Mind your Ps: A probabilistic model to aid the interpretation of molecular epidemiology data.
Assessing relatedness of pathogen sequences in clinical samples is a core goal in molecular epidemiology. Tools for Bayesian analysis of phylogeny, such as the BEAST software package, have been typically used in the analysis of sequence/time data in public health. However, they are computationally-, time-, and knowledge-intensive, demanding resources that many laboratories do not have available or cannot allocate frequently. To evaluate a faster and simpler alternative method to support the routine interpretation of sequence data for epidemiology, we obtained sequences for two regions in the measles virus genome, N-450 and MF-NCR, from patient samples of genotypes B3, D4 and D8 taken between 2011 and 2017 in the UK and Romania. A mathematical model incorporating time, possible shared ancestry and the Poisson distribution describing the number of expected substitutions at a given time point was developed to exclude epidemiological relatedness between pairs of sequences. The model was validated against the commonly used Bayesian phylogenetic method using an independent dataset collected in 2017-19. We demonstrate that our model, using time and sequence information to predict whether two samples may be related within a given time frame, minimises the risk of erroneous exclusion of relatedness. An easy-to-use implementation in the form of a guide and spreadsheet is provided for convenient application. The proposed model only requires a previously calculated substitution rate for the locus and pathogen of interest. It allows for an informed but quick decision on the likelihood of relatedness between two samples within a time frame, without the need for phylogenetic reconstruction, thus facilitating rapid epidemiological interpretation of sequence data. This work was funded by the United Kingdom Health Security Agency (UKHSA). The World Health Organization European Regional Office funded Aurora Fernández-García and Mihaela Lazar training visits to UKHSA.


Quantitative multiparametric MRI as a promising tool for the assessment of early response to neoadjuvant chemotherapy in bladder cancer.
Magnetic resonance imaging (MRI) has been applied to predict the neoadjuvant chemotherapy (NAC) response of bladder cancer at an early stage, but the performance remains poor. A tool for the selection of patients with muscle-invasive bladder cancer (MIBC) with high probability of benefitting from NAC is not yet available. We designed a prospective study to assess a quantitative MRI for predicting the early response of MIBC to NAC. All individuals underwent a time-course MRI at pre-NAC, 24 h after initial cisplatin medication (24 h-NAC) and post-NAC.Chemosensitivity was evaluated according to pathological response.The transfer constant (Ktrans), plasma volume (Vp), extravascular extracellular space (Ve), and apparent diffusion coefficient (ADC) were quantitated based on dynamic contrast-enhanced and diffusion-weighted imaging.Quantitative RECIST criteria were constructed by modelling pre-NAC and 24 h-NAC MRI measures, and then compared with conventional RECIST by using pre- and post-NAC MRI measures. In this pilot study, a total of 24 patients were enrolled into the study. Eight patients were pathologically confirmed to be NAC-responders. After a thorough evaluation of these parameters, different parameters showed good discrimination at different point in time. ROC curves showed quantitative MRI can predict the response to NAC, especially ADC_M (AUC = 0.859, P = 0.005) and ADC index (AUC = 0.844, P = 0.007) at pre-NAC timing and ADC_M (AUC = 0.816, P = 0.013) at 24 h-NAC timing. Then, a qRECIST model was established for predicting NAC sensitivity, with AUC of 0.91, TP rate of 0.8, and accuracy of 0.75. The diagnostic performance of mpMRI parameters for NAC response is excellent. The qRECIST derived between pre- and 24 h NAC MRI could predict the early response of MIBC to NAC and help for candidate selection.


Manganese levels in infant formula and young child nutritional beverages in the United States and France: Comparison to breast milk and regulations.
Exposure to high levels of manganese (Mn) in children has recently been associated with adverse neurodevelopmental effects. Current infant formula regulations for Mn content were set between 1981 (United States), 2006 (European Union, France), and 2007 (Codex Alimentarius) prior to the publication of much of the growing body of research on the developmental neurotoxicity of Mn. In this study, we sought to measure the concentrations of Mn in some infant formulas and young child nutritional beverages available on the United States (US) and French markets using ion beam analysis by particle induced X-ray emission (PIXE) spectrometry and then compare the analytical results to concentrations reported in the literature for breast milk and applicable infant formula regulations and guidelines. We were particularly interested in measuring Mn concentrations in product types for which there is very little data from previous surveys, especially soy-based, rice-based, goat-milk based, chocolate-flavored, and nutritional beverages for young children that are not regulated as infant or follow-on formulas (e.g. "toddler formulas" and "toddler powders"). We purchased 44 infant formulas and young child nutritional beverage products in the US and France with varying protein sources (cow-milk, goat-milk, soy, rice) labelled for birth to 3 years. We selected these samples using maximum variation sampling to explore market extremes to facilitate comparisons to regulatory limits. Since this sampling method is non-probabilistic, other inferences cannot be made beyond this set of samples to the overall markets. We used ion beam analysis to measure the concentrations of Mn in each product. The range of measured Mn concentrations in the products is 160-2,800 μg/L, substantially higher than the 3-6 μg/L mean Mn concentration reported in human breast milk. All products satisfied national and Codex Alimentarius Commission (CAC) international standards for minimum Mn content in infant formulas; however, 7/25 of the products purchased in the US exceeded the CAC Guidance Upper Level of 100 μg Mn/kcal for infant formula.


Emerging roles of metaplasticity in behaviour and disease.
Since its initial conceptualisation, metaplasticity has come to encompass a wide variety of phenomena and mechanisms, creating the important challenge of understanding how they contribute to network function and behaviour. Here, we present a framework for considering potential roles of metaplasticity across three domains of function. First, metaplasticity appears ideally placed to prepare for subsequent learning by either enhancing learning ability generally or by preparing neuronal networks to encode specific content. Second, metaplasticity can homeostatically regulate synaptic plasticity, and this likely has important behavioural consequences by stabilising synaptic weights while ensuring the ongoing availability of synaptic plasticity. Finally, we discuss emerging evidence that metaplasticity mechanisms may play a role in disease causally and may serve as a potential therapeutic target.


Comparison of trabecular bone structure in individuals with healthy periodontium and stage III/IV, grade C periodontitis by fractal analysis.
The aim was to perform fractal analysis (FA) to compare differences in trabecular microarchitecture in interdental and antegonial regions on panoramic radiographs in periodontally healthy patients and those with stage III/IV, grade C periodontitis, and to compare the effects of patient age and sex on FA results. Clinical and radiographic records from 33 periodontally healthy individuals and 28 individuals with aggressive periodontitis were obtained from the faculty archives. Three regions of interest (ROIs) were chosen bilaterally from interdental bone around the mandibular first molar and canine and the antegonial region. The mean fractal dimension (FD) values of the ROIs were calculated. Significance of differences was established at P < .05. FD values of all 3 ROIs in the periodontitis group were significantly lower than values in the control group (P ≤ .004). FD was not affected by patient age (P = .357) or sex (P = .216). There were no significant correlations between FD and age in either group (P ≥ .093). FD values differed significantly between sexes in only one ROI. FA can effectively detect trabecular microarchitectural differences in patients with aggressive periodontitis compared to periodontally healthy individuals. This technique might be useful in predicting the susceptibility of patients to periodontal disease.


Air Contamination by Mercury, Emissions and Transformations-a Review.
The present and future air contamination by mercury is and will continue to be a serious risk for human health. This publication presents a review of the literature dealing with the issues related to air contamination by mercury and its transformations as well as its natural and anthropogenic emissions. The assessment of mercury emissions into the air poses serious methodological problems. It is particularly difficult to distinguish between natural and anthropogenic emissions and re-emissions from lands and oceans, including past emissions. At present, the largest emission sources include fuel combustion, mainly that of coal, and "artisanal and small-scale gold mining" (ASGM). The distinctly highest emissions can be found in South and South-East Asia, accounting for 45% of the global emissions. The emissions of natural origin and re-emissions are estimated at 45-66% of the global emissions, with the largest part of emissions originating in the oceans. Forecasts on the future emission levels are not unambiguous; however, most forecasts do not provide for reductions in emissions. Ninety-five percent of mercury occurring in the air is Hg0-GEM, and its residence time in the air is estimated at 6 to 18 months. The residence times of its HgII-GOM and that in Hgp-TPM are estimated at hours and days. The highest mercury concentrations in the air can be found in the areas of mercury mines and those of ASGM. Since 1980 when it reached its maximum, the global background mercury concentration in the air has remained at a relatively constant level.


Efficacy and safety of oral vs vaginal misoprostol for cervical priming before hysteroscopy: A systematic review and meta-analysis.
There is great controversy regarding the most effective route for cervical priming before diagnostic or operative hysteroscopy. To evaluate the evidence from published randomized clinical trials (RCTs) about the efficacy and safety of oral vs vaginal misoprostol for cervical priming before hysteroscopy. Electronic databases including PubMed, Cochrane Library, Scopus and Web of Science were searched using the relevant keywords. All RCTs assessing the effect of oral vs vaginal misoprostol before hysteroscopy for cervical priming were considered. One hundred and ten studies were identified, of which eight studies were deemed eligible for this review. The extracted outcomes were: cervical canal width, ease of dilatation, time for cervical dilatation and adverse effects (nausea, vomiting, diarrhoea, bleeding, fever, abdominal pain/uterine cramping and any complications during the procedure). All statistical analyses were completed using RevMan. Eight RCTs with 768 patients were included in this meta-analysis. Cervical canal width did not differ significantly between the two routes of misoprostol administration [mean difference -0.25 mm, 95% confidence interval (CI) -0.92-0.42; p = 0.47]. However, the vaginal route was significantly superior to the oral route for reducing the time for cervical dilatation (standardized mean difference 0.17, 95% CI 0.02-0.32; p = 0.03). No significant differences in adverse effects were found between the routes, except for diarrhoea which was significantly less prevalent with vaginal administration of misoprostol (risk ratio 2.48, 95% CI 1.17-5.26; p = 0.02). Oral and vaginal administration of misoprostol before hysteroscopy were similar in terms of cervical canal width, ease of dilatation and various adverse effects, except that the vaginal route was associated with faster cervical dilatation and lower prevalence of diarrhoea.


