Exploration of the regulatory effect of miR-21 on breast cancer cell line proliferation and invasion as well as the downstream target genes.
To study the regulatory effects of miR-21 on breast cancer cell line proliferation and invasion as well as the downstream target genes. Breast cancer cell lines MCF-7 were cultured and transfected with miR-21 mimics and the corresponding negative control mimics (NC mimics), and then MTS kits were used to detect cell viability. Transwell experiment was used to detect cell invasion ability, and fluorescence quantitative PCR was used to detect the expression of proliferation and invasion-related genes in cells. 24 h after transfection of miR-21 mimics and NC mimics, cell OD value and the number of invasive cells of miR-21 group were significantly higher than those of NC group, and mRNA contents of PDCD-4, FasL, PTEN, RhoB, Maspin, TIMP3 and RECK in cells were significantly lower than those of NC group. miR-21 can promote the proliferation and invasion of breast cancer cell lines, and its downstream target genes include PDCD-4, FasL, PTEN, RhoB, Maspin, TIMP3 and RECK.


Somatosensory evoked potential assessment of the inferior alveolar nerve following third molar extraction.
Injury to the inferior alveolar nerve can occur during 3rd molar removal. In this study, 14 patients who had 3rd molars removed were evaluated by 4 methods: 1) threshold to electrical stimulation, 2) visual analogue scale subjective ratings of electrical stimulation, 3) two-point discrimination in mental nerve area, and 4) analysis of somatosensory evoked potentials. The last technique proved to be the most sensitive of the methods, providing an objective evaluation as compared to other methods which require a subjective interpretation by the patient.


Individual effects of estrogens on a marine fish, Cunner (Tautogolabrus adspersus), extrapolated to the population level.
Endocrine-disrupting chemicals (EDCs) in the environment may alter the population dynamics of wildlife by affecting reproductive output. This study describes a matrix modeling approach to link laboratory studies on endocrine disruption with potential ecological effects. The experimental model used is cunner (Tautogolabrus adspersus), which inhabit estuarine and marine areas where sewage treatment and other discharges containing estrogenic EDCs are likely. To test the effects of estrogenic exposures on fecundity, reproductively active cunner were exposed in three separate experiments by implanting 17beta-estradiol, estrone, or 17alpha-ethynylestradiol subcutaneously in a slow-release matrix at 0.05, 0.5, and 2.5 mg/kg. Egg production per gram female and egg viability were determined daily for a 1-week preexposure period and then for a 2-week exposure period. The mean number of eggs produced per gram female and egg viability (%) were calculated for the initial preexposure period and the 2-week exposure period for each experiment. Significant changes were observed in egg production per gram female in the high-17beta-estradiol treatment (P = 0.07) and high-17alpha-ethynylestradiol treatment (P = 0.04). A significant increase was observed in egg viability (%) in the low-17alpha-ethynylestradiol treatment (39.0%; P < or = 0.05). Cunner population response was projected using an age-structured matrix population model parameterized with published survival and fecundity estimates. By incorporating reproductive response data from laboratory exposures, model projections were used to describe how reproductive changes by estrogen treatment could alter cunner population growth rate (lambda). Published by Elsevier Inc.


Assessment of certain biomarkers for predicting survival in response to treatment in dogs naturally infected with canine parvovirus.
Canine parvovirus (CPV) enteritis is an important cause of morbidity and mortality in puppies despite aggressive treatment. Identification of reliable biomarkers for CPV enteritis is essential to determine the severity, duration of hospitalization, and predict the clinical outcome. Meanwhile, the biomarkers will assist in decision-making with clients about the further course of treatment or euthanasia. The present study was conducted to evaluate the changes of total leukocyte count (TLC), neutrophil count, and serum concentrations of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), intestinal fatty acid binding protein-2 (IFABP-2), albumin, ceruloplasmin (Cp), cortisol, free triiodothyronine (FT3) and free thyroxine (FT4) in survivors and non-survivors as a predictor of the clinical outcome. Marked leukopenia, neutropenia, hypoalbuminemia, elevated levels of CK-MB, IFABP-2, Cp, and cortisol were noticed in CPV-infected dogs than healthy dogs but, LDH, FT3 and FT4 concentrations did not differ significantly. The CPV-infected non-survivors had persistent leukopenia, neutropenia and elevated CK-MB, IFABP-2, Cp and cortisol concentrations at 72 h of commencement of treatment. In CPV-infected survivors, TLC and neutrophil count were significantly increased, and CK-MB, IFABP-2, Cp and cortisol concentrations were significantly decreased at 72 h of commencement of treatment. The positive predictive values (PPVs) for survival using cut-off value of TLC (>3.2 × 103/μL), neutrophil count (>1.65 × 103/μL), CK-MB (≤234.50 U/L), IFABP-2 (≤7.61 ng/mL), Cp (≤0.605 g/L) and cortisol (≤16.90 ng/mL) were determined as 89.47%, 88.88%, 94.73%, 93.33%, 94.44% and 89.47%, respectively with better area under receiver operating characteristic (ROC) curve as well as sensitivity. The magnitude of decrease in TLC, neutrophil count, and increase in CK-MB, IFABP-2, Cp and cortisol concentrations at 72 h of initiation of treatment in dogs with parvoviral enteritis could be useful indicators for the prognosis of the disease. Based on sensitivity (%) and specificity (%) from ROC curve analysis and PPV (%), it is concluded that serum CK-MB concentration will serve as the most useful biomarker followed by Cp and absolute neutrophil count.


Definitive radiotherapy alone over 60 Gy for patients unfit for combined treatment to stage II-III non-small cell lung cancer: retrospective analysis.
Elderly patients with non-small cell lung cancer (NSCLC) are frequently treated with radiation therapy (RT) alone, due to poor performance status or underlying disease. We investigated the effectiveness of RT over 60 Gy administered alone to NSCLC patients who were unfit or rejecting for combination treatment. From April 2002 to July 2010, 83 patients with stage II-III NSCLC, aged over 60 years, treated by RT alone with a curative aim were analyzed. Radiation was targeted to the primary tumor and clinically involved lymph nodes. A total dose of 66 Gy in 30 fractions (2.2 Gy/fraction) was delivered once daily (5 fractions weekly). One month after completing RT, initial tumor responses were evaluated. Median age of patients was 73 years (range, 60 - 82 years). The median survival time was 18.6 months (range, 2-135). The actuarial overall survival rates at 2 and 3 years were 39 % and 23 %, and cause-specific survival rate at 2 and 3 years were 57 % and 47 %, respectively. When primary tumor was controlled, the 2- and 3-year CSS were 56 % and 45 %, but 32 % and 23 % in those patients with local failure, respectively (P = 0.017). Additionally, the local control rate was associated with the initial tumor response (P = 0.01). No patient experienced grade 4+ toxicity. For stage II-III NSCLC patients aged over 60 years and unfit or rejecting for combination treatment, RT alone showed promising result. Long-term disease control can be expected if an early tumor response to radiation is achieved, which could result in improved overall survival rates.


[Discrimination and classification based on characteristics of bucco-dental data].
Discriminant analysis and its corresponding classification procedures are illustrated by means of two practical applications pertaining to a dental health survey. The discriminating variables refer to dental caries, oral hygiene, periodontal diseases and fracture of anterior teeth. Their relative discriminating power is discussed.


Feeling gutted in chronic kidney disease (CKD): Gastrointestinal disorders and therapies to improve gastrointestinal health in individuals CKD, including those undergoing dialysis.
Chronic kidney disease (CKD) affects 9.1% of the population worldwide. CKD may lead to structural and functional gastrointestinal alterations, including impairment in the intestinal barrier, digestion and absorption of nutrients, motility, and changes to the gut microbiome. These changes can lead to increased gastrointestinal symptoms in people with CKD, even in early grades of kidney dysfunction. Gastrointestinal symptoms have been associated with lower quality of life and reduced nutritional status. Therefore, there has been considerable interest in improving gastrointestinal health in this clinical population. Gastrointestinal health can be influenced by lifestyle and medications, particularly in advanced grades of kidney dysfunction. Therapies focused on gastrointestinal health have been studied, including the use of probiotics, prebiotics, and synbiotics, yielding limited and conflicting results. This review summarizes the alterations in the gastrointestinal tract structure and function and provides an overview of potential nutritional interventions that kidney disease professionals can provide to improve gastrointestinal health in individuals with CKD.


Pig production in the Solomon Islands. III. The influence of breed, diet and housing on reproduction and growth.
In the Solomon Islands pigs grow slowly and sows have small litters. An experiment using 124 pigs in 16 litters from eight sows compared the effect of village breed, village diet and village husbandry which encouraged infection of pigs with Stephanurus dentatus, with the effect of European breed, commercial rations and a system of management which ensured freedom from S. dentatus infection on the productivity of pigs. It was shown that the village diet was markedly inferior to the commercial rations and had by far the greatest influence of any of the three factors studied on the parameters measured. The village breed was not inferior in litter size or growth rate when fed on the village diet, but was inferior in growth on the commercial diet. No harmful effects of the village husbandry system were detected on either type of pig but this may have been due to the lightness of S. dentatus infections.


Osmotic stress relief antibiotic tolerance of 1,8-cineole in biofilm persister cells of Escherichia coli O157:H7 and expression of toxin-antitoxin system genes.
The control of E. coli activity from forming biofilm and persister cells is an essential factor in both the health and food industries. The efficacy of antimicrobial treatment is often limited due to their low penetrability as biofilm formation protect cells within from physical or chemical threats. Among other factors, osmotic stress has shown to have a high capacity to enhance the antimicrobial activities against various pathogens. Thus, this study aimed to test the hypothesis that the antimicrobial activity of cineole (CN) could be enhanced under osmotic stress to inhibit biofilm and persister cells. Time-kill analysis revealed that CN under NaCl-induced osmotic stress (CN-S) had better inhibitory effect on E. coli biofilm. 5% CN-S altered the integrity, hydration, motilities and exopolysaccharide production of E. coli cells. Also, the outer membrane permeability, surface roughness and hydrophobicity which determine initial cell adhesion, aggregation and colony assembly were significantly perturbed. Furthermore, the expression levels of virulence genes stx1, stx2, eae, flhD, and the TA system antitoxin genes mazE, hipB were downregulated. When applied to cucumber, the rate of increase in internalized bacterial cells significantly reduced after storage at 4 °C for 48 h. Thus, the results suggested that the application of osmotic stress could minimize the working concentration of antimicrobials in real food systems, which could be helpful in counteracting the growing concern of microbial resistance.


