept in real systems, we decipher in fixed cells both the colors and the axial positions of single molecules in regular localization microscopy data.


Test to Protect Family and Self-A Hepatitis B Screening and Care-Linkage Initiative in the Coastal Mississippi Vietnamese Community.
Although Asian Americans and Pacific Islanders represent less than 5% of the U.S. population, they represent approximately half of all people living with chronic hepatitis B virus (HBV). Harrison, Hancock, and Jackson counties are home to the largest portion of Vietnamese individuals in Mississippi, and have high prevalence rates of HBV. Most people living with HBV do not know they are infected. In 2015, Mississippi State Department of Health began a five-year initiative to implement system-level, evidence-based, community-informed strategies to address HBV in the Vietnamese population of Harrison, Hancock, and Jackson Counties of Mississippi's Gulf Coast region. Presented are results from focus groups conducted with the Vietnamese population that define health issues affecting the Vietnamese community, health care services availability, and knowledge, beliefs, and attitudes regarding HBV and screening. Findings from the focus groups were used to develop a culturally and linguistically tailored HBV screening and care-linkage initiative for the prioritized population.


Antibody technology in proteomics.
Today's proteomic analyses are generating increasing numbers of biomarkers, making it essential to possess highly specific probes able to recognize those targets. Antibodies are considered to be the first choice as molecular recognition units due to their target specificity and affinity, which make them excellent probes in proteomics. In the post-genomic era and with high-throughput techniques available, the goal is to discriminate between all individual proteins from the proteome including their splice variants and post-translationally modified derivatives. Aided by advances in generation, selection and engineering of antibody-based recognition units, antibody fragments provide tools for detection of high- as well as low-abundant analytes even in complex, non-fractionated proteomes in conjunction with usage of small amounts of samples and reagents. In addition, large consortia aim at generating vast numbers of antibody-based recognition units suitable for future diagnostics and therapeutics.


Mediation Analyses of the Mechanisms by Which Socioeconomic Status, Comorbidity, Stroke Severity, and Acute Care Influence Stroke Outcome.
Low socioeconomic status (SES) is associated with increased risk of death and disability after stroke, but interventional targets to minimize disparities remain unclear. We aim to assess the extent to which SES-based disparities in the association between low SES and death and dependency at 3 months after stroke could be eliminated by offsetting differences in comorbidity, stroke severity, and acute care. This nationwide register-based cohort study included all 72 hospitals caring for patients with acute stroke in Sweden. All patients registered with an acute ischemic stroke in the Swedish Stroke Register in 2015-2016 who were independent in activities of daily living (ADL) during stroke were included. Data on survival and SES the year before stroke were retrieved by cross-linkage with other national registers. SES was defined by education and income and categorized into low, mid, and high. Causal mediation analysis was used to study the absolute risk of death and ADL dependency at 3 months depending on SES and to what extent hypothetical interventions on comorbidities, stroke severity, and acute care would equalize outcomes. Of the 25,846 patients in the study, 6,798 (26.3%) were dead or ADL dependent 3 months after stroke. Adjusted for sex and age, low SES was associated with an increased absolute risk of 5.4% (95% CI 3.9%-6.9%; p < 0.001) compared with mid SES and 10.1% (95% CI 8.1%-12.2%; p < 0.001) compared with high SES. Intervening to shift the distribution of all mediators among patients with low SES to those of the more privileged groups would result in absolute reductions of these effects by 2.2% (95% CI 1.2%-3.2%; p < 0.001) and 4.0% (95% CI 2.6%-5.5%; p < 0.001), respectively, with the largest reduction accomplished by equalizing stroke severity. Low SES patients have substantially increased risks of death and ADL dependency 3 months after stroke compared with more privileged patient groups. This study suggests that if we could intervene to equalize SES-related differences in the distributions of comorbidity, acute care, and stroke severity, up to 40 of every 1,000 patients with low SES could be prevented from dying or becoming ADL dependent.


The effects of various dietary levels of phytase and available phosphorus on performance of laying hens.
Data previously obtained from our laboratory indicated that addition of 300 U of phytase/kg diet supported optimal long-term performance of laying hens (20 to 70 wk) fed a corn-soybean meal (SBM) diet containing 0.10% available phosphorus (AP). Our primary objective was to determine if a phytase level lower than 300 units/kg is adequate for a commercial strain of Single Comb White Leghorn laying hens (n = 504) fed a corn-SBM diet containing no supplemental P (0.10% AP). Dietary treatments consisted of the corn-SBM basal diet (0.10% AP, 3.8% Ca, and 17% CP) supplemented with 0, 100, 200, 250, or 300 U of phytase/kg, 0.05% inorganic P (0.15% AP), and a positive control diet containing 0.45% AP. Each of the seven dietary treatments was fed to six replicate groups of 12 hens from 20 to 60 wk of age. No significant differences in performance were observed among treatments during the first 8 wk of the experiment. By 28 wk of age, the 0.10% AP diet, with no supplemental phytase or P, resulted in significantly lower (P < 0.05) egg production and body weight compared with all other dietary treatments. Feed consumption, feed efficiency, and egg yield were subsequently depressed by 32 wk of age in hens fed the 0.10% AP diet. No other significant differences among treatments were observed for performance averaged over the entire 40-wk experimental period. The mean daily AP intake of hens fed the 0.15% AP, 0.45% AP, and 0.10% AP + phytase diets was 155, 474, and 103 mg, respectively. The results of this study indicate that phytase improves the utilization of P in corn-SBM diets for laying hens and that corn-SBM diets containing 0.10% AP + 100 units of phytase/kg diet or 0.15% AP supported egg production performance that was not significantly different (P > 0.05) from that of hens fed a corn-SBM diet containing 0.45% AP.


The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.
Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.


Non-equilibrium cation distribution and enhanced spin disorder in hollow CoFe2O4 nanoparticles.
We present magnetic properties of hollow and solid CoFe(2)O(4) nanoparticles that were obtained by annealing of Co(33)Fe(67)/CoFe(2)O(4) (core/shell) nanoparticles. Hollow nanoparticles were polycrystalline whereas the solid nanoparticles were mostly single crystal. Electronic structure studies were performed by photoemission which revealed that particles with hollow morphology have a higher degree of inversion compared to solid nanoparticles and the bulk counterpart. Electronic structure and the magnetic measurements show that particles have uncompensated spins. Quantitative comparison of saturation magnetization (M(S )), assuming bulk Néel type spin structure with cationic distribution, calculated from quantitative XPS analysis, is presented. The thickness of uncompensated spins is calculated to be significantly large for particles with hollow morphology compared to solid nanoparticles. Both morphologies show a lack of saturation up to 7 T. Moreover magnetic irreversibility exists up to 7 T of cooling fields for the entire temperature range (10-300 K). These effects are due to the large bulk anisotropy constant of CoFe(2)O(4) which is the highest among the cubic spinel ferrites. The effect of the uncompensated spins for hollow nanoparticles was investigated by cooling the sample in large fields of up to 9 T. The magnitude of horizontal shift resulting from the unidirectional anisotropy was more than three times larger than that of solid nanoparticles. As an indication signature of uncompensated spin structure, 11% vertical shift for hollow nanoparticles is observed, whereas solid nanoparticles do not show a similar shift. Deconvolution of the hysteresis response recorded at 300 K reveals the presence of a significant paramagnetic component for particles with hollow morphology which further confirms enhanced spin disorder.


Surface plasmon resonance sensor for domoic acid based on grafted imprinted polymer.
A molecularly imprinted polymer (MIP) film for domoic acid (DA) was synthesised by direct photo-grafting onto a gold chip suitable for a surface plasmon resonance (SPR) based bioanalytical instrument system, the BIAcore 3000. The gold surface was first functionalised with a self-assembled monolayer of 2-mercaptoethylamine and subsequent carbodiimide chemistry was performed for covalent attachment of the photoinitiator, 4,4'-azobis(cyanovaleric acid). This ensured that the formation of the MIP thin film, comprising 2-(diethylamino) ethyl methacrylate as functional monomer and ethylene glycol dimethacrylate as cross-linker, occurred only at the surface level. Optimisation and control over the grafting procedure were achieved using contact angle measurements and atomic force microscope (AFM) imaging. The surface grafting resulted in the formation of thin and homogeneous MIP film with thickness of 40 nm. A competitive binding assay was performed with free DA and its conjugate with horseradish peroxidase, which was used as a refractive label. The sensor was evaluated for its sensitivity, cross-reactivity, and robustness by using a BIAcore 3000. Likewise, monoclonal antibodies acting as natural receptors for the toxin were studied with the same BIAcore system. Results of a comparison between the artificial and natural receptors are reported. In contrast to monoclonal antibodies, the regeneration of MIP chip did not affect its recognition properties and continuous measurement was possible over a period of at least 2 months.


