Co-immunization of cattle with a vaccine against babesiosis and Lactobacillus casei increases specific IgG1 levels to Babesia bovis and B. bigemina.
The effect of Lactobacillus casei administered along with a live attenuated vaccine vs. bovine babesiosis (VAC) on induction of IgG1 and IgG2 antibodies to Babesia bovis and Babesia bigemina was assessed by the indirect fluorescent antibody test (IFAT) in bovines of an endemic babesiosis area before (day 0) and after vaccination (days 15 and 30). We previously reported that L. casei increases the efficiency of VAC under controlled conditions and under extreme conditions in the field; however, the levels of IgG1 and IgG2 antibodies to B. bovis and B. bigemina are not known in vaccinated animals. Twenty-one dairy cows were allocated into three groups (seven animals per group): unvaccinated, vaccinated with VAC and vaccinated simultaneously with VAC and L. casei (VAC-LC). All animals were kept in a babesiosis endemic area at Tlalixcoyan, Veracruz. At days 15 and 30 after vaccination, the average levels of IgG1 to B. bovis and to B. bigemina were significantly higher in VAC-LC group than levels observed in VAC and control groups (P<0.01). Levels of IgG2 were similar in VAC and VAC-LC groups but higher than in the control group (P<0.01). When tested in in vitro cultures of B. bovis, sera from VAC-LC group significantly inhibited parasite growth as compared with the sera of the other two groups. It is suggested that the efficiency improvement of VAC, in part, is due to the L. casei boost of IgG1 over IgG2 antibodies to B. bovis and B. bigemina when the bacteria is co-inoculated with this vaccine.


Ixazomib Versus Placebo as Postinduction Maintenance Therapy in Newly Diagnosed Multiple Myeloma Patients: An Analysis by Age and Frailty Status of the TOURMALINE-MM4 Study.
The TOURMALINE-MM4 trial demonstrated a significant and clinically meaningful progression-free survival (PFS) benefit with ixazomib versus placebo as postinduction maintenance in nontransplant, newly-diagnosed multiple myeloma patients, with a manageable and well-tolerated toxicity profile. In this subgroup analysis, efficacy and safety were assessed by age (< 65, 65-74, and ≥ 75 years) and frailty status (fit, intermediate-fit, and frail). In this analysis, PFS benefit with ixazomib versus placebo was seen across age subgroups, including patients aged < 65 years (hazard ratio [HR], 0.576; 95% confidence interval [CI], 0.299-1.108; P = .095), 65-74 years (HR, 0.615; 95% CI, 0.467-0.810; P < .001), and ≥ 75 years (HR, 0.740; 95% CI, 0.537-1.019; P = .064). PFS benefit was also seen across frailty subgroups, including fit (HR, 0.530; 95% CI, 0.387-0.727; P < .001), intermediate-fit (HR, 0.746; 95% CI, 0.526-1.058; P = .098), and frail (HR, 0.733; 95% CI, 0.481-1.117; P = .147) patients. With ixazomib versus placebo, rates of grade ≥ 3 treatment-emergent adverse events (TEAEs; 28-44% vs. 10-36%), serious TEAEs (15-29% vs. 3-29%), and discontinuation due to TEAEs (7-19% vs. 5-11%) were higher or similar across age and frailty subgroups, and generally somewhat higher in older age groups and intermediate-fit/frail patients in both arms. Treatment with ixazomib versus placebo did not adversely affect patient-reported quality-of-life scores across age and frailty status subgroups. Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous patient population.


Regulation of epithelial Na+ channel activity by conserved serine/threonine switches within sorting signals.
The PY and YXXphi motifs are canonical sorting signals involved in trafficking. Nedd4-2 and the mu(2)-subunit of the AP-2 complex target these motifs to facilitate internalization. Epithelial Na(+) channel (ENaC) subunits contain both motifs in their cytosolic COOH termini where they overlap ((S/T)PPPXYX(S/T)phi). Just preceding the PY and embedded within the YXXphi motifs are conserved serine/threonine. We test here whether these conserved Ser/Thr modulate ENaC activity by influencing the function of the internalization domains. We find that co-expression of dominant-negative dynamin (K44A) with ENaC increases channel activity. Conversely, co-expression of Nedd4-2 and epsin with ENaC decrease activity. Alanine substitution of the conserved Thr(628) preceding the PY motif in gamma-mENaC had no effect on basal activity. Channels with this mutation, however, responded to K44A and epsin but not Nedd4-2. Similarly, mutation of the proline repeat in the PY motif of gamma-mENaC disrupted only Nedd4-2 regulation having no effect on regulation by K44A and epsin. Alanine substitution of the conserved Thr within the YXX motif of gamma-mENaC (T635A) increased basal activity. Channels containing this mutation responded to Nedd4-2 but not K44A and epsin. Channels containing the T635(D/E) substitution in gamma-mENaC did not have increased basal activity and responded to Nedd4-2 but not K44A. The double mutant T628A,T635A did not respond to Nedd4-2 or K44A. Mutation of Thr(628) and Thr(635) also disrupted ENaC precipitation with the mu(2)-subunit of the AP-2 complex. Moreover, the YXXphi motif, independent of the PY motif, was sufficient to target degradation with T635A disrupting this effect. These results demonstrate that the overlapping PY and YXXphi motifs in ENaC are, in some instances, capable of independent function and that the Ser/Thr just preceding and within these domains impact this function.


Intracellular and in vivo oxygen sensing using phosphorescent iridium(III) complexes.
Molecular oxygen plays an indispensable role as a terminal electron acceptor in the electron transport chain in mitochondria. Acute or chronic oxygen deprivation (hypoxia) in organisms results in various diseases, and the elucidation of the pathogenic mechanism of hypoxia-related diseases and various cellular responses to hypoxia is an urgent issue. Optical oxygen imaging methods using phosphorescent probes have opened up techniques for noninvasive imaging of the intracellular and tissue oxygen status, and oxygen-sensitive probes play a key role in the development of this approach. We expect that phosphorescent Ir(III) complexes can serve as new oxygen-sensing probes for intracellular and intravascular oxygen imaging in vivo.


Anti-acetylcholinesterase and toxicity against Artemia salina of chitosan microparticles loaded with essential oils of Cymbopogon flexuosus, Pelargonium x ssp and Copaifera officinalis.
Essential oils (EOs) are bioactive compounds with therapeutic potential for use as alternatives or as support to conventional treatments. However, EOs present limitations, such as sensibility to environmental factors, which can be overcome through microencapsulation. The objective of this study was to produce, by spray drying, chitosan microparticles (CMs) loaded with EO of Lemongrass (Cymbopogon flexuosus), Geranium (Pelargonium x ssp) and Copaiba (Copaifera officinalis). Physicochemical and biological characterization of these microparticles showed that CMs presented spherical morphology, had an average size range of 2-3 μm with positive zeta potential (ZP) values, and enhanced thermal stability, compared to free EO. The encapsulation efficiency (EE) ranged from 4.8-58.6%, depending on the oil's properties. In vitro EO release from CMs was determined at different pHs, with 94% release observed in acid media. All microparticles were non-hemolytic at concentrations of up to 0.1 mg·mL-1. EOs and CMs presented acetylcholinesterase (AChE) inhibition activity (IC 50 ranged from 11.92 to 28.18 μg·mL-1). Geranium and Copaiba EOs presented higher toxicity against Artemia salina, and greater inhibition of acetylcholinesterase, indicating potential bioactivity for Alzheimer's disease (AD). Our findings demonstrate that CM systems may show promise for the controlled release of these EOs.


High-risk oral leukoplakia is associated with aberrant promoter methylation of multiple genes.
Early detection of oral squamous cell carcinomas (OSCCs) is urgently needed to improve the prognosis and quality of life (QOL) of patients. Oral leukoplakias (OLs), known as the most common premalignant lesions in the oral cavity, often precede OSCCs. Especially, OLs with dysplasia are known to have a high risk of malignant transformation. Here, we searched for the promoter methylation characteristic of high-risk OLs. To identify methylation-silenced genes, a combined analysis of methylated DNA immunoprecipitation (MeDIP) - CpG island (CGI) microarray analysis and expression microarray analysis after treatment with a demethylating agent was performed in two OSCC cell lines (Ca9-22 and HSC-2). The methylation statuses of each gene were examined by methylation-specific PCR. A total of 52 genes were identified as candidates for methylation-silenced genes in Ca9-22 or HSC-2. The promoter regions of 13 genes among the 15 genes randomly selected for further analysis were confirmed to be methylated in one or more of five cell lines. In OSCC tissues (n = 26), 8 of the 13 genes, TSPYL5, EGFLAM, CLDN11, NKX2-3, RBP4, CMTM3, TRPC4, and MAP6, were methylated. In OL tissues (n = 24), seven of the eight genes, except for EGFLAM, were found to be methylated in their promoter regions. There were significantly greater numbers of methylated genes in OLs with dysplasia than in those without dysplasia (p < 0.0001). OLs at high risk for malignant transformation were associated with aberrant promoter methylation of multiple genes.


Long-term ex situ normothermic perfusion of human split livers for more than 1 week.
Current machine perfusion technology permits livers to be preserved ex situ for short periods to assess viability prior to transplant. Long-term normothermic perfusion of livers is an emerging field with tremendous potential for the assessment, recovery, and modification of organs. In this study, we aimed to develop a long-term model of ex situ perfusion including a surgical split and simultaneous perfusion of both partial organs. Human livers declined for transplantation were perfused using a red blood cell-based perfusate under normothermic conditions (36 °C) and then split and simultaneously perfused on separate machines. Ten human livers were split, resulting in 20 partial livers. The median ex situ viability was 125 h, and the median ex situ survival was 165 h. Long-term survival was demonstrated by lactate clearance, bile production, Factor-V production, and storage of adenosine triphosphate. Here, we report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol.


High ethanol fermentation performance of the dry dilute acid pretreated corn stover by an evolutionarily adapted Saccharomyces cerevisiae strain.
Ethanol fermentation was investigated at the high solids content of the dry dilute sulfuric acid pretreated corn stover feedstock using an evolutionary adapted Saccharomyces cerevisiae DQ1 strain. The evolutionary adaptation was conducted by successively transferring the S. cerevisiae DQ1 cells into the inhibitors containing corn stover hydrolysate every 12h and finally a stable yeast strain was obtained after 65 days' continuous adaptation. The ethanol fermentation performance using the adapted strain was significantly improved with the high ethanol titer of 71.40 g/L and the high yield of 80.34% in the simultaneous saccharification and fermentation (SSF) at 30% solids content. No wastewater was generated from pretreatment to fermentation steps. The results were compared with the published cellulosic ethanol fermentation cases, and the obvious advantages of the present work were demonstrated not only at the high ethanol titer and yield, but also the significant reduction of wastewater generation and potential cost reduction.