Vagus nerve stimulation during rehabilitative training enhances recovery of forelimb function after ischemic stroke in aged rats.
Advanced age is associated with a higher incidence of stroke and worse functional outcomes. Vagus nerve stimulation (VNS) paired with rehabilitative training has emerged as a potential method to improve recovery after brain injury but to date has only been evaluated in young rats. Here, we evaluated whether VNS paired with rehabilitative training would improve recovery of forelimb function after ischemic lesion of the motor cortex in rats 18 months of age. Rats were trained to perform the isometric pull task, an automated, quantitative measure of volitional forelimb strength. Once proficient, rats received an ischemic lesion of the motor cortex and underwent rehabilitative training paired with VNS for 6 weeks. VNS paired with rehabilitative training significantly enhances recovery of forelimb function after lesion. Rehabilitative training without VNS results in a 34% ± 19% recovery, whereas VNS paired with rehabilitative training yields a 98% ± 8% recovery of prelesion of forelimb function. VNS does not significantly reduce lesion size. These findings demonstrate that VNS paired with rehabilitative training enhances motor recovery in aged subjects in a model of stroke and may suggest that VNS therapy may effectively translate to elderly stroke patients.


The mechanism of insulin secretion after oral glucose administration V. Portal venous IRI concentration in dogs after ingestion of glucose.
Concentrations of immunoreactive insulin activity and of blood glucose were measured in portal and peripheral venous blood in six conscious dogs after oral administration of 1.0 g/kg glucose. Portal venous samples were obtained either by chronic catheterization or by direct puncture of the portal vein through a London-cannula. Portal venous IRI was already significantly increased 5 min after the onset of the stimulus. Peripheral venous IRI pattern reflected this early increase, but the peripheral venous blood glucose level was unchanged. The results indicate that the early peripheral venous IRI increase reflects a pancreatic insulin secretory reflex.


Sutton's law in epilepsy: because that is where the lesion is.
Successful epilepsy surgery requires unambiguous identification of the epileptogenic zone. This determination may be a challenge when the pre-surgical evaluation yields conflicting data. We evaluated an adult patient with a right insular mass, but a seizure semiology, interictal EEG, and ictal EEG, suggesting left temporal lobe epilepsy. Resection of the mass, a ganglioglioma, resulted in seizure freedom and disappearance of interictal left temporal lobe epileptiform discharges. This case illustrates the principle that in localization-related epilepsy, the money is usually in the mass.


Purified Tetrastigma hemsleyanum vines polysaccharide attenuates EC-induced toxicity in Caco-2 cells and Caenorhabditis elegans via DAF-16/FOXO pathway.
Ethyl Carbamate (EC), as a carcinogen widely found in fermented foods, was verified that its cytotoxicity was associated with oxidative stress. Polysaccharides from natural sources due to their antioxidative capacity have attracted great attention in the past time. In this study, purified polysaccharide from Tetrastigma hemsleyanum vines (TVP) with 64.89 kDA was extracted and conducted multiple analysis to identify its structural information. It could be discovered that TVP was composed of mannose, rhamnose, glucuronic acid, glucose, galactose, and arabinose. In vitro, TVP could inhibit cytotoxicity and genotoxicity, attenuate oxidative damage and mitochondrial dysfunction induced by EC in Caco-2 cells. Meanwhile, TVP could suppress apoptosis by mTOR and Bcl-2 signaling pathways, ameliorate oxidative via Sirt1-FoxO1 and Nrf2-Keap1 signaling pathways. In vivo, EC as well triggered the decline of survival and athletic ability in Caenorhabditis elegans (C. elegans) and TVP could reverse the decline. In the meantime, TVP could ameliorate oxidative damage in N2 and daf-2 (-) mutant but fail in daf-16 (-) mutant, which suggested that DAF-16 (FOXO) might affect the antioxidative protection of TVP in C. elegans. In brief, our results manifested that TVP could attenuate EC-induced cytotoxicity both in vitro and in vivo.


Treatments of heating and ultrasound improve the inhibition of gallocatechin gallate on tyrosinase.
Gallocatechin gallate (GCG), a catechin of tea polyphenols, possesses inhibitory ability against tyrosinase, but few studies have reported how common processing methods affect it. In this research, the influence of heating and ultrasound treatments on the inhibition of GCG against tyrosinase was explored by ultraviolet-visible absorption, fluorescence spectroscopy, high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry. Both heating and ultrasound treatments of GCG alone improved GCG's inhibitory ability against tyrosinase compared with the untreated, and a combination of heating and ultrasound treatment (100 °C, 20 min + 630 W, 20 min) further decreased the relative tyrosinase activity to 26.8%. The treated GCG exhibited a stronger fluorescence quenching effect on tyrosinase, but did not have any influence on the static quenching mechanism. Compared to the untreated GCG, the binding constants of treated GCG by heating, ultrasound and their combination with tyrosinase significantly increased, but the number of binding sites was still approximately one and the main driving force of the treated GCG was still hydrophobic interaction. After treatments of heating, ultrasound and their combination, the composition of GCG solutions was changed. The enhanced inhibition of treated GCG on tyrosinase may be due to partial conversion of GCG into epigallocatechin-3-gallate (EGCG) and gallic acid (GA), which may cooperate with GCG to better inhibit the enzyme activity. This study has provided some valuable information for the application of catechins against tyrosinase in food processing and cosmetic industry. © 2022 Society of Chemical Industry.


Effect of cyclic nucleotides on mitogen. Responsiveness of lymphocytes from patients undergoing dialysis.
Lymphocytes from 10 asymptomatic patients undergoing hemodialysis and from eight control subjects were repeatedly cultured with exposure to various concentrations of cyclic nucleotides and theophylline in addition to mitogen. The blastogenic response of the patients' lymphocytes was inhibited by molar concentrations of dibutyryl cyclic AMP which had much less or no inhibitory effected on the response of the control subjects' lymphocytes. This suppressive effect was not potentiated by theophylline. Cyclic GMP enhanced the proliferative response of the patients' lymphocytes as well as that of the controls. In contrast to absolute counts per minute per culture, the suppression by dibutyryl cyclic AMP of mitogen-induced blastogenesis noted in this study clearly separated the in vitro behavior of the patients' lymphocytes from that of the controls' lymphocytes and may serve as a useful marker of cellular dysfunction in such patients.


MATWIN: bridging the gap between academic research and industry.
MATWIN (Maturation and Accelerating Translation With INdustry) is part of the nationwide effort to support cancer innovation. This unique program is willing to support innovative research projects providing tools, resources, and staff dedicated to project leaders wishing to optimize the industrial attractiveness of their project. The overall objective is clear: fight cancer always more effectively.


Delivery of tissue plasminogen activator and streptokinase magnetic nanoparticles to target vascular diseases.
Thrombolytic therapy for acute myocardial infarction standardly makes use of the medications streptokinase (SK) and tissue plasminogen activator (tPA). In this study, the potential of silica-coated magnetic nanoparticles (SiO2-MNPs) as nanocarriers clinical thrombolytic therapy was investigated. SiO2-MNPs for use in targeted therapeutic delivery of tPA and SK were prepared using a combined technique incorporating controlled precipitation and hydrothermal methods. Response surface methodology (RSM) was employed to evaluate the efficiency of the SiO2-MNPs. The production of SK secreted from Streptococcus equi was enhanced using random mutagenesis. The tPA and SK A were encapsulated by means of a silanizing agent with a surface rich in 3-aminopropyltrimethoxysilane layered around the SiO2-MNPs. Blood clot lysis assays and fibrin-containing agarose plates were used to carry out in vitro thrombolysis testing. The optimum conditions for producing MNPs were found to be at pH=13 and at a temperature of 75°C for 45 min. Culture conditions of 2.75% NaCl concentration at initial pH=7.5 for 90 s under UV resulted in maximum SK activity. The tPA/SK-conjugated SiO2-MNPs (SiO2-MNP-tPA-SK) increased operating stability in whole blood and storage stability in a buffer by 92%. More effective thrombolysis using magnetic targeting was indicated by a 38% reduction in blood clot lysis time achieved with SiO2-MNP-tPA-SK compared to administering the SiO2-MNPs without guidance. The silica-coated magnetic nanocarriers developed in this study show potential for improved clinical thrombolytic therapy.


Impact of antiretroviral protocols on dynamics of AIDS progression markers.
To assess the "real life" effectiveness of different antiretroviral therapies (ART). A retrospective multicentre observational study in 150 HIV-1 vertically infected children on the progression to AIDS (study A), and in 61 HIV-1 infected children on the evolution of the most relevant markers of progression (study B). All children were categorised into four groups: untreated (NT); on monotherapy (MT); on combination therapy (dual-ART); and on potent ART (HAART). No child in the HAART group progressed to AIDS, whereas 14 children in the NT and seven in the MT groups progressed to AIDS, respectively, the differences being statistically significant. There was a mean increase of 8 units of %CD4+ per year; this was greater in the HAART group than in the other groups. The mean decrease in viral load was 0.65 log(10) copies/ml per year; this was greater in the HAART group than in the NT and MT groups. The HAART group had the lowest probability of returning to baseline %CD4+ and viral load. Potent ART had the greatest protective effect against progression to AIDS in this observational study.


Defect chemistry of polyfluorenes: identification of the origin of "interface defects" in polyfluorene based light-emitting devices.
Deprotonation of hydroxy terminated polyfluorenes results in a greenish emission also providing a rational explanation for so called "interface defects" in polymeric light-emitting devices (PLEDs).


Role of prostanoid EP3/1 receptors in mechanisms of emesis and defaecation in ferrets.
Prostanoid EP receptor agonists are used for a number of clinical indications but may be associated with gastric disturbance. In the present studies we used the ferret and sulprostone (30µg/kg, i.p.) to investigate the role of EP3/1 receptors in mechanisms of emesis and defaecation. The emetic response was antagonized significantly by (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenlypiperidine hydrochloride (CP-99,994; 10mg/kg, i.p.; P<0.05), but not by metoclopramide (0.3 and 3mg/kg), ondansetron (0.1 and 1mg/kg), or scopolamine (3mg/kg); promethazine (3mg/kg) potentiated emesis by approximately 82% (P<0.05). Out of the drugs tested, only scopolamine (3mg/kg) reduced significantly the defaecatory and/or tenesmus response (P<0.05). Bilateral abdominal vagotomy was ineffective to reduce sulprostone (30µg/kg, i.p.)-induced emesis and defaection and/or tenesmus. However, sulprostone (10µg, i.c.v.) administered into the fourth ventricle was emetic but did not induce defaection or tenesmus. These data suggests that the action of sulprostone to induce emesis and defaecation and/or tenesmus is largely independent of the abdominal vagal system, with emesis involving central mechanisms. Emetic mechanisms appear dissociated from those mediating defaecation and/or tenesmus.


