Scaffold compound L971 exhibits anti-inflammatory activities through inhibition of JAK/STAT and NFκB signalling pathways.
JAK/STAT and NFκB signalling pathways play essential roles in regulating inflammatory responses, which are important pathogenic factors of various serious immune-related diseases, and function individually or synergistically. To find prodrugs that can treat inflammation, we performed a preliminary high-throughput screening of 18 840 small molecular compounds and identified scaffold compound L971 which significantly inhibited JAK/STAT and NFκB driven luciferase activities. L971 could inhibit the constitutive and stimuli-dependent activation of STAT1, STAT3 and IκBα and could significantly down-regulate the proinflammatory gene expression in mouse peritoneal macrophages stimulated by LPS. Gene expression profiles upon L971 treatment were determined using high-throughput RNA sequencing, and significant differentially up-regulated and down-regulated genes were identified by DESeq analysis. The bioinformatic studies confirmed the anti-inflammatory effects of L971. Finally, L971 anti-inflammatory character was further verified in LPS-induced sepsis shock mouse model in vivo. Taken together, these data indicated that L971 could down-regulate both JAK/STAT and NFκB signalling activities and has the potential to treat inflammatory diseases such as sepsis shock.


Volume of Distribution is Unaffected by Metabolic Drug-Drug Interactions.
It has been recognized that significant transporter interactions result in volume of distribution changes in addition to potential changes in clearance. For drugs that are not clinically significant transporter substrates, it is expected that drug-drug interactions would not result in any changes in volume of distribution. An evaluation of this hypothesis proceeded via an extensive analysis of published intravenous metabolic drug-drug interactions, based on clinically recommended index substrates and inhibitors of major cytochrome P450 (CYP) isoforms. Seventy-two metabolic drug interaction studies were identified where volume of distribution at steady-state (Vss) values were available for the CYP index substrates caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), theophylline (CYP1A2), and tolbutamide (CYP2C9). Changes in exposure (area under the curve) up to 5.1-fold were observed; however, ratios of Vss changes have a range of 0.70-1.26, with one outlier displaying a Vss ratio of 0.57. These results support the widely held founding tenant of pharmacokinetics that clearance and Vss are independent parameters. Knowledge that Vss is unchanged in metabolic drug-drug interactions can be helpful in discriminating changes in clearance from changes in bioavailability (F) when only oral dosing data are available, as we have recently demonstrated. As Vss remains unchanged for intravenous metabolic drug-drug interactions, following oral dosing changes in Vss/F will reflect changes in F alone. This estimation of F change can subsequently be utilized to assess changes in clearance alone from calculations of apparent clearance. Utilization of this simple methodology for orally dosed drugs will have a significant impact on how drug-drug interactions are interpreted from drug development and regulatory perspectives.


Symptom management to alleviate thirst and dry mouth in critically ill patients: A randomised controlled trial.
Critically ill patients often experience coexisting symptoms. Thirst, in particular, appears to be an important symptom, having the highest prevalence, intensity, and induction of distress, and is significantly correlated with other symptoms. However, thirst and dry mouth are not usually assessed or treated. The aim of the study was to demonstrate the effectiveness of an intervention bundle to relieve thirst and dry mouth. The present study was a randomised controlled trial in which critically ill patients were allocated to an experimental or control group. The intervention bundles, including vitamin C sprays, peppermint water mouthwash, and a lip moisturiser, were provided to the experimental group for 3 days, whereas patients in the control group were exposed to the placebo interventions, including saline sprays, 40 °C water mouthwash, and wetting the lips with water. A total of 61 patients were recruited to the study; 65.6% (n = 41) were men, and the average age was 64.2 ± 16.8 years. The average decrease in thirst intensity and oral mucosa situation scores after the interventions was larger in the experimental group patients relative to controls (1.27 and 0.36 vs. 0.19 and 0.1 points, respectively; p < 0.05). Being male, scoring highly on the Acute Physiology and Chronic Health Evaluation II scale, not receiving diuretics, and having higher serum sodium levels were potential predictors of thirst and oral dryness. The interventional bundle used in this study was shown to be a promising approach that can relieve thirst intensity and dry mouth, which are pervasively distressful to critically ill patients. The study was registered on the www.Chictr.org.cn under the identification number ChiCTR1900022873.