Prevalance of obesity and overweight in northeastern peninsular Malaysia and their relationship with cardiovascular risk factors.
Height and body weight were measured in 2,284 subjects over 20 years old. The subjects were chosen by cluster sampling in 9 districts of Kelantan. Blood was drawn after an overnight fast for measurement of cholesterol (chol), triglyceride (TG), VLDL and HDL-Chol. Oral glucose tolerance test was performed with 75 g glucose. The overall prevalence of overweight [BMI (kg/m2) > or = 25-< or = 30] and obesity (BMI > 30) was 21.3% and 4.5% respectively. The overweight and obese were significantly younger than the lean subjects. The prevalence of hypercholesterolemia (chol > 5.2 mmol/l) in lean, overweight and obese subjects was 65.3%, 70.2% and 74.7%, respectively. Impaired glucose tolerance was found in 16.6% of the lean, 21.6% of the overweight and 32.0% of the obese subjects. Diabetes mellitus was found in 7.9% of the lean, 10.5% of the overweight and 6.7 of the obese subjects. 10.1% of lean, 13.2% of overweight and 23.3% of obese individuals were hypertensive. In conclusion, the high prevalence of overweight and obesity in Malaysia was associated with adverse lipid and glucose metabolism as well as poor blood pressure control.


Inhibition of allorecognition by a human class II MHC-derived peptide through the induction of apoptosis.
The interaction of the T-cell receptor with the major histocomatibility complex (MHC)-peptide complex is central to T-cell activation. Variation in the nature of the peptide bound within the groove of the MHC molecule may result in an altered T-cell response. Because some naturally processed peptides bound within the groove of the class II MHC molecule are derived from the MHC molecules themselves, we studied the inhibitory effects of synthetic class II MHC peptides on alloimmune responses in vitro. Three peptides derived from a highly conserved region of the class II MHC alpha chains inhibited the rat mixed lymphocyte response (MLR) in a dose-dependent manner, with the human HLA-DQA1 peptide also inhibiting the human and mouse MLR. No effect was seen on mitogen-induced T-cell proliferation. HLA-DQA1 inhibited cytolytic T lymphocyte (CTL) generation in a dose-response fashion, with no reduction in preformed CTL killing, suggesting that the inhibitory effect is targeted at CD4(+) T-cell function. Cell-cycle analysis by flow cytometry showed that restimulation of primed T cells in the presence of HLA-DQA1 resulted in increased apoptosis, whereas unstimulated cells were not affected. These data demonstrate that synthetic peptides derived from highly conserved regions of the class II MHC alpha chain can alter CD4(+) T-lymphocyte alloimmune responses in vitro, and this effect is mediated by the induction of apoptosis in activated T cells.


Exploring the geospatial epidemiology of breast cancer in Iran: identifying significant risk factors and spatial patterns for evidence-based prevention strategies.
Breast Cancer (BC) is a formidable global health challenge, and Iran is no exception, with BC accounting for a significant proportion of women's malignancies. To gain deeper insights into the epidemiological characteristics of BC in Iran, this study employs advanced geospatial techniques and feature selection methods to identify significant risk factors and spatial patterns associated with BC incidence. Using rigorous statistical methods, geospatial data from Iran, including cancer-related, sociodemographic, healthcare infrastructure, environmental, and air quality data at the provincial level, were meticulously analyzed. Age-standardized incidence rates (ASR) are calculated, and different regression models are used to identify significant variables associated with BC incidence. Spatial analysis techniques, including global and local Moran's index, geographically weighted regression, and Emerging hotspot analysis, were utilized to examine geospatial patterns, identify clustering and hotspots, and assess spatiotemporal distribution of BC incidence. The findings reveal that BC predominantly affects women (98.03%), with higher incidence rates among those aged 50 to 79. Isfahan (ASR = 26.1) and Yazd (ASR = 25.7) exhibit the highest rates. Significant predictors of BC incidence, such as marriage, tertiary education attainment rate, physician-to-population ratio, and PM2.5 air pollution, are identified through regression models. The study's results provide valuable information for the development of evidence-based prevention strategies to reduce the burden of BC in Iran. The findings underscore the importance of early detection, health education campaigns, and targeted interventions in high-risk clusters and adjacent regions. The geospatial insights generated by this study have implications for policy-makers, researchers, and public health practitioners, facilitating the formulation of effective BC prevention strategies tailored to the unique epidemiological patterns in Iran.


Nuclear pore disassembly from endoplasmic reticulum membranes promotes Ca2+ signalling competency.
The functionality of the endoplasmic reticulum (ER) as a Ca(2+) storage organelle is supported by families of Ca(2+) pumps, buffers and channels that regulate Ca(2+) fluxes between the ER lumen and cytosol. Although many studies have identified heterogeneities in Ca(2+) fluxes throughout the ER, the question of how differential functionality of Ca(2+) channels is regulated within proximal regions of the same organelle is unresolved. Here, we studied the in vivo dynamics of an ER subdomain known as annulate lamellae (AL), a cytoplasmic nucleoporin-containing organelle widely used in vitro to study the mechanics of nuclear envelope breakdown. We show that nuclear pore complexes (NPCs) within AL suppress local Ca(2+) signalling activity, an inhibitory influence relieved by heterogeneous dissociation of nucleoporins to yield NPC-denuded ER domains competent at Ca(2+) signalling. Consequently, we propose a novel generalized role for AL - reversible attenuation of resident protein activity - such that regulated AL (dis)assembly via a kinase/phosphatase cycle allows cells to support rapid gain/loss-of-function transitions in cellular physiology.


Transforming growth factor-beta1-regulated proteins in human endothelial cells identified by two-dimensional gel electrophoresis and mass spectrometry.
Transforming growth factor-beta (TGFbeta) is a potent regulator of angiogenesis affecting proliferation, differentiation and migration of endothelial cells. The effect of TGFbeta on endothelial cells depends on the origin of the cells and on the experimental conditions. Global analysis of TGFbeta signalling is expected to unveil mechanisms of this variability and identify novel targets of the growth factor. Here, we report proteome profiling of human microvascular endothelial cells obtained from dermis, which were treated with TGFbeta1 and compared to nontreated cells. We identified 54 proteins affected by TGFbeta1 using two-dimensional gel electrophoresis and peptide mass fingerprinting. Thirteen of the identified proteins are involved in various signalling processes. Seven proteins are involved in cytoskeleton rearrangements and six are involved in regulation of metabolism. Ten proteins were identical to predicted hypothetical proteins with no assigned functions. In agreement with the effect of TGFbeta1 on components of the cytoskeleton, TGFbeta1 induces actin cytoskeleton rearrangements. TGFbeta1 also affected expression of E2F6, p57Kip2, G(q)alpha, hnRNP A1 and myosin light chain proteins as shown by immunoblotting. Down-regulation of the transcriptional repressor E2F6 by TGFbeta1 correlated with a weak growth-inhibitory activity of TGFbeta1 on HMVEC-d cells. Twenty-five of the identified proteins have not previously been described as being regulated by TGFbeta1, providing new insights into TGFbeta1 signalling in endothelial cells.


'WNT-er is coming': WNT signalling in chronic lung diseases.
Chronic lung diseases represent a major public health problem with only limited therapeutic options. An important unmet need is to identify compounds and drugs that target key molecular pathways involved in the pathogenesis of chronic lung diseases. Over the last decade, there has been extensive interest in investigating Wingless/integrase-1 (WNT) signalling pathways; and WNT signal alterations have been linked to pulmonary disease pathogenesis and progression. Here, we comprehensively review the cumulative evidence for WNT pathway alterations in chronic lung pathologies, including idiopathic pulmonary fibrosis, pulmonary arterial hypertension, asthma and COPD. While many studies have focused on the canonical WNT/β-catenin signalling pathway, recent reports highlight that non-canonical WNT signalling may also significantly contribute to chronic lung pathologies; these studies will be particularly featured in this review. We further discuss recent advances uncovering the role of WNT signalling early in life, the potential of pharmaceutically modulating WNT signalling pathways and highlight (pre)clinical studies describing promising new therapies for chronic lung diseases.


Metacognition and learning transfer under uncertainty.
This study examined the possible correlation between metacognition and learning experience transfer of nursing students after engaging in an urgent and cognitively demanding clinical situation. This is a one-group post-test- only study design in which participants engaged in an emergency care scenario simulation and completed the Meta-Cognitive Awareness Scale - Domain Specific (MCAS-DS). Study results revealed that participants' metacognitive awareness is significantly correlated to the learning transfer (p=0.0001) and GPA (p=0.006). There is also a positive correlation between learning transfer and GPA (p=0.04), clinical settings-based training experience (p=0.021) and metacognitive confidence (p=0.0001). This study may imply that academic achievement can be used as a potential screening tool to identify students requiring metacognitive training. It may also imply that metacognitive abilities can be enhanced indirectly through considering factors that may influence the transfer of learning such as increasing the hours of clinical training.


Quality of life and response of negative symptoms in schizophrenia to haloperidol and the atypical antipsychotic remoxipride. The Canadian Remoxipride Group.
In a large, multicenter, double-blind study of the effect of haloperidol and the atypical antipsychotic remoxipride on improvement of negative symptoms in schizophrenia, quality of life was also assessed using a modified version of the Sickness Impact Profile (SIP). Compared with previous studies, this study had a longer duration (28 weeks), and the dose of the comparator, haloperidol, was much lower. At the end of the study, compared with the baseline, both treatment groups reported comparable improvement in negative symptoms as defined by the protocol (at least 20% improvement). Similarly, both groups showed comparable changes on global and multidimensional self-assessments of quality of life. All the subfactors of the modified version of the SIP were similar in both groups, except for the subfactor that relates to alertness behavior, which possibly reflects remoxipride's lack of any sedating properties compared with haloperidol. This study presents an approach for inclusion of quality of life as an outcome measure in the design of clinical trials of new antipsychotic medications.