[Aspects of pulmonary rheography in normal subjects (author's transl)].
The Authors studied the postural variations of right pulmonary circulation in 30 normal subjects with rheographic technique. In lying position the rheograms remain without modifications concerning the derivations's area (superior or middle or inferior right pulmonary lobes). In standing position the rheogram of superior lobe increases his area, that of inferior lobe decreases and that of middle lobe remains unvariated. This pattern of behaviour is early modified by cardiac or pulmonary diseases. Also if this technique is easy to perform and in our experience is reproducible, we think that we must accept his limits in view of lack of a very accurate and exact calibration.


Serum metabolomic profiling reveals potential biomarkers in systemic sclerosis.
Systemic sclerosis (SSc) is a chronic and systemic autoimmune disease marked by the skin and visceral fibrosis. Metabolic alterations have been found in SSc patients; however, serum metabolomic profiling has not been thoroughly conducted. Our study aimed to identify alterations in the metabolic profile in both SSc patients before and during treatment, as well as in mouse models of fibrosis. Furthermore, the associations between metabolites and clinical parameters and disease progression were explored. High-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS)/MS was performed in the serum of 326 human samples and 33 mouse samples. Human samples were collected from 142 healthy controls (HC), 127 newly diagnosed SSc patients without treatment (SSc baseline), and 57 treated SSc patients (SSc treatment). Mouse serum samples were collected from 11 control mice (NaCl), 11 mice with bleomycin (BLM)-induced fibrosis and 11 mice with hypochlorous acid (HOCl)-induced fibrosis. Both univariate analysis and multivariate analysis (orthogonal partial least-squares discriminate analysis (OPLS-DA)) were conducted to unravel differently expressed metabolites. KEGG pathway enrichment analysis was performed to characterize the dysregulated metabolic pathways in SSc. Associations between metabolites and clinical parameters of SSc patients were identified by Pearson's or Spearman's correlation analysis. Machine learning (ML) algorithms were applied to identify the important metabolites that have the potential to predict the progression of skin fibrosis. The newly diagnosed SSc patients without treatment showed a unique serum metabolic profile compared to HC. Treatment partially corrected the metabolic changes in SSc. Some metabolites (phloretin 2'-O-glucuronide, retinoyl b-glucuronide, all-trans-retinoic acid, and betaine) and metabolic pathways (starch and sucrose metabolism, proline metabolism, androgen and estrogen metabolism, and tryptophan metabolism) were dysregulated in new-onset SSc, but restored upon treatment. Some metabolic changes were associated with treatment response in SSc patients. Metabolic changes observed in SSc patients were mimicked in murine models of SSc, indicating that they may reflect general metabolic changes associated with fibrotic tissue remodeling. Several metabolic changes were associated with SSc clinical parameters. The levels of allysine and all-trans-retinoic acid were negatively correlated, while D-glucuronic acid and hexanoyl carnitine were positively correlated with modified Rodnan skin score (mRSS). In addition, a panel of metabolites including proline betaine, phloretin 2'-O-glucuronide, gamma-linolenic acid and L-cystathionine were associated with the presence of interstitial lung disease (ILD) in SSc. Specific metabolites identified by ML algorithms, such as medicagenic acid 3-O-b-D-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-beta-glucuronide, valproic acid glucuronide, have the potential to predict the progression of skin fibrosis. Serum of SSc patients demonstrates profound metabolic changes. Treatment partially restored the metabolic changes in SSc. Moreover, certain metabolic changes were associated with clinical manifestations such as skin fibrosis and ILD, and could predict the progression of skin fibrosis.


Residual hypernasality in repaired cleft palate.
This article reviews selected components of the speech process in children with a repaired cleft palate in order to provide the speech-language pathologist with a framework for decision-making in the selection of appropriate identification and management strategies. Discussion is offered which intends to clarify the phenomena of velopharyngeal valving, nasality, and hypernasality. With an understanding of these fundamental phenomena, suggestions are proposed for management approaches which may be applied to the more common bases of hypernasality in children with repaired clefts.


Introduction to Supercapacitors.
Guest editors Zhaojun Han, Ruopian Fang, Dewei Chu, Da-Wei Wang and Kostya (Ken) Ostrikov, introduce this Nanoscale Advances themed issue on supercapacitors.


A novel dendritic cell population in human blood: one-step immunomagnetic isolation by a specific mAb (M-DC8) and in vitro priming of cytotoxic T lymphocytes.
Originating from a common progenitor cell, dendritic cells (DC) appear to develop along early branched pathways into various yet ill-defined subpopulations residing at various sites throughout the body where they capture and present antigen in the most professional fashion. Here we give evidence for a unique subpopulation of human DC circulating in blood that account for 0.5-1% of blood leukocytes only, their most specific characteristic being the expression of a cell surface protein recognized by a novel monoclonal antibody (M-DC8) which enables their isolation by a one-step immunomagnetic procedure. The isolated cells (> 97% pure) present morphologically as typical dendritic cells. They express the Fc(gamma)RIII (CD16), so far not found on DC, and avidly phagocytose latex beads as well as opsonized erythrocytes. These cells not only present antigens efficiently to naive T cells but also induce purified CD8+ T cells to become alloantigen-specific cytotoxic cells. Furthermore, when loaded with a tyrosinase-derived peptide they stimulate T cells from normal donors and melanoma patients to exhibit MHC-restricted specific cytotoxicity against melanoma cells.


"Most of the cases are very similar.": Documenting and corroborating conflict-related sexual violence affecting Rohingya refugees.
In August 2017, a large population of Rohingya from northern Rakhine state in Myanmar fled to Bangladesh due to "clearance operations" by the Myanmar security forces characterized by widespread and systematic violence, including extensive conflict-related sexual violence (CRSV). This study sought to document the patterns of injuries and conditions experienced by the Rohingya, with a specific focus on sexual violence. Qualitative interviews were conducted with 26 health care professionals who cared for Rohingya refugees after their arrival in Bangladesh between November 2019 and August 2020. Health care workers universally reported hearing accounts and seeing evidence of sexual and gender-based violence committed against Rohingya people of all genders by the Myanmar military and security forces. They observed physical and psychological consequences of such acts against the Rohingya while patients were seeking care. Health care workers shared that patients faced pressure not to disclose their experiences of CRSV, likely resulted in an underreporting of the prevalence of sexual violence. Forced witnessing of sexual violence and observed increases in pregnancy and birth rates as a result of rape are two less-reported issues that emerged from these data. Healthcare workers corroborated previous reports that the Rohingya experienced CRSV at the hands of the Myanmar military and security forces. Survivors often revealed their experiences of sexual violence while seeking care for a variety of physical and psychological conditions. Stigma, cultural pressure, and trauma created barriers to disclosing experiences of sexual violence and likely resulted in an underreporting of the prevalence of sexual violence. The findings of this research emphasize the importance of offering universal and comprehensive trauma-informed services to all refugees with the presumption of high rates of trauma in this population and many survivors who may never identify themselves as such.


Understanding the role of food matrix on the digestibility of dairy products under elderly gastrointestinal conditions.
This study aimed to evaluate the effect of some elderly in vitro gastrointestinal (GI) conditions on proteolysis and lipolysis extent, calcium, vitamins A and D bioaccessibility and lactose release in milk, yogurt, fresh and aged cheeses. To evaluate the impact of the some oral, gastric and intestinal disorders appearing with ageing on dairy digestion, three in-vitro elderly models were applied (E1 (oral altered conditions), E2 (oral and gastric altered conditions) and E3 (oral, gastric and intestinal altered conditions)) plus a healthy adult one as control. Proteolysis extent was significantly affected by elderly GI alterations (p < 0.05) (around 40% of reduction compared to control), being fresh and aged cheese proteolysis the most affected with an important descrease in leucine release (18 and 25%, respectively). Calcium, vitamins A and D3 bioaccesibility and lactose release seemed not to be highly compromised in these models of elderly conditions; however, the micronutrients bioaccessibility was very dependent on dairy matrix's structure. Finally, the amount of the lipid hydrolyzed fraction of cheeses is not influenced in the investigated models.


Pituitary apoplexy associated with acute cerebral infarct.
We describe a case of pituitary apoplexy associated with acute cerebral infarction. A review of the literature regarding the pathogenesis of cerebral infarction in the presence of pituitary apoplexy is presented and management options proposed.


Immune suppression of JC virus gene expression is mediated by SRSF1.
Progressive multifocal leukoemcephalopathy (PML) is a fatal demyelinating disease caused by the human neurotropic JC virus (JCV). JCV infects the majority of the human population during childhood and establishes a latent/persistent life-long infection. The virus reactivates under immunosuppressive conditions by unknown mechanisms, resulting in productive infection of oligodendrocytes in the central nervous system (CNS). Given the fact that the natural occurrence of PML is strongly associated with immunosuppression, the functional and molecular interaction between glial cells and neuroimmune signaling mediated by soluble immune mediators is likely to play a major role in reactivation of JCV and the progression of the lytic viral life cycle leading to the development of PML. In order to explore the effect of soluble immune mediators secreted by peripheral blood mononuclear cells (PBMCs) on JCV transcription, primary human fetal glial (PHFG) cells were treated with conditioned media from PBMCs. We observed a strong suppression of JCV early as well as late gene transcription in cells treated with conditioned media from induced PBMCs. Using a variety of virological and molecular biological approaches, we demonstrate that immune mediators secreted by PBMCs induce the expression of SRSF1, a strong inhibitor of JCV gene expression, and inhibit the replication of JCV. Our results show that downregulation of SRSF1 in glial cells overcomes the suppression of JCV gene expression and its replication mediated by soluble immune mediators. These findings suggest the presence of a novel immune signaling pathway between glial cells and PBMCs that may control JCV gene expression during the course of viral reactivation.