Structural biology of the Bcl-2 family of proteins.
The proteins of the Bcl-2 family are important regulators of programmed cell death. Structural studies of Bcl-2 family members have provided many important insights into their molecular mechanism of action and how members of this family interact with one another. To date, structural studies have been performed on six Bcl-2 family members encompassing both anti- (Bcl-x(L), Bcl-2, KSHV-Bcl-2, Bcl-w) and pro-apoptotic (Bax, Bid) members. They all show a remarkably similar fold despite an overall divergence in amino acid sequence and function (pro-apoptotic versus anti-apoptotic). The three-dimensional structures of Bcl-2 family members consist of two central, predominantly hydrophobic alpha-helices surrounded by six or seven amphipathic alpha-helices of varying lengths. A long, unstructured loop is present between the first two alpha-helices. The structures of the Bcl-2 proteins show a striking similarity to the overall fold of the pore-forming domains of bacterial toxins. This finding led to experiments which demonstrated that Bcl-x(L), Bcl-2, and Bax all form pores in artificial membranes. A prominent hydrophobic groove is present on the surface of the anti-apoptotic proteins. This groove is the binding site for peptides that mimic the BH3 region of various pro-apoptotic proteins such as Bak and Bad. Structures of Bcl-x(L) in complex with these BH3 peptides showed that they bind as an amphipathic alpha-helix and make extensive hydrophobic contacts with the protein. These data have not only helped to elucidate the interactions important for hetero-dimerization of Bcl-2 family members but have also been used to guide the discovery of small molecules that block Bcl-x(L) and Bcl-2 function. In the recently determined structure of the anti-apoptotic Bcl-w protein, the protein was also found to have a hydrophobic groove on its surface capable of binding BH3-containing proteins and peptides. However, in the native protein an additional carboxy-terminal alpha-helix interacts with the hydrophobic groove. This is reminiscent of how the carboxy-terminal alpha-helix of the pro-apoptotic protein Bax binds into its hydrophobic groove. This interaction may play a regulatory role and for Bax may explain why it is found predominately in the cytoplasm prior to activation. The hydrophobic groove of the pro-apoptotic protein, Bid protein, is neither as long nor as deep as that found in Bcl-x(L), Bcl-2, or Bax. In addition, Bid contains an extra alpha-helix, which is located between alpha1 and alpha2 with respect to Bcl-x(L), Bcl-2, and Bax. Although there are still many unanswered questions regarding the exact mechanism by which the Bcl-2 family of proteins modulates apoptosis, structural studies of these proteins have deepened our understanding of apoptosis on the molecular level.


Functional outcomes of adults with left ventricular assist devices receiving inpatient rehabilitation.
To study the functional outcomes of patients with left ventricular assist devices (LVAD) who were receiving inpatient rehabilitation. This is a retrospective cohort study of adults with an implanted LVAD admitted to an acute inpatient rehabilitation unit (IRU) over a 14-month period from March 2010 through May 2011. A tertiary care hospital. This study included 11 patients with an implanted LVAD who required acute inpatient rehabilitation. All the patients with LVADs were included irrespective of the initial admitting diagnosis. Nine patients were admitted for cardiac diagnoses and underwent LVAD placement before their transfer to the IRU; 2 patients received LVADs before this hospital admission and were admitted for stroke. Demographic, clinical, and functional data were abstracted. Acute care length of stay (LOS), IRU LOS, and discharge disposition, along with IRU Functional Independence Measure (FIM) scores, were analyzed. The primary outcome measurements were IRU LOS, change in functional status (measured by the FIM), FIM efficiency (FIM gain/LOS), and discharge setting. The mean ± standard deviation (SD) IRU LOS was 17.5 ± 8.9 days. The mean ± SD FIM gain was statistically significant at 28.6 ± 10.2 (P < .0001), and compared favorably to benchmarks for mean FIM gains regionally (22.5) and nationally (23) for patients admitted to IRUs with a cardiac diagnosis. The mean (SD) FIM efficiency (FIM gain/IRU LOS) was 1.97 ± 1.1 compared with the regional mean of 2.27 and national mean of 2.28. Seven of the 11 patients were discharged directly home after inpatient rehabilitation, and 3 returned home after an additional acute hospital stay. One subject died after transfer back to the acute hospital service. The patients with LVADs in this study achieved clinically meaningful functional gains from inpatient rehabilitation that compared favorably with national benchmarks for patients with cardiac diagnoses. The majority of the subjects were successfully discharged home. IRUs should consider implementing rehabilitation programs for this growing patient population.


Tumor induction in intact and regenerating liver of adult rats by a single treatment with methylazoxymethanol acetate.
Methylazoxymethanol (MAM) acetate was given once i.p. to intact adult rats and to rats at 24 h after partial hepatectomy. In each group, tumors developed as early as 10 months. The incidence of neoplastic nodules and of hepatocellular carcinomas in the carcinogen-treated intact adult rats was approximately 70% and, in the rats treated after partial hepatectomy, it was approximately 80%. The data suggest that both dividing and resting liver cells are sensitive to the tumor-initiating effects of methylazoxymethanol acetate.


Facilitation of the lordosis reflex of female rats from the ventromedial nucleus of the hypothalamus.
1. Effects of electrical stimulation of hypothalamic ventromedial nucleus (v.m.n.) on the lordosis reflex of female rats were examined in ovariectomized and oestrogen-primed animals with chronically implanted electrodes. 2. Lordosis triggered either by manual cutaneous stimulation or by male mounting, was facilitated by electrical stimulation of the v.m.n. 3 A gradual increase in lordosis performance followed a relatively long period of stimulation; never less than 15 min and usually about 1 hr of stimulation was necessary for maximum facilitation. Following the termination of stimulation, the performance returned gradually to the control level during a 5--8 hr period. 4. The optimal frequency of stimulation was between 10 and 30 Hz. Threshold for effective facilitation was, on the average, 12.5 microA. 5. Stimulation tended to induce larger facilitation when applied to the lateral side of v.m.n. 6. Pre-treatment with oestrogen was necessary to obtain facilitation by v.m.n. stimulation. The threshold dosage of oestrogen was 2.5 microgram per animal. 7. Stimulation was effective in adrenalectomized rats, in dexamethasone-primed animals, and in rats pre-treated with exogenous progesterone. Thus, adrenal prodesterone release is not required for the v.m.n. facilitation of lordosis. 8. Medial preoptic stimulation with the same parameters suppressed the lordosis reflex. 9. The v.m.n. participates in the control of lordosis by a facilitatory output. The delay before facilitation implies that the v.m.n. is not in the direct reflex-arc for the execution of lordosis. Rather, a summation or interaction process with an unusually long time course is involved.


Managing Breast Cancer: Echoes from Patients in Lagos, Nigeria.
Breast cancer is ranked second as the cause of cancer death among women. Of importance to the management of breast cancer is the interaction processes between the patients and their professional caregivers or healthcare providers. Against this background, this study explores the experiences of Nigerian women as breast cancer patients and their interaction with their caregivers in the management of their condition. The study was cross-sectional in design. Twenty diagnosed breast cancer patients participated in the study and were purposively selected using convenience and snow balling sampling technique. Patients affirmed that they were initially afraid when diagnosed but overcame their fear based on caregivers' supports. Physical interactions and the use of mobile phones were common means of communication while the fear of death and financial burden of the disease were of major concerns to the patients. The majority of the patients were satisfied with the quality of care and treatment received in the private hospitals as they were encouraged and supported. It was discovered that professional caregivers are germane to patients' survival from shock and adequate information on how to manage their condition and live a normal life.


Weakened interaction of ATG14 and the SNARE complex blocks autophagosome-lysosome fusion contributes to fluoride-induced developmental neurotoxicity.
Fluoride is capable of inducing developmental neurotoxicity, but the mechanisms involved remain unclear. We aimed to explore the role of autophagosome-lysosome fusion in developmental fluoride neurotoxicity, particularly focusing on the interaction between ATG14 and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. We developed in vivo models of Sprague-Dawley rats exposed to sodium fluoride (NaF) from the pregnancy of parental rats until the offspring were two months old and in vitro models of NaF and/or Ad-ATG14-treated SH-SY5Y cells. We assessed neurobehavioral changes in offspring and further investigated the effects of NaF exposure on autophagic flux, apoptosis, autophagosome-lysosome fusion, and the interaction between ATG14 and the SNARE complex. NaF exposure impaired offspring learning and memory capabilities and induced the accumulation of autophagosomes and autophagic flux blockage and apoptosis, as indicated by increased LC3-II, p62, and cleaved-caspase-3 expression in vivo and in vitro. In addition, NaF treatment downregulated the protein expression of ATG14 and the SNARE complex and induced autophagosome-lysosome fusion blockage as evidenced by decreased ATG14, STX17, SNAP29, and VAMP8 expression and diminished colocalization of autophagosomes and lysosomes in vivo and in vitro. Furthermore, ATG14 upregulation enhanced the interaction of ATG14 and the SNARE complex to facilitate autophagosome-lysosome fusion, thereby restoring autophagic flux and alleviating NaF-induced apoptosis. In conclusion, NaF exhibited developmental neurotoxicity by restraining the interaction of ATG14 with the SNARE complex and hindering autophagosome-lysosome fusion, thereby participating in the occurrence and development of fluoride neurotoxicity. Notably, ATG14 upregulation protects against developmental fluoride neurotoxicity, and ATG14 may serve as a promising biomarker for further epidemiological investigation.


Continuous Renal Replacement Therapy among Patients with COVID-19 and Acute Kidney Injury.
Acute kidney injury (AKI) is a common complication among patients with COVID-19 and acute respiratory distress syndrome. Reports suggest that COVID-19 confers a pro-thrombotic state, which presents challenges in maintaining hemofilter patency and delivering continuous renal replacement therapy (CRRT). We present our initial experience with CRRT in critically ill patients with COVID-19, emphasizing circuit patency and the association between fluid balance during CRRT and respiratory parameters. Retrospective chart review of 32 consecutive patients with COVID-19 and AKI managed with continuous venovenous hemodiafiltration with regional citrate anticoagulation (CVVHDF-RCA) according to the University of Michigan protocol. Primary outcome was mean CRRT circuit life per patient during the first 7 days of CRRT. We used simple linear regression to assess the relationship between patient characteristics and filter life. We also explored the relationship between fluid balance on CRRT and respiratory parameters using repeated measures modeling. Patients' mean age was 54.8 years and majority were Black (75%). Comorbidities included hypertension (90.6%), obesity (70.9%) diabetes (56.2%), and chronic kidney disease (40.6%). Median CRRT circuit life was 53.5 [interquartile range 39.1-77.6] hours. There was no association between circuit life and inflammatory or pro-thrombotic laboratory values (ferritin p = 0.92, C-reactive protein p = 0.29, D-dimer p = 0.24), or with systemic anticoagulation (p = 0.37). Net daily fluid removal during the first 7 days of CRRT was not associated with daily (closest recorded values to 20:00) PaO2/FIO2 ratio (p = 0.21) or positive end-expiratory pressure requirements (p = 0.47). We achieved adequate CRRT circuit life in COVID-19 patients using an established CVVHDF-RCA protocol. During the first 7 days of CRRT therapy, cumulative fluid balance was not associated with improvements in respiratory parameters, even after accounting for baseline fluid balance.