NADPH-cytochrome P450 reductase-mediated denitration reaction of 2,4,6-trinitrotoluene to yield nitrite in mammals.
While the biodegradation of 2,4,6-trinitrotoluene (TNT) via the release of nitrite is well established, mechanistic details of the reaction in mammals are unknown. To address this issue, we attempted to identify the enzyme from rat liver responsible for the production of nitrite from TNT. A NADPH-cytochrome P450 reductase (P450R) was isolated and identified from rat liver microsomes as the enzyme responsible for not only the release of nitrite from TNT but also formation of superoxide and 4-hydroxyamino-2,6-dinitrotoluene (4-HADNT) under aerobic conditions. In this context, reactive oxygen species generated during P450R-catalyzed TNT reduction were found to be, at least in part, a mediator for the production of 4-HADNT from TNT via formation of 4-nitroso-2,6-dinitrotoluene. P450R did not catalyze the formation of the hydride-Meisenheimer complex (H(-)-TNT) that is thought to be an intermediate for nitrite release from TNT. Furthermore, in a time-course experiment, 4-HADNT formation reached a plateau level and then declined during the reaction between TNT and P450R with NADPH, while the release of nitrite was subjected to a lag period. Notably, the produced 4-HADNT can react with the parent compound TNT to produce nitrite and dimerized products via formation of a Janovsky complex. Our results demonstrate for the first time that P450R-mediated release of nitrite from TNT results from the process of chemical interaction of TNT and its 4-electron reduction metabolite 4-HADNT.


Cloxacillin distribution in the rabbit eye after intravenous injection.
Distribution of isotopically labelled and intravenously injected cloxacillin was studied in rabbit eye. The antibiotic concentration determined by liquid scintillation counting proved to be a reliable measure of the total antibiotic concentration when controlled by microbiological assay. In the rabbit eye after an intravenous injection of 50 mg/kg of cloxacillin sodium, longlasting antibiotic concentration regarded as therapeutic against penicillinase producing staphylococci was obtained in all vascularized ocular structures and in the cornea. The antibiotic present in the iris and ciliary body, and in the retina and choroid preparations, proved to be partly intravascular, whereas it penetrated better into the extravascular tissue compartment of the sclera and limbal area. Cloxacillin failed to achieve a therapeutic antibiotic concentration in the vitreous body and in the lens. Administration of probenecid had an enhancing effect on ocular cloxacillin concentration allowing improved drug diffusion into the eye by means of an elevated plasma concentration. No specific ocular effect of probenecid was noticed. Therapeutic concentration of cloxacillin in the aqueous humour, otherwise barely achieved, was more satisfactorily obtained with a previous injection of probenecid.


Occupational safety and HIV risk among female sex workers in China: a mixed-methods analysis of sex-work harms and mommies.
Female sex workers (FSWs) in China are exposed to multiple work-related harms that increase HIV vulnerability. Using mixed-methods, we explored the social-ecological aspects of sexual risk among 348 FSWs in Beijing. Sex-work harms were assessed by property stolen, being underpaid or not paid at all, verbal and sexual abuse, forced drinking; and forced sex more than once. The majority (90%) reported at least one type of harm, 38% received harm protection from 'mommies' (i.e., managers) and 32% reported unprotected sex with clients. In multivariate models, unprotected sex was significantly associated with longer involvement in sex work, greater exposure to harms, and no protection from mommies. Mommies' protection moderated the effect of sex-work harms on unprotected sex with clients. Our ethnography indicated that mommies played a core role in sex-work networks. Such networks provide a basis for social capital; they are not only profitable economically, but also protect FSWs from sex-work harms. Effective HIV prevention interventions for FSWs in China must address the occupational safety and health of FSWs by facilitating social capital and protection agency (e.g., mommies) in the sex-work industry.


The long-term outcome of hepatitis B infection in hemodialysis patients.
Little information on the long-term outcome of hepatitis B virus (HBV) infection in hemodialysis patients is available. We studied 49 hemodialysis patients, seen at three centers between 1969 and 1985, who developed HBV infection. Patients were studied retrospectively and followed for up to 10 years (mean 52 +/- 5 months). Only 20% (n = 10) of patients converted to hepatitis B surface antigen (HBsAg) negative, the majority of whom did so within 6 months of becoming HBsAg positive. Twenty-nine percent (n = 14) of patients developed chronic elevation of liver enzymes which remitted in one patient. Only one patient died from liver disease. We conclude that HBV infection in hemodialysis patients more often results in persistent antigenemia and chronic elevation of liver enzymes than is the case in patients without kidney disease. However, the risk of death from liver disease is low.


Scoping Review of Multidisciplinary Care in Tourette Syndrome.
To review current multidisciplinary care practices in patients with Tourette syndrome (TS). Individuals with TS can have multiple symptoms and comorbidities and require treatment to encompass all of their needs. A multidisciplinary research or care model approaches the situation/problem from all sides and uses multiple perspectives. A database search of Medline (using Pubmed), PsychINFO, and Scopus was performed using keywords related to multidisciplinary care and TS. The authors then screened the results for relevant information using a standardized extraction form to collect data. Next, relevant codes from text analysis were extracted with a final list agreed on with author consensus. Finally, we inferred common themes. The search revealed 2304 citations, and 87 were selected for full-text analysis. One additional article was identified by manual search. Thirty-one citations were deemed relevant. Multidisciplinary team members typically included a psychiatrist or child psychiatrist, a neurologist or child neurologist, and a psychologist or therapist at the core. Four primary benefits were associated with multidisciplinary care: establishing the diagnosis, managing the complexity of TS and its associated comorbidities, averting complications, and evaluating advanced therapies. Limitations include possible poor team dynamics and rigidity in the approach leading to an algorithmic treatment plan. A multidisciplinary care model for TS is the preferred model advocated by patients, physicians, and organizations. This scoping review reveals that the impetus for multidisciplinary care rests on four primary benefits, but there is a lack of empirical evidence for defining and evaluating its use.


Mechanical Thrombectomy with the Novel NeVa M1 Stent Retriever: Do the Drop Zones Represent a Risk or a Benefit?
The NeVa M1 thrombectomy device is a novel hybrid-cell stent retriever with multifunctional zones for optimized retrieval of resistant clots located in the M1 segment of the middle cerebral artery. The objective was to evaluate the safety and efficacy of the NeVa in a "real-life" setting. Twenty-nine consecutive patients (median age: 77 years) treated with the NeVa M1 for acute ischemic stroke of the M1 segement were retrospectively reviewed. First-pass and final modified thrombolysis in cerebral infarction (mTICI) scores, device-related complications, symptomatic intracranial hemorrhage, and 90-day modified Rankin scale (mRS) scores are reported. Primary outcome parameters were first-pass mTICI 2b-3 reperfusion and mRS 0-2 at 90 days. Median National Institutes of Health Stroke Scale scores decreased from 16 to 12 after treatment. mTICI 2b-3 reperfusion rates were 55% after the first pass, 79% after 1-2 passes, and 100% after the final pass. mTICI 2c-3 was obtained in 48% after the first pass, 62% after 1-2 passes, and 72% after the final pass. Rescue treatment was performed in 4 patients (14%). Device-related complications included 1 asymptomatic caroticocavernous fistula, 1 asymptomatic M2 dissection, and 1 symptomatic intracranial hemorrhage. The procedure-related vasospasm rate was 48%. A 90-day mRS of 0-2 was achieved by 31%. The NeVa M1 provides a high first-pass complete reperfusion rate with an adequate safety profile. To retrieve resistant clots, the stent design exerts high mechanical traction forces, which may trigger vasospasm and vessel wall damage. Large, comparative studies are warranted to draw a definite conclusion on this device.


Improved operational stability of biosensors based on enzyme-polyelectrolyte complex adsorbed into a porous carbon electrode.
A novel porous active carbon is utilized in order to adsorb the diethylaminoethyl-dextran (DEAE-dextran)-enzyme stabilized complexes, for the construction of highly stable biosensors. The interaction of DEAE-dextran with the examined enzymes increases dramatically the operational stabilization of the sensors, without adverse effects on the enzyme activity. At the same time, the porous active carbon allows for high enzyme loading, good electrical contact and low resistance throughout the sensing element. Glucose oxidase and horseradish peroxidase are used as model enzymes in this study to construct biosensors, with very good reproducibility (less than 5% RSD). As a result, the glucose sensor exhibits very long operational stability (over a period of 5 months), while the hydrogen peroxide sensor retains its initial activity after several weeks.


[Lacrimal Duct Obstruction in Adults].
The tearing eye (epiphora) is the guiding symptome of nasolacrimal duct obstruction. Depending on the localization of stenosis, mucopurulent lacrimal discharge occurs additionally. These symptoms induce alterations of the optical system and can cause severe complications such as acute phlegmonous dacryocystitis. The grade of suffering in these patients is very high. For the diagnosis, patient's history, ocular surface conditions and inspection (macro-/microscopically) as well as palpation of the lacrimal region are essential examinations. Moreover, functional and anatomical tests enable a classification of nasolacrimal duct obstruction regarding grade of stenosis (incomplete vs. complete), type (functional vs. mechanical), and localization (pre-, intra-, postsaccal). ENT consultation prior to lacrimal surgery is obligate. Through this, a purposeful therapeutic intervention is warranted. Surgical methods consist of minimally invasive transcanalicular procedures or anastomosing surgeries. Dependent on the clinical findings, these treatment options can be applied in a patient centered therapeutic concept.