Improved survival in both men and women with diabetes between 1980 and 2004--a cohort study in Sweden.
In Sweden, diabetes prevalence is increasing in spite of unchanged incidence, indicating improved survival. In recent US studies mortality in diabetic subjects has decreased over three decades, but only in men. Our aim was to study mortality over time in diabetic subjects. The annual Swedish Living Conditions Survey from 1980 to 2004 has been record-linked to the Cause of Death Register in order to study trends in mortality risk for those reporting diabetes as a chronic illness. Survival and the relative mortality risk within 5 years of follow-up have been calculated for a random sample of men and women aged 40-84 years with (n = 3,589) and without diabetes (n = 85,685) for the period 1980 to 2004. Poisson regression models were used. The age-adjusted mortality risk relative to non-diabetics within 5 years of follow-up for men was doubled during all periods. The relative risk for women was initially about 2.5, with a substantial drop in mortality in 1995-1999 to 1.45 although it increased to 1.90 in the last period. Using models that took into consideration the presence of heart disease, hypertension, daily smoking, and socio-economic status at the initial interview did not change the relative mortality risk. The age-adjusted 10-year observed survival rate for men with diabetes increased from 41.4% 1980-1984 to 51.5% in 1995-1999. The observed survival for women increased from 43.7% to 61.0%. Survival rates have improved in subjects with diabetes since the early 1980s, more so in women than in men, thereby decreasing the gap to non-diabetic women.


Effects of traumatic brain injury on cerebral high-energy phosphates and pH: a 31P magnetic resonance spectroscopy study.
Traumatic injuries to the CNS produce tissue damage both through mechanical disruption and through more delayed autodestructive processes. Delayed events include various biochemical changes whose nature and time course remain to be fully elucidated. Magnetic resonance spectroscopy (MRS) techniques permit repeated, noninvasive measurement of biochemical changes in the same animal. Using phosphorus MRS, we have examined certain biochemical responses of rats over an 8-h period following lateralized brain injury (1.5-2.5 atmospheres) using a standardized fluid-percussion model recently developed in our laboratory. Following injury, the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) showed a biphasic decline: The first decline reached its nadir (4.8 +/- 0.4 to 2.8 +/- 0.7) by 40 min post-trauma with recovery by 100 min, followed by a second decline by 2 h that persisted for the remaining 6-h observation period (mean 2.5 +/- 0.5). The first, but not the second, decrease in PCr/Pi was associated with tissue acidosis (pH 7.10 +/- 0.03 to 6.86 +/- 0.11). No changes in ATP occurred at any time during the injury observation period. Such changes may be indicative of altered mitochondrial energy production following brain injury, which may account for the reduced capacity of the cell to recover from traumatic injury.


Hydranencephaly associated with interruption of bilateral internal carotid arteries.
Hydranencephaly is a rare and fatal central nervous system disorder where all or nearly all of the bilateral cerebral hemispheres are absent. The extensive hollow cerebrum is replaced with cerebrospinal fluid. Clinically, the differential diagnoses of hydranencephaly include severe hydrocephalus and alobar holoprosencephaly. Nearly all cases are sporadic, involving approximately 1 in 5000 continuing pregnancies. The exact main cause is still unknown, but hydranencephaly is usually found to develop secondarily to the occlusion of cerebral arteries above the supraclinoid level. We present the case of a 1-month-old male infant with hydranencephaly initially thought to be severely hydrocephalus via routine antenatal intrauterine sonography performed at 35 weeks of gestation. Hydranencephaly was confirmed by brain sonography, brain magnetic resonance imaging and magnetic resonance angiography postnatally. We discuss several imaging features that are helpful in distinguishing hydranencephaly from extreme hydrocephaly. Different theories that have been recently proposed regarding the origin of hydranencephaly are reviewed.


Left atrial wall hematoma as a consequence of percutaneous coronary angioplasty.
Intramural left atrial dissection and hematoma as a complication of a coronary stenting procedure is a very rare entity. We report the case of a 73-year-old man who underwent percutaneous coronary angioplasty for a severe stenosis of the left circumflex coronary artery, complicated by a left atrial intramural hematoma, and was successfully treated with via a minimally invasive port-access surgical approach.


Comparative immunoelectron microscopy with monoclonal antibodies on yellow fever virus-infected cells: pre-embedding labelling versus immunocryoultramicrotomy.
To study the intra- and extracellular distribution of yellow fever virus 17D (YFV)-specific antigens, pre-embedding immunoelectron microscopy (IEM) and IEM on ultrathin frozen sections were carried out comparatively using monoclonal antibodies (MAB) and YFV-infected cells. In addition, three electron-dense marker systems (IgG-ferritin and IgG-gold and protein A-gold) were compared for their efficiency in detecting bound MAB. Pre-embedding immuno-labelling was performed in microtest plates followed by in situ embedding and immunocryoultramicrotomy was performed using pellets of sucrose-infused cells. In both procedures, cells were prefixed with different concentrations of glutaraldehyde (GA). In pre-embedding IEM virus-specific antigens could be detected on the envelopes of extracellular virions with YFV-neutralizing MAB. Using immunocryoultramicrotomy, neutralizing MAB bound to intracellular mature virions as well as to viral antigens incorporated into cytoplasmic membranes. A concentration of 1% GA destroyed antigenicity entirely, while with 0.25% and 0.1% GA immunoreactivity was retained for more than 3 mth. Some highly reactive MAB labelled antigen significantly in pre-embedding IEM, when used at concentrations of 1 ng/ml. Immunocryoultramicrotomy was 10-100 times less sensitive. On cryosections colloidal gold was the marker of choice, due to the fact that it showed less nonspecific sticking to intracellular components and that it was easily detectable on highly contrasted cryosections. Owing to their higher sensitivity, IgG-ferritin conjugates were preferred in pre-embedding IEM.


Pressure-related torticollis: an unusual manifestation of pseudotumor cerebri.
A 9-year-old boy with pseudotumor cerebri who presented with neck pain and an accompanying torticollis is described. The patient exhibited bony abnormalities of the upper cervical spine and facial asymmetry that suggested a congenital torticollis. Reduction of the increased cerebrospinal fluid pressure by lumbar puncture resulted in a prompt and dramatic resolution of the cervical symptoms and signs. Increased cerebrospinal fluid pressure should be added to the list of those disorders that may give rise to reversible torticollis.


Prognostic Factors of Long-term Survival Following Radical Resection for Ampullary Carcinoma.
The incidence of adenocarcinoma of the ampulla of Vater has been increasing over the past years. Nevertheless, it is still a rare disease and the prognostic factors predicting long-term survival are not sufficiently clarified. This study aims to evaluate the association between histopathological characteristics and long-term survival of patients with ampullary cancer after curative resection, as well as the efficiency of immunohistochemical expression of CK7, CK20, and CDX2 to distinguish the histopathological (intestinal or pancreaticobiliary) patterns. Demographic, histopathological data, pTNM stage, and immunohistochemical expression patterns were collected from 65 patients with adenocarcinoma of the ampulla of Vater. Five and 10-year overall and disease-free survival rates after curative resection were determined. Of the 65 patients with ampullary carcinoma, 47 (72%) underwent radical resection. The 5- and 10-year overall survival rate was 46% and 37%, respectively. Our results demonstrate that the main prognostic factors were the presence and number of lymph node metastases, lymph node ratio (LNR), differentiation grade, and lymphovascular invasion. After multivariate analysis, only lymph node ratio ≥ 20% remained an independent prognostic factor of survival (HR: 2.63 95% CI: 1.05-6.61; p = 0.039). Here, we demonstrated more evidence that the lymph node metastases are associated with poor prognosis in ampullary carcinoma. Particularly, the relation between the number of metastatic lymph nodes and the number of harvested lymph node (LNR) should be considered a major prognostic factor.


Genetic polymorphism and prostate cancer aggressiveness: a case-only study of 1,536 GWAS and candidate SNPs in African-Americans and European-Americans.
Genome-wide association studies have established a number of replicated single nucleotide polymorphisms (SNPs) for susceptibility to prostate cancer (CaP), but it is unclear whether these susceptibility SNPs are also associated with disease aggressiveness. This study evaluates whether such replication SNPs or other candidate SNPs are associated with CaP aggressiveness in African-American (AA) and European-American (EA) men. A 1,536 SNP panel which included 34 genome-wide association study (GWAS) replication SNPs, 38 flanking SNPs, a set of ancestry informative markers, and SNPs in candidate genes and other areas was genotyped in 1,060 AA and 1,087 EA men with incident CaP from the North Carolina-Louisiana Prostate Cancer Project (PCaP). Tests for association were conducted using ordinal logistic regression with a log-additive genotype model and a 3-category CaP aggressiveness variable. Four GWAS replication SNPs (rs2660753, rs13254738, rs10090154, rs2735839) and seven flanking SNPs were associated with CaP aggressiveness (P < 0.05) in three genomic regions: One at 3p12 (EA), seven at 8q24 (5 AA, 2 EA), and three at 19q13 at the kallilkrein-related peptidase 3 (KLK3) locus (two AA, one AA and EA). The KLK3 SNPs also were associated with serum prostate-specific antigen (PSA) levels in AA (P < 0.001) but not in EA. A number of the other SNPs showed some evidence of association but none met study-wide significance levels after adjusting for multiple comparisons. Some replicated GWAS susceptibility SNPs may play a role in CaP aggressiveness. However, like susceptibility, these associations are not consistent between racial groups.


A 3D microfluidic liver model for high throughput compound toxicity screening in the OrganoPlate®.
We report the development, automation and validation of a 3D, microfluidic liver-on-a-chip for high throughput hepatotoxicity screening, the OrganoPlate LiverTox™. The model is comprised of aggregates of induced pluripotent stem cell (iPSC)-derived hepatocytes (iHep) seeded in an extracellular matrix in the organ channel and co-cultured with endothelial cells and THP-1 monoblasts differentiated to macrophages seeded in the vascular channel of the 96 well Mimetas OrganoPlate 2-lane. A key component of high throughput screening is automation and we report a protocol to seed, dose, collect and replenish media and add assay reagents in the OrganoPlate 2-lane using a standard laboratory liquid handling robot. A combination of secretome measurements and image-based analysis was used to demonstrate stable 15 day cell viability, albumin and urea secretion. Over the same time-period, CYP3A4 activity increased and alpha-fetoprotein secretion decreased suggesting further maturation of the iHeps. Troglitazone, a clinical hepatotoxin, was chosen as a control compound for validation studies. Albumin, urea, hepatocyte nuclear size and viability staining provided Robust Z'factors > 0.2 in plates treated 72 h with 180 μM troglitazone compared with a vehicle control. The viability assay provided the most robust statistic for a Robust Z' factor = 0.6. A small library of 159 compounds with known liver effects was added to the OrganoPlate LiverTox model for 72 h at 50 μM and the Toxicological Prioritization scores were calculated. A follow up dose-response evaluation of select hits revealed the albumin assay to be the most sensitive in calculating TC50 values. This platform provides a robust, novel model which can be used for high throughput hepatotoxicity screening.


