Patient-Centered Outcome Measures in Lung Cancer Trials.
Scientific communities focusing on cancer research have urged for the development of trials that address patient-centered outcome measures instead of solely focusing on cancer as a disease-centered process. This is important for a patient with lung cancer because of the rapid course of disease and generally poor prognosis. We set out to determine the characteristics and study objectives of the current clinical trials in pulmonary malignancies. The United States National Institutes of Health clinical trial registry was searched on April 23rd 2015, for currently recruiting phase I, II, or III clinical trials in lung cancer. Trial characteristics and study objectives were extracted from the registry website. Of the 419 clinical trials included in this review, patient-centered outcome measures are investigated in a minority of the trials. Outcome measures as quality of life, functional capacity, and health care utilization are included in a small number of trials (20, 4, and 2 % respectively). Treatment completion is included in 1 % of the trials. Research goals are most frequently toxicity (78 %) and progression-free survival (76 %). Patient-centered outcome measures are included in a minority of the currently recruiting clinical trials in pulmonary malignancies. If we do not investigate these outcome measures, it is not possible to increase our knowledge of the optimal treatment, as this should aim to optimize the patient's wellbeing as well as the course of disease. One option could be to incorporate combinations of patient- and disease-centered endpoints, for instance by using overall treatment utility or quality-adjusted outcome measures.


Toxicological effects, residue levels and risks of endocrine-disrupting chemicals in Chinese medicine: a review.
Traditional Chinese medicine (TCM) that is used worldwide possesses the satisfactory function of disease prevention, treatment and health care, and this natural medicine seems to be favored due to its low side effects. Endocrine disrupting chemicals (EDCs), which exist in all aspects of our lives, may interfere with the synthesis, action and metabolism of human sex steroid hormones, resulting in the development and fertility problems as well as obesity and the disturbance of energy homeostasis. From planting to processing, TCM may be polluted by various EDCs. Many studies pay attention to this problem, but there are still few reviews on the residues and toxicity risks of EDCs in TCM. In this paper, researches related to EDCs in TCM were screened. The possible contamination sources of TCM from planting to processing and its toxic effects were introduced. Moreover, the residues of metals, pesticides and other EDCs in TCM as well as the health risks of human exposure to EDCs through ingestion of TCM materials were reviewed.


Optothermal grid activation of microflow with magnetic nanoparticle thermophoresis for microfluidics.
We report focused light-induced activation of intense magnetic microconvection mediated by suspended magnetic nanoparticles in microscale two-dimensional optothermal grids. Fully anisotropic control of microflow and mass transport fluxes is achieved by engaging the magnetic field along one or the other preferred directions. The effect is based on the recently described thermal diffusion-magnetomechanical coupling in synthetic magnetic nanofluids. We expect that the new phenomenon can be applied as an efficient all-optical mixing strategy in integrated microfluidic devices. This article is part of the theme issue 'Transport phenomena in complex systems (part 2)'.


Hyperglycemia and cancer in human lung carcinoma by means of Raman spectroscopy and imaging.
Raman spectroscopy and Raman imaging were used to identify the biochemical and structural features of human cancer lung cells (CCL-185) and the cancer cells supplemented with glucose and deuterated glucose at normal and hyperglycemia conditions. We found that isotope substitution of glucose by deuterated glucose allows to separate de novo lipid synthesis from exogenous uptake of lipids obtained from the diet. We demonstrated that glucose is largely utilized for de novo lipid synthesis. Our results provide a direct evidence that high level of glucose decreases the metabolism via oxidative phosphorylation in mitochondria in cancer cells and shifts the metabolism to glycolysis via Warburg effect. It suggests that hyperglycemia is a factor that may contribute to a more malignant phenotype of cancer cells by inhibition of oxidative phosphorylation and apoptosis.


Decennial Analysis of Interventional Left Atrial Appendage Closure.
Data on long-term follow-up (LTFU) after interventional closure of the left atrial appendage (LAAC) in patients with nonvalvular atrial fibrillation (AF) are scarce. We sought to determine the outcome of patients after LAAC with the first generation device. The Cardioangiologisches Centrum Bethanien (CCB) LAAC registry database was analyzed. Between October 2001 and July 2007, 45 AF patients (23 male, mean age 71 ± 6 years; mean CHA2 DS2 -VaSc 4.3 ± 1.7 [range 1-7]; mean HASBLED score 3.3 ± 1.2 [1-5]) received LAAC. Postimplant dual-platelet inhibition with clopidogrel 75 mg/day and aspirine (ASA) 300 mg/day was prescribed for 6 months, followed by ASA 300 mg indefinitely. The primary endpoint was defined as any thrombembolic complication and/or any bleeding complication. The median FU was 7.4 years (1-12.4 years) resulting in 292 patient years. Fourteen patients died due to heart failure (n = 4), noncardiac reasons (n = 7), or due to unknown etiology (n = 3). No patient died from a bleeding or a stroke. Five ischemic strokes occurred at a median of 794 days (range 304-3,706 days) after LAAC. The observed annual stroke rate was 1.7% (RR 0.43; 95% CI 0.24-0.74; P = 0.0028). In 6 patients bleeding occurred (2 acute procedural, 4 during follow-up). The observed annual bleeding rate was 2.1% (RR 0.56; 95% CI 0.48-0.66; P < 0.0001). During LTFU after LAAC in patients with nonvalvular AF, lower event rates than expected are observed for both thrombembolic and bleeding complications.


A small bowel fistula extending into a metastatic tumour due to lung carcinoma.
We report the case of a 63-year-old man who presented with an abdominal mass that was subsequently found to be a metastasis of small cell lung carcinoma into which the small bowel had fistulized. After a detailed diagnostic workup, the involved segment of the small bowel was resected along with the mass. The patient is alive and well six months after surgery. Lung carcinoma metastases to the bowel and mesentery are rare. Resection of the metastatic mass gives the best palliation and improves short-term survival.


How predictive is a cervical smear suggesting glandular neoplasia?
The prevalence of endocervical adenocarcinoma and its precursors has increased, in part due to increased diagnostic awareness of these lesions. To date, limited information has been published regarding the predictive value of glandular abnormalities in cervical smears. This study details the histological follow up of 418 cervical smears showing glandular abnormality, reported in our department over a six year period from 1993 to 1998. Histological follow up was available for 395 of the 418 smears (94.50%). The overall positive predictive value (PPV) for this group of smears was 72.66% for either significant glandular or squamous pathology (at least low grade cervical glandular intraepithelial neoplasia or CIN2 on follow up biopsy), and 55.70% for significant glandular pathology alone. Examination of subcategories of abnormal glandular smear showed that the PPV increased with the degree of abnormality reported within the smears.


A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for haemopoietic stem cell mobilisation in patients with severe active rheumatoid arthritis.
Autologous haemopoietic stem cell transplantation (HSCT) represents a potential therapy for severe rheumatoid arthritis (RA). As a prelude to clinical trails, the safety and efficacy of haemopoietic stem cell (HSC) mobilisation required investigation as colony-stimulating factors (CSFs) have been reported to flare RA. A double-blind, randomised placebo-controlled dose escalation study was performed. Two cohorts of eight patients fulfilling strict eligibility criteria for severe active RA (age median 40 years, range 24-60 years; median disease duration 10.5 years, range 2-18 years) received filgrastim (r-Hu-methionyl granulocyte(G)-CSF) at 5 and 10 microg/kg/day, randomised in a 5:3 ratio with placebo. Patients were unblinded on the fifth day of treatment and those randomised to filgrastim underwent cell harvesting (leukapheresis) daily until 2 x 10(6)/kg CD34+ cells (haemopoietic stem and progenitor cells) were obtained. Patients were assessed by clinical and laboratory parameters before, during and after filgrastim administration. RA flare was defined as an increase of 30% or more in two of the following parameters: tender joint count, swollen joint count or pain score. Efficacy was assessed by quantitation of CD34+ cells and CFU-GM. One patient in the 5 microg/kg/day group and two patients in the 10 microg/kg/day group fulfilled criteria for RA flare, although this did not preclude successful stem cell collection. Median changes in swollen and tender joint counts were not supportive of filgrastim consistently causing exacerbation of disease, but administration of filgrastim at 10 microg/kg/day was associated with rises in median C-reactive protein and median rheumatoid factor compared with placebo. Other adverse events were well recognised for filgrastim and included bone pain (80%) and increases in alkaline phosphatase (four-fold) and lactate dehydrogenase (two-fold). With respect to efficacy, filgrastim at 10 microg/kg/day was more efficient with all patients (n = 5) achieving target CD34+ cell counts with a single leukapheresis (median = 2.8, range = 2.3-4.8 x 10(6)/kg, median CFU-GM = 22.1, range = 4.2-102.9 x 10(4)/kg), whereas 1-3 leukaphereses were necessary to achieve the target yield using 5 microg/kg/day. We conclude that filgrastim may be administered to patients with severe active RA for effective stem cell mobilisation. Flare of RA occurs in a minority of patients and is more likely with 10 than 5 microg/kg/day. However, on balance, 10 microg/kg/day remains the dose of choice in view of more efficient CD34+ cell mobilisation.


Effects of a heat-labile factor(s) in normal serum on the interferon-inducing activity of Newcastle disease virus (NDV). Brief report.
The effect of fresh serum on the interferon-inducing activity of Newcastle disease virus (NDV) was studied. Infectivity in fertile eggs, hemolytic activity in human erythrocytes and interferon-inducing activity in mouse L cells and mouse spleen cells were all reduced by treatment of NDV with fresh serum from humans or guinea pigs, while hemagglutinating (HA) activity remained unchanged. The interferon-inducing ability of UV-inactivated NDV was also similarly reduced after treatment with serum. The serum effects were decreased by heating at 56 degrees C for 30 minutes or the addition of 10 mM EDTA. These results suggest that a heat-labile serum factor(s) such as complement or certain enzyme(s) reduced the hemolytic activity and consequently the penetrating activity of NDV, and that interferon-inducing activity was related to the hemolytic but not to the HA activity of NDV particles. Thus, it was concluded that the hemolytic activity of NDV was necessary for interferon induction in both mouse L cells and mouse spleen cells.


Treatment of writer's cramp : a follow up study.
The paper describes the usefulness of a treatment method for writer's cramp. Three cases of writer's cramp are described and in all the three, the response to treatment has been good after treatment and on follow up.