Abusive head trauma, protocols, and legal concerns in a South American Country.
The abusive head trauma (AHT) is a form of child abuse and is a frequent entity all over de world. It is particularly unique among medical diagnoses because of the legal implications imposed by the diagnosis. Therefore, it has been the subject of much legal controversy over the decades. Knowledge of the clinical signs and imaging findings of abusive head trauma is vitally important for early diagnosis. An oriented anamnesis, as well as a complete physical examination and obtaining adequate images of the central nervous system, play a significant role in confirming the presumptive diagnosis. The interdisciplinary approach (pediatricians, neurosurgeons, neuroradiologists, social workers, and other specialists) is the key in the management of these patients. The purpose of this article is to familiarize the pediatric neurosurgeon with some of the more common medicolegal issues surrounding AHT as well as to discuss legal commitments and ethical obligations of the neurosurgeon in Argentina (South America) based on 2 clinical cases.


MiR-185-5p regulates the development of myocardial fibrosis.
Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac fibrosis and could serve as potential therapeutic targets for myocardial fibrosis. Analysis for cardiac samples from sudden cardiac death victims with extensive myocardial fibrosis as the primary cause of death identified dysregulation of miR-185-5p. Analysis of resident cardiac cells from mice subjected to experimental cardiac fibrosis model showed induction of miR-185-5p expression specifically in cardiac fibroblasts. In vitro, augmenting miR-185-5p induced collagen production and profibrotic activation in cardiac fibroblasts, whereas inhibition of miR-185-5p attenuated collagen production. In vivo, targeting miR-185-5p in mice abolished pressure overload induced cardiac interstitial fibrosis. Mechanistically, miR-185-5p targets apelin receptor and inhibits the anti-fibrotic effects of apelin. Finally, analysis of left ventricular tissue from patients with severe cardiomyopathy showed an increase in miR-185-5p expression together with pro-fibrotic TGF-β1 and collagen I. Our data show that miR-185-5p targets apelin receptor and promotes myocardial fibrosis.


Role of amylose and amylopectin in PVA-starch hybrid cryo-gels networks formation from liquid-liquid phase separation.
The role of amylose and amylopectin in the formation of cryogels based on Poly(vinyl alcohol) (PVA) and starch is poorly understood. A systematic investigation of simplified systems containing PVA, amylose, and/or amylopectin constitutes the basis to predict the final features of PVA/starch cryogels by knowing their composition, and the amylose content of the employed raw starches. Pre-gel solutions and cryogels containing PVA/amylose, PVA/amylopectin, and PVA/amylose/amylopectin in variable ratios were investigated employing small-angle X-ray scattering (SAXS), confocal laser scanning microscopy (CLSM), differential scanning calorimetry (DSC), and rheological measurements. The gel fraction (G%) of 23 samples with variable compositions was calculated and plotted to predict the G% (the gel fraction) of any PVA/amylose/amylopectin mixing ratio. We report on how the PVA, amylose, and amylopectin composition affect the properties of the final polymer blend and cryogel formation. In particular, PVA/amylose and PVA/amylopectin show different behaviors with respect to cryogel formation. We show that is possible to predict cryogel formation by using the simple G% parameter for any PVA/amylose/amylopectin mixing ratio, ruling out the starch botanical origin in the gel formation. The results reported in this work represent a simple tool, able to predict the formation of high-quality biobased materials that can replace fully synthetic materials with a significantly positive impact on our ecosystem.


Not only perception but also grasping actions can obey Weber's law.
Weber's law, the principle that the uncertainty of perceptual estimates increases proportionally with object size, is regularly violated when considering the uncertainty of the grip aperture during grasping movements. The origins of this perception-action dissociation are debated and are attributed to various reasons, including different coding of visual size information for perception and action, biomechanical factors, the use of positional information to guide grasping, or, sensorimotor calibration. Here, we contrasted these accounts and compared perceptual and grasping uncertainties by asking people to indicate the visually perceived center of differently sized objects (Perception condition) or to grasp and lift the same objects with the requirement to achieve a balanced lift (Action condition). We found that the variability (uncertainty) of contact positions increased as a function of object size in both perception and action. The adherence of the Action condition to Weber's law and the consequent absence of a perception-action dissociation contradict the predictions based on different coding of visual size information and sensorimotor calibration. These findings provide clear evidence that human perceptual and visuomotor systems rely on the same visual information and suggest that the previously reported violations of Weber's law in grasping movements should be attributed to other factors.


Single chamber atrial pacing: an underused and cost-effective pacing modality in sinus node disease.
To determine the safety and cost effectiveness of single chamber atrial pacing in patients with sinus node disease. Retrospective follow up study. Tertiary referral centre. 81 patients with single chamber atrial pacemakers implanted between 1992 and 1996. The development of high grade atrioventricular block resulting in a further pacemaker procedure. The cost savings of changing our current pacing practice to conform with British Pacing and Electrophysiology Group guidelines. During the follow up period, four patients (5.8%) required a further procedure to upgrade their atrial pacemaker to a dual chamber system owing to the development of high grade atrioventricular block. In 1995 and 1996, 343 pacemakers were implanted in patients with sinus node disease; 19 (5.5%) received single chamber atrial pacemakers and 271 (79%) dual chamber pacemakers. If the current pacing practice was changed so that all patients received single chamber atrial pacemakers, with revision for symptomatic atrioventricular block, savings in excess of 206,000 Pounds would have been made in the two year period. Atrial pacing in patients with sinus node disease is underused. The need for patients to undergo further procedures owing to the development of atrioventricular block is small and significant cost savings could be made by changing pacemaker practice.


A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population.
The P56S mutation in the VAPB gene causes ALS8. Eight families, comprising more than 1,500 individuals of whom about 200 are affected, are now known to carry this mutation. Seven are of Portuguese-Brazilian ancestry and one of African-Brazilian ancestry. Haplotype analysis shows a common founder for all families regardless of ancestry, with a founding event 23 generations ago (95% CI 13-39), consistent with the Portuguese colonization of Brazil.


Risk Factors and In-Hospital Outcomes following Tracheostomy in Infants.
To describe the epidemiology, risk factors, and in-hospital outcomes of tracheostomy in infants in the neonatal intensive care unit. We analyzed electronic medical records from 348 neonatal intensive care units for the period 1997 to 2012, and evaluated the associations among infant demographics, diagnoses, and pretracheostomy cardiopulmonary support with in-hospital mortality. We also determined the trends in use of infant tracheostomy over time. We identified 885 of 887 910 infants (0.1%) who underwent tracheostomy at a median postnatal age of 72 days (IQR, 27-119 days) and a median postmenstrual age of 42 weeks (IQR, 39-46 weeks). The most common diagnoses associated with tracheostomy were bronchopulmonary dysplasia (396 of 885; 45%), other upper airway anomalies (202 of 885; 23%), and laryngeal anomalies (115 of 885; 13%). In-hospital mortality after tracheostomy was 14% (125 of 885). On adjusted analysis, near-term gestational age (GA), small for GA status, pulmonary diagnoses, number of days of forced fraction of inspired oxygen >0.4, and inotropic support before tracheostomy were associated with increased in-hospital mortality. The proportion of infants requiring tracheostomy increased from 0.01% in 1997 to 0.1% in 2005 (P < .001), but has remained stable since. Tracheostomy is not commonly performed in hospitalized infants, but the associated mortality is high. Risk factors for increased in-hospital mortality after tracheostomy include near-term GA, small for GA status, and pulmonary diagnoses.


On the Ca2+ elevation in vascular endothelial cells due to inositol trisphosphate-sensitive store receptors activation: A data-driven modeling approach.
Agonist-induced Ca2+ signaling is essential for the regulation of many vital functions in endothelial cells (ECs). A broad range of stimuli elevate the cytosolic Ca2+ concentration by promoting a pathway mediated by inositol 1,4,5 trisphosphate (IP3) which causes Ca2+ release from intracellular stores. Despite its importance, there are very few studies focusing on the quantification of such dynamics in the vascular endothelium. Here, by using data from isolated ECs, we established a minimalistic modeling framework able to quantitatively capture the main features (averaged over a cell population) of the cytosolic Ca2+ response to different IP3 stimulation levels. A suitable description of Ca2+-regulatory function of inositol 1,4,5 trisphosphate receptors (IP3Rs) and corresponding parameter space are identified by comparing the different model variants against experimental mean population data. The same approach is used to numerically assess the relevance of cytosolic Ca2+ buffering, as well as Ca2+ store IP3-sensitivity in the overall cell dynamics. The variability in the dynamics' features observed across the population can be explained (at least in part) through variation of certain model parameters (such as buffering capacity or Ca2+ store sensitivity to IP3). The results, in terms of experimental fitting and validation, support the proposed minimalistic model as a reference framework for the quantification of the EC Ca2+ dynamics induced by IP3Rs activation.


The in vitro absorption of microfine zinc oxide and titanium dioxide through porcine skin.
Microfine metallic oxides such as titanium dioxide or zinc oxide have been found to be highly protective against harmful UV rays. Because their long-term use could potentially lead to health effects if significant amounts of these microfine metallic oxides would be absorbed through the skin, the in vitro absorption of microfine zinc oxide and titanium oxide in cosmetic formulations through porcine skin was investigated. In the experiments with a microfine zinc oxide formulation, the mean total recoveries of Zn were in the range from 102% to 107% of the total Zn applied. Virtually the total amount of applied Zn was recovered in the first five tape strips. The amounts of Zn found in the skin membrane and the receptor fluid were comparable in untreated, vehicle treated or test substance treated skin preparations. The absorption-time plots from diffusion cells treated with the vehicle did not differ from those treated with the ZnO containing formulation. In the experiments with microfine titanium dioxide formulations T-Lite SF-S and T-Lite SF, mean total recoveries of Ti ranged from 98% to 100% and 86% to 93% of the total Ti applied, respectively. Virtually the total amount of applied Ti could be removed from the skin surface by washing. The amounts of titanium found in the tape strips and skin preparations were in the order of the analytical determination limit. No Ti was found in the receptor fluid at any sampling time. The results show that neither zinc or titanium ions nor microfine zinc oxide or titanium dioxide particles were able to penetrate porcine stratum corneum. Therefore, from the absence of internal exposure we conclude that their use in sunscreens does not pose a health risk.