Heparin-neutralizing activity, total progressive antithrombin and ethanol gel test in acute chest pain.
92 patients admitted to a cardiac monitoring unit with chest pain were investigated. The mean heparin-neutralizing activity of the 34 patients with severe myocardial infarction was found to be significantly different from the mean of 70 normal controls. However, there was considerable overlap between individual observations and the normal range. Only 5 of the 34 patients with severe myocardial infarction had antithrombin levels outside the normal range. In patients with a severe myocardial infarct tested on the 2nd and 3rd day after infarction there was s significant increase in the number of positive ethanol gel tests compared with the other patients studied.


Evaluation of rapid tests for diagnosis of acute hepatitis E.
Hepatitis E virus diagnosis still presents difficulties due to discordant results among diagnostic tests. The aim of this study was to evaluate the performance of two rapid tests for detection of anti-HEV IgM antibodies. The rapid tests were compared with three commercial anti-HEV ELISA assays and one Real-Time PCR assay on 59 sera from patients with acute viral non-AC hepatitis. The presence of anti-HEV IgM antibodies was evaluated by two rapid tests (Wantai and Assure) on 25 HEV RNA positive samples. Anti-HEV IgM antibodies were detected in 24/25 and 23/25 samples respectively. The sensitivity and specificity of Wantai and Assure Rapid tests were evaluated using the 25 HEV RNA positive samples and 50 HEV RNA negative samples (including sera from acute-phase HAV and HBV infections and blood donors). Overall, the sensitivity of Wantai Rapid and Assure Rapid tests was 96.1% and 92.6% respectively; the specificity of the 2 tests was 100%. Our data suggest the potential use of anti-HEV IgM rapid assays as a first line test in primary health care settings, particularly useful for patients with chronic liver disease or pregnant women who urgently need an antiviral treatment.


Interspecific competition models derived from competition among individuals.
This paper demonstrates how discrete-time models describing population dynamics of two competing species can be derived in a bottom-up manner by considering competition for resources among individuals and the spatial distribution of individuals. The competition type of each species is assumed to be either scramble, contest, or an intermediate between them. Individuals of two species are distributed over resource sites or patches following one of three distribution functions. According to the combination of competition types of the two species and the distribution of individuals, various interspecific competition models are derived. Furthermore, a general interspecific competition model that includes various competition models as special cases is derived for each distribution of individuals. Finally, this paper examines dynamics of some of the derived competition models and shows that the likelihood of coexistence of the two species varies greatly, depending on the type of spatial distribution of individuals.


What is "obesity"--an analysis of referral letters to an obesity unit.
To evaluate the quality of referral letters concerning obese patients from general practice and other specialities to an obesity unit. Retrospective analysis of referral letters in 500 consecutive patient records. Academic specialist obesity unit. Most letters came from general practice (70%), followed by internal medicine/endocrinology (12%). Information on body weight was missing in 13% of all referrals and on height in 24%. Waist circumference was mentioned in 1%. Relevant data substantiating possible comorbidities, in particular the metabolic syndrome, was missing in 92-97%. Relevant medication was indicated in 22% of the referrals. On a 3-point, graded global evaluation scale of the referral quality, only 7% of all letters were found to be 'ideal'. The low professional quality of these referrals may reflect the fact that physicians find the term 'obesity' enough to warrant the referral without further specifications. An alternative explanation for the inadequate referrals is the well documented negative attitude of physicians, who consider obesity as sloth and as a self-inflicted condition, not necessitating further medical details.


Bidirectional attack on the actin cytoskeleton. Bacterial protein toxins causing polymerization or depolymerization of actin.
The actin cytoskeleton is one of the major targets of bacterial protein toxins. The family of binary actin-ADP-ribosylating toxins, including Clostridium difficile transferase CDT, Clostridium perfringens iota toxin and Clostridium botulinum C2 toxin, modifies arginine-177 of actin. Thereby actin polymerization is blocked. By contrast, actin polymerization is facilitated by the tripartite Photorhabdus luminescens toxin complex including TccC3, which modifies actin at threonine-148. The review discusses both toxin families in respect to recent findings.


Acute diabetes insipidus in severe head injury: a prospective study.
The incidence and risk factors for acute diabetes insipidus after severe head injury and the effect of this complication on outcomes have not been evaluated in any large prospective studies. We conducted a prospective study of all patients admitted to the surgical ICU of a Level I trauma center with severe head injury (head Abbreviated Injury Score [AIS] >or= 3). The following potential risk factors with p < 0.2 on bivariate analysis were included in a stepwise logistic regression to identify independent risk factors for diabetes insipidus and its association with mortality: age, mechanism of injury (blunt or penetrating), blood pressure, Glasgow Coma Scale, Injury Severity Score, head and other body area AIS, skull fracture, cerebral edema and shift, intracranial hemorrhage, and pneumocephaly. There were 436 patients (blunt injuries, 392; penetrating injuries, 44); 387 patients had isolated head injury. Diabetes insipidus occurred in 15.4% of all patients (blunt, 12.5%; penetrating, 40.9%; p < 0.0001) and in 14.7% of patients with isolated head injury (blunt, 11.8%; penetrating, 39.5%; p < 0.0001). The presence of major extracranial injuries did not influence the incidence of diabetes insipidus. Independent risk factors for diabetes insipidus in isolated head injury were Glasgow Coma Scale<or=8, cerebral edema, and head AIS>3. Diabetes insipidus was an independent risk factor for death (adjusted odds ratio, 3.96; 95% CI [1.65, 9.72]; adjusted p value = 0.002). The incidence of acute diabetes insipidus in severe head injury is high, especially in penetrating injuries. Independent risk factors for diabetes insipidus include a Glasgow Coma Scale<or=8, cerebral edema, and head AIS>3. Acute diabetes insipidus was associated with significantly increased mortality.


Evaluation of fluoride and sodium hypochlorite solutions during the electrochemical dissolution of conventional NiTi instruments and Gold thermomechanically treated NiTi instruments.
To compare the dissolution time of two solutions, a fluoride solution and a sodium hypochlorite solution, both saturated with sodium chloride, during the electrochemical dissolution of instruments consisting of conventional nickel-titanium alloy and Gold thermomechanically treated nickel-titanium alloy. Two solutions, an NaF solution consisting of 12 g L-1 NaF with 180 g L-1 NaCl and an NaOCl solution consisting of 2.5% NaOCl with 180 g L-1 NaCl, were evaluated in a polarization test of a sample of 48 ProTaper Universal F1 (PTU F1) and WaveOne Gold Small (WOGS) instruments. The electric potentials were 0.5 V and 5 V for the NaF and NaOCl solutions, respectively. The electrochemical cell consisted of three electrodes for the polarization test of the PTU F1 and WOGS instruments, which had 6 mm of the tip immersed in the test solutions. The electric current was recorded for 540 s. If complete dissolution of the immersed tip occurred in less than the expected time, the experiment was considered complete. The time variations (in seconds) of the instruments in the solutions were measured. Data were subjected to statistical analysis using the Mann-Whitney, Kruskal-Wallis and Dunn tests. The corrosion patterns of the instruments were evaluated by scanning electron microscopy (SEM). The NaF and NaOCl solutions were associated with significantly different (P = 0.000) dissolution times of the instrument, with mean values of 12.96 s and 83.63 s, respectively. There was no significant difference (P = 0.649) in dissolution time between the PTU F1 and WOGS instruments. NaF and NaOCl solutions were able to electrochemically dissolve PTU F1 and WOGS instruments. However, the NaF solution achieved dissolution in significantly less time.


Glycemic reduction alters white blood cell counts and inflammatory gene expression in diabetes.
Systemic inflammation contributes to cardiovascular disease in patients with type 2 diabetes, and elevated white blood cell (WBC) counts are an established risk factor. Our goal is to describe changes in WBCs and inflammatory markers after glycemic reductions in diabetes. This study enrolled 63 subjects with poorly controlled diabetes, defined as hemoglobin A1c (HbA1c) ≥8% [64 mmol/mol]. Circulating granulocytes and mononuclear cells were separated by histopaque double-density protocol. Inflammatory markers from these isolated WBCs were assessed at baseline and after 3 months of medical management. After 3 months, significant glycemic reduction, defined as a decrease in HbA1c ≥ 1.5%, occurred in 42 subjects. Fasting plasma glucose decreased by 47% (165.6 mg/dL), and HbA1c decreased from 10.2 ± 1.8 to 6.8 ± 0.9. Glycemic reductions were associated with a 9.4% decrease in total WBC counts, 10.96% decrease in neutrophils, and 21.74% decrease in monocytes. The mRNA levels of inflammatory markers from granulocytes and mononuclear cells decreased, including receptor for advanced glycation endproducts; S100 calcium binding proteins A8, A9, A12; krüppel-like factor 5; and IL-1. Also, circulating levels of IL-1β and C-reactive protein decreased. Insulin dose was a mediator between HbA1c and both total WBC and neutrophil counts, but not changes in WBC inflammatory markers. In contrast, the 17 subjects without significant glycemic reductions showed no significant differences in their WBC counts and proteins of inflammatory genes. Significant glycemic reduction in subjects with poorly controlled diabetes led to reduced circulating WBC counts and inflammatory gene expression.


Influence of processing on pharmacokinetic of typical constituents in radix polygoni multiflori after oral administration by LC-ESI-MS/MS.
The processed radix polygoni multiflori (P-RPM) are produced from the raw radix polygoni multiflori (R-RPM) steamed with black bean juice, but the two traditional Chinese medicines are used to treat the different diseases in clinic. In order to clarify the influence of processing on pharmacological properties of radix polygoni multiflori, an investigation was carried out to compare the pharmacokinetics of typical constituents after oral administration of P-RPM and R-RPM extracts A simple, rapid and sensitive high performance liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was developed and validated for the simultaneous determination of gallic acid, polydatin, 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside (PM-SG), resveratrol, and emodin in rat plasma. Male Sprague-Dawley rats were orally administered the two extracts with approximately the same dosage. It was found that gallic acid was distributed as opened one-compartment model while polydatin, PM-SG and emodin were fitted to an open two-compartment model after oral administration of raw and processed radix polygoni multiflori extract. Cmax and AUC of gallic acid were increased (P<0.01), but Cmax and AUC of PM-SG were descreased (P<0.05). AUC of polydatin and emodin were similar with that of PM-SG. However, resveratrol was not detected in plasma collected at certain intervals following oral administration of the two extracts. These results indicate that influence of the processing could improve the bioavailability of gallic acid and reduce the absorption of PM-SG, polydatin and emodin in rats. The LC-MS/MS method could be used to evaluate the effect of processing on pharmacokinetic of typical constituents in radix polygoni multiflori after oral administration.