Molecular biology of Philadelphia chromosome in chronic granulocytic leukaemia and acute lymphoblastic leukaemia.
In classical t(9;22) translocation, as observed in chronic granulocytic leukemia (CGL), a hybrid DNA unit is produced, including a rearranged PHL gene, previously known as bcr (breakpoint cluster region) plus the translocated c-abl gene from chromosome 9: a hybrid bcr-abl protein, p210 is formed, with increased tyrosine kinase activity. Such DNA rearrangement, with a p210 protein synthesis, is also found in cases of Philadelphia-positive acute lymphoblastic leukemia (ALL), but in apparently similar cases the bcr gene is not rearranged, and a novel p190 abl-related protein can be found; c-abl rearrangement has also been observed.It is thus established that correlations between cytogenetic and molecular events can be found in CGL and ALL, as in other haemopoietic malignancies: translocation and possible rearrangement of the c-abl oncogene seem of particular importance in this case.


Development of a Machine Learning Model to Predict Recurrence of Oral Tongue Squamous Cell Carcinoma.
Despite diagnostic advancements, the development of reliable prognostic systems for assessing the risk of cancer recurrence still remains a challenge. In this study, we developed a novel framework to generate highly representative machine-learning prediction models for oral tongue squamous cell carcinoma (OTSCC) cancer recurrence. We identified cases of 5- and 10-year OTSCC recurrence from the SEER database. Four classification models were trained using the H2O ai platform, whose performances were assessed according to their accuracy, recall, precision, and the area under the curve (AUC) of their receiver operating characteristic (ROC) curves. By evaluating Shapley additive explanation contribution plots, feature importance was studied. Of the 130,979 patients studied, 36,042 (27.5%) were female, and the mean (SD) age was 58.2 (13.7) years. The Gradient Boosting Machine model performed the best, achieving 81.8% accuracy and 97.7% precision for 5-year prediction. Moreover, 10-year predictions demonstrated 80.0% accuracy and 94.0% precision. The number of prior tumors, patient age, the site of cancer recurrence, and tumor histology were the most significant predictors. The implementation of our novel SEER framework enabled the successful identification of patients with OTSCC recurrence, with which highly accurate and sensitive prediction models were generated. Thus, we demonstrate our framework's potential for application in various cancers to build generalizable screening tools to predict tumor recurrence.


Route of ethanol administration and gastric acid output during chronic conditions.
The effect of intravenous or intragastric ethanol on gastric secretion was determined in chronic ethanol-fed and matched control rats. In vivo, basal and histamine-stimulated acid outputs were inhibited by acute intragastric ethanol to a greater extent in chronic control rats than in ethanol-fed rats. In contrast, intravenous ethanol stimulated basal and potentiated histamine (H)-stimulated acid output (blocked by cimetidine but not atropine) in ethanol-fed rats but not in chronic control rats. Serum gastrin levels were not significantly altered by ethanol. In vitro, mucosal ethanol inhibited basal and H-stimulated acid secretion by mucosae from chronic control and ethanol-fed rats, but serosal ethanol did not significantly alter acid secretion. In conclusion, chronic ethanol intake results in higher acid outputs following acute exposure to intravenous or intragastric ethanol or in vitro exposure to mucosal ethanol as compared to studies using matched control rats.


High risk of obstructive sleep apnea, insomnia, and daytime sleepiness among commercial motor vehicle drivers.
We investigated the prevalence of sleep problems, such as obstructive sleep apnea (OSA), insomnia, and daytime sleepiness in commercial motor vehicle (CMV) drivers compared with that in the general population. This is a cross-sectional study comparing sleep habits and sleep problems in 110 truck drivers with 1001 matched controls from the general population. The assessment was based on self-administered questionnaires that included the Berlin questionnaire, the insomnia severity index, and the Epworth sleepiness scale (ESS). Multivariate regression analysis was performed to determine whether CMV drivers were independently associated with these sleep problems compared with controls. The prevalence of a high risk of OSA and insomnia was 35.5% and 15.2%, respectively, in CMV drivers, which was significantly higher than in controls with a prevalence of 12.2% and 4.1%, respectively (P < 0.001 for both). Although CMV drivers showed higher ESS scores than controls, the prevalence of daytime sleepiness did not differ between the two groups (19.1% vs. 16.8%, P = 0.54). After adjusting for covariates, CMV drivers had 3.68 times higher odds (95% CI 2.29-5.84) of OSA and 2.97 times higher odds (95% CI, 1.46-6.06) of insomnia compared with controls. However, the degree of daytime sleepiness was not independently associated with CMV drivers. The prevalence of OSA and insomnia in CMV drivers was higher than that in the general population. Daytime sleepiness was associated with increased BMI, depression, OSA, and short sleep duration, regardless of CMV driving as an occupational factor.


Phosphatase systems in Paramphistomum explanatum Fischoeder, 1901.
Extracts of adult Paramphistomum explanatum have been shown to contain high concentration of acid phosphomonoesterase with maximum activity at pH 4.5. The enzyme has been characterized by an exhibition of an unexpected increase in the inhibitory action of a mercury at 1 mM concentration by EDTA. With a lower concentration of mercury (0.1 mM and below) EDTA gave partial protection against inhibition. Different concentrations of magnesium and cobalt activated the enzyme while fluoride, copper, arsenate, tartrate and p-mercuribenzoate brought about inhibition. EDTA, glycine, glutathione and sodium azide had no effect. There was an indication of the presence of alkaline phosphomonoesterase at pH 10.0. The Km for p-nitrophenyl phosphate hydrolysis was 0.45 mM at pH 4.5.


Nitrogen mass balance and uptake velocity for eutrophic reservoirs in the Brazilian semiarid region.
The nitrogen (N) cycle from the catchment to the downstream reservoir is complex, particularly the quantification of N losses. However, in order to assess the nitrogen impact in a reservoir ecosystem, simplified models may be applicable regarding the TN load production and the magnitude of lake TN removal. This study presented a methodology to perform and validate a TN mass balance to further calibrate a simplified coefficient for TN losses (vf.) in 29 tropical semiarid reservoirs. The study reservoirs were highly productive ecosystems with an average total nitrogen (TN) concentration, accounting for all measurements in all reservoirs, ranging from 0.59 to 3.84 mg L-1. Regarding the production of TN load, the median values ranged from 4.35 to 2,499.43 t year-1 with median of 80.34 t year-1. The TN loads were estimated through an annual mass balance over a 24-year period. The median of the estimates was compared with reference values obtained by using the export modelling coefficient. The correlation between the median estimated and reference loads resulted in satisfactory agreement (r2 0.88) and reinforced the reliability of the mass balance alternative. From the validated TN loads, the TN uptake velocity (vf) was estimated for all reservoirs (44.9 ± 20.1 m year-1) and could be described as a general function of the water residence time. The reservoirs of the study region have demonstrated higher vf than temperate lakes and reservoirs and similar vf with Latin America/Caribbean ones. As expected, reservoirs of warmer climates tend to present intensified N loss processes compared to lakes and reservoirs of temperate regions. The methodology proposed in the present study can be used to potentially improve water quality management in tropical semiarid reservoirs.


Drainage or lavage as a salvage manoeuvre after intrathecal drug errors: A systematic review with therapeutic recommendations.
Cerebrospinal fluid (CSF) drainage and lavage are reported to reduce drug exposure after inadvertant intrathecal drug administration errors. This reviews aims to provide recommendations for this salvage technique, with regard to methodology, effectiveness and adverse events. Systematic review. A search in the databases of Embase, Medline, Web of Science, Cochrane Central Register of Randomized Trials and Google Scholar was performed in 2022. All reports of individual patient data with CSF drainage or lavage with a percutaneous lumbar access for an intrathecal drug error were included. The primary outcome is the description and count of CSF drainage or lavage, such as times and volume of drainage, volume of replacement and type of replacement fluid. Secondary outcomes are the effects, adverse events and overall outcome. 58 cases were found, of which 24 were paediatric cases. There was a large variance in methodology, with regard to volume t and type of replacement fluid. In 45% of the cases the intrathecal drug removal continued. The effects were specifically reported in 27 cases, all demonstrated drug removal based on drug concentrations in the CSF (n = 20) and clinical signs (n = 7). Adverse effects were sought for in 17 cases and found intracranial haemorrhage in 3 cases. No interventions were required for these adverse events and the only reported long-term sequelae in these three patients was short-term memory impairment up to 6 months after the event (n = 1). The overall outcome depended largely on the causative agent. This review shows that CSF drainage or lavage leads to intrathecal drug removal, but it is unsure if this intervention leads to improved overall patient outcome. Based on aggregated data from case reports, we provide recommendations that may guide clinicians. The risk-benefit ratio should be weighed on a case-to-case basis.


Proximity to livestock farms and COVID-19 in the Netherlands, 2020-2021.
In the Netherlands, during the first phase of the COVID-19 epidemic, the hotspot of COVID-19 overlapped with the country's main livestock area, while in subsequent phases this distinct spatial pattern disappeared. Previous studies show that living near livestock farms influence human respiratory health and immunological responses. This study aimed to explore whether proximity to livestock was associated with SARS-CoV-2 infection. The study population was the population of the Netherlands excluding the very strongly urbanised areas and border areas, on January 1, 2019 (12, 628, 244 individuals). The cases are the individuals reported with a laboratory-confirmed positive SARS-CoV-2 test with onset before January 1, 2022 (2, 223, 692 individuals). For each individual, we calculated distance to nearest livestock farm (cattle, goat, sheep, pig, poultry, horse, rabbit, mink). The associations between residential (6-digit postal-code) distance to the nearest livestock farm and individuals' SARS-CoV-2 status was studied with multilevel logistic regression models. Models were adjusted for individuals' age categories, the social status of the postal code area, particulate matter (PM10)- and nitrogen dioxide (NO2)-concentrations. We analysed data for the entire period and population as well as separately for eight time periods (Jan-Mar, Apr-Jun, Jul-Sep and Oct-Dec in 2020 and 2021), four geographic areas of the Netherlands (north, east, west and south), and for five age categories (0-14, 15-24, 25-44, 45-64 and > 65 years). Over the period 2020-2021, individuals' SARS-CoV-2 status was associated with living closer to livestock farms. This association increased from an Odds Ratio (OR) of 1.01 (95% Confidence Interval [CI] 1.01-1.02) for patients living at a distance of 751-1000 m to a farm to an OR of 1.04 (95% CI 1.04-1.04), 1.07 (95% CI 1.06-1.07) and 1.11 (95% CI 1.10-1.12) for patients living in the more proximate 501-750 m, 251-500m and 0-250 m zones around farms, all relative to patients living further than 1000 m around farms. This association was observed in three out of four quarters of the year in both 2020 and 2021, and in all studied geographic areas and age groups. In this exploratory study with individual SARS-CoV-2 notification data and high-resolution spatial data associations were found between living near livestock farms and individuals' SARS-CoV-2 status in the Netherlands. Verification of the results in other countries is warranted, as well as investigations into possible underlying exposures and mechanisms.