Biophysical interactions between pancreatic cancer cells and pristine carbon nanotube substrates: Potential application for pancreatic cancer tissue engineering.
Novel synthetic biomaterials able to support direct tissue growth and retain cellular phenotypical properties are promising building blocks for the development of tissue engineering platforms for accurate and fast therapy screening for cancer. The aim of this study is to validate an aligned, pristine multi-walled carbon nanotube (CNT) platform for in vitro studies of pancreatic cancer as a systematic understanding of interactions between cells and these CNT substrates is lacking. Our results demonstrate that our CNT scaffolds-which are easily tuneable to form sheets/fibers-support growth, proliferation, and spatial organization of pancreatic cancer cells, indicating their great potential in cancer tissue engineering. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1637-1644, 2018.


Concanavalin A binding sites on the erythrocytes of normal and genetically dystrophic chickens.
Red blood cells (RBCs) were obtained from genetically dystrophic chickens (Dy) and age-matched controls (C). Dy-RBCs had a lower titer of agglutination to concanavalin A (Con A) compared to C-RBCs. In order to ascertain the difference in agglutination, Con A binding on RBCs was studied, using 125I-labeled Con A ([125I]Con A) and ferritin conjugate to Con A (Fer-Con A). Kinetic analysis of [125I]Con A binding to Dy-RBCs showed a reduction of major binding sites of Con A. There was no difference in the apparent association constant for the major binding sites of Con A between Dy-RBCs and C-RBCs. Quantitative analysis of Con A binding site distribution on RBCs using Fer-Con A showed a remarkable diminution of ferritin particles tagged on the surface of Dy-RBCs. There was no significant difference in the distribution pattern of ferritin particles between Dy-RBCs and C-RBCs.


Identification of the structural proteins of VP1 and VP2 of a novel mud crab dicistrovirus.
Mud crab dicistrovirus (MCDV), a newly identified single-stranded positive RNA virus, is an important pathogen that causes serious economic losses to mud crab aquaculture. In this study, MCDV was purified, and three structural proteins of MCDV were separated by SDS-PAGE. The N-terminal 15 amino acids were sequenced and aligned with the main structural proteins of other dicistrovirus. The three structural proteins were named VP1, VP2 and VP3. Monoclonal antibodies (MAbs) against the two main structural proteins, VP1 and VP2, were prepared, and the two structural proteins were then identified using these MAbs. The results of Western blot analyses demonstrated that five MAbs recognised VP1 and two recognised VP2. The results of immunogold transmission electron microscopy (IEM) revealed that the epitopes of the two structural proteins recognised by the MAbs were located at the outer surface of the virions, which suggested that the two structural proteins are MCDV capsid proteins. The identification of the two structural proteins of MCDV is useful for studying their functions, as well as the mechanism of infection and the pathogenesis of MCDV.


Validity of the two-minute step test for healthy older adults.
In healthy older adults, the two-minute step test (2MST) does not have its concurrent validity tested against the six-minute walk test (6MWT), which is a valid cardiorespiratory fitness test frequently applied in geriatric samples. To derive an equation to predict 6MWT from 2MST and to observe the agreement between observed and estimated 6MWT distances. 6MWT and 2MST were measured in 51 older adults (72.9±4.6 years) from community multicomponent exercise programs. Multiple linear regression derives the predictive equation of 6MWT walked distance (dependent outcome) from steps obtained in 2MST, age, sex, and body mass index (independent outcomes). Correlation between 6MWT and 2MST was strong (r=0.696, p<0.001). The regression equation showed good agreement with measured values, when 6MWT was below 600 m. The equation stands as a novel approach to obtaining a valid 6MWT estimation from the 2MST. 2MST is easier and faster, representing an alternative approach when time and space are limited.


Downregulation of apoptosis revealed by laser microdissection and cDNA microarray analysis of related genes in rat liver preneoplastic lesions.
Regulation of cell proliferation and apoptosis plays a key role in tumor development. To elucidate mechanisms underlying hepatocarcinogenesis, patterns of gene expression, including apoptosis-related genes, were compared between glutathione S-transferase placental form (GST-P)-positive preneoplastic foci and surrounding tissue in the rat. Lesions were induced with a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg bw) and then 100 ppm 2-acetylaminofluorene (2-AAF)-containing diet combined with two-thirds partial hepatectomy. Frozen sections of the livers were applied for immunohistochemical staining of GST-P, and both positive foci and surrounding negative areas were harvested by laser microdissection. Total RNAs were extracted and amplified with T7 polymerase to allow gene expression analysis by cDNA microarray assays. In the GST-P-positive foci, altered levels were observed for many genes, mostly related to metabolism or catalysis, with increased expression of testosterone-repressive prostate message-2 (TRPM-2), which is reported to act as a protective factor against apoptosis, and decreased expression of thymus-expressed acidic protein (TEAP), which is considered to promote apoptosis. The results indicate that rat liver preneoplastic lesions might be protected against apoptosis and that the approach adopted is useful for clarification of mechanisms underlying hepatocarcinogenesis.


Measuring use of evidence based psychotherapy for posttraumatic stress disorder.
To improve methods of estimating use of evidence-based psychotherapy for posttraumatic stress disorder in the Veteran's health administration, we evaluated administrative data and note text for patients newly enrolling in six VHA outpatient PTSD clinics in New England during the 2010 fiscal year (n = 1,924). Using natural language processing, we developed machine learning algorithms that mimic human raters in classifying note text. We met our targets for algorithm performance as measured by precision, recall, and F-measure. We found that 6.3 % of our study population received at least one session of evidence-based psychotherapy during the initial 6 months of treatment. Evidence-based psychotherapies appear to be infrequently utilized in VHA outpatient PTSD clinics in New England. Our method could support efforts to improve use of these treatments.


Defined solid-angle counter with variable geometry.
We describe a defined solid-angle counter for the standardization of radioactive sources of alpha-particle emitters. It has been built with the aim of combining good counting efficiencies, low uncertainties and flexibility of operation. The distance between source and detector can be changed in a continuous way with a precision guide and a ball screw from 8 to 19cm, which correspond to counting efficiencies between 0.023 and 0.004 for small size sources. A linear encoder allows the accurate determination of the source position. Alpha spectra of the sources are measured with an implanted silicon detector with an active area of 2000mm(2). Uncertainties, excluding counting statistics, are below 0.1%.


Behçet's disease with gastrointestinal involvement associated with myelodysplasia in a patient with congenital panhypopituitarism.
Myelodysplastic syndromes (MDS) are hematologic disorders characterised by peripheral cytopenias and the hystologic features of hematologic dysplasia. Their association with autoimmune manifestations have been suggested by several authors: recently, the appearance of Behçet's disease during MDS has been reported. We describe the occurrence of MDS in a patient affected by Behçet's syndrome with gastrointestinal involvement and congenital panhypopituitarism.


Discerning Seizure-Onset v. Propagation Zone: Pre-and-Post-Operative Resting-State fMRI Directionality and Boerwinkle Neuroplasticity Index.
The goal of this study was to determine resting state fMRI (rs-fMRI) effective connectivity (RSEC) capacity, agnostic of epileptogenic events, in distinguishing seizure onset zones (SOZ) from propagation zones (pZ). Consecutive patients (2.1-18.2 years old), with epilepsy and hypothalamic hamartoma, pre-operative rs-fMRI-directed surgery, post-operative imaging, and Engel class I outcomes were collected. Cross-spectral dynamic causal modelling (DCM) was used to estimate RSEC between the ablated rs-fMRI-SOZ to its region of highest connectivity outside the HH, defined as the propagation zone (pZ). Pre-operatively, RSEC from the SOZ and PZ was expected to be positive (excitatory), and pZ to SOZ negative (inhibitory), and post-operatively to be either diminished or non-existent. Sensitivity, accuracy, positive predictive value were determined for node-to-node connections. A Parametric Empirical Bayes (PEB) group analysis on pre-operative data was performed to identify group effects and effects of Engel class outcome and age. Pre-operative RSEC strength was also evaluated for correlation with percent seizure frequency improvement, sex, and region of interest size. Of the SOZ's RSEC, only 3.6% had no connection of significance to the pZ when patient models were individually reduced. Among remaining, 96% were in expected (excitatory signal found from SOZ → pZ and inhibitory signal found from pZ → SOZ) versus 3.6% reversed polarities. Both pre-operative polarity signals were equivalently as expected, with one false signal direction out of 26 each (3.7% total). Sensitivity of 95%, specificity 73%, accuracy of 88%, negative predictive value 88%, and positive predictive value of 88% in identifying and differentiating the SOZ and pZ. Groupwise PEB analysis confirmed SOZ → pZ EC was excitatory, and pZ → SOZ EC was inhibitory. Patients with better outcomes (Engel Ia vs. Ib) showed stronger inhibitory signal (pZ → SOZ). Age was negatively associated with absolute RSEC bidirectionally but had no relationship with Directionality SOZ identification performance. In an additional hierarchical PEB analysis identifying changes from pre-to-post surgery, SOZ → pZ modulation became less excitatory and pZ → SOZ modulation became less inhibitory. This study demonstrates the accuracy of Directionality to identify the origin of excitatory and inhibitory signal between the surgically confirmed SOZ and the region of hypothesized propagation zone in children with DRE due to a HH. Thus, this method validation study in a homogenous DRE population may have potential in narrowing the SOZ-candidates for epileptogenicity in other DRE populations and utility in other neurological disorders.


Protein preparation, crystallization and preliminary X-ray analysis of imidazolonepropionase from Bacillus subtilis.
Imidazolonepropionase (EC 184.108.40.206) is the third enzyme of the histidine degradation pathway that has been conserved from bacteria to eukaryotes. The enzyme is the only one with unknown three-dimensional structure in this pathway. In this work, Bacillus subtilis imidazolonepropionase (HutI) was expressed in E. coli and purified to homogeneity. After thrombin digestion, high quality crystals were obtained by hanging-drop vapor diffusion method. The best crystal diffracted to 2.0 A and belonged to the space group P2(1) with unit-cell parameters a = 57.73 A, b = 106.34 A, c = 66.47 A, beta = 89.93 degrees .