Quality indicators for care of osteoarthritis in primary care settings: a systematic literature review.
Despite the high prevalence of osteoarthritis and the prominence of primary care in managing this condition, there is no systematic summary of quality indicators applicable for osteoarthritis care in primary care settings. This systematic review aimed to identify evidence-based quality indicators for monitoring, evaluating and improving the quality of care for adults with osteoarthritis in primary care settings. Ovid MEDLINE and Ovid EMBASE databases and grey literature, including relevant organizational websites, were searched from 2000 to 2015. Two reviewers independently selected studies if (i) the study methodology combined a systematic literature search with assessment of quality indicators by an expert panel and (ii) quality indicators were applicable to assessment of care for adults with osteoarthritis in primary care settings. Included studies were appraised using the Appraisal of Indicators through Research and Evaluation (AIRE) instrument. A narrative synthesis was used to combine the indicators within themes. Applicable quality indicators were categorized according to Donabedian's 'structure-process-outcome' framework. The search revealed 4526 studies, of which 32 studies were reviewed in detail and 4 studies met the inclusion criteria. According to the AIRE domains, all studies were clear on purpose and stakeholder involvement, while formal endorsement and use of indicators in practice were scarcely described. A total of 20 quality indicators were identified from the included studies, many of which overlapped conceptually or in content. The process of developing quality indicators was methodologically suboptimal in most cases. There is a need to develop specific process, structure and outcome measures for adults with osteoarthritis using appropriate methodology.


[Ultrasonic examination of the patency of proximal venous splenorenal anastomoses].
The ultrasonic investigation has established patency of splenorenal anastomoses in 13 of 19 patients examined. When the examination failed to surely estimate the patency the percutaneous transhepatic portography is indicated.


A resected case of liver metastases from extra-adrenal retroperitoneal paraganglioma with von Recklinghausen's disease 16 years after the initial surgery.
The patient was a 46-year-old man who had undergone resection for a bulky retroperitoneal tumor 16 years previously during a follow-up for von Recklinghausen's disease. Histopathological examination of the resected specimen showed that the tumor was an extra-adrenal paraganglioma. After the surgery, he had survived without any recurrence of the tumor. However, 16 years after the initial surgery, liver tumors were identified, and he was referred to our hospital for further investigation and treatment. Abdominal imaging modalities showed three masses in the left lateral segment of the liver. Fluorodeoxyglucose-positron emission tomography/computed tomography showed an abnormal uptake of fluorodeoxyglucose corresponding to the mass lesions. The patient was diagnosed with a metastatic paraganglioma based on histopathological examination of a liver mass biopsy. The patient underwent left lateral sectionectomy of the liver. Histopathological examination of the resected specimen revealed proliferating cells with basophilic cytoplasm and oval densely stained nuclei arranged in an alveolar pattern, which was similar to the findings of the initial resection specimen. Immunohistochemical staining was positive for synaptophysin and chromogranin A. Based on these findings, the resected tumors were histopathologically diagnosed with liver metastases from the retroperitoneal paraganglioma. We concluded that this is an extremely rare case of liver metastases occurring long after the initial resection of extra-adrenal peritoneal paraganglioma with von Recklinghausen's disease.


Isolation of photoprotective signal transduction mutants by systematic bioluminescence screening in Chlamydomonas reinhardtii.
In photosynthetic organisms, photoprotection to avoid overexcitation of photosystems is a prerequisite for survival. Green algae have evolved light-inducible photoprotective mechanisms mediated by genes such as light-harvesting complex stress-related (LHCSR). Studies on the light-dependent regulation of LHCSR expression in the green alga Chlamydomonas reinhardtii have revealed that photoreceptors for blue light (phototropin) and ultraviolet light perception (UVR8) play key roles in initiating photoprotective signal transduction. Although initial light perception via phototropin or UVR8 is known to result in increased LHCSR3 and LHCSR1 gene expression, respectively, the mechanisms of signal transduction from the input (light perception) to the output (gene expression) remain unclear. In this study, to further elucidate the signal transduction pathway of the photoprotective response of green algae, we established a systematic screening protocol for UV-inducible LHCSR1 gene expression mutants using a bioluminescence reporter assay. Following random mutagenesis screening, we succeeded in isolating mutants deficient in LHCSR1 gene and protein expression after UV illumination. Further characterization revealed that the obtained mutants could be separated into 3 different phenotype groups, the "UV-specific", "LHCSR1-promoter/transcript-specific" and "general photoprotective" mutant groups, which provided further insight into photoprotective signal transduction in C. reinhardtii.


Role of β3-adrenoceptors in regulation of retinal vascular tone in rats.
The aim of this study was to determine the role of β(3)-adrenoceptors in the action of endogenous catecholamines (adrenaline and noradrenaline) on rat retinal arterioles in vivo. Using an original high-resolution digital fundus camera, the rat ocular fundus images were captured. The diameter of retinal arterioles contained in the images was measured. Both systemic blood pressure and heart rate were recorded continuously. Adrenaline (0.3-5.0 μg/kg/min, i.v.) increased the diameter of retinal arterioles, mean blood pressure and heart rate in a dose-dependent manner. Under blockade of β(1)/β(2)-adrenoceptors with propranolol (2 mg/kg, i.v. bolus followed by 100 μg/kg/min infusion), adrenaline decreased the diameter of retinal arterioles. Similar observation was made under treatment with the β(3)-adrenoceptor antagonist L-748337 (50 μg/kg, i.v.). The pressor response to adrenaline was enhanced by propranolol, but not by L-748337. The positive chronotropic action of adrenaline was markedly prevented by propranolol, whereas it was unaffected by L-748337. Noradrenaline (0.03-1.0 μg/kg/min, i.v.) decreased the diameter of retinal arterioles but increased the mean blood pressure and heart rate. The effects of noradrenaline on retinal arteriolar diameter and blood pressure were unaffected by propranolol or L-748337. The positive chronotropic action of noradrenaline was almost completely abolished by propranolol. These results suggest that β(3)-adrenoceptors play crucial roles in vasodilator responses to adrenaline of retinal arterioles but have minor or no effect on noradrenaline-induced responses. The results also indicate that the functional role of β(3)-adrenoceptors may be more important than that in peripheral resistance vessels.


Long-Range Energetic Changes Triggered by a Proline Switch in the Signal Adapter Protein c-CrkII.
The signal adapter protein c-CrkII from chicken but not from human uses isomerization at Pro238 in the SH3C domain to regulate the activity of the SH3N domain. The different behavior of human and chicken c-CrkII originates from only two differences in sequence, at positions 239 after Pro238 and 272 in the N-Src loop of SH3C. We analyzed the kinetics of substrate binding to SH3N and an assay for its coupling with Pro238 isomerization in SH3C to identify the molecular path from Pro238 to the substrate binding site of SH3N. The trans→cis isomerization at Pro238 and a relocation of Phe239 re-organize the energetics of a hydrophobic cluster in the N-Src loop of SH3C and re-shape this region to optimize its interactions with SH3N. Concomitantly, the backbone becomes strained at Met272. We suggest that, in human c-CrkII, movement at position 239 and strain at position 272 are not tolerated because the β-branched residues Ile239 and Val272 restrain the backbone mobility and thus destabilize the cis Pro238 form.


New data on the fine structure of Deuteramoeba mycophaga CCAP 1586/1 (Amoebozoa, Tubulinea).
The genus Deuteramoeba is one of the six amoebae genera belonging to the best-known amoeba family - Amoebidae (Amoebozoa, Tubulinea), containing such a popular species as Amoeba proteus. However, members of other genera of the family Amoebidae are much less known, and most of the studies of their morphology and ultrastructure date back to the 1970s and 1980s. Since these "classical" species are believed to be "well studied", their morphology and fine structure rarely become a subject of re-investigation. The absence of modern morphological data may be critical when molecular data of the type strain are not available, and the only way to identify a species is by morphological comparison. For this paper, we performed an ultrastructural study of the strain CCAP 1586/1 - the type strain of the species Deuteramoeba mycophaga. Our study revealed new details of the nuclear structure, including a peripheral layer of filaments and a heterogeneous nucleolus, and provided new data on the cytoplasmic inclusions of this species. We performed a whole-genome amplification of the DNA from a single amoeba cell followed by NGS sequencing and searched for genetic evidence for the presence of a putative nuclear parasite detected in 2017, but found no evidence for the presence of Opisthosporidia.


Student engagement in pharmacology courses using online learning tools.
To assess factors influencing student engagement with e-tools used as a learning supplement to the standard curriculum in pharmacology courses. A suite of 148 e-tools (interactive online teaching materials encompassing the basic mechanisms of action for different drug classes) were designed and implemented across 2 semesters for third-year pharmacy students. Student engagement and use of this new teaching strategy were assessed using a survey instrument and usage statistics for the material. Use of e-tools during semester 1 was low, a finding attributable to a majority (75%) of students either being unaware of or forgetting about the embedded e-tools and a few (20%) lacking interest in accessing additional learning materials. In contrast to semester 1, e-tool use significantly increased in semester 2 with the use of frequent reminders and announcements (p<0.001). The provision of online teaching and learning resources were only effective in increasing student engagement after the implementation of a "marketing strategy" that included e-mail reminders and motivation.


Sequence and characteristics of the Bifidobacterium longum gene encoding L-lactate dehydrogenase and the primary structure of the enzyme: a new feature of the allosteric site.
The gene ldh, encoding L-lactate dehydrogenase (LDH; EC 184.108.40.206) of Bifidobacterium longum aM101-2, was cloned in Escherichia coli using an oligodeoxyribonucleotide hybridization probe. The amino acid (aa) sequence, deduced from the sequence of the cloned DNA, was consistent with the results of protein chemical analysis of B. longum LDH. The transcription start points (tsp) in B. longum were identified by S1 nuclease mapping. A sequence, GTAGCAA-(14 bp)-TTATAGA, which is located a few bp upstream from the tsp, was assigned as the promoter of this ldh gene. In the 3'-noncoding region, there were two structures that strongly resembled the Rho-independent transcriptional termination signal of E. coli. Therefore, the B. longum ldh gene might form a monocistronic unit. The deduced primary structure of B. longum LDH had 40% identity with LDHs from Thermus caldophilus, Bacillus stearothermophilus, Lactobacillus casei and dogfish muscle. Most bacterial LDHs are allosterically regulated by fructose 1,6-bisphosphate (FBP), while the vertebrate LDHs are not. The anion-binding site of vertebrate LDHs has been thought to correspond to the FBP-binding site of bacterial LDHs. Although the B. longum LDH was regulated by FBP, the charge properties of aa residues in the putative FBP-binding site of the LDH were closer to those of the vertebrate LDHs than to those of bacterial LDHs.