Pharmacists' perceptions of their practice: a comparison between Alberta and Northern Ireland.
To explore how community pharmacists from Alberta, Canada, and Northern Ireland, UK, describe what a pharmacist does and to compare their responses. Two hundred community pharmacists were interviewed using the telephone. The interviewer who introduced himself as a researcher asked two questions about the period over which the participants had been practising pharmacy and the way they describe what a pharmacist does. Responses were categorised into three categories: patient-centred, product-focused and ambiguous. Word-cloud analysis was used to assess the use of patient-care-related terms. Of the responses from community pharmacists in Alberta, 29% were categorised as patient-centred, 45% as product-focused and 26% as ambiguous. In Northern Ireland, 40% of the community pharmacists' responses were categorised as patient-centred, 39% as product-focused and 21% as ambiguous. Community pharmacists in Northern Ireland provided more patient-centred responses than community pharmacists in Alberta (P=0.013). The word-cloud analysis showed that 'medicine' and 'dispense' were the most frequently reported terms. It also highlighted a relative lack of patient-care-related terms. The findings of the present study are suggestive of some movement towards patient-centredness; however, product-focused practice still predominates within the pharmacy profession in Alberta and Northern Ireland. The relative lack of patient-care-related terms suggests that patient care is still not the first priority for pharmacists in both Alberta and Northern Ireland.


Catalogues of EQ-5D-3L Health-Related Quality of Life Scores for 199 Chronic Conditions and Health Risks for Use in the UK and the USA.
Health-related quality of life (HRQoL) measures are essential in economic evaluation, but sometimes primary sources are unavailable, and information from secondary sources is required. Existing HRQoL UK/US catalogues are based on earlier diagnosis classification systems, amongst other issues. A recently published Danish catalogue merged EQ-5D-3L data from national health surveys with national registers containing patient information on ICD-10 diagnoses, healthcare activities and socio-demographics. To provide (1) UK/US EQ-5D-3L-based HRQoL utility population catalogues for 199 chronic conditions on the basis of ICD-10 codes and health risks and (2) regression models controlling for age, sex, comorbidities and health risks to enable predictions in other populations. UK and US EQ-5D-3L value sets were applied to the EQ-5D-3L responses of the Danish dataset and modelled using adjusted limited dependent variable mixture models (ALDVMMs). Unadjusted mean utilities, percentiles and adjusted disutilities based on two ALDVMMs with different control variables were provided for both countries. Diseases from groups M, G, and F consistently had the smallest utilities and the largest negative disutilities: fibromyalgia (M797), sclerosis (G35), rheumatism (M790), dorsalgia (M54), cerebral palsy (G80-G83), post-traumatic stress disorder (F431), dementia (F00-2), and depression (F32, etc.). Risk factors, including stress, loneliness, and BMI30+, were also associated with lower HRQoL. This study provides comprehensive catalogues of UK/US EQ-5D-3L HRQoL utilities. Results are relevant in cost-effectiveness analysis, for NICE submissions, and for comparing and identifying facets of disease burden.


Coupled optical rate determinations of amino acid oxidase activity.
Methods are described in which liberation of ammonia from amino acid substrates by the D- and L-amino acid oxidases may be coupled with the NADH-dependent reductive amination of 2-oxoglutarate catalysed by exogenous glutamate dehydrogenase (L-glutamate: NAD oxidoreductase (deaminating), EC 184.108.40.206). The inhibition of D-amino acid oxidase (D-amino acid:O2 oxidoreductase (deaminating), EC 18.104.22.168) by ADP needed to activate and stabilise glutamate dehydrogenase was relieved by FAD, and the substrate was D-alanine at approximately 6-fold Km concentration. Neither FAD or FMN were required in the L-amino acid oxidase (L-amino acid:O2 oxidoreductase (deaminating), EC 22.214.171.124) assay; this utilised L-leucine as substrate in a concentration approximately 7-fold the Km value. The methods were reasonably sensitive and precise, and a linear relationship between activity and enzyme concentration prevailed up to an absorbance change of 0.050 per min. They have the advantage of being amenable to automation and to employment of fluorescence techniques should greater sensitivity be required.


Association between endothelial dysfunction and otoneurological symptoms in children with sickle cell disease.
To evaluate the association between endothelial dysfunction and otoneurological symptoms and vaso-occlusive phenomena in children with sickle cell disease (SCD). Cross-sectional study with 54 children, aged between 6 and19 years of age, of whom 28 had genotype SS and 26 apparently healthy (AA genotype) whose parents or guardians, or the children themselves, filled out a questionnaire designed to assess their otoneurological symptoms. All the individuals were submitted assessment of endothelial function by flow-mediated dilation (FMD) percentage with reactive hyperemia of brachial artery Doppler. Otoneurological symptoms (tinnitus and/or vertigo) predominated in the SCD group (46.4 vs. 15.4%; p = 0.006). A negative correlation was observed between FMD percentage and time of evolution of vertigo SCD (r = -0.432; p = 0.022) and the linear regression analysis demonstrated that for every reduction in FMD percentage there was an increase in time of evolution of vertigo of 1.79 months (β = -1.79; p = 0.022). The positive correlation between episodes of painful crisis and time of evolution of vertigo (r = 0.3; p = 0.04). The presence of vascular endothelial damage in the labyrinthine artery in patients with SCD is capable of compromising the semicircular canals, shown by clinical expression of otoneurological symptoms, such as vertigo. In the present study, an association was observed between endothelial dysfunction with otoneurological symptoms and otoneurological symptoms and vaso-occlusive phenomena in SCD.


Integrating nursing science in the education process.
With the present shortage of nursing faculty and the imminent retirement of current faculty, clinical nurses are encouraged to step into academia, bringing their enthusiasm, knowledge, and clinical experience. As nurses enter the world of nursing education, they will face two challenges: the paradigm shift from clinical nursing to learning process, and the vast diversity of students. Turning to the foundations of nursing, a young nurse educator generated teaching-learning strategies through integration of nursing sciences as a guide to becoming an effective educator.


Discordant genotypic resistance and HIV-1 genetic diversity from paired plasma and cerebrospinal fluid samples in Chinese settings.
In the highly active antiretroviral therapy era, the incidence of human immunodeficiency virus (HIV)-associated neurocognitive disorder remains high with the improved survival. The prevalence of resistance differs across geographical areas and HIV subtypes. Currently, little information on the resistance patterns in the central nervous system (CNS) is available in Chinese settings. In this study, we sequenced and analyzed the pol gene from paired cerebrospinal fluid and plasma samples of 34 Chinese HIV-infected patients. We found that eight subjects harbored mutations that confer drug resistance, and of these, six subjects exhibited discordant resistance patterns between the CNS and the blood. The levels of viral diversity in the CNS were significantly higher than those in the blood (p < 0.0001). Our results contribute to improving our understanding of HIV neuropathogenesis and help to optimize neuro-acquired immunodeficiency syndrome treatment.


Neuroimaging in psychiatry: an update on neuroimaging in the clinical setting.
We offered guidance on the role of structural and functional neuroimaging modalities for the general psychiatrist and for trainees in the clinical setting. We outlined the utility of neuroimaging modalities in the clinical setting, specifically with a view to understanding the pathophysiology of manifestations of disease. Both structural and functional neuroimaging modalities have a clear role in diagnostic evaluation in the spectrum of neurodegenerative disorders. Whilst the role of neuroimaging in patients with mood, anxiety and psychotic disorders is less clear, structural and functional imaging modalities have utility in the clinical setting in the form of diagnostic refinement and in understanding the pathophysiology of disorders, towards explaining manifestations and planning treatment.


Light inhibition of fumarase in Arabidopsis leaves is phytochrome A-dependent and mediated by calcium.
Inhibition of fumarase activity in the light has been studied in Arabidopsis in relation to the involvement of phytochrome. Using knockout phytochrome mutants, we observed that the main regulator of FUM1 gene transcription, encoding the mitochondrial form of fumarase, is phytochrome A. The active form of phytochrome A suppressed FUM1 expression, while the expression of the FUM2 gene encoding the cytosolic form of fumarase was unaffected both in darkness and in light. The nuclear concentration of Ca(2+) was modulated by red and far-red light. We suggest that the signal transduction mechanism operates via Ca(2+) activation of expression of the gene encoding the transcription factor PIF3, which binds to promoters of phytochrome-regulated genes and inhibits FUM1 expression.


Cerebral microbleeds are related to subjective cognitive failures: the RUN DMC study.
Cerebral small vessel disease (SVD), including white matter lesions (WML) and lacunar infarcts, is related to objective cognitive impairment but also to subjective cognitive failures (SCF). SCF have reported to be an early predictor of dementia. Cerebral microbleeds (MB) are another manifestation of SVD and have been related to cognitive impairment, but the role of MB in SCF has never been studied. We therefore investigated whether MB are related to SCF among non-demented elderly individuals with SVD, independent of coexisting WML and lacunar infarcts. The RUN DMC study is a prospective cohort study among 503 older persons with cerebral SVD between 50 and 85 years of age. All participants underwent FLAIR and T2* scanning. SCF, subjective memory failures (SMF), and subjective executive failures (SEF) were assessed. The relation between SCF and the presence, number and location of MB was assessed by linear regression analyses adjusted for age, sex, education, depressive symptoms, cognitive function, total brain volume, normalized hippocampal volume, territorial infarcts, WML, and lacunar infarcts. MB were present in 11%. We found a relation between the presence, total number and lobar located MB, and SCF, SMF, and SEF and the reported progression of these failures, especially in participants with good objective cognitive function. In conclusion, MB are related to SCF independent of co-existing WML and lacunar infarcts, especially in those with good objective cognitive performance. These results suggest that MB are associated with the earliest manifestations of cognitive impairment. MB may help us to understand the role of the ever-expanding spectrum of SVD in cognitive impairment.