Phenotypic differentiation of members of the family Vibrionaceae using miniaturized biochemical tests.
Enzymatic hydrolysis of 27 different chromogenic substrates and the assimilation of 44 carbon sources by 144 strains of Vibrio species of clinical importance, Aeromonas hydrophila and Plesiomonas shigelloides were studied by standardized micromethods. Some classical biochemical tests were also performed using the test kit TTE-AS (Flow Laboratories GmbH, Meckenheim, FRG). Reading of results was done automatically by a photometer and test data were recorded and stored by a microcomputer. All species investigated could be differentiated using a set of 16 miniaturized biochemical tests which are: Indole production, esculin hydrolysis, lysine decarboxylase, ornithine decarboxylase, arginine dihydrolase, fermentation of sucrose, enzymatic hydrolysis of o-nitrophenyl-beta-D-galactopyranoside, gamma-L-glutamic acid-p-nitroanilide and the assimilation of L-arabinose, D-cellobiose, D-mannose, sucrose, D-mannitol, i-inositol, acetate and DL-lactate. Comparing the TTE-AS tests to conventional test results, 94.4% overall agreement was found. 87.6% of the miniaturized assimilation tests agreed to literature data. The described tests are easy to perform and seem to be suitable for routine laboratory use.


Correction: Formation of plutonium(IV) silicate species in very alkaline reactive media.
Correction for 'Formation of plutonium(IV) silicate species in very alkaline reactive media' by Paul Estevenon et al., Dalton Trans., 2021, 50, 12528-12536, DOI: 10.1039/D1DT02248B.


Emerging contaminants removal from effluents with complex matrices by electrooxidation.
The electrooxidation of methiocarb and bisphenol A was studied in complex matrices, namely, simulated and real sanitary landfill leachate samples, using a boron-doped diamond anode. With simulated sanitary landfill leachate samples, the influence of the type and ratio of carbon source (glucose/humic acid) and electrolyte (NaCl or Na2SO4) on the emerging contaminants removal was assessed. Using real sanitary landfill leachate, the influence of current density was evaluated. The experimental results showed that electrooxidation, using a boron-doped diamond anode, can be successfully utilized to degrade methiocarb and bisphenol A when present in complex matrices, such as sanitary landfill leachate, and that methiocarb is more easily oxidized than bisphenol A. Furthermore, it was found that the presence of chloride and high humic acid content increases emerging contaminants removal rate, showing that electrooxidation at boron-doped diamond is particularly adequate to solve the problems raised by sanitary landfill leachate, even when contaminated with emerging contaminants.


Adaptive responses to glucose restriction enhance cell survival, antioxidant capability, and autophagy of the protozoan parasite Trichomonas vaginalis.
To establish an infection in the vagina, Trichomonas vaginalis must adapt to various environmental cues for survival and further replication. Nutrient competition by lactobacilli, the major normal vaginal flora, is one of the mechanisms to limit the growth of other microorganisms. Additionally, lactobacilli produce H2O2 that can reduce the genital infections caused by other pathogens. Thus, the ability to overcome the metabolic stresses, such as glucose restriction (GR), as well as the oxidative stresses, is critical for T. vaginalis to establish an infection. To gain insights into the molecular mechanisms of adaptation to GR, we utilized next-generation RNA sequencing (RNA-seq) to quantify the gene expression changes upon GR. Autophagy, a cytoprotective response to starvation, was monitored by using autophagy-specific staining, autophagy inhibition assay, and co-localization of autophagosomes with lysosomes. We demonstrated that GR promotes the survival of T. vaginalis. Besides, GR-cultivated cells exhibit higher H2O2 resistance. Our RNA-seq data revealed that genes involved in general energy metabolism were downregulated, whereas genes encoding glutamate metabolism-related aminotransferases were strikingly upregulated under GR. Furthermore, autophagy was first identified and characterized in T. vaginalis under GR. These data suggest that GR induces a metabolic reprogramming, enhancing antioxidant ability and autophagy for cellular homeostasis to maintain survival. Our work not only led to significant advances in understanding the transcriptional changes in response to GR but also provided possible strategies elicited by GR for T. vaginalis to adapt to the vaginal microenvironment.


Effects of hospital closure on mortality rates of the over-65 long-stay psychiatric population.
The closure of this 100-year-old hospital has allowed us to look at the effect on mortality of moving the whole over-65 long-stay population to other settings. Our results confirm that there is a slight excess of deaths during and immediately after these moves, but that there is no longer-term effect on mortality rates.


Voluntary blood pressure control using continuous systolic blood pressure biofeedback.
1. Ability to alter blood pressure (BP) acutely with continuous systolic (SBP) BP biofeedback was assessed in volunteers using a new non-invasive finger BP monitor. 2. Reliability of finger BP measurement was demonstrated in six hypertensive subjects (21-60 years), by beat-to-beat comparison with brachial intra-arterial BP over 90 min. Wide variation of BP was achieved by physiological manoeuvres. Mean error of finger BP was -3.0/-2.2 mmHg with intra-subject s.d. of 7.2/5.4 mmHg. 3. Thirteen normotensives (21-51 years) were paid to undergo 30 trials of SBP biofeedback in six sessions over 3 weeks. The SBP trend was displayed on a monitor with appropriately 'shaped' targets; each trial consisted of BP-raising and -lowering periods of 45 and 90 s respectively with intervening 45 s baselines. 4. Nine subjects raised BP, on analysis of the last 10 trials, by an average of 18.8 mmHg while five of the 13 successfully lowered BP by an average of 10.0 mmHg. BP lowering was best achieved by diminishing respiratory rate and depth, and muscular relaxation. 5. Demonstration of large BP reductions in five of 13 normotensives using strategies applicable to longer training sessions warrants further investigations in hypertensive subjects, focusing on mediating mechanisms and transfer of effect beyond the laboratory.


A morphological analysis of vasoactive intestinal polypeptide (VIP)-like immunoreactive neurons in the area dentata of the rat brain.
The general distribution and morphology of vasoactive intestinal polypeptide-like immunoreactive (VIP-LI) neurons in the area dentata (AD) have been studied using immunohistochemical methods on thick (70-120 micron) sections from the rat brain. The long (greater than or equal to 72 hours) incubation of free-floating sections in combination with a sensitive immunoperoxidase method resulted in extensive labeling of VIP-positive cell bodies, along with their dendritic and axonal processes in the hippocampal formation, including the area dentata. The VIP-positive cells are found in all parts of the area dentata, and plots of the distribution of individual cells showed that there is a preferential clustering of these neurons within, or in close proximity to, the granule cell layer, while the deep zones in the hilus are almost completely devoid of VIP-LI immunoreactive neurons. Throughout the long axis of the AD the number and relative position of the VIP-LI neurons remains rather constant. Analysis of the size and shape of the VIP-positive neurons in the AD shows a remarkable morphological heterogeneity, with the soma ranging from small (long axis: approximately 10 micron) ovoid or round, to large (long axis: approximately 25 micron) stellate or multipolar; of these the small to medium sized cells predominate. Comparisons between the morphology of neurons visualized with the VIP antibody and sections stained by the rapid Golgi method allow a rather conclusive classification of some of the VIP-stained neurons, while the classification of a majority of the VIP neurons remains tentative, perhaps because of the selective visualization by the rapid Golgi method of only certain cell types in the AD. On the basis of this comparison, several displaced granule cells in the molecular layer, as well as granule cells, small ovoid cells, and pyramidal basket cells in the granule cell layer have been identified as VIP-positive as determined by their somatic shape, dendritic branching pattern, and axonal projections. In addition, several VIP-positive neurons have been identified with less certainty. These include the dentate basket cell of Cajal, certain small cells in the molecular layer, and fusiform cells in the polymorph layer. Taken together the present results demonstrate the usefulness of "Golgi-like" immunoperoxidase staining for detailed classification of chemically defined neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


Chemometric discrimination of genetically modified Coffea arabica cultivars using spectroscopic and chromatographic fingerprints.
Multivariate statistical design and principal component analysis (PCA) applied to RP-HPLC-DAD and FTIR spectroscopic data were performed to investigate the fingerprints of four coffee cultivars, traditional red bourbon and three genetically modified cultivars. The design and response surface results showed that extraction dependence on solvent composition of one of the genetically modified cultivars, IAPAR 59, was very similar to that found for the red bourbon standard. PCA of the FTIR spectra obtained from all the simplex centroid design mixtures indicated that the 1:1 binary ethanol-dichloromethane solution resulted in the best separation of the four cultivars. The IPR 108 cultivar has more intense vibrational bands in the 3200-3,600 cm(-1) and 1100-1,600 cm(-1) regions indicating higher acid and fat levels than those of the other cultivars. The UV absorptions close to 275 nm of the RP-HPLC-DAD spectra are correlated with the strengths of the infrared absorptions between 3400 and 3,460 cm(-1) and can be explained by varying caffeine concentrations in the four cultivars.


Mucinous adenocarcinoma of the renal pelvis masquerading as xanthogranulomatous pyelonephritis.
Primary adenocarcinoma of the renal pelvis accounts for less than 1% of renal pelvis tumors. We encountered a patient who presented with long-term nephrolithiasis and hydronephrosis. The initial impression was xanthogranulomatous pyelonephritis. The postoperative histopathologic report showed mucinous adenocarcinoma of the renal pelvis with signet ring cell formation. Signet ring cell phenomenon is extremely rare in this kind of tumor. We describe the patient's clinical presentation, imaging findings, histopathologic examination, and immunohistochemistry results.


A phase II study of carboplatin and etoposide plus durvalumab for previously untreated extensive-stage small-cell lung cancer (ES-SCLC) patients with a poor performance status (PS): NEJ045A study protocol.
Small-cell lung cancer (SCLC) accounts for 12-15% of lung cancers and has a limited prognosis, with approximately one-third of SCLC patients having a poor performance status (PS). Patients with extensive-stage (ES) SCLC and a poor PS have a poor prognosis. For this population, overall survival from carboplatin and etoposide treatment is 7-8 months, and treatment development is an unmet medical need. Recently, the combination of an anti-PD-L1 (a ligand for programmed cell death 1) antibody and platinum-based chemotherapy has become the standard of care for ES-SCLC patients with a good PS (PS 0-1). We hypothesized that the combination of the anti-PD-L1 antibody durvalumab with carboplatin and etoposide would be feasible and effective for such patients. We initiated a multicenter phase II study of durvalumab combined with carboplatin and etoposide in previously untreated ES-SCLC patients with a poor PS (PS 2-3). Eligible patients will receive durvalumab plus carboplatin and etoposide every 3 to 4 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. The dosages of carboplatin and etoposide for the second and subsequent cycles will be adaptively determined based on the adverse events of the first cycle. A total of 56 patients (43 patients with a PS of 2 and 13 patients with a PS of 3) will be enrolled in this study, with a 24-month enrollment period and a 12-month follow-up. The primary endpoint is the tolerability of carboplatin and etoposide plus durvalumab in previously untreated ES-SCLC patients with a poor PS. The secondary endpoints are the 1-year survival rate, objective response rate, progression-free survival, overall survival, ratio of PS improvement, and safety. The results of this study are intended to establish the safety and efficacy of carboplatin and etoposide plus durvalumab in patients with ES-SCLC and a poor PS. Japan Registry of Clinical Trials (jRCT), jRCTs031200319. Registered 21 January 2021, https://jrct.niph.go.jp/en-latest-detail/jRCTs031200319.