Soil-applied selenite increases selenium and reduces cadmium in roots of Moringa oleifera.
Deficiency of selenium (Se) will lead to malnutrition and decreased immune function of the body. There is a common phenomenon of Se deficiency in foods. In this study, different concentrations of sodium selenite (Na2SeO3) were applied to Moringa oleifera grownin soil. The purpose was to explore the feasibility of Se biofortification of M. oleifera root. The effect of exogenous Se on the accumulation of Se and cadmium (Cd) in the roots of M. oleifera was studied by inductively coupled plasma mass spectrometry, and the mechanism of exogenous Se on the accumulation of Se and Cd in the roots was studied by Fourier transform infrared spectroscopy (FTIR) combined with principal component analysis and partial least squares regression analysis. The results showed that Na2SeO3 significantly affected the accumulation of Se and Cd in the roots (p < 0.05). The increase in Se was highest when Na2SeO3 was around 4.0 mg/kg, which increased by 315% compared with the control. The decrease in Cd was the lowest when Na2SeO3 was around 2.0 mg/kg, which decreased by 80% compared with the control. The results of FTIR analysis showed that Na2SeO3 treatment changed the carboxylate, phosphate radical, hemicellulose and protein in roots of M. oleifera, while the increase of Se was related to hemicellulose, protein, polysaccharide and lignin, and the decrease of Cd was related to hemicellulose and protein. The results showed that exogenous Se increased the accumulation of Se and inhibited the absorption of Cd. Therefore, the roots of M. oleifera can be used in Se biofortified products.


The association between surgeon subspecialty training and postoperative outcomes following surgery for pelvic organ prolapse.
Symptomatic pelvic organ prolapse is common and affects 25% to 35% of women worldwide. As this growing patient need is being met by surgeons from diverse training backgrounds, it is important to both characterize the differences in surgeon practice patterns and examine postoperative outcomes to ensure optimal patient care. To determine the association between surgeon specialty and postoperative outcomes following surgery for pelvic organ prolapse. This was a retrospective analysis using the American College of Surgeons National Surgical Quality Improvement Program Gynecologic reconstructive surgery targeted database between 2014 and 2018. Pelvic organ prolapse surgeries were identified using Current Procedural Terminology codes, and surgical cases performed by urogynecologists or obstetrician-gynecologists were included for analysis. The primary outcome was any 30-day postoperative complication following prolapse surgery. The secondary outcomes were any major or minor postoperative complications, genitourinary complications, reoperation, or readmission within 30-days following surgery. Descriptive statistics were used to characterize the cohort, and pairwise analyses were used to describe the differences between the cases performed by the surgeon specialties. Multivariable logistic regression was used to control for potential confounders. A total of 3358 women underwent prolapse surgery-68% performed by urogynecologists and 32% by obstetrician-gynecologists. The 30-day postoperative complication rate was higher for surgeries performed by obstetrician-gynecologists than for surgeries performed by urogynecologists (10.7% vs 7.0%, respectively; P<.001). There was no difference in the readmission rates between the 2 groups (2.1% vs 2.0%; P=1.000). However, the reoperation rates were higher for surgeries performed by obstetrician-gynecologists (1.8% vs 1.0%; P=.040). In a multivariable logistic regression model controlling for age, body mass index, American Society of Anesthesiology class, smoking, and type of concomitant surgery (hysterectomy, apical suspension, other prolapse surgery, obliterative procedure, or sling), prolapse surgery performed by a urogynecologist remained associated with nearly 40% lower odds of any 30-day postoperative complication (adjusted odds ratio, 0.62; 95% confidence interval, 0.48-0.80). Prolapse surgery performed by a urogynecologist is associated with lower odds of any 30-day postoperative complication than that performed by an obstetrician-gynecologist.


Hormetic dose responses induced by nickel oxide nanoparticles (NiONPs) on growth, biochemical, and antioxidant defense systems of Dracocephalum kotschyi.
The application of nickel oxide nanoparticles (NiONPs) in various fields leads to their release into soil and water and, consequently, interaction with plants. Unlike its bulk counterpart, the phytotoxic potential of NiONPs is relatively less studied, particularly in a hormesis framework. Hormesis is an interesting phenomenon characterized by low-dose stimulation and high-dose inhibition. Therefore, this study demonstrates the stimulatory and inhibitory effects of NiONPs on Dracocephalum kotschyi Boiss as a medicinal plant cultivated in a pot experiment carried out in a greenhouse for 3 weeks. High bioaccumulation of nickel (Ni) in roots of treated plants relative to shoots indicates higher oxidative damage. NiONPs induced hormetic effects on photosynthetic pigments, as at low concentration of 50 mg/L stimulated chlorophyll (2.8-46.7%), carotenoid (16%), and anthocyanin (5.9%) contents and at higher concentrations inhibited the content of these pigments. A hormetic response was observed in growth parameters, i.e., NiONPs induced shoot height (7.2%) and weight (33%) at 100 mg/L, while inhibited shoot and root length (14.5-16.1% and 28.7-42.7%) and weight (46.8-48.1% and 37-40.6%), respectively, at 1000 and 2500 mg/L. The treated plants declined the toxic effects and oxidative stress caused by NiONPs by activating non-enzymatic antioxidants (phenolic compounds and proline) and enzymatic antioxidants, i.e., increasing the levels of SOD, POD, CAT, and APX. Therefore, the present study investigated for the first time the different mechanisms and responses of D. kotschyi plants to NiONPs in a wide range of concentrations. The results suggest that NiONPs may act as an elicitor at lower concentrations in medicinal plants according to specific conditions. However, these NPs at higher concentrations induce oxidative stress and harmful effects on plants, so their use poses serious risks to human health and the environment.


Cross-species analysis of transcriptome emphasizes a critical role of TNF-α in mediating MAP2K7/AKT2 signaling in zearalenone-induced apoptosis.
Zearalenone (ZEN) is a widespread and transgenerational toxicant that can cause serious reproductive health risks, which poses a potential threat to global agricultural production and human health; its estrogenic activity can lead to reproductive toxicity through the induction of granulosa cell apoptosis. Herein, comparative transcriptome analysis, single-cell transcriptome analysis, and weighted gene co-expression network analysis (WGCNA) combined with gene knockout in vivo and RNA interference in vitro were used to comprehensively describe the damage caused by ZEN exposure on ovarian granulosa cells. Comparative transcriptome analysis and WGCNA suggested that the tumor necrosis factor (TNF)-α-mediated mitogen-activated protein kinase 7 (MAP2K7)/ AKT serine/threonine kinase 2 (AKT2) axis was disordered after ZEN exposure in porcine granulosa cells (pGCs) and mouse granulosa cells (mGCs). In vivo gene knockout and in vitro RNA interference verified that TNF-α-mediated MAP2K7/AKT2 was the guiding signal in ZEN-induced apoptosis in pGCs and mGCs. Moreover, single-cell transcriptome analysis showed that ZEN exposure could induce changes in the TNF signaling pathway in offspring. Overall, we concluded that the TNF-α-mediated MAP2K7/AKT2 axis was the main signaling pathway of ZEN-induced apoptosis in pGCs and mGCs. This work provides new insights into the mechanism of ZEN toxicity and provides new potential therapeutic targets for the loss of livestock and human reproductive health caused by ZEN.


Computer-assisted individualized lidocaine dosage: clinical evaluation and comparison with physician performance.
The performance of a computerized dosing aid in achieving a target serum concentration of lidocaine in the middle of the recommended therapeutic range (3.5 mg/L) was evaluated in 63 patients treated for acute ventricular arrhythmias. In all patients a serum concentration measurement was obtained shortly after starting lidocaine infusion. In 22 patients a microcomputer program based on a Bayesian forecasting technique was used for dosing recommendations, whereas in 41 the serum concentration was interpreted and the dose was adjusted by the unaided physician. Both groups were similar with respect to the average concentration achieved (control: 3.8 +/- 1.13 [SD] mg/L, computer-aided: 3.5 +/- 0.59 mg/L). However, the interindividual variability was significantly larger in the control group (95% confidence interval: 1.5 to 6.1 mg/L vs 2.3 to 4.7 mg/L [p less than 0.01]). Nine of the 41 patients in the control group had a lidocaine concentration outside the recommended therapeutic range of 2 to 5 mg/L compared to only 1 of 22 in the computer-aided group. Lidocaine concentrations greater than 2 mg/L were associated with significantly more effective suppression of ventricular arrhythmias (p less than 0.05). The results show that Bayesian forecasting outperforms the physician in early adjustment of lidocaine dosage based on serum concentration measurements.


Neurologic recovery after therapeutic hypothermia in patients with post-cardiac arrest myoclonus.
Early myoclonus in comatose survivors of cardiac arrest, even when it is not myoclonic status epilepticus (MSE), is considered a sign of severe global brain ischemia and has been associated with high rates of mortality and poor neurologic outcomes. We report on three survivors of primary circulatory cardiac arrests who had good neurologic outcomes (two patients with a CPC score=1 and one patient with a CPC score=2) after mild therapeutic hypothermia, despite exhibiting massive myoclonus within the first 4h after return of spontaneous circulation. The concept that early myoclonus heralds a uniformly poor prognosis may need to be reconsidered in the era of post-cardiac arrest mild therapeutic hypothermia.


Phosphorylation of the insulin receptor by casein kinase I.
Insulin receptor was examined as a substrate for the multipotential protein kinase casein kinase I. Casein kinase I phosphorylated partially purified insulin receptor from human placenta as shown by immunoprecipitation of the complex with antiserum to the insulin receptor. Analysis of the phosphorylated complex by polyacrylamide gel electrophoresis under nonreducing conditions showed a major phosphorylated band at the position of the alpha 2 beta 2 complex. When the phosphorylated receptor was analyzed on polyacrylamide gels under reducing conditions, two phosphorylated bands, Mr 95,000 and Mr 135,000, were observed which corresponded to the alpha and beta subunits. The majority of the phosphate was associated with the beta subunit with minor phosphorylation of the alpha subunit. Phosphoamino acid analysis revealed that casein kinase I phosphorylated only seryl residues. The autophosphorylated alpha 2 beta 2 receptor purified by affinity chromatography on immobilized O-phosphotyrosyl binding antibody was also a substrate for casein kinase I. Reduction of the phosphorylated alpha 2 beta 2 receptor indicated that casein kinase I incorporated phosphate into seryl residues only in the beta subunit.


Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404.
Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (Mpro), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 Mpro and SARS-CoV-2 Mpro and of rupintrivir in complex with SARS-CoV-2 Mpro were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC50 values of 47 μM and 101 μM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 Mpro. Equivalent IC50 values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 μM vs. 66 μM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay.