Surgical management of incidentally discovered diffusely infiltrating low-grade glioma.
OBJECTIVE Occasionally, diffusely infiltrating low-grade gliomas (LGGs) are identified as incidental findings in patients who have no signs or symptoms that can be ascribed to the tumors. The diagnosis of incidental, asymptomatic LGGs has become more frequent due to the vast increase in access to medical imaging technology. While management of these lesions remains controversial, early surgery has been suggested to improve outcome. The authors set out to identify and review the characteristics and surgical outcomes of patients who underwent surgical intervention for incidental LGG. METHODS All cases of LGG surgically treated between 2004 and 2016 at the authors' institution were analyzed to identify those that were discovered incidentally. Patients with incidentally discovered LGGs were identified, and their cases were retrospectively reviewed. An "incidental" finding was defined as an abnormality on imaging that was obtained for a reason not attributable to the glioma, such as trauma, headache, screening, or research participation. Kaplan-Meier analysis was performed to determine actuarial rates of overall survival, progression-free survival, and malignant progression-free survival. RESULTS In 34 (6.8%) of 501 adult patients who underwent surgery for LGG, the tumors were discovered incidentally. Headache (26%, n = 9) and screening (21%, n = 7) were the most common indications for brain imaging in this group. Four of these 34 patients had initial biopsy after the tumor was identified on imaging. In 5 cases, the patients opted for immediate resection; the remaining cases were managed with a "watch-and-wait" approach, with intervention undertaken only after radiological or clinical evidence of disease progression. The mean duration of follow-up for all 34 cases was 5 years. Twelve patients (35.3%) had disease progression, with an average time to progression of 43.8 months (range 3-105 months). There were 5 cases (14.7%) of malignant progression and 4 deaths (11.8%). Oligodendroglioma was diagnosed in 16 cases (47%) and astrocytoma in 15 (44%). Twenty-five patients (74%) had IDH1 mutation and demonstrated prolonged survival. Only 2 patients had mild surgery-related complications, and 16 patients (47%) developed epilepsy during the course of the disease. CONCLUSIONS In this retrospective analysis of cases of incidentally discovered LGGs, the tumors were surgically removed with minimal surgical risk. In patients with incidental LGGs there is improved overall survival relative to median survival for patients with symptomatic LGGS, which is likely attributable to the underlying favorable biology of the disease indicated by the presence of IDH1 mutation in 74% of the cases.


Non-pharmacological intervention for gastro-oesophageal reflux disease in primary care.
Up to 50% of patients with gastro-oesophageal reflux disease (GORD) have persistent symptoms despite taking proton pump inhibitors (PPIs) regularly. Lifestyle advice is available to patients, but no previous UK study has tested a behavioural change intervention to help patients self-manage their symptoms. To determine whether a primary care, nurse-led intervention to address behaviours that promote GORD symptoms results in symptom improvement, an increased sense of control, and a reduced requirement for prescribed medication. A group intervention focusing on diet and stress was delivered to patients with reflux symptoms, recruited in rural general practices. General practice in England. Forty-two subjects (male 19, female 23) aged 31-86 years took part. Pre- and post-intervention data were gathered using the Brief Illness Perception Questionnaire (BIPQ), the GORD Impact Scale (GIS), and the Hospital Anxiety and Depression Scale (HAD). There was a significant improvement (BIPQ P<0.001, GIS P = 0.008) 3 months after the intervention. There was no reduction in PPI use or change in HAD score. The greatest improvements were demonstrated in domains measuring the patient's sense of control, perception of symptoms, and understanding of reflux. Patients reported benefits including understanding relevant anatomy and physiology, learning behavioural techniques to change eating patterns and manage stress, identifying actual and potential triggers, and developing and executing action plans. An education programme for GORD enhances self-management, brings perceived symptom improvement, and promotes a sense of control at 3 months. This type of behavioural intervention, alongside medical management, could improve symptom control for reflux patients with refractory symptoms and should be the subject of a controlled trial.


Curcumin, demethoxycurcumin, and bisdemethoxycurcumin induced caspase-dependent and -independent apoptosis via Smad or Akt signaling pathways in HOS cells.
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and has also been associated with a high degree of malignancy and enhanced metastatic capacity. Curcumin (CUR) is well known for its anti-osteosarcoma activity. However, both demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are natural curcumin analogues/congeners from turmeric whose role in osteosarcoma development remains unknown. To evaluate the growth inhibitory effects of CUR, DMC and BDMC on osteosarcoma (HOS and U2OS), breast (MDA-MB-231), and melanoma (A2058) cancer cells, we employed the MTT assay, annexin V-FITC /7-AAD staining, and clonogenic assay. CUR,DMC, and BDMC all decreased the viability of HOS, U2OS, MDA-MB-231, and A2058 cancer cells. Additionally, CUR,DMC, and BDMC induced the apoptosis of HOS cells through activation of Smad 2/3 or repression of Akt signaling pathway. Furthermore, the combination of CUR,DMC, and BDMC synergistically reduced cell viability, colony formation and increased apoptosis than either two or a single agent in HOS cells. The combination of these three compounds could be used as a novel target for the treatment of osteosarcoma.


Sinogram restoration in computed tomography with an edge-preserving penalty.
With the goal of producing a less computationally intensive alternative to fully iterative penalized-likelihood image reconstruction, our group has explored the use of penalized-likelihood sinogram restoration for transmission tomography. Previously, we have exclusively used a quadratic penalty in our restoration objective function. However, a quadratic penalty does not excel at preserving edges while reducing noise. Here, we derive a restoration update equation for nonquadratic penalties. Additionally, we perform a feasibility study to extend our sinogram restoration method to a helical cone-beam geometry and clinical data. A restoration update equation for nonquadratic penalties is derived using separable parabolic surrogates (SPS). A method for calculating sinogram degradation coefficients for a helical cone-beam geometry is proposed. Using simulated data, sinogram restorations are performed using both a quadratic penalty and the edge-preserving Huber penalty. After sinogram restoration, Fourier-based analytical methods are used to obtain reconstructions, and resolution-noise trade-offs are investigated. For the fan-beam geometry, a comparison is made to image-domain SPS reconstruction using the Huber penalty. The effects of varying object size and contrast are also investigated. For the helical cone-beam geometry, we investigate the effect of helical pitch (axial movement/rotation). Huber-penalty sinogram restoration is performed on 3D clinical data, and the reconstructed images are compared to those generated with no restoration. We find that by applying the edge-preserving Huber penalty to our sinogram restoration methods, the reconstructed image has a better resolution-noise relationship than an image produced using a quadratic penalty in the sinogram restoration. However, we find that this relatively straightforward approach to edge preservation in the sinogram domain is affected by the physical size of imaged objects in addition to the contrast across the edge. This presents some disadvantages of this method relative to image-domain edge-preserving methods, although the computational burden of the sinogram-domain approach is much lower. For a helical cone-beam geometry, we found applying sinogram restoration in 3D was reasonable and that pitch did not make a significant difference in the general effect of sinogram restoration. The application of Huber-penalty sinogram restoration to clinical data resulted in a reconstruction with less noise while retaining resolution. Sinogram restoration with the Huber penalty is able to provide better resolution-noise performance than restoration with a quadratic penalty. Additionally, sinogram restoration with the Huber penalty is feasible for helical cone-beam CT and can be applied to clinical data.


Single-cell detection of mRNA expression using nanofountain-probe electroporated molecular beacons.
New techniques for single-cell analysis enable new discoveries in gene expression and systems biology. Time-dependent measurements on individual cells are necessary, yet the common single-cell analysis techniques used today require lysing the cell, suspending the cell, or long incubation times for transfection, thereby interfering with the ability to track an individual cell over time. Here a method for detecting mRNA expression in live single cells using molecular beacons that are transfected into single cells by means of nanofountain probe electroporation (NFP-E) is presented. Molecular beacons are oligonucleotides that emit fluorescence upon binding to an mRNA target, rendering them useful for spatial and temporal studies of live cells. The NFP-E is used to transfect a DNA-based beacon that detects glyceraldehyde 3-phosphate dehydrogenase and an RNA-based beacon that detects a sequence cloned in the green fluorescence protein mRNA. It is shown that imaging analysis of transfection and mRNA detection can be performed within seconds after electroporation and without disturbing adhered cells. In addition, it is shown that time-dependent detection of mRNA expression is feasible by transfecting the same single cell at different time points. This technique will be particularly useful for studies of cell differentiation, where several measurements of mRNA expression are required over time.


Troika of single particle tracking programing: SNR enhancement, particle identification, and mapping.
Single particle tracking (SPT) techniques provide a microscopic approach to probe in vivo and in vitro structure and reactions. Automatic analysis of SPT data with high efficiency and accuracy spurs the development of SPT algorithms. In this perspective, we review a range of available techniques used in SPT analysis programs. In addition, we present an example SPT program step-by-step to provide a guide so that researchers can use, modify, and/or write a SPT program for their own purposes.