Differential apoptotic pathways in human keratinocyte HaCaT cells exposed to UVB and UVC.
The induction of apoptosis in keratinocytes by ultraviolet (UV)-irradiation is considered to be a protective function against skin cancer. UV-induced DNA damage is a crucial event in UVB- and UVC-mediated apoptosis. However, the differences between the UVB- and UVC-induced apoptotic pathways remain unclear. Here we examine the differential mechanisms by which UVB and UVC irradiations induce keratinocyte apoptosis using human keratinocyte HaCaT cells. Differences in the production of (6-4)photoproducts ((6-4)PPs) and cyclobutane pyrimidine dimers (CPDs) were measured following irradiation with UVB and UVC at doses causing the same extent of apoptotic cell death. In addition, main apoptotic features, such as caspase activation and its regulation, were compared between UVB- and UVC-induced apoptosis. Exposures of 500 J/m(2) UVB and 100 J/m(2) UVC resulted in apoptosis to almost the same extent. At these apoptotic doses, the amounts of both (6-4)PPs and CPDs were significantly larger in the case of UVC irradiation than UVB irradiation; in parallel, the release of cytochrome c and Smac/DIABLO and the activation of caspases-9 following UVC irradiation were greater than after UVB irradiation. Importantly, caspase-8 activation occurred only in UVB-irradiated cells. Furthermore, the activation of caspase-8 was not inhibited by caspases-9 and -3 specific tetrapeptide inhibitors, indicating that the caspase-8 cleavage is not due to feedback from activation of caspases-9 and -3. Thus, these results clearly suggest that the reason apoptosis is induced to the same extent by UVB irradiation as by UVC irradiation, despite the lower production of photoproducts in DNA by UVB irradiation, is attributable to the additional activation of the caspase-8 pathway. Thus, UVB irradiation induces apoptosis through both mitochondrial (intrinsic) and caspase-8 activation (extrinsic) pathways, while UVC induces apoptosis only via the intrinsic pathway.


Comparison of single trough-based area under the concentration-time curve versus trough concentration for the incidence of vancomycin-associated nephrotoxicity.
While the revised 2020 consensus guideline recommends the use of area under the concentration-time curve (AUC)-guided vancomycin monitoring, collecting multiple vancomycin serum samples to calculate the AUC may cause clinical complications. The aim of the present retrospective study was to evaluate whether AUC-guided vancomycin monitoring, in which AUC was calculated based on a single trough concentration, is a better predictor of nephrotoxicity than trough-guided monitoring in patients receiving vancomycin therapy. A single-center, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous vancomycin for a documented or suspected infection and had their serum vancomycin trough concentration monitored between October 1, 2016 and September 30, 2020 were enrolled in the present study. Multivariate Cox proportional hazard analysis indicated that AUC (>600 μg•h/mL) was a significant risk factor for the incidence of acute kidney injury (AKI), while trough concentration (≥15 μg/mL) was not. Moreover, the AUC (>600 μg•h/mL) showed higher specificity and similar sensitivity to the trough concentration (≥15 μg/mL). Kaplan-Meier plots of the cumulative incidence of the AKI-free rate in patients indicated that the onset of AKI was significantly longer in patients with AUC ≤600 μg•h/mL than in patients with AUC >600 μg•h/mL (HR, 16.1; 95% CI, 6.3-41.2; p < 0.001). AUC based on a single trough concentration was a better predictor of nephrotoxicity than trough concentration.


Antigen-Antibody Complex-Guided Exploration of the Hotspots Conferring the Immune-Escaping Ability of the SARS-CoV-2 RBD.
The COVID-19 pandemic resulting from the spread of SARS-CoV-2 spurred devastating health and economic crises around the world. Neutralizing antibodies and licensed vaccines were developed to combat COVID-19, but progress was slow. In addition, variants of the receptor-binding domain (RBD) of the spike protein confer resistance of SARS-CoV-2 to neutralizing antibodies, nullifying the possibility of human immunity. Therefore, investigations into the RBD mutations that disrupt neutralization through convalescent antibodies are urgently required. In this study, we comprehensively and systematically investigated the binding stability of RBD variants targeting convalescent antibodies and revealed that the RBD residues F456, F490, L452, L455, and K417 are immune-escaping hotspots, and E484, F486, and N501 are destabilizing residues. Our study also explored the possible modes of actions of emerging SARS-CoV-2 variants. All results are consistent with experimental observations of attenuated antibody neutralization and clinically emerging SARS-CoV-2 variants. We identified possible immune-escaping hotspots that could further promote resistance to convalescent antibodies. The results provide valuable information for developing and designing novel monoclonal antibody drugs to combat emerging SARS-CoV-2 variants.


A Multimodal Qualitative Approach to Understanding Menstrual Health Equity among Adolescents and Young Adults.
Menstrual inequity-unequal access to menstrual health care or products-negatively affects well-being in relation to the menstrual cycle, a construct known as menstrual health. Few studies have explored menstrual inequities among adolescent and young adult populations in the United States. This multimodal qualitative research aimed to explore factors that influence the lived experience of menstruation among this population. This qualitative study consisted of individual interviews among menstruators ages 13-24, recruited from an urban academic medical center. Participants (N = 20) were a mean age of 19 years; 25% previously endorsed period poverty, and 90% were publicly insured. We conducted semi-structured interviews using participant video diaries in a video elicitation exercise. Data were coded by 2 investigators using thematic analysis driven by grounded theory. Emergent themes included the need to normalize menstruation, the need for comprehensive menstrual health education, and the need for menstrual products to be more accessible. Twelve youth prepared video diaries, and all reported positive experiences with the video process. This youth-centered, multimodal study is one of the first to qualitatively explore the lived experiences of menstruation among adolescents in the United States and identified key inequities in menstrual health from their own perspectives. Thematic findings were mapped onto a proposed framework for menstrual equity that can be applied to future research and efforts around policy change. More research is needed to assess the impacts of these policies.


[Non-chromaffin non-functioning aortosympathetic paraganglioma].
The paraganglia system is the largest component in the construction of the Disseminated Neuroendocrine System, comprising cells derived from the neural crest, with ability to synthesize and secrete catecholamines, hormones and peptides. A general explanation on the subject with a personal contribution is made.


Fluorescence quenching by competitive absorption between solid foods: Rapid and non-destructive determination of maize flour adulterated in turmeric powder.
Fluorescence quenching induced by competitive absorption between different components of solid foods was observed for the first time. By using front-face synchronous fluorescence spectroscopy (FFSFS) and fluorescence titration, competitive absorption between maize flour and turmeric powder was proven to occur between phenolic acids in maize flour and curcumin in turmeric powder. FFSFS was applied for the rapid and non-destructive determination of maize flour adulterated in turmeric powder. Prediction models were constructed by partial least square (PLS) regression based on unfolded total synchronous fluorescence spectra, and were validated by five-fold cross-validation and external validation, with the determination coefficient of prediction (Rp2) greater than 0.95, root mean square error of prediction (RMSEP) < 6%, relative error of prediction (REP) < 15% and residual predictive deviation (RPD) greater than 5. The limit of detection (LOD) of maize flour was approximately 9%. In addition, most relative errors for test samples were from -20% to 20%.


Changes in Intracellular and Extracellular Metabolites of Mixed Lactobacillus Strains Enhance Inhibition of Pathogenic Bacterial Growth and Lipopolysaccharide-Induced Alleviation of RAW264.7 Cellular Inflammation.
It is important to explore whether there are antagonistic and synergistic effects between different strains of Lactobacillus when developing mixed Lactobacillus strain products. In this study, we investigated the antagonistic and symbiotic effects of co-cultured Lactobacillus strains, as well as their amelioratory effects on lipopolysaccharide (LPS)-induced inflammation and oxidative stress in RAW264.7 cells. The Lactobacillus strains tested in this paper showed no antagonism. Co-culture of Lactiplantibacillus plantarum Y44 and L. plantarum AKS-WS9 was found to show inhibiting effects on the growth of Escherichia coli and Staphylococcus aureus. Additionally, the co-cultured Lactiplantibacillus plantarum Y44 and L. plantarum AKS-WS9 relieved inflammation in RAW264.7 cells induced by LPS by inhibiting the activation of NF-κB and P38 signaling pathways and down-regulating the expression of pro-inflammatory cytokines NO, ROS, iNOs and TNF-α. And the co-cultured Lactobacillus strains activated the Nrf2 signaling pathway in the LPS-induced RAW264.7 cells to promote the expression of antioxidant enzymes in response to oxidative stress. There was a difference in intracellular and extracellular metabolites between single or co-cultured Lactobacillus strains, and the co-cultured Lactobacillus strains significantly increased extracellular metabolites 4-chlorobenzaldehyde, psoromic acid, and 2-dodecylbenzenesulfonic acid and intracellular metabolites 9(S)-HODE, pyocyanin, and LysoPA. We inferred that the better antibacterial and anti-inflammatory ability of the co-cultured Lactobacillus strains were related to the changes in the metabolites of the co-cultured Lactobacillus strains. The co-cultured L. plantarum Y44 and L. plantarum AKS-WS9 strains exhibited better anti-inflammatory abilities and had the potential to alleviate the symptoms of inflammatory diseases as mixed probiotics.


Upregulation of lncRNA ADAMTS9-AS2 Promotes Salivary Adenoid Cystic Carcinoma Metastasis via PI3K/Akt and MEK/Erk Signaling.
Neurotropic infiltrative growth and distant metastasis are the main causes of death in salivary adenoid cystic carcinoma (SACC) patients. Long noncoding RNAs (lncRNAs) are involved in many human neoplasms, however, their potential roles in SACC are unclear. In our study, we found that ADAM metallopeptidase with thrombospondin type 1 motif, 9 (ADAMTS9) antisense RNA 2 (ADAMTS9-AS2) was significantly upregulated in SACC patients with metastasis and SACC-lung metastasis (LM) cells. Moreover, ADAMTS9-AS2 expression was closely associated with the prognosis and distant metastasis in SACC patients. Next, we found that c-myc could specifically bind to the promoter of ADAMTS9-AS2 and activated its transcription. Knockdown of ADAMTS9-AS2 significantly inhibited migration and invasion of SACC cells in vitro and distant lung metastasis in vivo. Furthermore, ADAMTS9-AS2, which mainly expressed in the cytoplasm, shared microRNA (miRNA) response elements with Integrin α6 (ITGA6). Overexpression of ADAMTS9-AS2 competitively bound to miR-143-3p that inhibited ITGA6 from miRNA-mediated degradation, and thus it activated the activity of PI3K/Akt and MEK/Erk signaling and facilitated SACC metastasis. In summary, ADAMTS9-AS2 promotes migration and invasion in SACC by competing with miR-143-3p. This sheds a new insight into the regulation mechanism of ADAMTS9-AS2, and it provides a possible application for the SACC treatment.