Applications of capillary electrophoresis with chemiluminescence detection in clinical, environmental and food analysis. A review.
This paper reviews the latest developments and analytical applications of chemiluminescence detection coupled to capillary electrophoresis (CE-CL). Different sections considering the most common CL systems have been included, such as the tris(2,2'-bipyridine)ruthenium(II) system, the luminol and acridinium derivative reactions, the peroxyoxalate CL or direct oxidations. Improvements in instrumental designs, new strategies for improving both resolution and sensitivity, and applications in different fields such as clinical, pharmaceutical, environmental and food analysis have been included. This review covers the literature from 2010 to 2015.


Adverse influence of younger age on outcome in patients with non-small cell lung carcinoma (NSCLC) treated with radiation therapy (RT) alone.
Treatment outcome of 63 patients younger than 50 years of age initiated on a course of once-daily definitive radiation therapy without concurrent or preirradiation chemotherapy for clinical Stages I-III unresected non-small cell lung carcinoma from 1978 to 1988 was compared to the outcome of 695 patients over the age of 50. Follow-up ranged from 24-110 months with follow-up until death in 88% of patients. The actuarial overall survival rate for all patients was 22% at 2 years with a median survival time of 11.5 months. Patients less than 50 and greater than or equal to 50 years old were similar in male:female ratio, distribution of histologic subtype, performance status, and extent of weight loss. Poorly differentiated histologic grade was more prevalent among the younger patients (59% vs 41%, p = .005). Ninety-four percent of younger patients and 86% of older patients had clinical stage III disease (p = NS). Survival was significantly worse for patients who were younger than 50 years old (p = .05), with a median survival time of 7.8 months. Median survival time for those patients 50 years of age or older was 12.4 months. Poorer survival outcome among young patients was most pronounced among patients with unfavorable characteristics of poor performance status (greater than or equal to 2) or weight loss (greater than 5%) (p = .002). Distant failure (p = .029) and brain failure (p = .003) as initial site of relapse was more common among younger patients. Among young patients, poor histologic grade was associated with both distant failure (p = .003) and brain metastasis (p = .002). The difference in distribution of histologic grade, incidence of distant failure, particularly in the brain, and poorer survival outcome among patients less than 50 may be indicative of more aggressive tumor behavior in the younger patients. These results indicate that patients less than 50 may require alternate treatment strategies. Age should be considered a stratification variable in non-operative randomized trials of non-small cell lung carcinoma which include patients with non-favorable characteristics.


ZIF-67-derived N-doped double layer carbon cage as efficient catalyst for oxygen reduction reaction.
The slow kinetic of oxygen reduction reaction (ORR) hampers the practical application of energy conversion devices, such as fuel cells, metal-air batteries. Here, an efficient ORR electrocatalyst consists of Co, Ni co-decorated nitrogen-doped double shell hollow carbon cage (Ni-Co@NHC) was fabricated by pyrolyzing Ni-doped polydopamine wrapped ZIF-67. During the preparation, polydopamine served as a protective layer can effectively prevent the aggregation of Co and Ni nanoparticles during the pyrolysis process, and at the same time forming a carbon layer to grow a double layer carbon cage. This unique hollow structure endows the catalyst with a high specific surface area as well as more exposed active sites. Also benefited from the synergistic effect between Ni and Co nanoparticles, the Ni-Co@NHC catalyst leads to an outstanding ORR performance of half-wave potential (E1/2, 0.862 V), outperforms that of commercial Pt/C catalyst. Additionally, when Ni-Co@NHC was used in the cathode for the zinc-air battery, the cell exhibits high power density (108 mW cm-2) and high specific capacity (806 mAh g-1) at 20 mA cm-2outperforming Pt/C. This work offers a promising design strategy for the development of high-performance ORR electrocatalysts.


Injury occurrence and mood states during a desert ultramarathon.
To describe injuries and illnesses presented and profile mood states and sleep patterns during a desert environment ultramarathon. Prospective study gathering data on mood states and injury patterns. : Gobi Desert, Mongolia. Eleven male competitors (mean mass, 83.7 ± 7.1 kg; body mass index, 24 ± 1.79 kg/m; age, 33 ± 11 years). Injuries were clinically assessed and recorded each day. Mood state was assessed using the Brunel Mood Scale. All subjects presented with abrasion injuries, dehydration, and heat stress. Vigor decreased over the first 6 days while fatigue increased (P < 0.05). Fatigue and vigor recovered on the final morning. The observed recovery was set against increasing levels of depression, tension, and confusion, which peaked at days 5/6 but returned to day 1 levels on the 7th day morning (P < 0.05). Mean sleep duration (6:17 ± 00:48 hours:minutes; lowest on day 6, 4:43 ± 01:54 hours:minutes) did not vary significantly across the 7 days but did correlate with mood alterations (P < 0.05). Increased anger and fatigue correlated strongly with sleep disruption (r = 0.736 and 0.768, respectively). Vigor and depression displayed a moderately strong correlation to sleep (r = 0.564 and -0.530). Injury patterns were similar to those reported in other adventure/ultradistance events. Consistent with previous work, data show increased fatigue and reduced vigor in response to an arduous physical challenge.


Discriminative and Geometry-Preserving Adaptive Graph Embedding for dimensionality reduction.
Learning graph embeddings for high-dimensional data is an important technology for dimensionality reduction. The learning process is expected to preserve the discriminative and geometric information of high-dimensional data in a new low-dimensional subspace via either manual or automatic graph construction. Although both manual and automatic graph constructions can capture the geometry and discrimination of data to a certain degree, they working alone cannot fully explore the underlying data structure. To learn and preserve more discriminative and geometric information of the high-dimensional data in the low-dimensional subspace as much as possible, we develop a novel Discriminative and Geometry-Preserving Adaptive Graph Embedding (DGPAGE). It systematically integrates manual and adaptive graph constructions in one unified graph embedding framework, which is able to effectively inject the essential information of data involved in predefined graphs into the learning of an adaptive graph, in order to achieve both adaptability and specificity of data. Learning the adaptive graph jointly with the optimized projections, DGPAGE can generate an embedded subspace that has better pattern discrimination for image classification. Results derived from extensive experiments on image data sets have shown that DGPAGE outperforms the state-of-the-art graph-based dimensionality reduction methods. The ablation studies show that it is beneficial to have an integrated framework, like DGPAGE, that brings together the advantages of manual/adaptive graph construction.


Leukoencephalopathies and metabolic diseases.
Leukoencephalopathies and metabolic diseases comprise a great number of heterogeneous disorders. Diagnosis of these disorders may be challenging at times, requiring sophisticated laboratory investigations. Magnetic resonance imaging (MRI) is useful in supporting diagnosis even though it bears problems of specificity. Quantitative MRI techniques, providing information on cerebral metabolites and tissue microstructure within and outside visible lesions, have proven to be important for understanding the pathogenic mechanisms leading to tissue damage and monitoring disease evolution and response to treatment. This has prompted a more extensive use of these techniques in the clinical setting as a complement to the traditional MRI.


[A woman with a painful swelling in the groin: the cyst of Nuck, a forgotten diagnosis].
The cyst of Nuck is a swelling in the inguinal canal caused by a hydrocele of the round ligament. This abnormality is a result of the absence or incomplete obliteration of the processus vaginalis during foetal development. A 44-year-old woman had suffered from a painful swelling in her right groin for 4 years. Extensive imaging and multiple punctures of the supposed cyst had no lasting results. Eventually, the swelling was identified as a cyst of Nuck, which was confirmed on operative exploration. After excision, the patient was relieved of all her symptoms. The cyst of Nuck is a clinical diagnosis. Imaging the swelling may give a misleading result and cause a delay in treatment.


Pro-inflammatory M1/Th1 type immune network and increased expression of TSG-6 in the eutopic endometrium from women with endometriosis.
The study aimed to explore the type 1 and type 2 cytokines expression in the endometrium from women affected by endometriosis compared to controls. The expression of TSG-6, a multifunctional protein involved in several inflammatory disease, was also evaluated. Study Design SETTING: Experimental clinical study. 10 patients affected by endometriosis and 11 controls. Patients underwent to an ultrasound transvaginal examination and a diagnostic hysteroscopy in order to exclude any uterine abnormality. All patients underwent endometrial biopsy using a Novak's curette. The endometrial expression of type 1 (IL- 1 β TNF-α, IL-8) and type 2 (IL-10) cytokines, and of TSG-6 was evaluated by immunohistochemistry and by real time PCR. The expression of TSG-6 was confirmed by western blot. Results of PCR analysis and of immunohistochemistry revealed an increased expression of IL-1β, TNF-α, IL-8 and of TSG-6 in the endometrium of endometriosic patients. IL-10 expression did not show any difference. An increased expression of pro-inflammatory type 1 cytokines was demonstrated in the endometrium from endometriosic patients, suggesting an endometrial environment harmful for implantation due to the prevalence of Th1 related immunity. An increased expression of TSG-6 was also demonstrated for the first time. Our findings concur to better define the inflammatory imbalance and the abnormal endometrial receptivity, reported in literature, of the eutopic endometrium of women affected by endometriosis.


Long-term safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis: an integrated analysis from 11 clinical trials.
Psoriasis in many patients is a chronic and recalcitrant disease that requires long-term treatment, reinforcing the importance of long-term safety data. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, is approved for treating patients with moderate-to-severe plaque psoriasis. To determine long-term safety of ixekizumab in psoriasis. Integrated safety data are presented from 12-week induction period, 12-60-week maintenance period, and from all ixekizumab-treated patients from 11 clinical studies. Exposure-adjusted incidence rates (IRs) per 100 patient-years are reported. Overall, 5689 patients accounted for 12 061.5 patient-years of ixekizumab exposure from 11 studies. Over 156 weeks, a total of 83.9% (n = 4775) of patients reported treatment-emergent adverse events (AEs). Most opportunistic infections (IR [95% confidence interval; CI] 1.8 [1.6, 2.1]) reported were mucocutaneous candidiasis. The IR (95% CI) for oral Candida infection was 0.9 (0.8, 1.1). There was no trend of increase in IR of AEs of special interest. Serious AEs were reported in 11.8% of patients; death occurred in 0.4% (n = 23) of patients. The 3-year, long-term maintenance treatment with ixekizumab did not show any new safety signals in patients with moderate-to-severe plaque psoriasis.