Maternal Hemoglobin Concentration during Gestation and Risk of Anemia in Infancy: Secondary Analysis of a Randomized Controlled Trial.
This study examined the relationship between maternal hemoglobin (Hb) concentration and the risk of anemia in infancy. This analysis included 17 193 women who entered the trial when they were ≥20 years of age, no more than 20 weeks of gestation, had mild or no anemia, and delivered singleton live births. Maternal Hb concentrations were measured in the first trimester and during 24-28 weeks of gestation; infant Hb concentrations were measured at 5-7 months and 11-13 months of life. The associations between maternal Hb concentrations and infant Hb concentrations were examined. Maternal Hb concentrations measured during 24-28 weeks of gestation, but not in the first trimester, were correlated with infant Hb concentrations measured at either of the 2 post-partum periods. The risk of infant anemia at 5-7 months of age increased when maternal Hb concentration was ≤109 g/L during 24-28 weeks of gestation (aOR, 1.95; 95% CI, 1.59-2.40) and 11-13 months of age (aOR, 1.72; 95% CI, 1.36-2.18), whereas the risk of anemia during 5-7 months of age as well as 11-13 months in infancy decreased when maternal Hb level at 24-28 weeks of gestation was 120-129 g/L (aOR for 5-7 months, 0.74 [95% CI, 0.64-0.85]; aOR for 11-13 months, 0.72 [95% CI, 0.61-0.85]), or ≥130 g/L (aOR for 5-7 months, 0.75 [95% CI, 0.63-0.90]; aOR for 11-13 months, 0.89 [95% CI, 0.73-1.08]). Low maternal Hb concentration during 24-28 weeks of gestation was associated with an increased risk of anemia in infancy, whereas high maternal Hb concentration was associated with a reduced risk of anemia. Clinicaltrials.gov: NCT00133744.


Identification and synthesis of an antigenic determinant common to human chorionic somatomammotropin and human growth hormone.
Human chorionic somatomammotropin (hCS) and human growth hormone (hGH), despite their different biological activities, show a remarkable degree of homology in their primary structure, which explains their immunological cross-reactivity. On the basis of the hydrophilicity profiles, we predicted that the sequence 165-174 would correspond to an antigenic determinant common to both hormones. The sequence 165-174 was synthesized in the solid phase and the ability to bind antibodies to hCS was tested by a radioimmunoassay at each step of the synthesis, without detaching the peptide from the resin. We found that the immunological sequence able to bind antibodies to hCS is that corresponding to 167-174. In similar experiments, we showed that the sequence 166-174 is able to bind antibodies to hGH. In the plaque-forming cell test using the synthetic fragment 166-174 bound to sheep red blood cells, we also observed that the ratio between the number of cells forming antibodies to hCS and to the 166-174 peptide was always between 0.45 and 0.73, thus suggesting that the 166-174 peptide represents a major determinant of hCS.


Safety and efficacy of CT-guided radioactive iodine-125 seed implantation as a salvage treatment for recurrent head and neck cancer after two or more courses of radiotherapy.
In the past, patients with recurrent head and neck cancer (rHNC) who had previously received a high dose of radiation and were unable to undergo surgery were mainly treated with palliative chemotherapy due to the high incidence of side effects from re-irradiation. With the development of radiotherapy technology, re-irradiation of recurrent lesions by radioactive iodine-125 seed implantation (RISI) has been proposed as a feasible therapeutic approach. This study aimed to investigate the safety and efficacy of computed tomography (CT)-guided RISI in the treatment of rHNC after two or more courses of radiotherapy, and to analyze the prognostic factors. Data of 33 patients with rHNC who received CT-guided RISI after two or more courses of radiotherapy were collected and statistically analyzed. The median cumulative dose of the previous radiotherapy was 110 Gy. Short-term efficacy was assessed by Response Evaluation Criteria in Solid Tumors (version 1.1) criteria, while adverse events were evaluated by Common Terminology Criteria for Adverse Events (version 5.0) criteria. The median gross tumor volume (GTV) was 29.5 cc, and the postoperative median dose to 90% of target volume (D90) was 136.8 Gy. For adverse reactions, enhanced pain was found in 3 (9.1%) patients, followed by grade 1 to 2 acute skin reactions in 3 (9.1%) patients, grade 2 to 3 late skin reactions in 2 (6.1%) patients, grade 1 to 2 early mucosal reactions in 4 (12.1%) patients, and mandibular osteonecrosis in 1 (3.0%) patient. Regarding the treatment efficacy, the 1- and 2-year local control (LC) rates were 47.8% and 36.4% (median LC time, 10 months), and the 1- and 2-year overall survival (OS) rates were 41.3% and 32.2% (median OS time, 8 months). The absence of adverse events was associated with better LC. CT-guided RISI, as a salvage therapy, demonstrated acceptable safety and efficacy in the treatment of rHNC after two or more courses of radiotherapy. This study was registered at Chinese Clinical Trial Register database (Registration No. ChiCTR2200063261 ) in September 2, 2022.


Ferritin as an assessment of iron stores in normal pregnancy.
In Glasgow, the iron stores in healthy women and in normal pregnant women on prophylactic iron supplementation have been assessed by measurement of plasma ferritin. Ferritin concentration fell progressively to a low level in late pregnancy suggesting that the average iron store was inadequate to meet the demands of pregnancy and that dietary iron supplements were therefore required. There was no evidence that iron supplementation led to excessive iron stores.


Naltrexone (50 mg) plus psychotherapy in alcohol-dependent patients: a meta-analysis of randomized controlled trials.
Alcoholism is a chronic and potentially fatal disease. One of the therapeutic options is pharmacotherapy with the opioid antagonist naltrexone in combination with psychotherapy. The objective of this review was to compare the clinical effectiveness of naltrexone (50 mg/day) versus that of a placebo in alcohol-dependent patients receiving psychotherapy. The clinical effectiveness of the treatment was assessed in accordance with the principles of systematic review, as outlined in the Cochrane Collaboration guidelines (Cochrane Reviewer's Handbook) and the guidelines of the Polish Agency for Health Technology Assessment (AHTAPol). Statistical significances in favor of the treatment modality were found in both the percentage of patients maintaining total abstinence and the percentage of relapsed patients. The analysis herein demonstrates that for short (12-16 weeks) period of treatment, a combination of naltrexone administration and psychotherapy results in high clinical efficacy with a safety profile comparable to that of the placebo in the treatment of alcohol-dependent patients. The side effects of naltrexone treatment are usually mild and transient.


Cognitive demands of face monitoring: evidence for visuospatial overload.
Young children perform difficult communication tasks better face to face than when they cannot see one another (e.g., Doherty-Sneddon & Kent, 1996). However, in recent studies, it was found that children aged 6 and 10 years, describing abstract shapes, showed evidence of face-to-face interference rather than facilitation. For some communication tasks, access to visual signals (such as facial expression and eye gaze) may hinder rather than help children's communication. In new research we have pursued this interference effect. Five studies are described with adults and 10- and 6-year-old participants. It was found that looking at a face interfered with children's abilities to listen to descriptions of abstract shapes. Children also performed visuospatial memory tasks worse when they looked at someone's face prior to responding than when they looked at a visuospatial pattern or at the floor. It was concluded that performance on certain tasks was hindered by monitoring another person's face. It is suggested that processing of visual communication signals shares certain processing resources with the processing of other visuospatial information.


Argonaute 2 promotes angiogenesis via the PTEN/VEGF signaling pathway in human hepatocellular carcinoma.
Argonaute2 (AGO2) protein is the active part of RNA-induced silencing complex, cleaving the target mRNA strand complementary to their bound siRNA. An increasing number of miRNAs has been identified as essential to angiogenesis of hepatocellular carcinoma (HCC). In this study we investigated how AGO2 affected HCC angiogenesis. Human HCC cell lines HepG2, Hep3B, Huh7, SMMC-7721, Bel-7404, MHCC97-H and LM-3, and human umbilical vein endothelial cells (HUVEC) were tested. The expression of AGO2 in HCC cells was knocked down with siRNA and restored using recombinant adenovirus expressing Ago2. The levels of relevant mRNAs and proteins were examined using RT-PCR, Western blot and EILSA. Nude mice were implanted with Huh7 or SMMC-7721 cells, and tumor volumes were measured. After the mice were euthanized, the xenograft tumors were used for immunohistological analysis. In 6 HCC cell lines, AGO2 protein expression was significantly correlated with VEGF expression (r=+0.79), and with VEGF secretion (r=+0.852). Knockdown of Ago2 in Huh7 cells and SMMC-7721 cells substantially decreased VEGF expression, whereas the restoration of AGO2 reversed both VEGF expression and secretion. Furthermore, knockdown of Ago2 significantly up-regulated the expression of PTEN (a tumor suppressor involved in the inhibition of HCC angiogenesis), and vice versa. Moreover, the specific PTEN inhibitor bisperoxovanadate (7, 14, 28 nmol/L) dose-dependently restored the expression of VEGF and the capacity of HCC cells to induce HUVECs to form capillary tubule structures. In the xenograft nude mice, knockdown of Ago2 markedly suppressed the tumor growth and decreased PTEN expression and CD31-positive microvascular in the xenograft tumors. A direct relationship exists between the miRNA processing machinery AGO2 and HCC angiogenesis that is mediated by the AGO2/PTEN/VEGF signaling pathway. The results suggest the high value of Ago2 knockdown in anti-angiogenesis therapy for HCC.