Malignancies of the ear in irradiated patients of nasopharyngeal carcinoma.
To report on the clinical profiles and treatment experiences of patients with second primary ear malignancy after treatment of nasopharyngeal carcinoma (NPC). Retrospective case series. A retrospective review of the clinical outcomes and pathology of 11 irradiated NPC patients who subsequently had second primary malignancies of the ear at a single institution. Ten tumors were squamous cell carcinoma and one tumor was chondrosarcoma occurring within the radiation field of previous treatment for NPC. The interval between previous radiotherapy and diagnosis of ear malignancy was 3 to 27 years with a median time of 17 years. Six tumors were located in the external auditory canal, two in the middle ear cavity, two in the periauricular region and one in the mastoid cavity. Four patients underwent surgery, and the other seven patients underwent surgery plus adjuvant radiotherapy. The 3-year disease-free and overall survival rates were 30.3% and 20%, respectively. Postirradiated malignancy of the ear is extremely rare, but is one of the causes of death for NPC long-term survivors despite curative-intended treatment with surgery plus adjuvant radiotherapy is instituted.


Composition analysis of falsified chloroquine phosphate samples seized during the COVID-19 pandemic.
The proliferation of falsified medicines can cause serious public health issues, particularly in the context of a global pandemic such as the actual COVID-19 pandemic. Our study involved eight chloroquine phosphate medicines seized in Cameroon, Democratic Republic of Congo and Niger during March and May 2020. These suspect samples were first analyzed in a screening phase using field tools such as handheld Raman spectroscopy (TruScan) and then in a confirmation phase using laboratory tools such as hyperspectral Raman imaging and High Performance Liquid Chromatography (HPLC). The results confirmed the falsified nature of the samples, highlighting the presence of metronidazole at low dose in four samples (16.6, 15.2, 15.2 and 14.5 mg/tab), too low levels of chloroquine in two samples (2.4 and 20.2 mg/tab), and substitution of chloroquine phosphate by paracetamol in one sample (255.7 mg/tab). The results also confirmed that four samples had been adulterated with paracetamol in trace amounts and two of them presented traces of chloramphenicol.


[Comparative experimental animal studies of the effects of various nuclear pharmaceuticals on the EEG].
Some of the radiopharmaceuticals presently recommended for cisternoscintigraphy were compared, in experiments on animals, for their effects upon bioelectric activity. On relaxed cats, electroencephalography did not show any effects upon bioelectric activity for 198 Au and 169 Yb Ca DTPA. One test animal each of seven and six cats examined using 169 Yb DTPA and 131 J HSA showed changes in the electroencephalogram subsequent to suboccipital application.


Marker-assisted selection to introgress rice QTLs controlling root traits into an Indian upland rice variety.
A marker-assisted back-crossing (MABC) breeding programme was conducted to improve the root morphological traits, and thereby drought tolerance, of the Indian upland rice variety, Kalinga III. This variety, the recurrent parent in the MABC, had not previously been used for quantitative trait locus (QTL) mapping. The donor parent was Azucena, an upland japonica variety from Philippines. Five segments on different chromosomes were targeted for introgression; four segments carried QTLs for improved root morphological traits (root length and thickness) and the fifth carried a recessive QTL for aroma. Some selection was made at non-target regions for recurrent parent alleles. We describe the selection made in three backcross (BC) generations and two further crosses between BC3 lines to pyramid (stack) all five target segments. Pyramids with four root QTLs were obtained in eight generations, completed in 6 years using 3,000 marker assays in a total of 323 lines. Twenty-two near-isogenic lines (NILs) were evaluated for root traits in five field experiments in Bangalore, India. The target segment on chromosome 9 (RM242-RM201) significantly increased root length under both irrigated and drought stress treatments, confirming that this root length QTL from Azucena functions in a novel genetic background. No significant effects on root length were found at the other four targets. Azucena alleles at the locus RM248 (below the target root QTL on chromosome 7) delayed flowering. Selection for the recurrent parent allele at this locus produced early-flowering NILs that were suited for upland environments in eastern India.


The use of microbial-earthworm ecofilters for wastewater treatment with special attention to influencing factors in performance: A review.
With the unique advantages of lower operational and maintenance cost, the use of microbial-earthworm ecofilters (MEEs) for the wastewater treatment has been increasing rapidly in the recent years. This paper provided an overview of the research activities on the use of MEEs for removing pollutants from various wastewater throughout the world. However, the long-term effective treatment performance and sustainable operation of this system still remain a challenge since the treatment performance would be affected by design parameters, operational conditions, and environmental factors. In order to promote the treatment performance, therefore, this paper also provided and summarized the influencing factors of pollutants removal in MEEs. The design parameters and operational conditions of MEEs include earthworm species and load, filter media type, hydraulic loading rate, nutrient load, packing bed height, chemical factors and temperature. Lastly, this review highlighted the further research on these issues to improve performance and sustainability of MEEs.


Risk assessment of postoperative pneumonia in children with neurologic disorders and obesity.
Postoperative pneumonia increases the risk of postsurgical mortality, making it a serious healthcare-associated complication. Children with preoperative neuromuscular impairments have a higher risk of postoperative pneumonia. Obesity is also a risk factor for postoperative pulmonary complications, including pneumonia. Moreover, obesity is increasingly prevalent among children living with a neurological diagnosis. Whether obesity increases the risk of postoperative pneumonia among children with neurologic diseases remains largely unknown. Therefore, we assessed the risk of postoperative pneumonia among children with neurologic diagnoses based on their obesity status. We analyzed a retrospective cohort of children ≤18 years from the National Surgical Quality Improvement Program (2012-2019) database who underwent inpatient orthopedic surgery. We used Cox proportional regression model to estimate the hazard ratio for the association between neurologic disorders and postoperative pneumonia. In addition, we included an interaction term between body mass index and neurologic disorders to evaluate the moderating effect of obesity status and then performed stratified analyses to compare the magnitude of hazard ratios across body mass index subgroups. A total of 60 745 children underwent inpatient orthopedic surgery during the study period, of whom 43.6% were healthy weight and 30.8% overweight/obese. The median age was 13 years (Interquartile range: 8-15). The incidence of postoperative pneumonia was higher among healthy weight patients with neurologic disorders than healthy weight patients without any neurologic disorders [Hazard ratio: 3.55 vs. 0.34]. Furthermore, the association between neurologic disorders and postoperative pneumonia was strongest among overweight patients than healthy weight or obese patients [Hazard ratio:11.88 vs. 9.45 vs. 4.40]. This observation was consistent across the various neurologic disorders analyzed. Childhood obesity buffered the association between neurologic disorders and postoperative pneumonia, consistent with an 'obesity paradox'. Further research exploring the underlying mechanisms for the obesity paradox in children with neurologic disorders is warranted.


Using the H-index to assess disease priorities for salmon aquaculture.
Atlantic salmon's (Salmo salar) annual aquaculture production exceeds 2M tonnes globally, and for the UK forms the largest single food export. However, aquaculture production is negatively affected by a range of different diseases and parasites. Effort to control pathogens should be focused on those which are most "important" to aquaculture. It is difficult to specify what makes a pathogen important; this is particularly true in the aquatic sector where data capture systems are less developed than for human or terrestrial animal diseases. Mortality levels might be one indicator, but these can cause a range of different problems such as persistent endemic losses, occasional large epidemics or control/treatment costs. Economic and multi-criteria decision methods can incorporate this range of impacts, however these have not been consistently applied to aquaculture and the quantity and quality of data required is large, so their potential for comparing aquatic pathogens is currently limited. A method that has been developed and applied to both human and terrestrial animal diseases is the analysis of published scientific literature using the H-index method. We applied this method to salmon pathogens using Web of Science searches for 23 pathogens. The top 3 H-indices were obtained for: sea lice, furunculosis, and infectious salmon anaemia; post 2000, Amoebic Gill Disease (AGD) replaced furunculosis. The number of publications per year describing bacterial disease declined significantly, while those for viruses and sea lice increased significantly. This reflects effective bacterial control by vaccination, while problems related to viruses and sea lice have increased. H-indices by country reflected different national concerns (e.g. AGD ranked top for Australia). Averaged national H-indices for salmon diseases tend to increase with log of salmon production; countries with H-Indices significantly below the trend line have suffered particularly large disease losses. The H-index method, supported by other literature analyses, is consistent with the nature and history of salmon diseases and so provides a useful quantitative measure for comparing different diseases in the absence of other measures.


Management of primary antibody deficiency with replacement therapy: summary of guidelines.
This article summarizes the guidelines for using replacement therapy in the management of patients who have primary antibody deficiency.


N'-(2-Hy-droxy-3-meth-oxy-benzyl-idene)pyrazine-2-carbohydrazide monohydrate.
In the title hydrated Schiff base, C13H12N4O3·H2O, the dihedral angle between the aromatic rings is 5.06 (11)° and an intra-molecular O-H⋯N hydrogen bond closes an S(6) ring. In the crystal, Ow-H⋯O and Ow-H⋯N (w = water) hydrogen bonds link the components into centrosymmetric tetra-mers (two Schiff bases and two water mol-ecules). Longer N-H⋯O hydrogen bonds link the tetra-mers into [010] chains. A weak C-H⋯O hydrogen bond and aromatic π-π stacking between the pyrazine and phenyl rings [centroid-centroid separations = 3.604 (2) and 3.715 (2) Å] are also observed.


Fertility of sows exposed to zearalenone and deoxynivalenol-a case report.
In a commercial breeding herd of 140 sows, the introduction of a lot of ensiled corn cob mix (CCM) contaminated with 6-11 mg deoxynivalenol and 3-5 mg zearalenone per kg dry matter (DM) into the ration of the pregnant sows and of the gilts immediately decreased its palatability. The contaminated CCM in the ration was reduced from 60% to 40% in the DM after 1 month and was completely eliminated after a further 2.5 months. The reproductive performance data of the herd during the 5 months after the introduction of the contaminated CCM (e.g. 88% non-return rate, 10.2 weaned piglets per litter, no abortion, no pseudopregnancy) were similar to the data obtained for the same period of the previous year. The high mycotoxin exposure thus had no obvious negative effects on fertility.