A cross talk between cellular signalling and cellular redox state during heat-induced apoptosis in a rat histiocytoma.
Increasing evidence provides support for oxidative stress to be closely linked to apoptosis. Reactive oxygen species (ROS) are thought to be involved in many forms of programmed cell death. Though heat shock is a universal phenomenon, BC-8, a macrophage-like cell line failed to mount a typical heat shock response. In the absence of heat shock proteins and functional p53, BC-8 cells undergo apoptosis through CD95 signaling. In the present study, we have investigated the role of ROS in the regulation of apoptosis in these cells. We show that cells transfected with hsp70 and functional p53 are resistant to heat-induced apoptosis through inhibition of CD95 expression and ROS induction. Furthermore, apoptosis in BC-8 cells resulted in two bursts of ROS generation, one correlated with heat stress and intracellular depletion of GSH and the other with Bax overexpression and cytochrome c release. Antioxidants could not protect these cells from heat-induced apoptosis and the death pathway seems to be dependent on initial signaling cascade subsequently altering the intracellular redox. Hence, our data suggest that ROS generation in BC-8 cells upon heat shock is facultative but not obligatory for apoptosis.


Congenital transmission of Trypanosoma congolense in mice.
Pregnant mice were infected with a strain of T. congolense which produces a chronic infection, to determine if congenital infection can occur. Some of the mice were killed before delivery and tissues of foetuses injected into clean male mice. Other mothers were allowed to deliver and the tissues of some of the 1-day-old young inoculated into male mice while the remaining members of each litter were suckled by the infected mother until weaning. Some but not all males infected from foetuses and 1-day-old young became infected, while the litter-mates suckled normally by their mothers did not show any infection. It seems that T. congolense, though not commonly found in tissues of the host, can cross the placental barrier and infect the foetus, but that young suckled by infected mothers may be protected from infection.


Arginine Methyltransferase PRMT7 Deregulates Expression of RUNX1 Target Genes in T-Cell Acute Lymphoblastic Leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with no well-established prognostic biomarkers. We examined the expression of protein arginine methyltransferases across hematological malignancies and discovered high levels of PRMT7 mRNA in T-ALL, particularly in the mature subtypes of T-ALL. The genetic deletion of PRMT7 by CRISPR-Cas9 reduced the colony formation of T-ALL cells and changed arginine monomethylation patterns in protein complexes associated with the RNA and DNA processing and the T-ALL pathogenesis. Among them was RUNX1, whose target gene expression was consequently deregulated. These results suggest that PRMT7 plays an active role in the pathogenesis of T-ALL.


Genotype 4 Hepatitis E virus replicates in the placenta, causes severe histopathological damage, and vertically transmits to fetuses.
Hepatitis E virus (HEV) infection in pregnant women causes adverse pregnancy outcomes, including maternal death, premature delivery, stillbirth, and fetal infection. However, the pathogenesis of maternal and fetal HEV infection is unclear. Placenta and placental appendixes were collected from HEV-4 infected pregnant women to explore the vertical transmission of HEV from mothers to fetuses. HEV-4 replicated in the placenta, placental membrane, and umbilical cord and was vertically transmitted from mothers to fetuses. HEV-4 placental infection resulted in serious histopathological damage, such as fibrosis and calcification, and severe inflammatory responses. Adverse maternal outcomes were observed in 38.5% of HEV-4 infected pregnant women. The distinct cytokine/chemokine expression patterns of HEV-infected pregnant women and nonpregnant women may contribute to the adverse pregnancy outcomes. Furthermore, the impaired maternal and fetal innate immune responses against HEV-4 facilitated viral replication during pregnancy. HEV-4 replicates in the placenta and is vertically transmitted from mothers to fetuses, causing severe histopathological damage.


Microbiome of the Aerodigestive Tract in Health and Esophageal Disease.
The diverse human gut microbiome is comprised of approximately 40 trillion microorganisms representing up to 1000 different bacterial species. The human microbiome plays a critical role in gut epithelial health and disease susceptibility. While the interaction between gut microbiome and gastrointestinal pathology is increasingly understood, less is known about the interaction between the microbiome and the aerodigestive tract. This review of the microbiome of the aerodigestive tract in health, and alterations in microbiome across esophageal pathologies highlights important findings and areas for future research. First, microbiome profiles are distinct along the aerodigestive tract, spanning the oral cavity to the stomach. In patients with reflux-related disease such as gastro-esophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma, investigators have observed an overall increase in gram negative bacteria in the esophageal microbiome compared to healthy individuals. However, whether differences in microbiome promote disease development, or if these shifts are a consequence of disease remains unknown. Interestingly, use of proton pump inhibitor therapy is also associated with shifts in the microbiome, with distinct shifts and patterns along the aerodigestive tract. The relationship between the human gut microbiome and esophageal pathology is a ripe area for investigation, and further understanding of these pathways may promote development of novel targets in prevention and therapy for esophageal diseases.


Data trimming, nuclear emissions, and climate change.
Ethics requires good science. Many scientists, government leaders, and industry representatives support tripling of global-nuclear-energy capacity on the grounds that nuclear fission is "carbon free" and "releases no greenhouse gases." However, such claims are scientifically questionable (and thus likely to lead to ethically questionable energy choices) for at least 3 reasons. (i) They rely on trimming the data on nuclear greenhouse-gas emissions (GHGE), perhaps in part because flawed Kyoto Protocol conventions require no full nuclear-fuel-cycle assessment of carbon content. (ii) They underestimate nuclear-fuel-cycle releases by erroneously assuming that mostly high-grade uranium ore, with much lower emissions, is used. (iii) They inconsistently compare nuclear-related GHGE only to those from fossil fuels, rather than to those from the best GHG-avoiding energy technologies. Once scientists take account of (i)-(iii), it is possible to show that although the nuclear fuel cycle releases (per kWh) much fewer GHG than coal and oil, nevertheless it releases far more GHG than wind and solar-photovoltaic. Although there may be other, ethical, reasons to support nuclear tripling, reducing or avoiding GHG does not appear to be one of them.


T-shirt size as a classification for body habitus in computed tomography (CT) and development of size-based dose reference levels for different indications.
To examine the impact of patient size on dose indices and develop size-based reference levels (50th and 75th percentiles) for 20 body CT exams for routine and organ-specific clinical indications. Based on effective diameter estimated from adult body CT, each acquisition was classified into T-shirt size as XXS, XS, S, M, L, XL, and XXL. Radiation dose indices for each size and each exam type were correlated. About 0.93 million CT exams from 256 CT facilities in the United States were analysed. Taking T-shirt size M as a reference, the CTDIvol for other sizes were: XXS (∼60%), XS (∼65%), S (∼75%), L (∼130%), XL (∼165%), XXL (∼210%), or grossly small patients received about 60% of the dose as compared to M sized patients and XXL required doubling the dose. Taking ratio of the dose indices of the largest to smallest size, it was evident that SSDE variation was much less (about 50%) than that in CTDIvol, but there was still nearly 40 to 220% variation in SSDE across the range of t-shirt sizes. The 50th and 75th percentile values are presented for CTDIvol, SSDE and DLP for each of the 20 CT exams and for each of the seven T-shirt sizes. A novel approach expressing body habitus in terms of T-shirt size is not only simple and intuitive, but it also provides a tool to have a perception of differences in dose metrices among patients of different body build.


The Trabecular Bone Score (TBS) Complements DXA and the FRAX as a Fracture Risk Assessment Tool in Routine Clinical Practice.
There is an increasing body of evidence that the trabecular bone score (TBS), a surrogate of bone microarchitecture extracted from spine DXA, could play an important role in the management of patients with osteoporosis or at risk of fracture. The current paper reviews this published body of scientific literature on TBS and answers the most relevant clinical questions. TBS has repeatedly been proven to be predictive of fragility fractures, current and future, and this is largely independent of BMD, CRF, and the FRAX, and when used in conjunction with any one of these measures, it consistently enhances their accuracy. There also is a growing body of evidence indicating that the TBS has particular advantages over BMD for specific causes of increased fracture risk, like chronic corticosteroid excess, type-2 diabetes, and chronic kidney disease, and patients being treated with anti-aromatase and primary hyperparathyroidism, conditions wherein BMD readings are often misleading. TBS enhances performance of the FRAX tool, where its greatest utility appears to lie in its ability to accurately classify those patients whose BMD level lies close to the intervention threshold, aiding in decisions on whether treatment is warranted or not. Furthermore, TBS has also particular advantages over BMD in secondary osteoporosis. While the role of TBS with monitoring could be important as the different molecules impact logically TBS to various degrees, large clinical trials are still needed.


Ovine cutaneous myiasis: effects on production and control.
Ovine cutaneous myiasis ('fly strike') remains a major sheep health problem in many areas of the world. Myiasis risk is the result of a complex interaction of factors, such as fly and host abundance, host susceptibility, climate and, critically, husbandry and management strategies, all of which change seasonally in space and time. Given the complexity of the interacting factors, changes in myiasis incidence are hard to predict, as accordingly are the optimal husbandry responses required to manage the problem. Here the important risk factors are briefly reviewed and the future changes in myiasis incidence under conditions of anticipated climate change are considered. It is concluded that future work should focus in particular on evaluating the optimum use of integrated management, such as the combination of insecticide and trap use, in different environments under a range of farming regimes.


Acrometastasis: The Tip of the Iceberg of Metastatic Disease from Thyroid Cancer. Two Cases Report.
Acrometastasis, especially in the hands and fingers, is a rare clinical condition resulting from primary cancers such as lung, breast, kidney, and, rarely, thyroid cancer. Acrometastasis tends to be the tip of the iceberg in patients with extensive systemic disease, which could be regional, pulmonary, skeletal, neurological, or all of them combined. Even though these tumors are clearly visible and symptomatic, the diagnosis is usually misleading because such distal metastatic disease is not thought of at first. In general, systemic treatments should be given to any patient presenting digital acrometastasis. We describe two cases of papillary thyroid carcinoma and digital acrometastasis as a sign of advanced disease.