Factors affecting the success rate of porcine embryo vitrification by the Open Pulled Straw method.
The objectives of this study were: (1) to evaluate the influence of porcine embryo developmental stage on in vitro embryo development after vitrification, (2) to study the efficiency of the one-step dilution procedure, compared with conventional warming, for vitrified embryos at different stages of development, and (3) to determine the influence of the embryo donor on the in vitro survival of vitrified embryos at morulae and blastocyst stages. Two to four cell embryos, morulae and blastocysts were collected by laparotomy from weaned crossbred sows (n=55). Vitrification and conventional warming were performed using the OPS procedure with Superfine Open Pulled Straws (SOPS). For one-step dilution, embryos were placed in 800 microl TCM199-HEPES containing 20% of new born calf serum and 0.13 M sucrose for 5 min. To evaluate development, two to four cell embryos, morulae and blastocysts were cultured in vitro for 120, 48 and 24h, respectively. Some fresh embryos from each developmental stage were not vitrified and cultured as controls. Embryos were morphologically evaluated for their developmental capacity during the in vitro culture by stereomicroscopy. The total cell number of embryos was assessed by Hoechst-33342 staining and fluorescence microscope observation. There was a significant effect of the stage of development on the in vitro survival, perihatching rate and the number of cells of embryos after vitrification and warming (Experiment 1; p<0.001). The survival and perihatching rates of two to four cell embryos were lower than those obtained for morulae and blastocysts (p<0.001). No differences (p>0.05) in survival rates were found between vitrified and fresh blastocysts. The warming procedure did not affect the development and total cell number of vitrified two to four cell embryos, morulae or blastocysts (Experiment 2). However, donor had a significant effect (p<0.001) on the in vitro development and the number of cells of morulae and blastocysts after vitrification and warming (Experiment 3). In conclusion, the embryo developmental stage and the embryo donor were important factors that affected the development of porcine embryos after OPS-vitrification and warming. OPS-vitrification and the one-step dilution are efficient procedures to be used with intact porcine morulae and blastocysts.


Development and validation of an educational video on nasopharyngeal and oropharyngeal suctioning.
The objective of this study was to develop and validate an educational video on nasopharyngeal and oropharyngeal suctioning. The use of videos in nursing education can improve students' skills in performing procedures. This was a methodological study. This study was performed in five steps: (1) development of the script for an educational video on nasopharyngeal and oropharyngeal suctioning; (2) content validation of the script by 10 nurse specialists; (3) development of the video; (4) content validation of the video by six nurse specialists; (5) cognitive testing by 51 nursing students regarding the understanding of the items, until the following requirements were met: (1) mean and median scores ≥4, with significant inter-rater agreement, according to the Wilcoxon test; (2) 95% confidence intervals >80 for the proportion of maximum scores, according to the binomial distribution. p values <0.05 were considered significant. After four rounds of evaluation by the specialists, the script was considered validated. The video was considered validated after two rounds of evaluation by specialists and students (p < 0.001). The video addressed the following topics: concept, indications, contraindications, required materials, appropriate technique, nursing notes and complications. The video script was created by using the Storyboard technique and validated by specialist nurses using the Delphi technique. Nursing students watched, analyzed and understood the video which may support them to improve their technical skills of this procedure.


Targeting an ultrasound contrast agent to folate receptors on ovarian cancer cells: feasibility research for ultrasonic molecular imaging of tumor cells.
The purpose of the study was to synthesize and characterize folate-targeted microbubbles (MB(F)) as an ultrasound contrast agent and to evaluate their affinity to the folate receptor (FR) in vitro. Folate-targeted microbubbles were prepared by incorporating 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]-folate into the lipid membrane of microbubbles. The diameter and concentration of the MB(F) were determined by a cell counter and sizer. The MB(F), control microbubbles (MB(C)), and MB(F) with a free folic acid block-ade were tested for binding specificity to human ovarian carcinoma SKOV3 cells, which overexpress the FR, by microscopy and confocal imaging, respectively. The basic physical characteristics of MB(F) were similar to those of MB(C). In the cell binding test, the adherence efficiency of MB(F) to the SKOV3 cells (mean +/- SD, 16 +/- 5 microbubbles per cell; P < .01) was significantly higher than that of MB(C) (0.7 +/- 0.4 microbubbles per cell) or MB(F) with the free folic acid blockade (0.7 +/- 0.6 microbubbles per cell). Folate-targeted microbubbles showed high affinity to SKOV3 cells with FR overexpression. They are potentially useful for ultrasonic molecular imaging and treatment of FR-positive tumors and warrant further investigation.


Influence of the genetic background and carrier protein on the antibody response to GnRH.
A vaccine against the gonadotropin releasing hormone (GnRH) is being developed as an immunological method for the treatment of prostatic enlargement. The work described here was aimed at investigating the influence of the genetic background on immune responses to GnRH conjugated to diphtheria toxoid (DT). Mice of different strains were injected with the conjugate and the antibody levels against GnRH and DT quantitated in order to examine the effect of genetic background on immune responses to the hapten and the carrier. All immunized animals produced antibodies to DT. Anti-GnRH antibodies were generated by all strains of mice except 129. The low anti-GnRH response in the 129 strain mice did not appear to be MHC-linked, as C57BL/6 mice, which bear the same MHC haplotype as 129 mice, were able to generate a strong anti-GnRH response. The non-responsiveness to the hapten (GnRH) in 129 strain mice was overcome by the use of an 'alternate carrier' approach.