Generalized sarcoidosis in two horses.
Equine sarcoidosis is a rare disorder usually characterized by exfoliative dermatitis, moderate to severe wasting, and sarcoidal granulomatous inflammation of multiple organ systems. It has an unknown aetiopathogenesis. The condition is not related to equine sarcoid. This case report describes generalized cutaneous and systemic sarcoidosis in an 11-year-old Trakehner mare (case A) and in a 7-year-old Dutch Warmblood gelding (case B). Case A was presented with cutaneous sarcoidosis on the head and body and was diagnosed on the basis of histological examination of skin. Case B presented with multiple subcutaneous nodules (2-15 cm in diameter) and the diagnosis was established at postmortem examination. Both horses showed distinctive histology of the skin with extensive lymphohistiocytic infiltration and Langhans-type multinucleated giant cells. Haematology and biochemistry revealed a normal total white blood cell count with a right shift in both horses. Case B was anaemic and had a slightly elevated total protein concentration with hyperglobulinaemia. Both horses were unresponsive to corticosteroids and were euthanized.


Vulvar melanoma: an analysis of prognostic factors and treatment patterns.
Melanoma comprises 5% to 10% of vulvar cancers and prognosis is poor. The purpose of this study was to identify prognostic factors and treatment patterns for vulvar melanoma using the National Cancer Database (NCDB). The NCDB was queried for patients with invasive vulvar melanoma from 2004-2015. Descriptive statistics were generated to describe clinical and treatment details. Multivariable Cox regression and the Kaplan-Meier method were used to examine overall survival (OS). 1,917 patients with vulvar melanoma met inclusion criteria. Median follow-up time was 32 months (range, 0-151 months). Older age, larger tumor size, advanced disease stage, increased Charlson-Deyo comorbidity score, and care at a non-academic center were independent predictors for decreased OS. Surgical management of the primary site, lymph node surgery, and insurance provided a significant survival benefit. Use of immunotherapy for vulvar melanoma has increased over time. Two-year OS with immunotherapy in patients with distant metastatic disease was higher, although this did not reach statistical significance (33% vs. 12%, p=0.054). Vulvar melanoma has a poor prognosis for those with regional and distant metastatic disease. Extent of disease, tumor size, and patient age are important prognostic factors. Other favorable factors included insurance and surgical management. The use of immunotherapy has increased over time and may improve survival in those with distant disease. These data support further investigation into the role of immunotherapy for vulvar melanoma to optimize outcomes.


Stimulation of rat liver glycogenolysis by vitamin B6: a role for adrenal catecholamines.
The administration of a single, 100-300 mg/kg ip, dose of a B6 vitamer to rats resulted in an almost immediate and gradual mobilization of the liver glycogen and a concomitant elevation of the serum glucose, with the order of potency being pyridoxal greater than pyridoxamine greater than pyridoxine. Since the B6 vitamer also stimulated the secretion of adrenal catecholamines and the accumulation of liver cAMP, and a pretreatment with selected blocking agents conferred significant protection against the glycogen depletion in the order of potency propranolol + phentolamine greater than propranolol greater than verapamil greater than phentolamine, a role for an adrenomedullary catecholamine-stimulated, beta-adrenoceptor-mediated, activation of the glycogen cascade system was suggested. This assumption was confirmed by verifying pyridoxal to possess virtually no effect on the liver glycogen of adrenalectomized rats.


Oncogenesis in HIV-infection.
The presence of human Kaposi's sarcoma associated herpesvirus-like sequences (KSHV) was examined in different epidemiological variants of Kaposi's sarcoma (KS) and in KS-derived cell cultures by polymerase chain reaction (PCR). KSHV DNA was present in all tumor biopsies of AIDS-associated KS (59 biopsies), endemic KS (26 biopsies; 21 African endemic KS, 5 Greek endemic KS), sporadic/classical KS (28 biopsies) and post-transplant/iatrogenic KS (6 of 7 biopsies). On the contrary, these sequences were only detected rarely in non-involved skin of KS patients (3 positive specimens of 12), in the peripheral blood mononuclear cells of HIV-infected patients (3 positive specimens of 54) and in lymphoma-biopsies (3 positive specimens of 47). Cell cultures derived from KS skin lesions were positive for KSHV DNA only in the first two passages. However, two longer-term positive cultures from a biopsy of a patient affected with sporadic KS and a biopsy of a patient affected with epidemic KS was identified. A strong association of KSHV with KS tissue was observed in all the different epidemiological variants of KS. Long-term positive KS-derived cell cultures will be an important tool to study the herpesvirus-like agent and to investigate its functional role in the initiation and progression of KS.


Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
Studies of yeast have shown that the SIR2 gene family is involved in chromatin structure, transcriptional silencing, DNA repair, and control of cellular life span. Our functional studies of human SIRT2, a homolog of the product of the yeast SIR2 gene, indicate that it plays a role in mitosis. The SIRT2 protein is a NAD-dependent deacetylase (NDAC), the abundance of which increases dramatically during mitosis and is multiply phosphorylated at the G(2)/M transition of the cell cycle. Cells stably overexpressing the wild-type SIRT2 but not missense mutants lacking NDAC activity show a marked prolongation of the mitotic phase of the cell cycle. Overexpression of the protein phosphatase CDC14B, but not its close homolog CDC14A, results in dephosphorylation of SIRT2 with a subsequent decrease in the abundance of SIRT2 protein. A CDC14B mutant defective in catalyzing dephosphorylation fails to change the phosphorylation status or abundance of SIRT2 protein. Addition of 26S proteasome inhibitors to human cells increases the abundance of SIRT2 protein, indicating that SIRT2 is targeted for degradation by the 26S proteasome. Our data suggest that human SIRT2 is part of a phosphorylation cascade in which SIRT2 is phosphorylated late in G(2), during M, and into the period of cytokinesis. CDC14B may provoke exit from mitosis coincident with the loss of SIRT2 via ubiquitination and subsequent degradation by the 26S proteasome.


The influence of physical environmental qualities on the social climate of supported housing facilities for people with severe mental illness.
The study investigates the extent to which the perceived physical environmental quality of housing facilities for people with severe mental illness accounts for perceived social environmental quality. Twenty facilities were assessed by people with psychiatric disabilities (residents), staff, and experts with regard to the physical environmental aspects of visual pleasantness, indirect environmental effects, overall physical quality, and the social environmental indicator of social relationship. The results suggest that residents' and staff's physical environmental quality perception accounts for social relationship quality perception, whereas experts' environmental assessment does not. Moreover, the staff reported a more positive social relationship perception than the residents.


Anti- and pro-oxidative mechanisms comparing the macular carotenoids zeaxanthin and lutein with other dietary carotenoids - a singlet oxygen, free-radical in vitro and ex vivo study.
The interactions of dietary carotenoids, and particularly the xanthophylls in the macula, with singlet oxygen and three different oxy-radicals, (hydroxyl radical, nitrogen dioxide and the superoxide radical anion) are compared using pulsed laser and γ-techniques. The results give possible molecular mechanisms for the switch from anti-oxidant (protection) by carotenoids to pro-oxidant (damage) by carotenoids. The participation of oxygen in radical mechanisms in the presence of different carotenoids is compared for the different radicals. It is shown that the mechanistic role of oxygen differs very significantly for anti-/pro-oxidation by hydroxyl radicals when compared to nitrogen dioxide. Lutein was found to be an extremely good cell protector against hydroxyl radicals at all oxygen concentrations, including under physiological conditions.


The confounding effect of biological maturity on talent identification and selection within youth Australian football.
This study measured the influence of biological maturity across numerous performance parameters for talent identification in Australian football. Anthropometry, estimated maturity status using a maturity ratio from anthropometric measurements and chronological age, motor competence, physical fitness and small-sided match involvements of 227 U13-U15 high-level academy athletes were assessed. Multivariate analysis of variance revealed significant moderate effects of maturity status on physical fitness (p = 0.008, ES = 0.07) and significant large effects on anthropometry (p = 0.001, ES = 0.20), but not on motor competence or match involvements. Univariate analyses of variance demonstrated significant large effects of maturity on anthropometry, but only one subset of physical fitness (i.e. lower-body power). U15 players selected into a U16 development programme were biologically older thandeselected players, despite selection being independent of maturity when a categorical descriptor was used. This study confirms that maturation affects anthropometry and certain measures of physical fitness in youth Australian football players, but not match involvements and motor competence. Furthermore, a player's maturity could affect selection and progression into advanced academy programmes. Involvements and motor competence should be included in multidimensional assessment batteries for Australian Football as they appear less confounded by maturity than fitness and anthropometry.


surviveR: a flexible shiny application for patient survival analysis.
Kaplan-Meier (KM) survival analyses based on complex patient categorization due to the burgeoning volumes of genomic, molecular and phenotypic data, are an increasingly important aspect of the biomedical researcher's toolkit. Commercial statistics and graphing packages for such analyses are functionally limited, whereas open-source tools have a high barrier-to-entry in terms of understanding of methodologies and computational expertise. We developed surviveR to address this unmet need for a survival analysis tool that can enable users with limited computational expertise to conduct routine but complex analyses. surviveR is a cloud-based Shiny application, that addresses our identified unmet need for an easy-to-use web-based tool that can plot and analyse survival based datasets. Integrated customization options allows a user with limited computational expertise to easily filter patients to enable custom cohort generation, automatically calculate log-rank test and Cox hazard ratios. Continuous datasets can be integrated, such as RNA or protein expression measurements which can be then used as categories for survival plotting. We further demonstrate the utility through exemplifying its application to a clinically relevant colorectal cancer patient dataset. surviveR is a cloud-based web application available at https://generatr.qub.ac.uk/app/surviveR , that can be used by non-experts users to perform complex custom survival analysis.