Prevalence of anaplasmosis and babesiosis in N'Dama cattle of the Gambia.
Sera from 184 N'Dama cattle randomly selected and averaging 2-7 years of age were tested for the presence of specific antibodies to Anaplasma marginale, Babesia bovis and B. bigemina, using one or more serological tests including complement fixation, rapid card agglutination and indirect fluorescent antibody (IFA). Tests for A. marginale and B. bovis were essentially negative. Utilising the IFA test 65% of the sera tested were positive for B. bigemina. Three randomly selected two-year-old N'Dama bulls were splenectomised. All three showed an acute recurrence of a B. bigemina parasitaemia. Two died following typical signs of acute babesiosis and a third recovered following diminazene therapy. No evidence of either B. bovis or A. marginale recrudescence was observed in the single surviving bull. Babesia bigemina appears endemic in the N'Dama cattle of The Gambia but no confirmed serological or clinical evidence of B. bovis or A. marginale was observed.


Relationship of serum TWEAK level to cytokine level, disease activity, and response to anti-TNF treatment in patients with rheumatoid arthritis.
To determine the serum concentration of tumour necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) in patients with rheumatoid arthritis (RA) and to investigate the relationship between TWEAK level and disease activity, proinflammatory cytokine levels, and response to anti-TNF treatment. Serum samples from 40 patients with RA, 40 patients with ankylosing spondylitis (AS), and 40 healthy subjects were collected. Serum samples from 26 patients with RA who received etanercept treatment were also collected in the 12th week of etanercept therapy. Serum TWEAK, TNFalpha, and interleukin (IL)-6 levels were determined by enzyme-linked immunosorbent assay (ELISA), and disease activity of RA was assessed according to the 28-joint count Disease Activity Score (DAS28). Patients with RA had significantly higher serum levels of TWEAK, TNFalpha, and IL-6 compared with controls (p<0.05). Patients with AS also had significantly higher serum levels of TNFalpha and IL-6 (p<0.05), but their serum TWEAK levels were not different from those of the controls. In patients with RA, serum TWEAK levels correlated with DAS28 (r(2) = 0.452, p = 0.012) and TNFalpha levels (r(2) = 0.653, p<0.001) but not with IL-6 levels. Among RA patients who were treated with etanercept, responders showed a significant decrease in serum TWEAK levels at the 12th week of treatment, whereas TWEAK levels in nonresponders were not different from their baseline levels. Serum levels of TWEAK were significantly elevated in patients with RA, and reflected disease activity and short-term response to etanercept treatment.


Immunoglobulin G and its function in the human respiratory tract.
Immunoglobulin G--which can be subdivided into four classes, each with different functional characteristics--is an important component of the host defense system of the respiratory tract. An excessive amount can be produced or can accumulate after airway irritation (exposure to cigarette smoke) or from immunologic stimulus of B-lymphocyte-plasma cells in types of hypersensitivity and interstitial lung diseases. Specific antibody activity can be identified in organic dust-induced hypersensitivity pneumonitis and asthma that contributes to disease pathogenesis. The availability of opsonic antimicrobial antibodies is essential for optimal function of phagocytes in uptake and containment of bacteria. With an absolute or functional deficiency of IgG, recurrent and chronic types of sinopulmonary infections occur. These extremes of IgG availability, either high levels (presumably excessive) or deficient, are discussed in this review.


Factors affecting xylanase functionality in the degradation of arabinoxylans.
Endo-beta-1,4-xylanases are key enzymes in the degradation of arabinoxylans, the main non-starch polysaccharides from grain cell walls. Due to the heterogeneity of arabinoxylans, xylanases with different characteristics are required in industrial applications but the choice of the enzyme is still largely empirical. Although the classification into glycoside hydrolase families greatly helped to derive mechanistic information on the catalytic and substrate specificity of xylanases, other factors e.g. their sensitivity to endogenous inhibitors, the presence of carbohydrate-binding module(s) and their degree of selectivity towards soluble versus insoluble substrate may play a role in determining the functionality of these enzymes in the degradation of arabinoxylans.


Understanding association of spleen system with earth on traditional Chinese medicine theory.
The association of spleen system including both spleen and stomach with earth, one of the five elements, is a part of the theory of five elements. Practitioners of Traditional Chinese Medicine (TCM) used the theory as a reasoning tool to illustrate the Zang-Fu organs' physiological functions and the interaction among them. The exploration of how the theory of that spleen system is associated with earth was created may provide insights into how five-element theory is applied to TCM practice. Using analogism as a method to explore the relationship between earth and spleen system in TCM. Chinese ancestors experienced and observed the features of earth from agricultural practice and used the knowledge for the explanation of spleen system functions including physiological functions, pathological characteristics and for the treatment of related illnesses. The theory of the five elements in TCM is a kind of metaphor, which depends on observation and exploration of the natural world and experience of human beings.


Asymmetric Epoxidation and Sulfoxidation Catalyzed by a New Styrene Monooxygenase from Bradyrhizobium.
Asymmetric epoxidation catalyzed with styrene monooxygenase (SMO) is a powerful enzymatic process producing enantiopure styrene epoxide derivatives. To establish a more diversified reservoir of SMOs, a new SMO from Bradyrhizobium sp. ORS 375, named BrSMO, was mined from the database and characterized. BrSMO was constituted of an epoxygenase component of 415 amino acid residues and an NADH-dependent flavin reductase component of 175 residues. BrSMO catalyzed the epoxidation of styrene and 7 more styrene derivatives, yielding the corresponding (S)-epoxides with excellent enantiomeric excesses (95- > 99% ee), with the highest activity achieved for styrene. BrSMO also catalyzed the asymmetric sulfoxidation of 7 sulfides, producing the corresponding (R)-sulfoxides (20-90% ee) with good yields.


Modified Diacetylmonoxime-Thiosemicarbazide Detection Protocol for Accurate Quantification of Urea.
Renewable photo-/electrocatalytic coreduction of CO2 and nitrate to urea is a promising method for high-value utilization of CO2 . However, because of the low yields of the urea synthesis by photo-/electrocatalysis process, the accurate quantification of low concentration urea is challenging. The traditional diacetylmonoxime-thiosemicarbazide (DAMO-TSC) method for urea detection has a high limit of quantification and accuracy, but it is easily affected by NO2 - in the solution, which limits its application scope. Thus, the DAMO-TSC method urgently requires a more rigorous design to eliminate the effects of NO2 - and accurately quantify urea in nitrate systems. Herein, a modified DAMO-TSC method is reported, which consumes NO2 - in solution through a nitrogen release reaction; hence, the remaining products do not affect the accuracy of urea detection. The results of detecting urea solutions with different NO2 - concentrations (within 30 ppm) show that the improved method can effectively control the error of urea detection within 3%.


Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats.
The mechanisms responsible for impaired regenerative ability after hepatic resection observed in chronic liver disease are not fully understood. We have examined the relationships between an altered expression of cell cycle-related proteins in regenerating liver after partial hepatectomy and the impaired regenerative process observed in fibrotic and cirrhotic rats. We performed 70% partial hepatectomy in both control and porcine serum-induced fibrotic rats, and 45% partial hepatectomy in thioacetamide-induced cirrhotic rats because of the high mortality associated with 70% partial hepatectomy. Liver regeneration was monitored by proliferating cell nuclear antigen labeling index and the expression of G1 regulatory cell cycle-related proteins was determined by immunoblot analysis. Compared with controls, hepatocyte DNA synthesis, and induction of cyclin D1 and p21(CIP1) proteins were delayed but not suppressed in porcine serum-induced fibrotic rats and markedly inhibited in thioacetamide-induced cirrhotic rats. p27(KIP1) protein levels were unaffected by partial hepatectomy and did not differ among all three groups. Two distinct rat models of liver fibrosis and cirrhosis showed markedly different proliferative responses after partial hepatectomy. The delay or failure of cyclin D1 induction, but not the increase of p21(CIP1) or p27(KIP1) might be responsible for their impaired liver regeneration.


The short-term activation of a rolipram-sensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL-5 cells is mediated by a cAMP-dependent phosphorylation.
To elucidate the mechanism causing the transient accumulation of intracellular cAMP in the FRTL-5 thyroid cell line, the short-term effect of thyroid-stimulating hormone (TSH) on phosphodiesterase (PDE) activity was studied. Together with an increase in cAMP levels, TSH produced a significant increase in total PDE activity as early as 3 min, with a maximal stimulation reached after 15 min. This short-term increase in PDE activity was dependent on the TSH concentration (ED50 = 4 x 10(-11) M TSH). Forskolin and dibutyryl cAMP produced an even larger stimulation than that produced by TSH, suggesting that the effect of TSH is mediated by cAMP. To determine the properties of the PDE forms activated by TSH, antibodies specific for the cAMP-PDEs were used to immunoprecipitate the PDEs present in control cells, and cells incubated for 15 min in the presence of 10 nM TSH. Comparison of the activity recovered in the immunoprecipitation pellets demonstrated that TSH produced more than a 2.5-fold increase in the cAMP-PDE form(s) recognized by this antibody. Conversely, the activity remaining in the supernatants was not affected by the TSH treatment. Most of the activity recovered in the immunoprecipitation pellets (90%) was inhibited by 10 microM Rolipram, an inhibitor specific for the high affinity cAMP-PDEs. No TSH stimulation of the Rolipram-insensitive PDE activity could be observed under these conditions. Western blot analyses with two different cAMP-PDE specific antibodies showed that a 15-min stimulation with TSH induced the appearance of a new band with electrophoretic mobility slower than the polypeptide present in unstimulated cells. The appearance of this band did not require ongoing protein synthesis because it occurred in the presence of cycloheximide. Metabolic [32P]orthophosphate labeling of intact FRTL-5 cells indicated that the TSH treatment caused an increased 32P incorporation into a polypeptide that co-purified with the stimulated PDE activity and had an electrophoretic mobility identical to that of the cAMP-PDE. Okadaic acid, a potent inhibitor of protein phosphatase 1 and protein phosphatase 2A, elicited a potentiation of the TSH-stimulated PDE activity. The stimulating of a PDE with the same immunological properties and Rolipram sensitivity as the cAMP-PDE stimulated by TSH in the intact cells was reproduced, in a cell-free system, by incubating soluble extracts from FRTL-5 cells with the catalytic subunit of cAMP-dependent protein kinase. These data provide evidence that TSH produces a rapid activation of a cAMP-PDE in the FRTL-5 cells through a cAMP-dependent phosphorylation.