Full genome analysis of Philippine indigenous subgenotype IA hepatitis A virus strains from Japanese patients with imported acute hepatitis A.
Hepatitis A virus (HAV) is the most common cause of infectious hepatitis worldwide. Although hepatitis A cases imported from South-East Asian countries, including the Philippines, have been reported in Japan, the molecular epidemiological data have been limited for these HAV-endemic countries. The full-length genomic sequences of HAV isolates were determined and subjected to the phylogenetic analyses. The HAV isolates (HA12-0796 and HA12-0938) obtained from two Japanese patients who developed acute hepatitis A in July 2012, 1 month after traveling to the Philippines, where they consumed undercooked shellfish, differed by only one nucleotide (nt) over the entire genome. These HAV isolates of genotype IA were 99.1-99.5% identical within 228-237 nt to those recovered from river water in the Philippines, suggesting that the HA12-0796 and HA12-0938 isolates represent HAV circulating in the Philippines. HAV isolates belonging to one of the two IA sublineages (IA-2) which were implicated in some of the mini-epidemics in 2010 in Japan are hypothesized to be connected with the Philippines. In support of this speculation, the present IA isolates (HA12-0796 and HA12-0938) shared 98.8% identity over the entire genome with one IA-2 isolate (HAJIH-Fukuo10) recovered from a Japanese female who developed a domestic HAV infection during the mini-epidemics. In the phylogenetic tree constructed based on the entire genome, these three isolates (HA12-0796, HA12-0938 and HAJIH-Fukuo10) segregated into a cluster with a bootstrap value of 100%. These results indicate that HAV isolates belonging to the IA-2 lineage might have been imported from the Philippines.


Latent infection with feline syncytial virus of cell cultures prepared from the kidneys of new-born kittens.
Feline syncytial virus infection was detected in 4 out of 30 secondary or tertiary cultures of kidney cells from new-born kittens. Such infection was not detected in any primary cell culture. The syncytia-forming virus was readily transmissible by infected cells. One strain was transmissible to heterologous (bovine and canine) secondary cells, but did not infect MDBK and PK-15 cell lines. Based on biochemical, untrastructural and serological characteristics, the virus was designated a member of the subfamily Spumavirinae of the family Retroviridae. As endogenous infection of primary cell cultures may not be detectable by cytopathic effect, it is suggested that only well-controlled secondary cat cells or cell lines should be used in work with feline viruses.


Safety of human MRI at static fields above the FDA 8 T guideline: sodium imaging at 9.4 T does not affect vital signs or cognitive ability.
To assess whether exposure to a 9.4 T static magnetic field during sodium imaging at 105.92 MHz affects human vital signs and cognitive function. Measurements of human vital signs and cognitive ability made before and after exposure to a 9.4 T MR scanner and a mock scanner with no magnetic field are compared using a protocol approved by the U.S. Food and Drug Administration (FDA). Exposure to a 9.4 T static magnetic field during sodium imaging did not result in a statistically significant change in the vital signs or cognitive ability of healthy normal volunteers. Vital sign and cognitive ability measurements made before and after sodium imaging at 9.4 T suggest that performing human MRI at 105.92 MHz in a 9.4 T static magnetic field does not pose a health risk.


Emissions of biogenic volatile organic compounds from adjacent boreal fen and bog as impacted by vegetation composition.
Peatland ecosystems emit biogenic volatile organic compounds (BVOC), which have a net cooling impact on the climate. However, the quality and quantity of BVOC emissions, and how they are regulated by vegetation and peatland type remain poorly understood. Here we measured BVOC emissions with dynamic enclosures from two major boreal peatland types, a minerotrophic fen and an ombrotrophic bog situated in Siikaneva, southern Finland and experimentally assessed the role of vegetation by removing vascular vegetation with or without the moss layer. Our measurements from four campaigns during growing seasons in 2017 and 2018 identified emissions of 59 compounds from nine different chemical groups. Isoprene accounted for 81 % of BVOC emissions. Measurements also revealed uptake of dichloromethane. Total BVOC emissions and the emissions of isoprene, monoterpenoids, sesquiterpenes, homoterpenes, and green leaf volatiles were tightly connected to vascular plants. Isoprene and sesquiterpene emissions were associated with sedges, whereas monoterpenoids and homoterpenes were associated with shrubs. Additionally, isoprene and alkane emissions were higher in the fen than in the bog and they significantly contributed to the higher BVOC emissions from intact vegetation in the fen. During an extreme drought event in 2018, emissions of organic halides were absent. Our results indicate that climate change with an increase in shrub cover and increased frequency of extreme weather events may have a negative impact on total BVOC emissions that otherwise are predicted to increase in warmer temperatures. However, these changes also accompanied a change in BVOC emission quality. As different compounds differ in their capacity to form secondary organic aerosols, the ultimate climate impact of peatland BVOC emissions may be altered.


Myotonia-like symptoms in a patient with spinal and bulbar muscular atrophy.
We describe the case of a 33-year-old man with a 4-year history of worsening muscle stiffness and weakness in his right hand. He showed elevated serum creatine kinase levels at the onset of muscle stiffness that was characterized by delayed muscle relaxation after voluntary contraction. This symptom often occurred during cold exposure, and was partially attenuated by sodium channel blockade. Electrodiagnostic findings in repetitive nerve stimulation, short-exercise, and cooling tests were normal. Electromyography showed chronic denervation potentials in his cranial, cervical, thoracic, and lumbosacral myotomes without myotonic discharge. He exhibited facial and tongue fasciculations, hypernasality, gynecomastia, neurogenic changes in muscle biopsy, and increased serum testosterone levels. Spinal and bulbar muscular atrophy (SBMA) was diagnosed on the basis of the CAG trinucleotide expansion in the gene coding androgen receptor. A myotonia-like symptom without myotonic discharge may present as an early neurological sign of SBMA, which possibly reflects a sodium channel dysfunction in skeletal muscles.


Surveillance of late-onset bleb leak, blebitis and bleb-related endophthalmitis--a UK incidence study.
To determine the incidence of late-onset bleb leak (BL), blebitis (B) and bleb-related endophthalmitis (BRE) after trabeculectomy surgery, and report the management approaches employed by UK ophthalmologists. Prospective case ascertainment study reporting of incident cases fulfilling the study definitions of BL, B and BRE through the reporting mechanism provided by the British Ophthalmic Surveillance Unit (BOSU; United Kingdom) for the period July 2007 to August 2008 (13 months). Two questionnaires completed at initial reporting and 6 months later were used to collect clinical details related to presentation, early and late management and outcome. Ninety-eight cases were reported to the British Ophthalmic Surveillance Unit during the study period. Seventy-one first questionnaires were returned (response rate 72.4%). Of these, 11 were erroneous/duplicated. Sixty second questionnaires were sent out, and of these 37 fully completed questionnaires were returned. Analysis was, therefore, based upon 60 initial and 37 follow-up questionnaires. Overall incidences were estimated for isolated bleb leak (0.22%), blebitis without bleb leak (0.1%), blebitis with bleb leak (0.11%), and BRE with or without bleb leak (0.17%). Visual outcome in the BL group was good; however, in the BRE group half the patients ended with visions of perception of light or worse. There was a great variance in the initial and late management of these conditions. Surgical intervention for bleb leak seemed to result in the best chance of leak closure. These complications of trabeculectomy surgery are relatively low but potentially visually devastating. This study updates the knowledge of the incidence of these complications, and suggests that no consistent management approach to any of the reported conditions was practised. In view of the potentially catastrophic consequences of these complications, formal guidance as to best practice would be beneficial, and further research to establish this is required.


Camk2a-Cre-mediated conditional deletion of chromatin remodeler Brg1 causes perinatal hydrocephalus.
Mammalian SWI/SNF-like BAF chromatin remodeling complexes are essential for many aspects of neural development. Mutations in the genes encoding the core subunit Brg1/SmarcA4 or other complex components cause neurodevelopmental diseases and are associated with autism. Congenital hydrocephalus is a serious brain disorder often experienced by these patients. We report a role of Brg1 in the pathogenesis of hydrocephalus disorder. We discovered an unexpected early activity of mouse Camk2a-Cre transgene, which mediates Brg1 deletion in a subset of forebrain neurons beginning in the late embryonic stage. Brg1 deletion in these neurons led to severe congenital hydrocephalus with enlargement of the lateral ventricles and attenuation of the cerebral cortex. The Brg1-deficient mice had significantly smaller subcommissural organs and narrower Sylvian aqueducts than mice that express normal levels of Brg1. Effects were non-cell autonomous and may be responsible for the development of the congenital hydrocephalus phenotype. Our study provides evidence indicating that abnormalities in Brg1 function result in defects associated with neurodevelopmental disorders and autism.


[Three dimensional finite element stress analysis in various class II cavity design on first maxillary premolar].
To evaluate the stress influence in different contour of class II cavity with different filling materials on first maxillary premolar. The stress distribution in two types and all three contours of class II cavity in maxillary premolar were analyzed by three dimensional finite element. The cavity was respectively filled with amalgam and composite resin; and the vertical and lateral stress force was calculated. In the different contours, the stress of composite restoration by slot design was close to that by dovetail design, and the stress of amalgam restoration by slot design, especially in vertical force, descended respectively at 41%,29% and 27%. When class II lesions is only limited in proximal region of the premolar, the filling of composite resin with slot design is recommended.


Experimental infection of human vascular endothelial cells by pathogenic and nonpathogenic hantaviruses.
To investigate whether the hantaviruses replicate in endothelial cells, we inoculated human umbilical vein endothelial cells with several pathogenic and nonpathogenic strains of hantavirus. Intracytoplasmic, virus-specific granular fluorescence was detected initially at three days postinoculation and nearly 100% of cells contained viral antigen at 10 days. Cytopathic effect or inclusion bodies were not observed. The in vitro demonstration of the susceptibility of endothelial cells to hantaviruses corroborates in vivo findings, and suggests that endothelial cells may serve as target cells in hemorrhagic fever with renal syndrome.


Amplified Ca2+ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation.
Intracellular Ca2+ dynamics shape malignant behaviors of cancer cells. Whereas previous studies focused on cultured cancer cells, we here used breast organoids and colonic crypts freshly isolated from human and murine surgical biopsies. We performed fluorescence microscopy to evaluate intracellular Ca2+ concentrations in breast and colon cancer tissue with preferential focus on intracellular Ca2+ release in response to purinergic and cholinergic stimuli. Inhibition of the sarco-/endoplasmic reticulum Ca2+ ATPase with cyclopiazonic acid elicited larger Ca2+ responses in breast cancer tissue, but not in colon cancer tissue, relative to respective normal tissue. The resting intracellular Ca2+ concentration was elevated, and ATP, UTP and acetylcholine induced strongly augmented intracellular Ca2+ responses in breast cancer tissue compared with normal breast tissue. In contrast, resting intracellular Ca2+ levels and acetylcholine-induced increases in intracellular Ca2+ concentrations were unaffected and ATP- and UTP-induced Ca2+ responses were smaller in colon cancer tissue compared with normal colon tissue. In accordance with the amplified Ca2+ responses, ATP and UTP substantially increased proliferative activity-evaluated by bromodeoxyuridine incorporation-in breast cancer tissue, whereas the effect was minimal in normal breast tissue. ATP caused cell death-identified with ethidium homodimer-1 staining-in breast cancer tissue only at concentrations above the expected pathophysiological range. We conclude that intracellular Ca2+ responses are amplified in breast cancer tissue, but not in colon cancer tissue, and that nucleotide signaling stimulates breast cancer cell proliferation within the extracellular concentration range typical for solid cancer tissue.