Sedation as an alternative method to lessen patient discomfort due to transrectal ultrasonography-guided prostate biopsy.
Despite being highly efficient for the relief of patient discomfort due to transrectal ultrasound (TRUS) guided prostate biopsy, periprostatic anesthesia is occasionally reported to be of limited use. We aimed to evaluate the efficacy of conscious sedation, an accepted method for lessening patient discomfort due to interventional radiological procedures and compare it with periprostatic anesthesia. 93 candidates for biopsy were randomised to three groups: group 1 (n = 31) received intravenous midazolam, group 2 (n = 31) received periprostatic lidocaine injection, whereas group 3 (n = 31) received no anesthetic before the procedure. After the biopsy patients were asked to express discomfort by visual anologue scale (VAS). The mean scores for groups 1 and 2 were significantly lower than that of group 3 (1.4 +/- 1.1 and 2.0 +/- 1.5 versus 4.7 +/- 1.6, respectively; p < 0.05 for both). For patients with VAS scores exceeding 4 (moderate to severe discomfort), a significant difference was calculated between groups 1 and 2 (3% versus 29%, p < 0.05) and between each and group 3 (3% and 29% versus 80%, respectively; p < 0.05 for each). Sedation is an alternative for increasing patient comfort during TRUS-guided prostate biopsy, especially in clinical situations like patient anxiety, young age, repeat biopsies or inflammatory anal diseases.


External quality assessment of p210 BCR-ABL1 transcript quantification by RT-qPCR: Findings and recommendations.
External quality assessment (EQA) is an essential tool for quality assurance of analytical testing processes of p210 BCR-ABL1 transcripts by RT-qPCR. As an EQA provider, the National Center for Clinical Laboratories organized an EQA scheme of p210 BCR-ABL1 testing in China for the first time to identify existing problems and ensure the reliability of p210 BCR-ABL1 testing. Using armored RNA technology, we first constructed pACYC-MS2-p210 and CG recombinant plasmids and expressed p210 and CG armored RNAs, with packaging segments of p210 BCR-ABL1 fusion gene (FG) and four common control gene (CG) transcripts. Using these armored RNAs, we prepared lyophilized p210 quality control (QC) sample panels and evaluated detection performance of participating laboratories in China. Of the 66 participating laboratories, great variation was found with coefficient of variation (CV%) of raw p210 BCR-ABL1 results basically ranging from 60.0% to 100.0%. In 24 International Scale (IS) laboratories, the CV% of results decreased from 82.4% to 61.6%, and the percentage of laboratories within 2-, 3-, and 5-fold of the median values increased from 78.2%, 87.0%, and 92.1% to 80.1%, 89.4%, and 97.2%, respectively, after conversion with a laboratory-specific conversion factor (CF); however, poorly converted results were also observed in laboratories resulting from changed components of RT-qPCR procedures. False-negative and false-positive results were also found in the EQA. Various problems were found for p210 BCR-ABL1 detection in the EQA. By solving the existing problems, the performance of p210 BCR-ABL1 detection can be improved, ensuring robust laboratory diagnostic capacities in China.


Sequential change detection and monitoring of temporal trends in random-effects meta-analysis.
Temporal changes in magnitude of effect sizes reported in many areas of research are a threat to the credibility of the results and conclusions of meta-analysis. Numerous sequential methods for meta-analysis have been proposed to detect changes and monitor trends in effect sizes so that meta-analysis can be updated when necessary and interpreted based on the time it was conducted. The difficulties of sequential meta-analysis under the random-effects model are caused by dependencies in increments introduced by the estimation of the heterogeneity parameter τ2 . In this paper, we propose the use of a retrospective cumulative sum (CUSUM)-type test with bootstrap critical values. This method allows retrospective analysis of the past trajectory of cumulative effects in random-effects meta-analysis and its visualization on a chart similar to CUSUM chart. Simulation results show that the new method demonstrates good control of Type I error regardless of the number or size of the studies and the amount of heterogeneity. Application of the new method is illustrated on two examples of medical meta-analyses. © 2016 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.


Lack of correlation between apoptosis and DNA single-strand breaks in X-irradiated human peripheral blood mononuclear cells in the course of ageing.
The dependence on age of both the basal and the X-radiation-induced levels of apoptosis was examined in human peripheral blood mononuclear cells (PBMC). In the same samples, the base value and the extent of induced DNA single-strand breaks were determined, using a sensitive and fast microplate assay. PBMC were isolated from blood of donors of various age groups (20-30, 40-60 and > 70 years of age) and X-irradiated ex vivo using a 6 MV linear accelerator to give a total exposure of 4 Gy. The mean basal levels of apoptosis in PBMC from donors in the 40-60 year age group and the > 70 year age group were found to be only slightly higher (by 20-10%) compared to that of the 20-30 year age group, whereas the extent of DNA damage strongly and significantly (P < 0.01) increased with age by up to 2-fold. In contrast to the extent of induced DNA damage, which steadily increased in the course of ageing by up to 1.8-fold, there was only a transient increase in the level of induced apoptosis to 1.5-fold in PBMC from X-irradiated blood (4 Gy photons) from donors aged 40-60 followed by a decrease to 0.9-fold in PBMC from old donors (>70), compared to age group 20-30. The results show that X-ray-induced apoptosis and DNA damage in PBMC are not correlated during ageing.


Testosterone:estradiol ratio changes associated with long-term tadalafil administration: a pilot study.
It has been reported that lack of sexual activity due to erectile dysfunction (ED) may be associated with testosterone (T) decline. To investigate whether the known changes in sex hormones associated with resumption of sexual activity are sustained in the long term. Primary endpoints were variations from baseline of steroid hormones: total T, free T (f T), and estradiol (E). Secondary endpoints were variations of erectile function domain scores at International Index of Erectile Function-5 (IIEF-5). In an open-label fashion, 20 patients (mean age 54.8 +/- 8.4 years) received tadalafil 10-20 mg on demand for 12 months. Exclusion criteria were those reported for phosphodiesterase inhibitors, including hypogonadism and hyperprolactinemia. Tadalafil assumption was safe and well tolerated (overall adverse effects in 15% of patients) and none discontinued medication. A significant decrease in E levels occurred at the end of the study (from 19.9 +/- 9.6 to 16.6 +/- 8.1 ng/dL, P = 0.042 vs. baseline), with parallel increase in the T:E ratio (26.3 +/- 15.3 to 32.6 +/- 17.7, P = 0.05), whereas no changes in T and f T serum levels were observed, respectively (411.4 +/- 131.4 to 434.2 +/- 177.1 ng/dL and 47.7 +/- 15.3 to 49.9 +/- 19.1 pmol/L, not significant). Interestingly, nonparametric subgroup analysis for related samples revealed that E decrease was detectable only in lean (N = 14) but not in obese (N = 6, body mass index > 27.5 kg/m2) subjects (17.8 +/- 10.1 vs. 13.5 +/- 6.8, P < 0.05). A net increase in IIEF-5 scores was observed at the endpoint (13.7 +/- 5.9 vs. 25.7 +/- 2.9, P < 0.0001). Sustained improvement in sexual function after 12 months of tadalafil administration is associated with increased T:E ratio mainly related to reduction of E levels. We hypothesize that androgen-estrogen cross-talk and possible inhibition of aromatase activity during chronic exposure to tadalafil might have a role in the regulation of erectile function.


Hedgehog signaling plays roles in epithelial cell proliferation in neonatal mouse uterus and vagina.
Both the uterus and vagina develop from the Müllerian duct but are quite distinct in morphology and function. To investigate factors controlling epithelial differentiation and cell proliferation in neonatal uterus and vagina, we focused on Hedgehog (HH) signaling. In neonatal mice, Sonic hh (Shh) was localized in the vaginal epithelium and Indian hh (Ihh) was slightly expressed in the uterus and vagina, whereas all Glioma-associated oncogene homolog (Gli) genes were mainly expressed in the stroma. The expression of target genes of HH signaling was high in the neonatal vagina and in the uterus, it increased with growth. Thus, in neonatal mice, Shh in the vaginal epithelium and Ihh in the uterus and vagina activated HH signaling in the stroma. Tissue recombinants showed that vaginal Shh expression was inhibited by the vaginal stroma and uterine Ihh expression was stimulated by the uterine stroma. Addition of a HH signaling inhibitor decreased epithelial cell proliferation in organ-cultured uterus and vagina and increased stromal cell proliferation in organ-cultured uterus. However, it did not affect epithelial differentiation or the expression of growth factors in organ-cultured uterus and vagina. Thus, activated HH signaling stimulates epithelial cell proliferation in neonatal uterus and vagina but inhibits stromal cell proliferation in neonatal uterus.


Growth factor receptor bound protein-7 regulates proliferation, cell cycle, and mitochondrial apoptosis of thyroid cancer cells via MAPK/ERK signaling.
It is of great significance to explore the molecular mechanism of thyroid cancer (TC) pathogenesis for its improvement and therapy. Growth factor receptor bound protein-7 (GRB7) has been regarded as an important regulatory gene in the developments of various malignant tumors. Our study aimed to illustrate the role of GRB7 in the TC pathology mechanism. Firstly, GRB7 was found to be significantly upregulated in 49 cases of TC tissues and 5 TC cell lines by using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. Silencing GRB7 with siRNA dramatically inhibited proliferation and induced cell cycle arrest in TC cells. Besides, GRB7 silence resulted in the decrease of adenosine triphosphate content, glucose uptake, and lactose production in TC cells and attenuated the activity and expression of mitochondrial respiratory complex. We also demonstrated that GRB7 downregulation increased the levels of Bax and caspase 3, and inhibited the expression of Bcl-2, suggesting the induced mitochondrial apoptosis. More importantly, our study proved that mitogen-activated protein kinase/extracellular-regulated protein kinases (MAPK/ERK) signaling played a crucial role in the regulation of GRB7 on TC cell functions. In general, the present research verified that GRB7 was upregulated during TC development and modulated the proliferation, cell cycle, and mitochondrial apoptosis of TC cells by activating MAPK/ERK pathway. This may provide a novel target for the therapeutic strategy of TC.


Rapid evolution of the male-specific antibacterial protein andropin gene in Drosophila.
Andropin, which encodes an antibacterial protein, is closely linked to the Cecropin gene cluster of D. melanogaster. Andropin and Cecropins are considered to have originated from one common ancestor. However, the expression pattern of Andropin is distinct from that of Cecropins, being restricted to the adult male ejaculatory duct. To elucidate the evolutionary process of Andropin, we have sequenced Andropin genes from D. melanogaster and its closely related species. In D. melanogaster, the nucleotide diversity of Andropin is remarkably low compared to that of Cecropin. In contrast, nonsynonymous substitutions of Andropin are conspicuously frequent between species. From genomic Southern analysis, Andropin-like genes are present in at least the melanogaster species subgroup. The series of present results suggests that Andropin was born in the course of constructing the Drosophila Cecropin gene family and then started to evolve rapidly, in contrast to Cecropins.