Cytogenetic abnormalities in patients with severe aplastic anemia.
Cytogenetic abnormalities have been described in a few patients with otherwise typical severe aplastic anemia (SAA), and the possible clonal nature of this disease is a controversial issue. Sixty-nine patients with acquired severe aplastic anemia underwent cytogenetic examination on bone marrow cells at the time of diagnosis (n = 34) and/or at least twice after immunosuppressive therapy (IS) (n = 35). We identified 2 major groups. Group A: 51 patients (74%) were normal and remained normal. Group B: 18 patients (26%) had at least one abnormal cytogenetic analysis. This second group could be further subdivided as follows: (B1) chromosomal abnormalities not present at first examination and acquired in the course of the disease (n = 7); (B2) clonal cytogenetic abnormalities present at first examination and persisting (n = 3); (B3) reversible cytogenetic abnormalities (n = 8). The most frequent abnormality was trisomy 8 (n = 8) followed by monosomy 7 (n = 2); 82% of patients are alive in group A and 61% in group B. Three patients developed acute leukemia, all from group B. This represents 4% of all patients or 17% of those with at least one abnormal cytogenetic test. Thus the majority of SAA patients have normal karyotypes in marrow cells at presentation and at follow-up. Patients with abnormal karyotypes exist and can be further subdivided into those with reversible and those with persistent abnormalities. The latter are at risk of developing myelodysplasia or acute leukemia.


Comparative study of DL-selenomethionine vs sodium selenite and seleno-yeast on antioxidant activity and selenium status in laying hens.
The aim of this study was to compare the effect of DL-selenomethionine (SM) with 2 routinely used Se sources, sodium selenite (SS) and seleno-yeast (SY), on relative bioavailability based on antioxidant activity and tissue Se content. Six hundred thirty 131-day-old brown laying hens were randomly assigned to 7 treatments for 168 d (24 wks) with 6 replicates of 15 hens per replicate. The SS and SY animals were supplemented a cornmeal and soybean diet that supplied a total Se 0.3 mg/kg whereas SM was added at 4 different levels to the total Se at 0.1, 0.3, 0.5 and 0.7 mg/kg. All hens fed the Se-supplemented diet showed higher glutathione peroxidase (GSH-Px) activity (P < 0.01), higher superoxide dismutase (SOD) activity (P < 0.05), lower malondialdehyde (MDA) content (P < 0.05) in plasma, and greater Se contents in egg yolks, albumen, leg muscle, breast muscle, liver, and plasma compared with those fed the control diet (P < 0.01). The organic sources (SY and SM) exhibited a greater ability to increase the GSH-Px activity (P < 0.01) and Se content in albumen (P < 0.01), leg, and breast muscles (P = 0.0099 and P = 0.0014, respectively) than the SS that was added at 0.3 mg Se/kg. The higher SM added levels increased the GSH-Px activity until the dose of 0.5mg Se/kg (P < 0.01).The greater Se concentrations in albumen, muscle and liver appeared in the higher SM-added level, as well as above the dose of 0.1 mg Se/kg (P < 0.01). In addition, hens fed the diet with SM accumulated more Se in albumen, leg, and breast muscle than those fed diets with SY (P < 0.05). These results confirmed the higher ability of organic Se sources to increase the antioxidant activity and Se deposition in egg albumen, leg, and breast muscles compared with SS, and demonstrated a significantly better efficiency of SM compared with SY for albumen and muscle Se enrichment.


Impact of the COVID-19 Pandemic on the Mental Health of Nurses and Auxiliary Nursing Care Technicians-A Voluntary Online Survey.
Pandemics impose an immense psychological burden on healthcare workers due to a combination of workplace stressors and personal fears. Nurses and auxiliary nursing care technicians (ANCTs) are on the front line of this pandemic and form the largest group in healthcare practice. The aim of this study is to determine the symptoms of depression and/or anxiety among nurses and ANCTs during the periods known as the first wave (March-June) and second wave (September-November) of theCOVID-19 pandemic in Spain. An observational cross-sectional study was carried out using an anonymous, self-administered questionnaire among nurses and ANCTs practising in Spain. During the first period, 68.3% and 49.6% of the subjects presented anxiety and depression, respectively, decreasing in the second period (49.5% for anxiety and 35.1% for depression). There were statistically significant differences between the different categories and periods (p < 0.001). The COVID-19 pandemic has negatively influenced mental health in nurses and ANCTs. Mental health should be monitored and coping strategies promoted to improve the health, productivity and efficiency of these professionals.


Evaluation of the efficacy of hematoxylin and eosin stain when xylene is completely replaced by turpentine or kerosene oil - A comparative study for oral tissues.
Microscopic examination of cells and tissues requires the preparation of very thin and good-quality sections mounted on glass slides and appropriately stained to demonstrate normal and abnormal structures. Before this step, the tissue must undergo preparatory treatment known as tissue processing. The various stages of tissue processing are dehydration, clearing, impregnation, and embedding, each with a particular duration for proper completion of the process. Xylene is the most frequently used clearing agent whose carcinogenic potential is well documented. Hence, attempts were made to substitute xylene with a biosafe clearing agent. The present study aimed to evaluate and compare the efficacy of hematoxylin and eosin stain (H and E stain) when xylene is completely replaced by turpentine or kerosene oil. A total number of 50 tissue samples were taken in the study, which included 40 study samples and 10 controls. All the samples were randomly separated into three groups and routine tissue processing and H and E staining were performed. The result was further subjected to statistical analysis by using Fisher's exact test. Group-1: Ten tissue samples were processed and H and E staining was done in xylene. Group-2: Twenty tissue samples were processed and H and E staining was done in turpentine oil. Group-3: Twenty tissue samples were processed and H and E staining was done in kerosene oil. Nuclear staining, cell morphology, and uniformity of staining were better in kerosene sections, while cytoplasmic and clarity of staining of turpentine sections were comparable with xylene sections. Turpentine and kerosene as clearing agents can be used in the future with certain modifications in their concentration and routine staining protocol.


The Application of Evidence-Based Medicine in Individualized Medicine.
The fundamental aim of healthcare is to improve overall health of the population by providing state-of-the-art healthcare for individuals at an affordable cost. The foundation for this system is largely referred to as "evidence-based medicine". Too often, evidence-based medicine is based solely on so-called "best research evidence", collected through randomized controlled trials while disregarding clinical expertise and patient expectations. As healthcare gravitates towards personalized and individualized medicine, such external clinical (research) evidence can inform, but never replace, individual clinical expertise. This applies in particular to orphan diseases, for which clinical trials are methodologically particularly problematic, and evidence derived from them is often questionable. Evidence-based medicine constitutes a complex process to allow doctors and patients to select the best possible solutions for each individual based on rapidly developing new therapeutic directions. This requires a revisit of the foundations of evidence-based medicine. A proposition as to how to manage evidence-based data in individualized immune-oncology is presented here.


Aging, subjective experience, and cognitive control: dramatic false remembering by older adults.
Recent research suggests that older adults are more susceptible to interference effects than are young adults; however, that research has failed to equate differences in original learning. In 4 experiments, the authors show that older adults are more susceptible to interference effects produced by a misleading prime. Even when original learning was equated, older adults were 10 times as likely to falsely remember misleading information and were much less likely to increase their accuracy by opting not to answer under conditions of free responding. The results are well described by a multinomial model that postulates multiple modes of cognitive control. According to that model, older adults are likely to be captured by misleading information, a form of goal neglect or deficit in inhibitory functions.


Detection of the low-density-lipoprotein receptor with biotin-low-density lipoprotein. A rapid new method for ligand blotting.
A new technique has been developed to identify low-density-lipoprotein (LDL) receptors on nitrocellulose membranes, after transfer from SDS/polyacrylamide gels, by ligand blotting with biotin-modified LDL. Modification with biotin hydrazide of periodate-oxidized lipoprotein sugar residues does not affect the ability of the lipoprotein to bind to the LDL receptor. Bound lipoprotein is detected with high sensitivity by a streptavidin-biotin-peroxidase complex, and thus this method eliminates the need for specific antibodies directed against the ligand. The density of the bands obtained is proportional to the amount of pure LDL receptor protein applied to the SDS/polyacrylamide gel, so that it is possible to quantify LDL receptor protein in cell extracts. Biotin can be attached to other lipoproteins, for example very-low-density lipoproteins with beta-mobility, and thus the method will be useful in the identification and isolation of other lipoprotein receptors.