Effects of spinal cord injury on synaptic inputs to sympathetic preganglionic neurons.
Spinal cord injuries often lead to disorders in the control of autonomic function, including problems with blood pressure regulation, voiding, defecation and reproduction. The root cause of all these problems is the destruction of brain pathways that control spinal autonomic neurons lying caudal to the lesion. Changes induced by spinal cord injuries have been most extensively studied in sympathetic preganglionic neurons, cholinergic autonomic neurons with cell bodies in the lateral horn of thoracic and upper lumbar spinal cord that are the sources of sympathetic outflow. After an injury, sympathetic preganglionic neurons in mid-thoracic cord show plastic changes in their morphology. There is also extensive loss of synaptic input from the brain, leaving these neurons profoundly denervated in the acute phase of injury. Our recent studies on sympathetic preganglionic neurons in lower thoracic and upper lumbar cord that regulate the pelvic viscera suggest that these neurons are not so severely affected by spinal cord injury. Spinal interneurons appear to contribute most of the synaptic input to these neurons so that injury does not result in extensive denervation. Since intraspinal circuitry remains intact after injury, drug treatments targeting these neurons should help to normalize sympathetically mediated pelvic visceral reflexes. Furthermore, sympathetic pelvic visceral control may be more easily restored after an injury because it is less dependent on the re-establishment of direct synaptic input from regrowing brain axons.


Discriminative Factors of Malignancy of Ipsilateral Nonmass Enhancement in Women With Newly Diagnosed Breast Cancer on Initial Staging Breast MRI.
Nonmass enhancement (NME) on breast MRI impacts surgical planning. To evaluate positive predictive values (PPVs) and identify malignancy discriminators of NME ipsilateral to breast cancer on initial staging MRI. Retrospective. Eighty-six women (median age, 48 years; range, 26-75 years) with 101 NME lesions (BI-RADS 4 and 5) ipsilateral to known cancers and confirmed histopathology. 1.5 T and 3.0 T dynamic contrast-enhanced fat-suppressed T1-weighted fast spoiled gradient-echo. Three radiologists blinded to pathology independently reviewed MRI features (distribution, internal enhancement pattern, and enhancement kinetics) of NME, locations relative to index cancers (contiguous, non-contiguous, and different quadrants), associated mammographic calcifications, lymphovascular invasion (LVI), axillary node metastasis, and radiology-pathology correlations. Clinical factors, NME features, and cancer characteristics were analyzed for associations with NME malignancy. Fisher's exact, Chi-square, Wilcoxon rank sum tests, and mixed-effect multivariable logistic regression were used. Significance threshold was set at P < 0.05. Overall NME malignancy rate was 48.5% (49/101). Contiguous NME had a significantly higher malignancy rate (86.7%) than non-contiguous NME (25.0%) and NME in different quadrants (10.7%), but no significant difference was observed by distance from cancer for non-contiguous NME, P = 0.68. All calcified NME lesions contiguous to the calcified index cancer were malignant. NME was significantly more likely malignant when index cancers were masses compared to NME (52.9% vs. 21.4%), had mammographic calcifications (63.2% vs. 39.7%), LVI (81.8% vs. 44.4%), and axillary node metastasis (70.8% vs. 41.6%). NME features with highest PPVs were segmental distribution (85.7%), clumped enhancement (66.7%), and nonpersistent kinetics (77.1%). On multivariable analysis, contiguous NME, segmental distribution, and nonpersistent kinetics were associated with malignancy. Malignancy discriminators of ipsilateral NME on staging MRI included contiguous location to index cancers, segmental distribution, and nonpersistent kinetics. 3 TECHNICAL EFFICACY: Stage 2.


Molecular and structural basis of TIGIT: Nectin-4 interaction, a recently discovered pathway crucial for cancer immunotherapy.
TIGIT (T cell immunoglobulin and ITIM domain) is an inhibitory receptor expressed on T and NK cells that interact with cell surface glycoprotein belonging to the nectin and nectin-like family of cell adhesion molecules, particularly nectin-2 and nectin-like 5 (PVR). Nectin-4 has been recently identified as a novel ligand for TIGIT and the interaction among them inhibits NK cell cytotoxicity. In this study, biophysical experiments were conducted to decipher the mechanism of this novel interaction, followed by structure-guided mutagenesis studies to map the nectin-4 binding interface on TIGIT. Using surface plasmon resonance, we deduced that TIGIT recognizes the membrane distal ectodomain of nectin-4 and the interaction is weaker than the well-characterized TIGIT: nectin-2 interaction. Deciphering the molecular basis of this newly identified interaction between TIGIT and nectin-4 will provide us important insight into the manipulation of this inhibitory signaling pathway, especially targeting cancer cells overexpressing nectin-4 that evade the immune surveillance of the body.


Primary diphtheria immunisation of adolescents and adults with low-dose vaccine, a survey of historic evidence from the literature.
The Public Health Agency of Sweden carried out a literature review on diphtheria vaccinations for seronegative people above 6 years of age with an uncertain vaccine history. The aim was to harmonise national Swedish recommendations with the current World Health Organization recommendations. There was no firm conclusion about dosage. Some low-dose vaccines used in the past had suboptimal potency, while others evoked adequate levels of antitoxin after three primary doses. We concluded that low-dose diphtheria vaccines that have been approved by a national medical products agency can be used for primary vaccination against diphtheria for individuals above 6 years of age.


Clinical diagnosis of bacterial vaginosis.
Bacterial vaginosis (often called nonspecific vaginitis or gardnerella vaginitis) is an incompletely understood disease whose initial diagnosis is often one of exclusion made when no trichomonads, yeast, or evidence of cervicitis is found during the initial examination of a woman complaining of a vaginal discharge. To increase the accuracy of the initial diagnosis, specific criteria were used before the clinical diagnosis of bacterial vaginosis was made. The presence of three of the following four criteria was necessary: 1) vaginal pH greater than 4.5; 2) clue cells on the saline wet mount; 3) thin, homogeneous-appearing discharge; or 4) positive potassium hydroxide "whiff test." A study on 100 consecutive women presenting to the emergency department with vaginal symptoms was done. Of those women meeting the criteria, 93% (54/58) obtained relief of their symptoms by treatment with metronidazole. Of those women not meeting the criteria, only 24% (10/42) were cured (P less than .001). The sensitivity, specificity, and total error rates of these criteria were 84, 89, and 14%, respectively.


Calculating the potential of C2 domains for membrane binding.
A recent report in Molecular Cell demonstrates the ability of electrostatic calculations to predict the membrane binding properties of structurally characterized C2 domains and assign probable membrane targeting functions to numerous uncharacterized C2 domains.


Grief of an adolescent when a sibling dies.
Grieving for losses that normally occur during adolescent development, and at the same time grieving the loss of a sibling cannot be clinically separated.


Exploring olfactory receptor family 7 subfamily C member 1 as a novel oral cancer stem cell target for immunotherapy.
The mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that share characteristics associated with normal stem cells, including self-renewal and multi-differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen-specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC-2 and HSC-3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G-protein-coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell-targeted immunotherapy, in CSC-targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen-A24-restricted OR7C1 oral CSC-specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC-targeted immunotherapy in oral cancer.


Clinical case estimates of lymphatic filariasis in an endemic district of Bangladesh after a decade of mass drug administration.
Bangladesh has a high burden of lymphatic filariasis (LF) disease. This survey estimated the current number of clinical cases in a historically endemic district after a decade of mass drug administration (MDA). A cluster survey was conducted in 30 villages of Nilphamari District. Ten households per village were randomly selected, and individuals with LF clinical conditions identified. Hydrocoele and lymphoedema (leg, arm, breast) cases were quantified and mapped, and differences by sex, age, severity of disease and episodes of acute dermatolymphangioadenitis attacks (ADLA) examined. From 1242 surveyed >10 years old 55 individuals (4.4%) with LF clinical conditions were identified. Males were mostly affected by hydrocoeles, and females by leg lymphoedema. Higher prevalence and more advanced stages of disease were found in older age groups. Overall low prevalence of severe clinical disease was found, which has positive implications for the elimination goal. Future planning of MMDP strategies will need to address the varying clinical conditions, severity of disease and impact of ADLAs affecting different sub-groups of the population. It will also be important to monitor for new cases, and examine the shift in age distribution of cases over time.


A comparison of the analgesic activities of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and 6-chloro-2[1-piperazinyl]pyrazine (MK 212).
Both the gamma-aminobutyric acid (GABA) mimetic, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and the serotonergic agonist, MK 212 (6-chloro-2[ 1-piperazinyl ]pyrazine) are effective analgesic agents in the mouse hot plate assay. Naltrexone, however, fails to reverse the analgesia elicited by either compound. Acute injection of THIP potentiates the morphine analgesia and chronic administration of THIP produces a functional tolerance to its analgesic effects. MK 212 antagonizes the analgesia induced by either morphine or THIP. These results support the postulate that GABAergic and serotonergic synapses represent two synaptic mechanisms which participate in the modulation of pain threshold in a manner that is independent from opioid receptors. Moreover, GABA and serotonin appear to be able to modulate opioid-mediated analgesia in an opposing manner with GABAergic mechanisms facilitating and serotonergic mechanisms inhibiting morphine-induced antinociception.


Studies on the apoproteins of the major lipoprotein of the yolk of hen's eggs III. Influence of salt concentration during isolation on the amount and composition of the apoproteins.
When the major lipoprotein of hen's eggs was prepared by centrifuging yolk in salt solutions, the ionic strength affected the apoprotein mixture. At high salt concentrations (ionic strength above about 2) more protein was present in the lipoprotein than at lower ionic strength. The extra protein was not removed by subsequently lowering the ionic strength. This extra protein consisted largely of proteins of high molecular weight, including, according to electrophoresis, gamma-livetin from the aqueous phase of yolk.


Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of in vivo and in vitro responses.
The efficacy of immunotherapy in cat-induced asthma was studied by use of a purified fraction of cat-pelt extract and a double-blind protocol. Nine active-treatment subjects who received a mean cumulative dose of cat allergen, 1 of 10.9 units, and eight placebo-treatment subjects completed the study. Active treatment resulted in significant reductions in bronchial sensitivity (p less than 0.05) and prick test titer (p less than 0.01). In addition, active treatment resulted in a significant delay in the onset of ocular (p less than 0.05) and pulmonary (p less than 0.02) symptoms on exposure to living cats. Significant increases in IgG antibody to cat allergen 1 (p less than 0.001) and cat albumin (p less than 0.01) also occurred with active treatment. There was no significant change in bronchial reactivity to methacholine or in the sensitivity of circulating basophils. These results confirm the validity of immunotherapy in allergic asthma where there is careful patient selection and well defined treatment preparations.


A feasibility study of a solid-state microdosimeter.
A solid-state silicon detector is a challenging device for microdosimetry, mainly because it can provide sensitive zones of the order of a micrometer. Moreover, these detectors are characterized by a high spatial and a good energy resolution. However, they may present some limitations, such as: (i) the minimum detectable energy which is limited by the electronic noise; (ii) radiation hardness; (iii) the geometry of the sensitive volume; (iv) the field-funnelling effect; (v) the non-tissue-equivalence of silicon. This work discusses a feasibility study of a microdosimeter based on a monolithic silicon telescope, consisting of a DeltaE and an E stage-detector, about 1 and 500 microm thick, respectively. Charges are collected separately in the two stage-detectors. The use of the DeltaE stage coupled with a tissue-equivalent converter was investigated as a solid-state microdosimeter. Irradiations with monoenergetic neutrons were performed at the INFN-Laboratori Nazionali di Legnaro (Italy). The field-funnelling effect appears to be negligible from the comparison of the experimental data with the results of Monte Carlo simulations, performed with the FLUKA code. The preliminary results of an analytical approach for the correction for geometrical effects and tissue-equivalence are also presented.


Accurate and fast algorithm of the molecular incomplete gamma function with a complex argument.
Several efficient algorithms for the accurate and fast calculation of the molecular incomplete gamma function Fm(z) with a complex argument z are developed. The complex incomplete gamma function is arising in molecular integrals over the gauge-including atomic orbitals. Two kinds of algorithms are recommended: (1) a high-precision version and (2) a fast version. The high-precision version is able to guarantee 15 significant figures (10(-15) in the relative error) and the fast version is able to guarantee 12 significant figures (10(-12) in the relative error), at worst, within the double-precision arithmetic. The fast version is about 5-20 times faster than the high-precision version. For most molecular calculations, the fast version will give a satisfied precision.


Effects of acute and chronic angiotensin receptor blockade on myocardial vascular blood volume and perfusion in a pig model of coronary microembolization.
Based on the reduction of ischemic cardiac events in clinical trials and experimental observations, inhibition of the effects of angiotensin II on coronary microcirculatory function may afford myocardial protection after injury. The immediate effects of intracoronary AT1 receptor blockade with irbesartan were examined in a pig model in the healthy myocardium and in acute ischemia induced by injection of 30-microm microspheres into the left anterior descending coronary artery (LAD). Electron-beam computed tomography was performed for in-vivo quantitative measurements of regional intramyocardial vascular blood volume (V(B)) and perfusion (F(M)), as well as left ventricular ejection fraction (LVEF) and muscle mass. Ratios of V(B) and F(M) in the anterior (LAD-supplied)/ inferior (control) myocardium were generated. At baseline, 0.2 mg/kg irbesartan injected into the LAD increased V(B) and F(M) ratios significantly by 27 +/- 8% and 51 +/- 13%, respectively. After anterior coronary microembolization, V(B) and F(M) ratios were 0.60 +/- 0.05 and 0.51 +/- 0.05, respectively, and were significantly increased by irbesartan (by 24 +/- 10% and by 36 +/- 11%, respectively). After 4 weeks of treatment with oral irbesartan (n = 7) or placebo (n = 7), an improved LVEF (56 +/- 4% v 44 +/- 4%, P = .046) was observed in irbesartan-treated animals, but no difference in LV end-diastolic volumes or muscle mass. Resting V(B) (0.95 +/- 0.06 v 0.76 +/- 0.06; P = .047) and F(M) (0.84 +/- 0.05 v 0.64 +/- 0.04; P = .016) ratios were significantly greater in irbesartan-treated animals. Using adenosine, there was a trend for higher V(B) and F(M) ratios in irbesartan- v placebo-treated animals. Therefore, in a pig model of acute myocardial ischemia, AT1 receptor blockade by irbesartan induced microvascular vasodilation and, ostensibly, conveyed myocardial protection. Long-term treatment with irbesartan resulted in moderate enhancements of resting V(B) and F(M) compared with placebo, suggesting a role for coronary microcirculatory effects of chronic AT1 receptor blockade in preserving LVEF.


Cognitive impairment as a barrier to utilizing preventive health services among older adults.
This study aimed to examine the influence of cognitive impairment on preventive health services utilization among older adults. The study sample came from 1995 to 2014 waves of the Health and Retirement Study (HRS), consisting of 19,644 adults aged 51 years or older. Mixed-effects logistic regression was used to analyze the influence of cognitive impairment, measured using the Telephone Interview for Cognitive Status, on the utilization of four types of preventive health care services, including flu shots, cholesterol tests, mammography for women, and prostate cancer screening for men. Persons with cognitive impairment with no dementia were less likely to receive cholesterol tests (OR=0.68, 95% CI=0.64-0.73, p<.001), flu shots (OR=0.86, CI=0.80-0.92, p<.001), mammograms (OR=0.88, CI=0.78-0.99, p<.05), and prostate cancer screenings (OR=0.71, CI=0.71-0.98, p<.05) compared with those without cognitive impairment. Having dementia was associated with a lower odds of receiving cholesterol tests (OR=0.42, CI=0.38-0.47, p<.001), flu shots (OR=0.65, CI=0.57-0.74, p<.001), mammograms (OR=0.70, CI=0.55-0.89, p<.01), and prostate cancer screening (OR=0.68, CI=0.47-0.99, p<.05). Cognitive impairment with or without dementia is a significant barrier to utilizing preventive health services among older adults. Targeted health promotion prevention and intervention strategies and caregiver education are warranted to improve preventive services among older adults with cognitive impairment.


Long term follow-up of hyperthyroid patients treated by subtotal thyroidectomy.
The early and long term complications of subtotal thyroidectomy in 306 hyperthyroid patients (multinodular goitre and diffuse hyperplasia) followed for up to 30 yr are reviewed. There were no perioperative deaths. Sixteen patients (5.2 per cent) had transient symptomatic hypocalcaemia, while 9 (2.9 per cent) had permanent hypocalcaemia. Permanent unilateral vocal cord paralysis occurred in 11 (3.6 per cent) patients (1.8 per cent of nerves at risk). Cumulative per cent (+/- s.e.m.) relapse and hypothyroid rates at 30 yr (life-table analysis) were 15.6 +/- 2.4 per cent and 20.5 +/- 2.1 per cent, respectively. Lifelong follow-up of post-thyroidectomy patients is mandatory because of the risk of relapse of hypothyroidism.


The impact of nanofertilizer on agro-morphological criteria, yield, and genomic stability of common bean (Phaseolus vulgaris L.).
The use of agricultural fertilizers is one of the methods to beat the desired enormous increase in universal food production. The application of nanotechnology in agriculture is regarded as one of the promising approaches to elevate crop production. Whereas mineral nutrients play a crucial role in the growth and yield of the common bean. The experiments were conducted to investigate the application effect of micronutrients as nanoparticles (MN-NPs) on the common ben plants. The trial was performed in the field in El-Menofya, Egypt, through two seasons (2019 & 2020) in a randomized complete block design with three replicates and four combinations of MN-NPs (ZnO, MnO2 and MoO3) with concentrations 0, 10, 20, 30, 40 mg/L as a foliar application. The data exhibited that the foliar application of MN-NPs significantly upgraded the vegetative growth characters, flower number/plant, photosynthetic pigments, and yield. The concentration of 40 mg/L of MN-NPs leads to improving the vegetative growth, flowering number, and yield characteristics of the common bean. While the biochemical components varied in their response to MN-NPs combinations. The recommended MN-NPs concentration to ameliorate the common bean growth and yield was 40 mg/L.


Comprehensive analysis of a cuproptosis-related ceRNA network implicates a potential endocrine therapy resistance mechanism in ER-positive breast cancer.
While adjuvant endocrine therapy (ET) may decrease the mortality rate of estrogen receptor-positive (ER+) breast cancer (BC), the likelihood of relapse and metastasis due to ET resistance remains high. Cuproptosis is a recently discovered regulated cell death (RCD), whose role in tumors has yet to be elucidated. Thus, there is a need to study its specific regulatory mechanism in resistance to ET in BC, to identify novel therapeutic targets. The prognostic cuproptosis-related genes (CRGs) in ER+ BC were filtered by undergoing Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses in TCGA-BRCA, and a CRGs risk signature was constructed using the correlation coefficient. Immune infiltration analysis, immune function analysis, tumor microenvironment (TME) analysis, immune checkpoint analysis, immunotherapy response analysis, drug sensitivity analysis, and pathway activation analysis were carried out among the high- and low-risk groups in turn. The central CRG of cuproptosis in ER+ BC resistance to ET was acquired through the intersection of protein interaction network (PPI) analysis, genes differentially expressed (DEGs) between human BC cells LCC9 and MCF-7 (GSE159968), and CRGs with prognostic significance in TCGA-BRCA ER+ BC. The miRNAs upstream of the core CRGs were predicted based on the intersection of 4 databases, miRDB, RNA22, miRWalk, and RNAlnter. Candidate miRNAs consisted of the intersection of predicted miRNAs and miRNAs differentially expressed in the LCC9 and MCF-7 cell lines (GSE159979). Candidate lncRNAs were the intersection of the differential lncRNAs from the LCC9 and MCF-7 cell lines and the survival-related lncRNAs obtained from a univariate Cox regression analysis. Pearson's correlation analysis was performed between mRNA-miRNA, miRNA-lncRNA, and mRNA-lncRNA expression separately. We constructed A risk signature of 4-CRGs to predict the prognosis of ER+ BC in TCGA-BRCA, a risk score = DLD*0.378 + DBT*0.201 + DLAT*0.380 + ATP7A*0.447 was used as the definition of the formula. There were significant differences between the high- and low-risk groups based on the risk score of 4-CRGs in aspects of immune infiltration, immune function, expression levels of immune checkpoint genes, and signaling pathways. DLD was determined to be the central CRG of cuproptosis in ER+ BC resistance to ET through the intersection of the PPI network analysis, DEGs between LCC9 and MCF-7 and 4-CRGs. Two miRNAs hsa-miR-370-3p and hsa-miR-432-5p were found taking DLD mRNA as a target, and the lncRNA C6orf99 has been hypothesized to be a competitive endogenous RNA that regulates DLD mRNA expression by sponging off hsa-miR-370-3p and hsa-miR-432-5p. This study built a prognostic model based on genes related to cuproptosis in ER+ BC. We considered DLD to be the core gene associated with resistance to ET in ER+ BC via copper metabolism. The search for promising therapeutic targets led to the establishment of a cuproptosis-related ceRNA network C6orf99/hsa-miR-370-3p and hsa-miR-432-5p/DLD.