[V(T)/ t(I) relationship during steady-state exercise on a treadmill at the intensity close to second ventilatory threshold].
Few works have approached the study of the tidal volume/inspiratory time (V(T)/ t(I)) relationship during long and constant load exercise in treadmill. The aim of the present study was to analyze the relationship V(T)/ t(I) to an intensity corresponding to the mean point among the two ventilatory thresholds. Twenty-four males have participated, carrying out two tests in treadmill: (1) maximal incremental test and (2) a 30 minutes constant load test at the intensity corresponding to the mean point among the two ventilatory thresholds. The respiratory parameters, acid-base parameters and lactate concentration was analysed during the constant load test. The breakpoint of relationship V(T)/ t(I) during the maximum test was reached at V(T) 2886 (465) mL, tI 0.57 (0.10) s and oxygen uptake (VO2) 4606 (532.9) mL/min. During the effort at constant load the relationships V(T)/ t(I), and tI/ tTOT (inspiratory time/total time) were significantly lower to those corresponding to the breakpoint of Hering-Breuer (PHB). Although the lactate concentration was superior to 4 mmol/L, the parameters of the acid-base state stayed inside the limits that allowed to conclude the whole test. A value of the relationship V(T)/ t(I) is adopted below the PHB, determinated with a maximum test, during an effort of 30 minutes at an intensity corresponding to the mean point among the two ventilatory thresholds. Both, carbon dioxide pressure end tidal values (Pet CO2) and the acid-base state, stay stable and below the values corresponding to the PHB.


Bagging Nearest-Neighbor Prediction independence Test: an efficient method for nonlinear dependence of two continuous variables.
Testing dependence/correlation of two variables is one of the fundamental tasks in statistics. In this work, we proposed an efficient method for nonlinear dependence of two continuous variables (X and Y). We addressed this research question by using BNNPT (Bagging Nearest-Neighbor Prediction independence Test, software available at https://sourceforge.net/projects/bnnpt/). In the BNNPT framework, we first used the value of X to construct a bagging neighborhood structure. We then obtained the out of bag estimator of Y based on the bagging neighborhood structure. The square error was calculated to measure how well Y is predicted by X. Finally, a permutation test was applied to determine the significance of the observed square error. To evaluate the strength of BNNPT compared to seven other methods, we performed extensive simulations to explore the relationship between various methods and compared the false positive rates and statistical power using both simulated and real datasets (Rugao longevity cohort mitochondrial DNA haplogroups and kidney cancer RNA-seq datasets). We concluded that BNNPT is an efficient computational approach to test nonlinear correlation in real world applications.


Electrophysiologic findings in carotid sinus massage.
Thirty patients with carotid sinus syndrome were electrophysiologically studied. In 14 patients carotid sinus massage was performed during atrial and ventricular stimulation, and the conduction times were measured. The AH-time was prolonged by more than 120 ms in 6 patients (20%); the HV-time was prolonged in 6 patients by more than 55 ms (20%); 5 patients had bundle branch block (16.7%); The sinus node recovery time was prolonged in 7 out of 27 patients (26%). Ten patients (33%) did not have additional electrophysiologic abnormalities. There was a predominance of carotid sinus syndrome on the right side. During carotid sinus massage there was a significant increase of the AH-time, but there were no significant changes of the HV-time or the width of the QRS-complexes. Twenty-one patients developed an atrial asystole and 9 patients an atrial bradycardia and an additional AV-block. There was a longer AH-time and a longer prolongation of the AH-time in the patients who developed an AV-block. Twelve out of 14 patients (85.7%) developed an AV-block during carotid sinus massage and atrial pacing. During ventricular pacing 5 of 14 patients (35.7%) revealed a complete retrograde block before carotid sinus massage and 5 of the remaining 9 patients developed a total retrograde block during carotid sinus massage. Consequently, in 71.4% of the patients with carotid sinus syndrome complete retrograde conduction block and atrial asystole can be expected during attacks of ventricular asystole and simultaneous ventricular pacing. In conclusion, there is a high incidence of additional disturbances of the sinus node function and AV-conduction in patients with carotid sinus syndrome. AAI pacemakers are contraindicated due to the common development of additional AV-block during carotid sinus massage. Physiologic pacing might contribute to better hemodynamics, particularly in patients with the mixed type of carotid sinus syndrome.


On the presence of extraneuronal catecholamine in the iris of the rat: a scanning microfluorimetric study.
Formaldehyde-induced fluorescence (FIF) of noradrenalin (NA) was studied in histochemical preparations of the rat iris. With the aid of a two-dimensional microfluorimetric scanning method, quantitative information was obtained from neuronal and non-neuronal elements selectively. Spectral analysis and fluorimetric studies showed the existence of extraneuronal NA in the iris of untreated rats. Surgical and pharmacological (reserpine, amphetamine, imipramine, nialamide) manipulation of sympathetic neurotransmission-induced changes in extraneuronal fluorescence, which did not parallel changes in fluorescence of neuronal elements. A positive relationship was found between changes in extraneuronal fluorescence and the postsynaptic effect (pupil diameter). We hypothesize that extraneuronal catecholamine (CA) fluorescence is a histochemical parameter for synaptic neurotransmission.


Thrombosis in the pulmonary vein stump after left upper lobectomy as a possible cause of cerebral infarction.
Thrombus in the stump of the pulmonary vein (PV) is not a well-known complication after lung resection, and it has the potential to cause embolism to vital organs. To clarify the frequency, risk factors, and cause of this complication, a retrospective clinical study of patients who underwent lobectomy was performed. The study evaluated 193 patients with primary lung cancer who underwent lobectomy from 2005 to 2011 and contrast-enhanced chest computed tomography (CT) within 2 years after lobectomy. Contrast-enhanced CT was retrospectively interpreted to check for thrombus in the PV stump. The operative procedures were 65 right upper lobectomies, 14 right middle lobectomies, 40 right lower lobectomies, 52 left upper lobectomies (LUL), and 22 left lower lobectomies. Thrombus developed in the PV stump in 7 of the 193 patients (3.6%) after lobectomy. All patients with thrombus had undergone LUL, and 13.5% of those who had undergone LUL developed thrombus. Univariate analyses revealed that LUL and operation time were significant risk factors and that adjuvant chemotherapy was marginally significant. It appears that thrombus may be attributable to the length of the PV stump. Measurement of the length of the PV stump using 3-dimensional CT images of the PV revealed that the stump of the left superior PV was longer than the others. Thrombus in the PV stump occurred in 13.5% of patients after LUL. These findings suggest that contrast-enhanced CT should be recommended for patients after LUL to help identify those with a high risk for thromboembolism.


The role of lung macrophages in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) as a common, preventable and treatable chronic respiratory disease in clinic, gets continuous deterioration and we can't take effective intervention at present. Lung macrophages (LMs) are closely related to the occurrence and development of COPD, but the specific mechanism is not completely clear. In this review we will focus on the role of LMs and potential avenues for therapeutic targeting for LMs in COPD.


Willingness to vaccinate against Novel COVID-19 and contributing factors for the acceptance among nurses in Qassim, Saudi Arabia.
The aim of the article is to determine the level of COVID-19 vaccine acceptance among nurses. It also aimed to identify contributing factors of COVID-19 vaccine hesitancy among nurses in Qassim, Saudi Arabia. This cross-sectional study was carried out on nurses working in Ar-Rass general hospital and primary care centers, Qassim, Saudi. A self-administered questionnaire was collected between 27/11/2020 to 7/12/2020. The questionnaire consists of socio-demographics, knowledge, and practice in regard to coronavirus, attitude toward vaccinations, coronavirus vaccine acceptance, and reasons for hesitancy. Out of 468 nurses, 334 nurses completed the survey. Overall, (236) 70.7% of nurses were willing to uptake coronavirus vaccine, which is a relatively high acceptance rate. 78.7% believe that COVID-19 vaccination should be mandatory once available. The main four reasons for hesitancy were the lack of knowledge 23.1%, long term adverse effects 17.7%, short-term side effects of the vaccine 9.3%, non-effective vaccine 8.7%. The findings presented in this study can help Saudi Arabian health authorities to tailor educational campaigns for nurses and development of effective vaccination programs to increase the novel vaccine acceptance and uptake among nurses' population.


Characterization of binding of Gal beta 4GlcNAc-specific lectins from Erythrina cristagalli and Erythrina corallodendron to glycosphinogolipids. Detection, isolation, and characterization of a novel glycosphinglipid of bovine buttermilk.
The lectins from seeds of Erythrina cristagalli and Erythrina corallodendron were characterized for binding to glycolipids, using a chromatogram binding assay, a microtiter well assay, and glycolipids coated on erythrocytes. Both lectins bound to glycolipids having a terminal Gal beta 4GlcNAc sequence and also, with similar affinity, to glycolipids with terminal Fuc alpha 2Gal beta 4GlcNAc (blood group H determinant on a type 2 chain). All other substitutions of Gal beta 4GlcNAc tested abolished the binding. A binding epitope for the Erythrina lectins was considered by comparison of minimum energy conformations of binding and nonbinding glycolipids. A non-acid glycolipid, with lectin binding activity, was found in bovine buttermilk. By mass spectrometry and proton NMR spectroscopy it was shown to be a branched hexaglycosylceramide with the structure Gal beta 4Glc-NAc beta 6(Gal beta 4GlcNAc beta 3)Gal beta 4Glc beta Cer. This glycosphingolipid has not been reported before.


Polysialylation of the neural cell adhesion molecule: interfering with polysialylation and migration in neuroblastoma cells.
Polysialic acid represents a unique posttranslational modification of the neural cell adhesion molecule (NCAM). It is built as a homopolymer of up to 150 molecules of alpha 2-8-linked sialic acids on N-glycans of the fifth immunoglobulin-like domain of NCAM. Besides its role in cell migration and axonal growth during development, polysialic acids are closely related to tumor malignancy as they are linked to the malignant potential of several tumors, such as undifferentiated neuroblastoma. Polysialic acid expression is significantly more frequent in high-grade tumors than in low-grade tumors. It is synthesized in the Golgi apparatus by the activity of two closely related enzymes, the polysialyltransferases ST8SiaII and ST8SiaIV. Interestingly, polysialylation of tumors is not equally synthesized by both polysialyltransferases. It has been shown that especially the ST8SiaII gene is not expressed in some normal tissue, but is strongly expressed in tumor tissue. Here we summarize some knowledge on the role of polysialic acid in cell migration and tumor progression and present novel evidence that interfering with polysialylation using unnatural sialic acid precursors decreases the migration of neuroblastoma cells.