Anticholinesterase and antioxidant activity of Drynaria quercifolia and its ameliorative effect in scopolamine-induced memory impairment in mice.
Drynaria quercifolia is an epiphytic fern distributed all over Bangladesh with traditional use in treating neurological disorders and other ailments. Although several pharmacological activities of D. quercifolia have been investigated, the neuroprotective potential of this plant is still unexplored. In this study, we evaluated the in vitro anticholinesterase and antioxidant activities of D. quercifolia and the neuroprotective effect in scopolamine-induced memory-impaired mouse model. The crude methanol extract (DCM) of the plant was fractionated to prepare n-hexane (DHF), chloroform (DCF), ethyl acetate (DEF), and aqueous (DAF) factions. All the fractions were evaluated for anticholinesterase activity by modified Ellman's method and the antioxidant activity by several in vitro assays such as DPPH and hydroxyl free radicals scavenging, reducing power, and inhibition of brain lipid peroxidation. The effect of the most active fractions (both DCF and DEF) on learning and memory was assessed in scopolamine-induced mouse model of memory-impairment by Morris water maze tasks. Biochemical assays were performed in brain tissue. The active compound was isolated and characterized by chromatographic, spectroscopic, and molecular docking methods. Phytochemical analysis demonstrated a high content of phenolic and flavonoid in DEF. In vitro studies revealed a strong antioxidant power of DEF and anticholinesterase activity of DCF. Both the DCF and DEF significantly (P˂0.05) reduced the escape latency time in the Morris's water maze tasks, and increased the time spent in the northeast quadrant in the probe trial. Biochemical data demonstrated that treatment with DCF and DEF at different doses significantly (P˂0.0001) inhibited acetylcholinesterase activity, restored GSH levels, and reduced MDA levels in the brain of scopolamine-induced memory-impaired mice, indicating the protective effect of D. quercifolia, possibly by acetylcholinesterase inhibition and oxidative stress prevention. Chromatographic methods of separation led to he isolation of catechin and protocatechuric acid from DEF and 3,4-dihydroxy benzoic acid from DCF. The structure of the compounds was determined by studies of their 1H-NMR spectra. Molecular docking as well as in vitro study suggests the anticholinesterase and antioxidant activity of the isolated compounds. Our study suggested that the extracts of D. quercifolia, due to anticholinesterase and antioxidant activity, ameliorate the scopolamine-induced memory impairment in mice and thus may represent therapeutics in the treatment of Alzheimer's disease.


Solitary pulmonary metastases at first recurrence of osteosarcoma: Presentation, treatment, and survival of 219 patients of the Cooperative Osteosarcoma Study Group.
To evaluate patient and tumour characteristics, treatment and their impact on survival in patients with a solitary pulmonary metastasis at first relapse of high-grade osteosarcoma. Two-hundred and nineteen consecutive patients who had achieved a complete surgical remission and then developed a solitary pulmonary metastasis at first recurrence of high-grade osteosarcoma were retrospectively reviewed. Two hundred and three (94.9%) of 214 patients achieved a second complete remission. After a median time from initial diagnosis of osteosarcoma to first relapse of 2.3 years (range, 0.3-18.8 years), actuarial post-relapse overall survival after 2 and 5 years was 72.0% and 51.2%. Post-relapse event-free survival was 39.1% and 31.1%. Median follow-up time was 3.2 years (range, 0.1-29.4 years). A longer time until first relapse and diagnosis due to imaging were positive prognostic factors in uni- and multivariate analyses, as were a second complete surgical remission and, in regard to death, the absence of a subsequent relapse. The use of salvage chemotherapy and radiotherapy were not associated with patient outcomes, nor was the surgical approach (thoracoscopy vs. thoracotomy) nor the exploration (uni- vs. bilateral). Approximately half of the patients who experience a solitary pulmonary relapse at first recurrence of osteosarcoma remain alive 5 years after this first relapse. Only one third will remain disease-free. A complete surgical resection of the lesion is essential for long-term survival while relapse chemotherapy does not seem to improve survival. Innovative therapies are required to improve outcomes.


The influence of child pain catastrophizing and parent behavior on health-related quality of life in pediatric sickle cell disease.
Literature suggests that a child's appraisal of pain and parent responses to pain are critical in predicting health-related outcomes. In youth with sickle cell disease (SCD), few investigations have examined child pain catastrophizing, and even fewer have examined the role that parents play in responding to SCD pain within the family context. The purpose of the current study was to examine the relationship between pain catastrophizing, parent response to child SCD pain, and health-related quality of life (HRQoL). The sample (N = 100) included youth with SCD (ages 8-18) and their parent. Parents completed a demographic questionnaire and the Adult Responses to Child Pain Symptoms; youth completed the Pain Catastrophizing Scale and Pediatric Quality of Life Inventory-SCD Module. Findings indicated that pain catastrophizing, parent minimization, and parent encouragement/monitoring significantly predicted HRQoL. Minimizing and encouragement/monitoring parent responses moderated the relationship between pain catastrophizing and HRQoL, such that parent minimizing weakened the relationship and parent encouragement/monitoring strengthened the relationship. Paralleling pediatric chronic pain literature, findings suggest that pain catastrophizing predicts HRQoL in youth with SCD. However, findings from moderation analyses diverge from the chronic pain literature; data suggest that encouragement/monitoring responses strengthen the negative relationship between child pain catastrophizing and HRQoL. Child pain catastrophizing and parent response to SCD pain may be appropriate targets for clinical intervention to improve HRQoL. Future studies should strive to better understand parent responses to SCD pain.


Dopamine receptors in the striatum and limbic system of various strains of mice: relation to differences in responses to apomorphine.
Dopamine receptors, defined as [3H]spiroperidol binding sites, had similar population parameters in the limbic forebrain of C57BL/6, Albino Swiss and DBA/2 mice, but the parameters of the striatal populations were different: not only the densities differed among themselves, but the KD value of the striatal dopamine receptors of DBA/2 mice was significantly higher than that in the two remaining strains. Behavioral responses of Albino Swiss mice to apomorphine: biphasic effect of apomorphine on locomotor activity and stereotypy characterized by high motility, frequent rearing and sharp, not very frequent bites, were similar to those described earlier for C57BL/6 mice, and differed from those reported for DBA/2 mice. The results suggest that the difference in responding to apomorphine in various strains of mice may be related to differences in their striatal dopamine receptors.


Inhibin and reproductive aging in women.
The monotropic FSH rise is the sentinel endocrine event that first indicates a woman is approaching the end of her reproductive potential. While a deficiency in inhibin has long been postulated as the immediate cause of the monotropic FSH rise, this has only recently been demonstrated to actually occur. It is our current hypothesis that when the number of preantral follicles in both ovaries drop below a threshold, then there is a subtle decrease in inhibin B which leads to the monotropic FSH rise which, in turn, accelerates follicular depletion and the attainment of the menopause.


Hemodynamic conditions alter axial and circumferential remodeling of arteries engineered ex vivo.
We previously demonstrated that growth and remodeling was stimulated in arteries elongated ex vivo using step increases in axial strain. Viability and vasoactivity were similar to fresh arteries, however there was a substantial decrease in the ultimate circumferential stress. To test the hypothesis that the subphysiological perfusion conditions (i.e., low pressure and flow) previously used caused the reduction, arteries were subjected to the identical elongation protocol (50% increase over 9 days) while being perfused with physiological levels of flow, viscosity and pulsatile pressure. A significant increase in unloaded length was achieved by elongation under both perfusion conditions, although the increase was less under physiological (7 +/- 1%) than under subphysiological conditions (19 +/- 2%, p < 0.005). When length at physiological stress was estimated using mechanical testing data the values were similar. The ultimate circumferential stress of arteries elongated under physiological conditions was increased (33%), whereas the ultimate axial stress was decreased (50%) as compared with arteries elongated under subphysiological conditions. Elongated arteries under both perfusion conditions showed significant increases in proliferation and collagen mass, and similar viability and appearance to fresh arteries. These data suggest that there is substantial cross-talk between perfusion conditions and axial strain that modulates arterial remodeling and length.


Patellofemoral Bone Marrow Lesions: Natural History and Associations With Pain and Structure.
To describe the natural history of patellofemoral (PF) joint bone marrow lesions (BMLs) over 2.6 years and associations between changes in PF joint BMLs, knee pain, and knee cartilage morphology in older adults over 5 years. A prospective population-based cohort study of men and women ages 50-80 years (mean age 63 years, n = 406) was performed. PF joint BMLs, knee cartilage volume, and cartilage defect scores (range 0-4) were measured using the Whole-Organ Magnetic Resonance Imaging Score system at baseline and at 2.6 years. Knee pain was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at baseline and at 5 years. At baseline, 27% (n = 109) had PF joint BMLs; 24% of these increased (WOMAC score change of ≥1) at followup, 44% persisted, 32% decreased, and 21% resolved completely. Of those without PF joint BMLs at baseline, 20% of participants developed PF joint BMLs over 2.6 years. In multivariable analyses, a change in PF joint BMLs was deleteriously associated with a change in total knee pain (β = 0.67, 95% confidence interval [95% CI] 0.03, 1.31) and knee pain when going up/down stairs (β = 0.24, 95% CI 0.04, 0.44) over 5 years. Baseline PF joint and tibiofemoral joint cartilage volume were protective for PF joint BMLs (relative risk [RR] 0.69, 95% CI 0.52, 0.90 for PF joint), while baseline PF joint cartilage defects were associated with an increase in PF joint BMLs (RR 1.73, 95% CI 1.38, 2.17) over 2.6 years. TF joint cartilage defects were not associated with increases in PF joint BMLs. PF joint BMLs are not static, and change is clinically relevant. PF joint cartilage morphology predicts increases in PF joint BMLs.


Extreme rates and heterogeneity in insect DNA evolution.
DNA-DNA hybridization studies of insects, more specifically Drosophila and cave crickets, have revealed interesting patterns of genome evolution that contrast markedly with what has been seen in other taxa, especially mammals and birds. Insect genomes are composed of sections of single-copy DNA with extreme variation in rates of evolutionary change. This variation is more extreme than between introns and exons; introns fall into the relatively conserved fraction of the genome. Attempts to calculate absolute rates of change in Drosophila DNA have all led to estimates some 5-10 times faster than those found in most vertebrates; this is true even for the more conservative part of the nuclear genome. Finally we point out that morphological similarity, chromosomal similarity, and/or ability to form interspecific hybrids is often associated with quite high levels of single-copy DNA divergence in insects as compared to mammals and birds.