Early dementia diagnosis, MCI-to-dementia risk prediction, and the role of machine learning methods for feature extraction from integrated biomarkers, in particular for EEG signal analysis.
Dementia in its various forms represents one of the most frightening emergencies for the aging population. Cognitive decline-including Alzheimer's disease (AD) dementia-does not develop in few days; disease mechanisms act progressively for several years before clinical evidence. A preclinical stage, characterized by measurable cognitive impairment, but not overt dementia, is represented by mild cognitive impairment (MCI), which progresses to-or, more accurately, is already in a prodromal form of-AD in about half cases; people with MCI are therefore considered the population at risk for AD deserving special attention for validating screening methods. Graph analysis tools, combined with machine learning methods, represent an interesting probe to identify the distinctive features of physiological/pathological brain aging focusing on functional connectivity networks evaluated on electroencephalographic data and neuropsychological/imaging/genetic/metabolic/cerebrospinal fluid/blood biomarkers. On clinical data, this innovative approach for early diagnosis might provide more insight into pathophysiological processes underlying degenerative changes, as well as toward a personalized risk evaluation for pharmacological, nonpharmacological, and rehabilitation treatments.


Mechanical analysis of eyelid morphology.
From a mechanical instability perspective a double eyelid is a double-folded thin film structure on a curved substrate, caused by compression as the film "slides" on the substrate. The underlying mechanics issues, in particular the requirements for forming a double folded structure, are studied using a modeling/simulation framework. A minimalist model is employed to explore the wrinkle to fold transition. Refined and enriched models are further developed based on anatomical structures, which demonstrate three critical factors for the formation of double layer folding of the eyelid. First, a crease line in the eyelid is essential where the local bending rigidity is relatively weak. Second, the skin above the crease line should be thin and wide enough. Third, the skin below the crease line should have a relatively large effective stiffness so it can be lifted as a whole when the eyes open. When the eye is opened beyond about 40% of its initial wrinkle wavelength, the double-folded structure emerges. Various types of eyelid morphologies are discussed based on the mechanistic model. The study provides useful insights for surgery, cosmetics, and morphogenesis, as well as microfabrication.


Frailty predicts short-term incidence of future falls among British community-dwelling older people: a prospective cohort study nested within a randomised controlled trial.
Although population-based studies have shown frailty predicted future falls, their follow-up periods were one year or longer and short-term fall risks associated with frailty are unknown. A prospective cohort study nested within a randomised controlled trial was conducted to examine associations between frailty and short-term incident future falls among community-dwelling older people. Two hundred forty eight community-dwelling people > =65 years without history of > =three falls and allocated to a usual care arm of exercise intervention trial were prospectively monitored for falls over 24 weeks. Frailty index (FI) was constructed from 40 deficits at baseline. The future fall risks according to frailty status was examined using logistic regression models. Of 248 participants, 46 were classified as frail and 57 had one or more falls during follow-up. Both each 0.01 increase in FI and frailty defined as FI > =0.25 were significantly associated with higher risks of future falls in multivariate logistic regression models adjusted for age, gender and history of two falls in the previous year (odds ratio (OR) = 1.05, 95 % confidence interval (95 % CI) = 1.02-1.07, p < 0.001; OR = 3.04, 95 % CI = 1.53-6.02, p = 0.001, respectively). Receiver operating characteristic (ROC) curve analysis showed FI predicted future falls with fair accuracy with area under ROC curve of 0.62 (95 % CI = 0.53-0.71, p < 0.01). Frailty was a significant and independent predictor of short-term future falls among community-dwelling older people who had volunteered for a physical activity study. It is important for healthcare practitioners to recognise frailty as a risk factor of imminent future falling even in older people who appear to be ageing well.


Regiospecific intestinal absorption of the HIV protease inhibitor L-735,524 in beagle dogs.
To evaluate regional intestinal absorption and the feasibility of sustained release dosage form development for an HIV protease inhibitor, L-735,524, L-735,524 free base or sulfate salt was administered orally as suspension, solution or in solid dosage forms to fasted or fed Beagle dogs. Delayed-release dosage forms with "slow" or "fast" in vitro dissolution rates were evaluated in vivo to assess plasma concentration profiles. In addition, drug was administered directly into the jejunum or colon of animals, and drug concentrations determined in portal circulation to characterize absorption from these sites. L-735,524 sulfate was well absorbed orally form a solution or capsule formulation if fasted animals' stomachs were preacidified with citric acid solution. A free base suspension, delivered in divided doses to fed animals, was also well absorbed. Prototype extended release dosage forms of L-735,524 produced a reduction in peak plasma levels but failed to prolong absorption and extend plasma concentrations compared to an immediate release capsule. Administration of L-735,524 sulfate solution (pH < 3) as bolus solution or by infusion into the jejunum resulted in rapid but incomplete absorption compared to oral gavage. The free base suspension (pH 6.5) delivered into jejunal or colonic regions did not produce measurable systemic plasma concentrations. Extended release formulations did not prolong absorption of L-735,524 in dogs. Optimal L-735,524 absorption was dependent on solubility in an acidic environment in the duodenum.


Neurophysiological and magnetic resonance studies in a patient with hemiballismus.
A case of hemiballismus is reported. Magnetic resonance imaging revealed a cavernous hemangioma in the mesencephalon. The hemiballismus in the biceps and triceps muscles was associated with prolonged bursts of EMG activity.


Role of coronary flow regulation and cardiac-coronary coupling in mechanical dyssynchrony associated with right ventricular pacing.
Mechanical dyssynchrony (MD) affects left ventricular (LV) mechanics and coronary perfusion. To understand the multifactorial effects of MD, we developed a computational model that bidirectionally couples the systemic circulation with the LV and coronary perfusion with flow regulation. In the model, coronary flow in the left anterior descending (LAD) and left circumflex (LCX) arteries affects the corresponding regional contractility based on a prescribed linear LV contractility-coronary flow relationship. The model is calibrated with experimental measurements of LV pressure and volume, as well as LAD and LCX flow rate waveforms acquired under regulated and fully dilated conditions from a swine under right atrial (RA) pacing. The calibrated model is applied to simulate MD. The model can simultaneously reproduce the reduction in mean LV pressure (39.3%), regulated flow (LAD: 7.9%; LCX: 1.9%), LAD passive flow (21.6%), and increase in LCX passive flow (15.9%). These changes are associated with right ventricular pacing compared with RA pacing measured in the same swine only when LV contractility is affected by flow alterations with a slope of 1.4 mmHg/mL2 in a contractility-flow relationship. In sensitivity analyses, the model predicts that coronary flow reserve (CFR) decreases and increases in the LAD and LCX with increasing delay in LV free wall contraction. These findings suggest that asynchronous activation associated with MD impacts 1) the loading conditions that further affect the coronary flow, which may explain some of the changes in CFR, and 2) the coronary flow that reduces global contractility, which contributes to the reduction in LV pressure.NEW & NOTEWORTHY A computational model that couples the systemic circulation of the left ventricular (LV) and coronary perfusion with flow regulation is developed to study the effects of mechanical dyssynchrony. The delayed contraction in the LV free wall with respect to the septum has a significant effect on LV function and coronary flow reserve.


Has network meta-analysis resolved the controversies related to bowel preparation in elective colorectal surgery?
There are discrepancies in the guidelines on preparation for colorectal surgery. While intravenous antibiotics (IV) are usually administered, the use of mechanical bowel preparation (MBP) and/or oral antibiotics (OA) is controversial. A recent network meta-analysis (NMA) demonstrated that the addition of OA reduced incisional surgical site infections (iSSIs) by more than 50%. We aimed to perform a NMA including only the highest quality randomized clinical trials (RCTs) in order to determine the ranking of different treatment strategies and assess these RCTs for methodological problems that may affect the conclusions of the NMAs. A NMA was performed according to PRISMA guidelines. RCTs of adult patients undergoing elective colorectal surgery with appropriate antibiotic cover and with at least 250 participants recruited, clear definition of endpoints and duration of follow-up extending beyond discharge from hospital were included. The search included Medline, Embase, Cochrane and SCOPUS databases. Primary outcomes were iSSI and anastomotic leak (AL). Statistical analysis was performed in Stata v.15.1 using frequentist routines. Ten RCTs including 5107 patients were identified. Treatments compared IV (2218 patients), IV + OA (460 patients), MBP + IV (1405 patients), MBP + IV + OA (538 patients) and OA (486 patients). The likelihood of iSSI was significantly lower for IV + OA (rank 1) and MBP + IVA + OA (rank 2), reducing iSSIs by more than 50%. There were no differences between treatments for AL. Methodological issues included differences in definition, assessment and frequency of primary endpoint infections and the limited number of participants included in some treatment options. While this NMA supports the addition of OA to IV to reduce iSSI it also highlights unanswered questions and the need for well-designed pragmatic RCTs.