The 30-15 intermittent fitness test: accuracy for individualizing interval training of young intermittent sport players.
The objective of this study was to gather evidence supporting the accuracy of the 30-15 Intermittent Fitness Test (30-15IFT) for individualizing interval training of young intermittent sport players. In 59 young intermittent sport players (age, 16.2 +/- 2.3 years), we observed the relationships between the maximal running speed (MRS) reached at the end of the 30-15IFT (MRS30-15IFT) and physiological variables elicited by shuttle intermittent runs, including maximal oxygen uptake, explosive power of lower limbs, and the ability to repeat intense exercise bouts through cardiorespiratory recovery kinetics during exercise. To observe the capacity of the 30-15IFT to prescribe suitable running intensities for interval training sessions, we compared heart rates (HRs) reached during 3 series of intermittent runs, where distances were set according to the MRS30-15IFT and to MRS reached with 2 popular continuous field tests: the University of Montreal track test and the 20-m shuttle run test. The results show that the MRS30-15IFT is significantly correlated with all physiological variables elicited by shuttle intermittent runs (P < 0.05). Although mean HR were not different among the 3 series of intermittent runs, HR recorded during the runs based on MRS30-15IFT presented significantly less interindividual variation than when the continuously determined MRS were used as reference speeds. In conclusion, we can say that the 30-15IFT leads to an MRS that simultaneously takes into account various physiological qualities elicited when performing shuttle intermittent runs. For scheduling interval training sessions, the MRS30-15IFT appears to be an accurate reference speed for getting players with different physiological profiles to a similar level of cardiorespiratory demand and thus for standardizing training content.


Community diagnosis: its uses in the training of community health workers and in primary health care in East Africa.
Over the last 20 years, medical schools in Uganda, Kenya and Tanzania have been developing teaching programs in community health which have placed increasing emphasis on community diagnosis. This process, which involves students, health workers and the community, is a team effort to obtain a wide variety of information using epidemiologic methods and to establish priorities for health action. The programs which are developed following community diagnosis often rely on primary health workers and small health centers for their execution. Experience in community diagnosis is an important element in the training of health workers. Such experience is also an excellent means of teaching the management skills that are essential for operating primary health care programs. This paper traces the evolution of the methods of community diagnosis used in East Africa.


Pharmacology of the high-affinity apamin receptor in rabbit heart.
Apamin is a potent blocker of calcium-activated small conductance potassium (SK) channels in neurons, liver, skeletal muscle and ileum smooth muscle, but not in cardiac muscle. Cardiac muscle is devoid of SK channels; however, in isolated, single ventricular myocytes apamin is an extremely potent blocker of the L-type calcium current, and the anti-arrhythmic drug quinidine reverses apamin block. To characterize the receptor binding properties and pharmacology of the apamin receptor in heart. The binding properties of the apamin receptor were determined by rapid filtration of purified rabbit heart membranes. Monoiodinated apamin binds to a labile, membrane-bound protein in heart membranes at a single, high-affinity site (KD = 8.07 +/- 2.14 pM and Bmax = 686 +/- 167 fmoles/mg protein, significant run test at P = 0.05 for a one site fit). 125I-apamin binding is dose-dependently inhibited by apamin, scyllatoxin, quinidine, amiloride, as well as a variety of di- and trivalent cations that are classical blockers of L-type calcium channels (e.g. Co2+, Cd2+, Mn2+, La3+, Gd3+). The cardiac apamin receptor is also critically dependent upon pH, temperature and KCl, and co-purifies in the same membrane fraction as L-type cardiac Ca2+ channels. The apamin receptor in rabbit heart P2 membranes has pharmacological and biochemical properties in common with both an SK channel and an L-type Ca2+ channel.


Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis.
In this study, we have investigated the role of the cannabinoid CB(2) (CB(2)) receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB(2) receptor in TNF-alpha-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB(2) receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-alpha, MIP-1alpha, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB(2) receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB(2) receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.


Analyzing transfer learning impact in biomedical cross-lingual named entity recognition and normalization.
The volume of biomedical literature and clinical data is growing at an exponential rate. Therefore, efficient access to data described in unstructured biomedical texts is a crucial task for the biomedical industry and research. Named Entity Recognition (NER) is the first step for information and knowledge acquisition when we deal with unstructured texts. Recent NER approaches use contextualized word representations as input for a downstream classification task. However, distributed word vectors (embeddings) are very limited in Spanish and even more for the biomedical domain. In this work, we develop several biomedical Spanish word representations, and we introduce two Deep Learning approaches for pharmaceutical, chemical, and other biomedical entities recognition in Spanish clinical case texts and biomedical texts, one based on a Bi-STM-CRF model and the other on a BERT-based architecture. Several Spanish biomedical embeddigns together with the two deep learning models were evaluated on the PharmaCoNER and CORD-19 datasets. The PharmaCoNER dataset is composed of a set of Spanish clinical cases annotated with drugs, chemical compounds and pharmacological substances; our extended Bi-LSTM-CRF model obtains an F-score of 85.24% on entity identification and classification and the BERT model obtains an F-score of 88.80% . For the entity normalization task, the extended Bi-LSTM-CRF model achieves an F-score of 72.85% and the BERT model achieves 79.97%. The CORD-19 dataset consists of scholarly articles written in English annotated with biomedical concepts such as disorder, species, chemical or drugs, gene and protein, enzyme and anatomy. Bi-LSTM-CRF model and BERT model obtain an F-measure of 78.23% and 78.86% on entity identification and classification, respectively on the CORD-19 dataset. These results prove that deep learning models with in-domain knowledge learned from large-scale datasets highly improve named entity recognition performance. Moreover, contextualized representations help to understand complexities and ambiguity inherent to biomedical texts. Embeddings based on word, concepts, senses, etc. other than those for English are required to improve NER tasks in other languages.


Multidisciplinary management of a fused maxillary central incisor moved through the midpalatal suture: A case report.
Fusion of teeth is a developmental anomaly. It occurs at the stage of tooth formation, which determines the shape and size of the tooth crown, when one or more teeth fuse at the dentin level during the morphodifferentiation of the dental germs. Such teeth show macrodontia and may cause crowding, as well as esthetic and endodontic problems. In this article, we report a rare case of a maxillary central incisor fused to a supernumerary tooth showing labial and palatal talon cusps, which was orthodontically moved across the midpalatal suture. A 13-year-old Caucasian boy sought treatment for the unesthetic appearance of his maxillary central incisor and anterior crowding. He was rehabilitated successfully via a multidisciplinary approach involving orthodontic, nonsurgical endodontic, periodontal, and prosthodontic treatments. After a 26-month treatment period, the patient's macroesthetics and microesthetics were improved. The overall improvement of this macrodontic tooth and its surrounding tissues through multidisciplinary treatment was documented using cone-beam computed tomography.


Selenite and selenomethionine promote HL-60 cell cycle progression.
The essential role of selenium (Se) in nutrition is well established. The elucidation of the mechanisms by which selenium regulates the cell cycle can lead to a better understanding of the nature of selenium's essentiality and its role in disease prevention. In this study, the effects of selenium deficiency or adequacy (0.25 micromol/L selenite or selenomethionine) on HL-60 cell cycle progression were examined in serum-free media. Selenium was critical for promotion of HL-60 cell growth. Cell-cycle analysis revealed that selenium deficiency caused a decrease in G1 phase cells that corresponded to an increase in G2 and sub-G1 phase cells. Gene array analysis suggested that c-Myc, cyclin C, proliferating cell nuclear antigen, cyclin-dependent kinase (cdk)1, cdk2, cdk4, cyclin B and cyclin D2 mRNA levels were lower in selenium-deficient cells than in the cells supplemented with 0.25 micromol/L selenomethionine. The decrease in the c-Myc mRNA level in selenium-deficient cells was confirmed by reverse transcription-polymerase chain reaction analysis. Furthermore, the phosphorylation state of total cellular protein was higher (57%) in selenium-supplemented cells than in selenium-deficient cells. Collectively, these results suggest a novel role for selenium at 0.25 micromol/L in up-regulation of the expression of numerous cell cycle-related genes and total cellular phosphorylated proteins in HL-60 cells in serum-free culture media. This leads to the promotion of cell cycle progression, particularly G2/M transition and/or the reduction of apoptosis, primarily in G1 cells. These observations may have additional implications for understanding the nature of selenium's essentiality.


Src SH3/2 domain-mediated peripheral accumulation of Src and phospho-myosin is linked to deregulation of E-cadherin and the epithelial-mesenchymal transition.
Elevated Src kinase in epithelial cancer cells induces adhesion changes that are associated with a mesenchymal-like state. We recently showed that Src induces dynamic integrin adhesions in KM12C colon cancer cells, whereas E-cadherin-dependent cell-cell contacts become disorganized. This promotes a fibroblastic-like morphology and expression of the mesenchymal marker vimentin. Furthermore, Src-induced deregulation of E-cadherin, and the associated mesenchymal transition, is dependent on integrin signaling (Avizienyte et al., Nat. Cell Biol. 2002, 4, 632-638), although the nature of downstream signals that mediate these Src- and integrin-dependent effects are unknown. Here we show that the SH2 and SH3 domains of Src mediate peripheral accumulation of phospho-myosin, leading to integrin adhesion complex assembly, whereas loss of SH2 or SH3 function restores normal regulation of E-cadherin and inhibits vimentin expression. Inhibitors of MEK, ROCK, or MLCK also suppress peripheral accumulation of phospho-myosin and Src-induced formation of integrin-dependent adhesions, whereas at the same time restoring E-cadherin redistribution to regions of cell-cell contact. Our data therefore implicate peripheral phospho-myosin activity as a point of convergence for upstream signals that regulate integrin- and E-cadherin-mediated adhesions. This further implicates spatially regulated contractile force as a determinant of epithelial cell plasticity, particularly in cancer cells that can switch between epithelial and mesenchymal-like states.