Specificity of early-career general practitioners' problem formulations in patients presenting with dizziness: a cross-sectional analysis.
Dizziness is a common and challenging clinical presentation in general practice. Failure to determine specific aetiologies can lead to significant morbidity and mortality. We aimed to establish frequency and associations of general practitioner (GP) trainees' (registrars') specific vertigo provisional diagnoses and their non-specific symptomatic problem formulations. A cross-sectional analysis of Registrar Clinical Encounters in Training (ReCEnT) cohort study data between 2010 and 2018. ReCEnT is an ongoing, prospective cohort study of registrars in general practice training in Australia. Data collection occurs once every 6 months midtraining term (for three terms) and entails recording details of 60 consecutive clinical consultations on hardcopy case report forms. The outcome factor was whether dizziness-related or vertigo-related presentations resulted in a specific vertigo provisional diagnosis versus a non-specific symptomatic problem formulation. Associations with patient, practice, registrar and consultation independent variables were assessed by univariate and multivariable logistic regression. Australian general practice training programme. The training is regionalised and delivered by regional training providers (RTPs) (2010-2015) and regional training organisations (RTOs) (2016-2018) across Australia (from five states and one territory). All general practice registrars enrolled with participating RTPs or RTOs undertaking GP training terms. 2333 registrars (96% response rate) recorded 1734 new problems related to dizziness or vertigo. Of these, 546 (31.5%) involved a specific vertigo diagnosis and 1188 (68.5%) a non-specific symptom diagnosis. Variables associated with a non-specific symptom diagnosis on multivariable analysis were lower socioeconomic status of the practice location (OR 0.94 for each decile of disadvantage, 95% CIs 0.90 to 0.98) and longer consultation duration (OR 1.02, 95% CIs 1.00 to 1.04). A specific vertigo diagnosis was associated with performing a procedure (OR 0.52, 95% CIs 0.27 to 1.00), with some evidence for seeking information from a supervisor being associated with a non-specific symptom diagnosis (OR 1.39, 95% CIs 0.92 to 2.09; p=0.12). Australian GP registrars see dizzy patients as frequently as established GPs. The frequency and associations of a non-specific diagnosis are consistent with the acknowledged difficulty of making diagnoses in vertigo/dizziness presentations. Continuing emphasis on this area in GP training and encouragement of supervisor involvement in registrars' diagnostic processes is indicated.


Associations between time zone changes, travel distance and performance: A retrospective analysis of 2013-2020 National Hockey League Data.
Many studies have investigated the role that travel plays in athletic performance. However, these studies lacked a holistic representation of travel. For instance, they do not consider travel distance and uniquely focuses on travel direction. An open source (www.evolving-hockey.com) provided NHL (2013-2020) game data. In total, this resulted in 17,088 regular season games. Linear and quadratic versions of time zone change (TZΔ) and adjusted jet lag (AJL) were formulated. TZΔ captured circadian delay/advance based on travel for a game, with each TZ going eastward and westward reflected by -1 and +1, respectively. AJL advances TZΔ by allowing TZ acclimation, with each day resulting in a 1-unit change towards circadian neutral. AJL is a season-long rolling summation, which was computed using two different travel approaches: Approach A (AJL_A) assumes travel the day before each game, whereas Approach B (AJL_B) was designed to prioritize being home. A standardized flight tracker determined travel distance for each game. Team ability differences, characterized as difference in total season points, served as an analytic covariate. Outcome variables included goal differential, difference between actual and expected Fenwick save percentage (dFSv%), and goals saved above average (GSAA). GameDistance (β = -0.14, p = 0.0007), AJL_B2 (β = -0.15, p = 0.0006), and their interaction (p = 0.0004) associated with GoalDifferential. GameDistance (β = -0.18, p = 0.02) and AJL_B2 (β = 0.12, p = 0.03) associated with dFSv%, whereas only AJL_B2 (β = 0.03, p = 0.05) associated with GSAA. Results suggest that circadian change, in both direction, and greater traveled distance can negatively impact NHL athletes.


Long-Term Trends in Stroke Survivors Discharged to Care Homes: The South London Stroke Register.
Background and Purpose- Care homes provide care to many stroke survivors, yet little is known about changes in care home use over time. We aim to determine trends in discharge to care homes, to explore the characteristics of stroke survivors over time (1995-2018), and to identify the associations between these characteristics and discharge to care homes poststroke. Methods- Using data from the South London Stroke Register between 1995 and 2018, we estimated the proportions discharged to care homes and their characteristics over time, assessed by tests for trends. Multivariable logistic regression models were built to assess the associations between their characteristics and discharge destination. Results- Of 4172 stroke survivors, 484 (12%) were discharged to care homes. This proportion has decreased from 24% in 1995 to 2000 to 5% in 2013 to 2018. The mean age of those discharged to care homes has increased over time, from 73 to 75 (P<0.001). Among stroke survivors discharged to a care home, the proportion with a prestroke Barthel Index <15 has also increased over time from 7% to 21% (P=0.027), while the proportion with a 7-day poststroke Barthel Index <15 remains largely unchanged over time (93% in 1995-2000, 90% in 2013-2018). The characteristics most strongly associated with discharge to care homes were (odds ratio [95% CI]) age (1.05 [1.04-1.07] per year), stroke subtype (hemorrhagic; 0.64 [0.43-0.95]), stroke severity (Glasgow Coma Scale score, <13; 1.67 [1.19-2.35]), failed swallow test at admission (1.65 [1.20-2.25]), 7-day poststroke Barthel Index <15 (3.58 [2.20-6.03]), and a longer hospital stay (1.02 [1.02-1.03] per day). Conclusions- Over >20 years, there has been an 80% reduction in the proportion of stroke survivors discharged to care homes, influenced by changes in the demographics, disability, and stroke care in the underlying stroke population. In those moving to care homes, the level of poststroke disability remains high, requiring continued attention and investment.


New insights into cell cycle and DNA damage response machineries through high-resolution AMICO quantitative imaging cytometry.
Progress in biology and medicine research is being driven by development of new instrumentation and associated methodologies which open analytical capabilities that expand understanding of complexity of biological systems. Application of cytometry, which is now widely used in so many disciplines of biology, is the best example of such a progress. Recent publications push the envelope in expanding capabilities of cytometry by introducing a high resolution imaging cytometry defined as Automated Microscopy for Image CytOmetry (AMICO). This instrumentation is utilized to further elucidate mechanisms of the cell cycle progression and also the DNA damage response. This approach is going beyond the presently possible analytical technologies regarding throughput and depth of information. The possibility of multiparametric analysis combined with the high resolution mapping of individual constituents of cell cycle and DNA damage response machineries provides new tools to probe molecular mechanism of these processes. The capability of analysis of proximity of these constituents to each other offered by AMICO is a novel and potentially important approach that can be used to elucidate mechanisms of other biological processes.


Effect of Ge Content on the Formation of Ge Nanoclusters in Magnetron-Sputtered GeZrOx-Based Structures.
Ge-rich ZrO2 films, fabricated by confocal RF magnetron sputtering of pure Ge and ZrO2 targets in Ar plasma, were studied by multi-angle laser ellipsometry, Raman scattering, Auger electron spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction for varied deposition conditions and annealing treatments. It was found that as-deposited films are homogeneous for all Ge contents, thermal treatment stimulated a phase separation and a formation of crystalline Ge and ZrO2. The "start point" of this process is in the range of 640-700 °C depending on the Ge content. The higher the Ge content, the lower is the temperature necessary for phase separation, nucleation of Ge nanoclusters, and crystallization. Along with this, the crystallization temperature of the tetragonal ZrO2 exceeds that of the Ge phase, which results in the formation of Ge crystallites in an amorphous ZrO2 matrix. The mechanism of phase separation is discussed in detail.


[Neural engineering and neural prostheses].
The motivation of the brain-computer interface (BCI) research and its potential applications are introduced in this paper. Some of the problems in BCI-based medical device developments are also discussed.


Advantage provided by iron for Escherichia coli growth and cultivability in drinking water.
The presence of iron, used both as a nutrient and as an electron acceptor, was demonstrated to give an advantage to Escherichia coli bacteria in drinking water. Slight additions of ferrous sulfate to water with initial low iron concentrations led to a significant increase in the number of E. coli bacteria. The presence of ferric oxide in water under anaerobic conditions increased bacterial cultivability.


Dextromethorphan inhibits 5-hydroxytryptamine uptake by human blood platelets and decreases 5-hydroxyindoleacetic acid content in rat brain.
The effect of dextromethorphan on the uptake and metabolism of 5-hydroxytryptamine (5-HT) was studied in human blood platelets and in rat brain. In the concentration of 120 nM dextromethorphan inhibited the uptake of 5-HT (1 mu-M) into platelets by 50%. The corresponding concentrations of imipramine and methadone under similar conditions were 22 and 590 nM, respectively. Dextromethorphan (20 to 40 mg kg-1) decreased the concentration of brain 5-hydroxyindoleacetic acid (5-HIAA) and the probenecid-induced accumulation of 5-HIAA time- and dose-dependently. However, dextromethorphan did not alter the pargyline-induced changes in brain 5-HT metabolism. Dextromethorphan-induced changes in brain 5-HT metabolism could arise from the inhibition of the re-uptake of 5-HT into neurons.


FUNDC1-dependent mitophagy induced by tPA protects neurons against cerebral ischemia-reperfusion injury.
Autophagy of mitochondria, termed mitophagy, plays an important role in cerebral ischemia-reperfusion (IR) injury, but the mechanism is not yet clear. Tissue-type plasminogen activator (tPA) is the most important thrombolytic drug in the clinical treatment of ischemic stroke and has neuroprotective effects. Here, we explored the effects of tPA on neuronal apoptosis and mitophagy following IR. We found that knocking out the tPA gene significantly aggravated brain injury and increased neuronal apoptosis and mitochondrial damage. Exposure of neurons to tPA reduced injury severity and protected mitochondria. Further studies demonstrated that this protective effect of tPA was achieved via regulation of FUNDC1-mediated mitophagy. Furthermore, we found that tPA enhanced the expression level of FUNDC1 by activating the phosphorylation of AMPK. In summary, our results confirm that tPA exerts neuroprotective effects by increasing the phosphorylation of AMPK and the expression of FUNDC1, thereby inhibiting apoptosis and improving mitochondrial function.


Sleep-disordered breathing and daytime sleepiness predict children's reading ability.
Sleep problems are common in children and are known to detrimentally affect language and cognitive abilities, as well as academic achievement. We aimed to investigate effects of sleep on oral word and non-word reading in a large, cross-sectional sample of children. Of 428 children who attended a public psychological science event, 339 children aged 4-14 years (mean 8;10 ± 2;2) took part. Parents completed two sleep questionnaires (Children's Sleep Habits Questionnaire and Sleep-Disordered Breathing Questionnaire) whilst children completed the Test of Word Reading Efficiency. Hierarchical multiple linear regression assessed whether parentally reported sleep problems were able to predict word and non-word oral reading speeds as measures of sight word reading and phonemic decoding efficiency, respectively. Children with parent-reported increased sleep-disordered breathing, daytime sleepiness, and shorter sleep latency had poorer performance on the reading task for both words and non-words, as well as the total combined score. The models explained 6-7% of the variance in reading scores. This study illustrates associations between sleep and word and non-word reading. The small but significant effect is clinically meaningful, especially since adverse factors affecting children's reading ability are cumulative. Thus, for children with multiple risk factors for poor reading ability, sleep problems may be another avenue for treatment. Since reading ability is a strong predictor of later academic success and life outcomes, our study provides important evidence to suggest that children with sleep problems should also be screened for literacy difficulties, and children with literacy difficulties be screened for sleep problems.