Detection of Trypanosoma cruzi infection in naturally infected dogs and cats using serological, parasitological and molecular methods.
Domestic dogs and cats are major domestic reservoir hosts of Trypanosoma cruzi and a risk factor for parasite transmission. In this study we assessed the relative performance of a polymerase chain reaction assay targeted to minicircle DNA (kDNA-PCR) in reference to conventional serological tests, a rapid dipstick test and xenodiagnosis to detect T. cruzi infection in dogs and cats from an endemic rural area in northeastern Argentina. A total of 43 dogs and 13 cats seropositive for T. cruzi by an immunosorbent assay (ELISA) and an indirect hemagglutination assay (IHA), which had been examined by xenodiagnosis, were also tested by kDNA-PCR. kDNA-PCR was nearly as sensitive as xenodiagnosis for detecting T. cruzi-infectious dogs and cats. kDNA-PCR was slightly more sensitive than xenodiagnosis in seropositive dogs (91% versus 86%, respectively) and cats (77% against 54%, respectively), but failed to detect all of the seropositive individuals. ELISA and IHA detected all xenodiagnosis-positive dogs and both outcomes largely agreed (kappa coefficient, κ=0.92), whereas both assays failed to detect all of the xenodiagnosis-positive cats and their agreement was moderate (κ=0.68). In dogs, the sensitivity of the dipstick test was 95% and agreed closely with the outcome of conventional serological tests (κ=0.82). The high sensitivity of kDNA-PCR to detect T. cruzi infections in naturally infected dogs and cats supports its application as a diagnostic tool complementary to serology and may replace the use of xenodiagnosis or hemoculture.


[Hyperplasia of the thyroid gland. Surgical indications and treatment (author's transl)].
The surgical indications of a benign multinodular euthyroid struma are: compression of trachea and oesophagus or a possible malignity of the lesion. The operation of choice is a bilateral subtotal lobectomy. To avoid postoperative vocal cord paralysis or hypocalcemia due to damage of the parathyroid glands, it is important to demonstrate systematically the recurrent nerve and spare the inferior thyroid artery.


Elevated urinary levels of carcinogenic N-nitrosamines in patients with urinary tract infections measured by isotope dilution online SPE LC-MS/MS.
N-nitrosamines (NAms) are well-documented for their carcinogenic potential. Human exposure to NAms may arise from the daily environment and endogenous formation via the reaction of secondary amines with nitrites or from bacteria infection. We describe the use of isotope dilution online solid-phase extraction (SPE) LC-MS/MS to quantify nine NAms in human urine. This method was validated and further applied to healthy subjects and patients with urinary tract infection (UTI). N-nitrosodimethylamine (NDMA), N-nitrosomethylethylamine (NMEA), N-nitrosopyrrolidine (NPYR) and N-nitrosomorpholine (NMOR) were analyzed with an APCI source, while N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPIP), N-nitrosodi-n-propylamine (NDPA), N-nitrosodibutylamine (NDBA) and N-nitrosodiphenylamine (NDPhA) were quantified with an ESI source, due to their effect on the sensitivity and chromatography. NDMA was the most abundant N-nitrosamine, while NDPhA was firstly identified in human. UTI patients had three to twelve-fold higher concentrations for NDMA, NPIP, NDEA, NMOR and NDBA in urine than healthy subjects, and the NAms were significantly decreased after antibiotics treatment. NDMA concentrations were also significantly correlated with the pH value, leukocyte esterase activity or nitrite in urines of UTI patients. Our findings by online SPE LC-MS/MS method evidenced that UTI patients experienced various NAms exposures, especially the potent carcinogen NDMA, which was likely induced by bacteria infection.


Chemical characterization and source identification of PM2.5 in Luoyang after the clean air actions.
Luoyang is a typical heavy industrial city in China, with a coal-dominated energy structure and serious air pollution. Following the implementation of the clean air actions, the physicochemical characteristics and sources of PM2.5 have changed. A comprehensive study of PM2.5 was conducted from October 16, 2019 to January 23, 2020 to evaluate the effectiveness of previous control measures and further to provide theory basis for more effective policies in the future. Results showed that the aerosol pollution in Luoyang in autumn and winter is still serious with the average concentration of 91.1 μg/m3, although a large reduction (46.9%) since 2014. With the contribution of nitrate increased from 12.5% to 25.1% and sulfate decreased from 16.7% to 11.2%, aerosol pollution has changed from sulfate-dominate to nitrate-dominate. High NO3-/SO42- ratio and the increasing of NO3-/SO42- ratio with the aggravation of pollution indicating vehicle exhaust playing an increasingly important role in PM2.5 pollution in Luoyang, especially in the haze processes. Secondary inorganic ions contributed significantly to the enhancement of PM2.5 during the pollution period. The high value of Cl-/Na+ and EC concentration indicate coal combustion in Luoyang is still serious. The top three contributor sources were secondary inorganic aerosols (33.3%), coal combustion (13.6%), and industrial emissions (13.4%). Close-range transport from the western and northeastern directions were more important factors in air pollution in Luoyang during the sampling period. It is necessary to strengthen the control of coal combustion and reduce vehicle emissions in future policies.


Global and Local Tensor Factorization for Multi-criteria Recommender System.
In multi-criteria recommender systems, matrix factorization characterizes users and items via latent factor vectors inferred from user-item rating patterns. However, two-dimensional matrix factorization models may not be able to cope with the recommendation problem that involves additional criterion-specific rating data. This study introduces a tensor factorization method to handle three-dimensional user-item-criterion rating data. Moreover, we observe that using single global tensor factorization alone may not be sufficient to characterize diverse preferences among different groups of users, and a combined global and local tensor factorization method (GLTF) for multi-criteria recommendation is thus proposed. One key benefit of the GLTF is that it can leverage global user-item-criterion rating patterns while also exploiting local user-subset specific rating behaviors to jointly infer the latent factor representations for users, items, and specific item criteria. Experimental results, which used real-life data available to the public, demonstrated that the GLTF is superior to well-established baseline methods.


Low DNA HTLV-2 proviral load among women in São Paulo City.
HTLV-2 infections are almost always asymptomatic, and diseases associated with the infection are rarely reported. Little information is available on the relationship between HTLV-2 proviral load and gender or expression of disease, especially among patients with HIV-1 co-infection. We studied 77 HTLV-2-infected subjects followed in our clinic for the last 9 years; 53 (69%) of them were co-infected with HIV-1. HTLV-2 DNA proviral load (PVL) was measured by real time PCR, a test with a sensitivity of 10 in 10(4) PBMCs. Six of 53HTLV-2/HIV-1 cases had a myelopathy (all of them had undetectable PVL of HTLV-2). Only 3 of 35 women (2 out of 3 co-infected with HIV) had a detectable PVL, whereas 10 of 42 men had a detectable PVL. Regardless of their HIV status women had significantly lower PVL than men (10 vs. 43 copies/10(4) PBMCs, p<0.05). We noticed the occurrence of myelopathy in HTLV-2/HIV-1 co-infected patients, with undetectable HTLV-2 viral load. There was a sex difference in viral load for HTLV-2, what may be the result in mode of transmission or acquisition of the virus.


Embolisation of iatrogenic lumbar artery bleed causing psoas haematoma following elective lumbar puncture.
The case of a female patient in her 50s presenting as a surgical emergency with abdominal pain and a positive Obraztsova's sign. Seven days prior to the presentation, a lumbar puncture (LP) had been performed to investigate severe headaches and exclude a subarachnoid haemorrhage. The patient was subsequently found to have an acute lumbar arterial bleed causing haemodynamic instability and a psoas haematoma. An emergency lumbar artery embolisation procedure was performed by the interventional radiology department in order to stabilise the bleed. The patient made a full recovery prior to discharge.


Co@Carbon and Co 3 O4@Carbon nanocomposites derived from a single MOF for supercapacitors.
Developing a composite electrode containing both carbon and transition metal/metal oxide as the supercapacitor electrode can combine the merits and mitigate the shortcomings of both the components. Herein, we report a simple strategy to prepare the hybrid nanostructure of Co@Carbon and Co3O4@Carbon by pyrolysis a single MOFs precursor. Co-based MOFs (Co-BDC) nanosheets with morphology of regular parallelogram slice have been prepared by a bottom-up synthesis strategy. One-step pyrolysis of Co-BDC, produces a porous carbon layer incorporating well-dispersed Co and Co3O4 nanoparticles. The as-prepared cobalt-carbon composites exhibit the thin layer morphology and large specific surface area with hierarchical porosity. These features significantly improve the ion-accessible surface area for charge storage and shorten the ion transport length in thin dimension, thus contributing to a high specific capacitance. Improved capacitance performance was successfully realized for the asymmetric supercapacitors (ASCs) (Co@Carbon//Co3O4@Carbon), better than those of the symmetric supercapacitors (SSCs) based on Co@Carbon and Co3O4@Carbon materials (i.e., Co@Carbon//Co@Carbon and Co3O4@Carbon//Co3O4@Carbon). The working voltage of the ASCs can be extended to 1.5 V and show a remarkable high power capability in aqueous electrolyte. This work provides a controllable strategy for nanostructured carbon-metal and carbon-metal oxide composite electrodes from a single precursor.


Characterization of peripheral-type benzodiazepine binding sites on human lymphocytes and lymphoma cell lines and their role in cell growth.
Peripheral-type benzodiazepine binding sites (PBRs) are ubiquitous in mammalian tissues. However, the physiological role of PBRs has not yet been clarified. In this study we characterized a saturable and high affinity binding site for [3H]Pk 11195 (isoquinoline carboxamide derivative) on human lymphocytes and different lymphoma cell lines. Binding parameters of the human T-lymphoma cell line CCRF-CEM came closest to values for lymphocyte binding. Thus, the CCRF-CEM cell line appears to be a suitable lymphocyte cell model for further study of PBRs. To evaluate the pharmacological specificity of binding to human lymphocytes and CCRF-CEM cells we investigated the potency of different ligands to displace [3H]Pk 11195 from its binding site. Pk 11195 was found to be the most potent inhibitor followed by 4'-chlorodiazepan (Ro5-4864) and diazepam (range of inhibition constants from 6.7 x 10(-9) M to 3.6 x 10(-7) M), whereas ligands specific for the central-type receptor like clonazepam and flumazenil had no displacing potency in the tested concentration range (10(-10)-10(-4) M). Since it was assumed that PBRs might be involved in the regulation of cell growth and differentiation, we studied the influence of PBR ligands on cell growth and survival using a quantitative colorimetric assay (MTT). Ligands which bind selectively to PBRs inhibited cell multiplication in vitro. However, half-effective concentrations (EC50) were in the micromolar range and above therapeutic in vivo concentrations (range of EC50 values from 2.4 x 10(-5) M to 1.5 x 10(-4) M). Clonazepam and flumazenil had no inhibiting potency in the tested concentration range (10(-10)-10(-4) M). Although the difference between values for displacing potency and ability to inhibit cell multiplication cannot be explained as yet, it is interesting that all PBR-ligands followed the same sequence in displacing [3H]Pk 11195 and inhibiting cell multiplication and that central type ligands were ineffective in both assays. This association suggest a mediating role of PBR binding in cell growth.