Traditional Chinese medicine on treating ureteral calculi: A systematic review and meta-analysis protocol.
Ureteral calculi generally refer to the temporary obstruction of the human body after the ureteral stenosis. When the ureteral stones are not discharged in time, they can grow in the original site, causing the patient to have corresponding clinical manifestations, such as: renal colic, hematuria, etc, when severe, can cause renal obstruction and hydronephrosis, seriously endangering the patient's health. Ureteral calculi usually occur in young and middle-aged people. The peak age of the disease is between 20 and 50 years old. It also occurs in the young and middle-aged labor force. The men incidence rate is 2 to 3 times that of women. Ureteral calculi is one of the current refractory diseases, and the effect after treatment with integrated Chinese and Western medicine is remarkable. We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet; Nature, Science online and China Journal Full-text Database (CNKI), China Biomedical Literature CD-ROM Database (CBM), and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to November 2018. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of ureteral. This systematic review will evaluate the efficacy and safety of Traditional Chinese medicine for ureteral. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process Trial.Registration number: PROSPERO CRD42019137095.


[The motor activity study segment as pilot study of The Child and Adolescent Health Survey].
In the Health Survey for Children and Adolescents the examination of motor activity is one aspect of physical health covered by the study. This underlines the importance of physical activity for physical development in early years. This first representative child and adolescent study for Germany intends to obtain data on motor activity and to allow for the implementation of specific intervention programmes encouraging physical activity. The specific general conditions under which the survey is conducted restrict the selection and scope of possible instruments to a minimal programme, including fitness tests, strength in combination with endurance and coordinative skills as well as flexibility. In a pilot study the suitability, feasibility and the obtained evidence of selected single motor tests were tested. This article explains the choice of instruments and methods used in the examination of physical fitness. It also discusses methodological difficulties which affect the standardisation of tests and the requirements regarding personnel. A major concern of the pilot study was the evaluation of tested instruments with regard to gender and age differences. For the main survey the following tests are recommended: coordination (balancing backwards, one-leg-footing, sideway jumping), perseverance (sit-ups, push-ups), and flexibility (trunk bending).


Antibody-conjugated gold nanoparticle-based immunosensor for ultra-sensitive detection of troponin-T.
The technology presented in this study demonstrates the feasibility of integrating nanostructures onto the surface of an electrical platform to achieve enhanced detection of the cardiac biomarker, troponin-T. A polymer microcontact printing technique was modified using printed circuit boards as molds for the application of gold nanoparticles onto microelectrode-patterned glass substrates. The microelectrodes were designed to support electrical impedance spectroscopy measurements and fabricated using standard photolithography methods. Capture antibodies specific to troponin-T were functionalized onto the surface of gold nanoparticles by using a thiol-based cross-linking molecule. The antibody-conjugated gold nanoparticles were stamped onto the electrodes using a matching pattern imprinted onto an elastomeric mold. As a control to validate the efficacy of the nanotextured surface on the glass substrate, an electroplated printed circuit board was also used. The incorporation of gold nanoparticles showed significant amplification of the electro-ionic signals generated through binding of the antigen to its capture antibody. Enhanced sensitivity was demonstrated through detection of the target biomarker in the femtogram per milliliter range in buffer solution and biological media. In the absence of gold nanoparticles, the sensor demonstrated detection of troponin-T at higher concentration points. This study illustrates a robust method for developing a more sensitive, label-free biosensor.


Sol Sherry lecture in thrombosis: molecular events in acute inflammation.
The inflammatory response is characterized by a multistep molecular interaction between "signaling" cells, such as endothelial cells, and "responding" cells, such as neutrophils and monocytes. In the first step, selectins produced by signaling cells mediate the tethering of responding cells at sites of inflammation. Subsequently, an additional mediator expressed by signaling cells activates the tethered responding cells. Under pathological conditions, the same mechanism is invoked in inappropriate ways: (1) by prolonged presentation of selectins on the cell surface and (2) by the unregulated production of oxidized phospholipids that mimic the normal secondary signaling molecule, platelet-activating factor (PAF). The enzyme PAF acetylhydrolase (PAF-AH) inactivates PAF and oxidized phospholipids and constitutes an "off" switch that suppresses inflammation. Inhibition of normal PAF-AH function or inactivating mutations of the PAF-AH gene can lead to increased susceptibility to inflammatory disease. These studies have relevance to atherosclerosis and thrombosis, because inflammation is a central feature of both.


Formation of Food Grade Microemulsion with Rice Glycosphingolipids to Enhance the Oral Absorption of Coenzyme Q10.
The purpose of this study is to examine the possible use of rice glycosphingolipids (RGSLs) as an emulsifier to form food grade microemulsions (mean particle size, 10-20 nm) and improve the absorption of CoQ10 with a poor solubility property by prepared emulsion. Because RGSLs could act as an auxiliary emulsifying agent, its addition to the surfactant/oil mixture decreased the emulsion's particle size. This suggests that RGSLs exist between the water and oil phases to decrease oil droplet size via reduced interfacial tension. CoQ10-loaded microemulsion was also successfully prepared with RGSLs and powdered after freeze-drying with a cryoprotectant. CoQ10's solubility in freeze-dried particles was dramatically improved compared to that of CoQ10 powder. Moreover, oral absorption of CoQ10 was significantly enhanced when administered via CoQ10-loaded microemulsion. The area under the plasma concentration-time curve for the microemulsion improved up to seven-fold compared to CoQ10 powder. The use of RGSLs could, therefore, be an effective processing technique for improving CoQ10's solubility and absorption.


Nondestructive sampling of human skeletal remains yields ancient nuclear and mitochondrial DNA.
Museum curators and living communities are sometimes reluctant to permit ancient DNA (aDNA) studies of human skeletal remains because the extraction of aDNA usually requires the destruction of at least some skeletal material. Whether these views stem from a desire to conserve precious materials or an objection to destroying ancestral remains, they limit the potential of aDNA research. To help address concerns about destructive analysis and to minimize damage to valuable specimens, we describe a nondestructive method for extracting DNA from ancient human remains. This method can be used with both teeth and bone, but it preserves the structural integrity of teeth much more effectively than that of bone. Using this method, we demonstrate that it is possible to extract both mitochondrial and nuclear DNA from human remains dating between 300 BC and 1600 AD. Importantly, the method does not expose the remains to hazardous chemicals, allowing them to be safely returned to curators, custodians, and/or owners of the samples. We successfully amplified mitochondrial DNA from 90% of the individuals tested, and we were able to analyze 1-9 nuclear loci in 70% of individuals. We also show that repeated nondestructive extractions from the same tooth can yield amplifiable mitochondrial and nuclear DNA. The high success rate of this method and its ability to yield DNA from samples spanning a wide geographic and temporal range without destroying the structural integrity of the sampled material may make possible the genetic study of skeletal collections that are not available for destructive analysis.


[Appropriateness of prescription of exercise stress test, echocardiography, Holter monitoring and vascular echography].
The aim of this study was to evaluate the appropriateness of prescription of non-invasive cardiological tests (exercise stress test, echocardiography, Holter monitoring and vascular echography), consecutively performed in our outpatient laboratory during 4 weeks. We collected the following data: the appropriateness of prescription (according to the Italian Federation of Cardiology guidelines); test indications; the prescribing physician (cardiologist/non-cardiologist); type of prescription (elective/urgent); clinical utility (useful/useless) and result (normal/abnormal) of each test. We evaluated 960 prescriptions (320 exercise tests; 282 echocardiograms; 158 Holter tests; 200 vascular echographies). Test indications were appropriate (class I) in 37%, doubtfully appropriate (class II) in 39% and inappropriate (class III) in 24% of the cases. The appropriateness was slightly better for vascular echography and echocardiography (class I: 44% and 43%, respectively), markedly worse for exercise test (class I: 27%). The tests were considered useful in 46% and abnormal in 39% of the cases. Cardiologist-prescribed exams resulted more often appropriate (class I: 53 vs 30%; class II: 41 vs 38%; class III: 6 vs. 32%; p = 0.0001), more often useful (74 vs. 34%; p = 0.0001) and more frequently abnormal (43 vs. 37%; p = 0.05), when compared to non-cardiologist-prescribed exams. No differences in appropriateness, utility and test result have been detected between elective and urgent exams. Exercise test, echocardiogram and Holter monitoring resulted more often appropriate and useful when prescribed by cardiologists. This study confirms that only one third of prescriptions for non-invasive cardiological tests are appropriate. Cardiologist-prescribed exams are more often appropriate, useful and abnormal.


The structure of an acylated inositol mannoside in the lipids of propionic acid bacteria.
1. Lipids were extracted from five strains of Propionibacterium with chloroform-methanol mixtures and fractionated by chromatography on silicic acid. 2. All five extracts contained a glycolipid composed of fatty acids, inositol and mannose in the molar proportions 2:1:1. 3. Hydrolysis of the glycolipid with alkali gave a mixture of fatty acids and O-alpha-d-mannopyranosyl-(1-->2)-myoinositol. 4. Analysis of the fatty acids by g.l.c. showed that they were predominantly straight- and branched-chain isomers of pentadecanoic acid and heptadecanoic acid. 5. The location and distribution of the fatty acid residues in the molecule was established by periodate oxidation studies and mass spectrometry. The structure of the major glycolipid is 1-O-pentadecanoyl-2-O-(6-O-heptadecanoyl-alpha-d-mannopyranosyl)myoinositol. 6. The glycolipids are located in the membrane; the cell walls are devoid of lipid. 7. Possible functions of the glycolipid are discussed.


Benefits of using the Liverpool Care Pathway in end of life care.
The Liverpool Care Pathway (LCP) is an integrated care pathway used to manage terminally ill patients in their final days or hours of life. It was developed by the Marie Curie Palliative Care Institute Liverpool to incorporate 'gold standard' care associated with the hospice setting into mainstream healthcare. The LCP has been advocated by the National Institute for Health and Clinical Excellence and the Department of Health for use in the care of dying patients. A literature review was undertaken to determine whether there is sufficient evidence that the LCP represents best practice in end of life care and whether patients cared for using the LCP receive better end of life care. Eight research articles were selected for inclusion in the review. The key themes of symptom management, communication and documentation were identified, and the research surrounding these themes was analysed. The analysis showed that use of the LCP promotes better care for patients in the terminal stage of illness; however, some weaknesses in the research were identified and recommendations have been made for further research and future practice.


Renal catabolism of 125I-glicentin.
The renal catabolism of 125I-glicentin has been studied in vivo by the disappearance of this peptide from the plasma of bilaterally nephrectomized, ureteral-ligated, or normal rats and by using tubular microinfusion techniques. In addition the catabolism of glicentin by the isolated, perfused kidney has been studied. Results from in vivo studies demonstrated that half-disappearance time was lower in control (59.5 +/- 1.8 min) than in bilaterally nephrectomized rats (97.2 +/- 2.6 min), and this value was significantly higher than that of ureteral-ligated animals (83.2 +/- 1.1 min, P less than 0.005). Microinfusion experiments revealed that when 125I-glicentin was injected into the proximal tubule, no trichloroacetic-precipitable radioactivity was recovered in the urine, whereas most of inulin injected was recovered. By contrast most of the 125I-glicentin injected into the distal tubule was recovered in the urine. In isolated kidney experiments, organ clearance rate of 125I-glicentin averaged 0.88 +/- 0.10 ml/min, a value significantly higher than that of glomerular filtration rate (0.72 +/- 0.06 ml/min, P less than 0.005, paired data), and both parameters showed a close linear relationship (r = 0.90). Urinary clearance of glicentin was negligible. These results demonstrate that the kidney plays a major role in the catabolism of glicentin, mainly by glomerular filtration and tubular catabolism. The site of tubular catabolism appears to be the proximal tubule. Peritubular uptake was minimal.


Fermentation product butane 2,3-diol induces Ca2+ transients in E. coli through activation of lanthanum-sensitive Ca2+ channels.
The results here are the first demonstration of a physiological agonist opening Ca2+ channels in bacteria. Bacteria in the gut ferment glucose and other substrates, producing alcohols, diols, ketones and acids, that play a key role in lactose intolerance, through the activation of Ca2+ and other ion channels in host cells and neighbouring bacteria. Here we show butane 2,3-diol (5-200mM; half maximum 25mM) activates Ca2+ transients in E. coli, monitored by aequorin. Ca2+-transient magnitude depended on external Ca2+ (0.1-10mM). meso-Butane 2,3-diol was approximately twice as potent as 2R,3R (-) and 2S,3S (+) butane 2,3-diol. There were no detectable effects on cytosolic free Ca2+ of butane 1,3-diol, butane 1,4-diol and ethylene glycol. The glycerol fermentation product propane 1,3-diol only induced significant Ca2+ transients in 10mM external Ca2. Ca2+ butane 2,3-diol Ca2+ transients were due to activation of Ca2+ influx, followed by activation of Ca2+ efflux. The effect of butane 2,3-diol was abolished by La3+, and markedly reduced as a function of growth phase. These results were consistent with butane 2,3-diol activating a novel La3+-sensitive Ca2+ channel. They have important implications for the role of butane 2,3-diol and Ca2+ in bacterial-host cell signalling.


Increased protein nitration in mitochondrial diseases: evidence for vessel wall involvement.
Mitochondrial diseases (MD) are heterogeneous disorders because of impairment of respiratory chain function leading to oxidative stress. We hypothesized that in MD the vascular endothelium may be affected by increased oxidative/nitrative stress causing a reduction of nitric oxide availability. We therefore, investigated the pathobiology of vasculature in MD patients by assaying the presence of 3-nitrotyrosine in muscle biopsies followed by the proteomic identification of proteins which undergo tyrosine nitration. We then measured the flow-mediated vasodilatation as a proof of altered nitric oxide generation/bioactivity. Here, we show that 3-nitrotyrosine staining is specifically located in the small vessels of muscle tissue and that the reaction is stronger and more evident in a significant percentage of vessels from MD patients as compared with controls. Eleven specific proteins which are nitrated under pathological conditions were identified; most of them are involved in energy metabolism and are located mainly in mitochondria. In MD patients the flow-mediated vasodilatation was reduced whereas baseline arterial diameters, blood flow velocity and endothelium-independent vasodilatation were similar to controls. The present results provide evidence that in MD the vessel wall is a target of increased oxidative/nitrative stress.


NIH EXAMINER: conceptualization and development of an executive function battery.
Executive functioning is widely targeted when human cognition is assessed, but there is little consensus on how it should be operationalized and measured. Recognizing the difficulties associated with establishing standard operational definitions of executive functioning, the National Institute of Neurological Disorders and Stroke entered into a contract with the University of California-San Francisco to develop psychometrically robust executive measurement tools that would be accepted by the neurology clinical trials and clinical research communities. This effort, entitled Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER), resulted in a series of tasks targeting working memory, inhibition, set shifting, fluency, insight, planning, social cognition and behavior. We describe battery conceptualization and development, data collection, scale construction based on item response theory, and lay the foundation for studying the battery's utility and validity for specific assessment and research goals.


High glucose-induced endothelial progenitor cell dysfunction.
Vascular complications contribute significantly to morbidity and mortality of diabetes mellitus. The primary cause of vascular complications in diabetes mellitus is hyperglycaemia, associated with endothelial dysfunction and impaired neovascularization. Circulating endothelial progenitor cells was shown to play important roles in vascular repair and promoting neovascularization. In this review, we will demonstrate the individual effect of high glucose on endothelial progenitor cells. Endothelial progenitor cells isolated from healthy subjects exposed to high glucose conditions or endothelial progenitor cells isolated from diabetic patients exhibit reduced number of endothelial cell colony forming units, impaired abilities of differentiation, proliferation, adhesion and migration, tubulization, secretion, mobilization and homing, whereas enhanced senescence. Increased production of reactive oxygen species by the mitochondria seems to play a crucial role in high glucose-induced endothelial progenitor cells deficit. Later, we will review the agents that might be used to alleviate dysfunction of endothelial progenitor cells induced by high glucose. The conclusions are that the relationship between hyperglycaemia and endothelial progenitor cells dysfunction is only beginning to be recognized, and future studies should pay more attention to the haemodynamic environment of endothelial progenitor cells and ageing factors to discover novel treatment agents.


[Potential neurocognitive consequences of infection by human respiratory syncytial virus].
Human respiratory syncytial virus (RSV) infection remains as a major cause of morbidity and mortality among pediatric population. Immune response is poor and unable to establish a long term effective protection against this virus. Of particular interest has been the description of extrapulmonary manifestations of RSV infection in liver, kidney, endocrine system, heart and brain, associated to infection of peripheral blood. In the central nervous system (CNS), recent studies in animals have suggested long term neurocognitive impairment due to a direct damage from the virus. This was prevented in rats by a recombinant BCG vaccine expressing a nucleoprotein N of RSV that produces an effective immune response against the virus, not allowing its dissemination to the CNS. These findings in animal models highlight the importance of conducting more specific studies in children affected with severe infection by RSV. Therefore, our group is currently conducting an assessment of the possible long-term cognitive impairment in children under 2 years. The results of this study could be a strong argument to continue looking for an effective method for protecting against RSV infection.


Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice.
Thyroid cancer comprises different clinical and histological entities. Whereas differentiated (DTCs) malignancies are sensitive to radioiodine therapy, anaplastic (ATCs) and medullary (MTCs) tumors do not uptake radioactive iodine and display aggressive features associated with a poor prognosis. Moreover, in a majority of DTCs, disease evolution leads to the progressive loss of iodine sensitivity. Hence, iodine-refractory DTCs, along with ATCs and MTCs, require alternative treatments reflective of their different tumor biology. In the last decade, the molecular mechanisms promoting thyroid cancer development and progression have been extensively studied. This has led to a better understanding of the genomic landscape, displayed by thyroid malignancies, and to the identification of novel therapeutic targets. Indeed, several pharmacological compounds have been developed for iodine-refractory tumors, with four multi-target tyrosine kinase inhibitors already available for DTCs (sorafenib and lenvatinib) and MTCs (cabozantib and vandetanib), and a plethora of drugs currently being evaluated in clinical trials. In this review, we will describe the genomic alterations and biological processes intertwined with thyroid cancer development, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors. Furthermore, given the existing preclinical evidence, we will briefly discuss the potential role of immunotherapy as an additional therapeutic strategy for the treatment of thyroid cancer.