Myocardial injury due to lightning.
The report deals with a 27-year-old male who was standing in a tent and was injured by lightning as it struck a tree about 1.5 m away. He immediately lost consciousness and exhibited ventricular fibrillation when the emergency physician arrived. A clinical picture of hypoxaemic brain damage emerged after initially successful resuscitation. Brain death was diagnosed on the fifth day after injury. The discrete external findings (remaining arborescent skin marks) contrasted markedly with the severe thermal damage to the pectoral muscle and cardiac musculature found during the autopsy. The histological cardiac findings indicated severe acute myocardial infarction affecting virtually all parts of the myocardium.


Q-T interval (QT(C)) in patients with cirrhosis: relation to vasoactive peptides and heart rate.
Prolonged Q-T interval (QT) has been reported in patients with cirrhosis who also exhibit profound abnormalities in vasoactive peptides and often present with elevated heart rate (HR). The aim of this study was to relate QT to the circulating level of endothelins (ET-1 and ET-3) and calcitonin gene-related peptide (CGRP) in patients with cirrhosis. In addition, we studied problems with HR correction of QT. Forty-eight patients with cirrhosis and portal hypertension were studied during a haemodynamic investigation. Circulating levels of ETs and CGRP were determined by radioimmunoassays. Correction of QT for HR above 60 beats per min was performed using the methods described by Bazett (QT(C)) and Fridericia (QT(F)). Prolonged QT(C) (above 440 ms), found in 56% of the patients, was related to the presence of significant portal hypertension and liver dysfunction (p < 0.05 to 0.001), but not to elevated ET-1, ET-3 or CGRP. When corrected according to Bazett, QT(C) showed no significant relation to differences in HR between patients (r = 0.07, ns). QTF showed some undercorrection of HR (r = -0.36; p < 0.02). During HR variation in the individual patient, QT(C) revealed a small but significant overcorrection (2.6 ms per heartbeat per min; p < 0.001). This value was significantly (p < 0.02) smaller with QTF (1.2 ms per heartbeat per min). The prolonged QT(C) in cirrhosis is related to liver dysfunction and the presence of portal hypertension, but not to the elevated powerful vasoconstrictor (ET-1) or vasodilator (CGRP, ET-3) peptides. The problems with correction of the QT for elevated HR in cirrhosis are complex, and the lowest HR should be applied for determination of the QT.


Key metalloproteinase-mediated pathways in the kidney.
Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs) belong to the metzincin family of zinc-containing multidomain molecules, and can act as soluble or membrane-bound proteases. These enzymes inactivate or activate other soluble or membrane-expressed mediator molecules, which enables them to control developmental processes, tissue remodelling, inflammatory responses and proliferative signalling pathways. The dysregulation of MMPs and ADAMs has long been recognized in acute kidney injury and in chronic kidney disease, and genetic targeting of selected MMPs and ADAMs in different mouse models of kidney disease showed that they can have detrimental and protective roles. In particular, MMP-2, MMP-7, MMP-9, ADAM10 and ADAM17 have been shown to have a mainly profibrotic effect and might therefore represent therapeutic targets. Each of these proteases has been associated with a different profibrotic pathway that involves tissue remodelling, Wnt-β-catenin signalling, stem cell factor-c-kit signalling, IL-6 trans-signalling or epidermal growth factor receptor (EGFR) signalling. Broad-spectrum metalloproteinase inhibitors have been used to treat fibrotic kidney diseases experimentally but more targeted approaches have since been developed, including inhibitory antibodies, to avoid the toxic side effects initially observed with broad-spectrum inhibitors. These advances not only provide a solid foundation for additional preclinical studies but also encourage further translation into clinical research.


Systematic review of nonpharmacological analgesic interventions for common needle-related procedure in newborn infants and development of evidence-based clinical guidelines.
The aim of this literature review was to develop clinical guidelines for the prevention and control of needle-related pain in newborn infants. The guidelines were developed by the Italian Society of Neonatology, using the Grading of Recommendations, Assessment, Development and Evaluation approach, based on the assessment of 232 papers published between 1986 and 2015. The quality of the evidence was high or moderate for some behavioural and nonpharmacological interventions. There was sufficient evidence to strongly support the use of nonpharmacological interventions for common needle-related procedures in newborn infants. Combined interventions seemed to be more effective in relieving procedural pain.


Identification of PhoB binding sites of the yibD and ytfK promoter regions in Escherichia coli.
By using a lacZ operon fusion genomic library of the Escherichia coli 0157:H7 Sakai, we identified phosphate-starvation-inducible (psi) promoters located upstream of the yibD and ytfK genes. They have been previously proposed to belong to the phosphate regulon (pho regulon) by Beak and Lee (2006), based on the DNA array and in vivo transcriptional experiments. However, the direct interaction of these promoters with the activator protein of the pho regulon, PhoB, has not been determined. We determined the binding regions of PhoB in these promoter regions by DNase I footprinting. Both regions contained two pho boxes similar to the consensus sequence for PhoB binding.


Single gene encodes glycophospholipid-anchored and asymmetric acetylcholinesterase forms: alternative coding exons contain inverted repeat sequences.
Polymorphic forms of acetylcholinesterase are tethered extracellularly either as dimers membrane-anchored by a glycophospholipid or as catalytic subunits disulfidelinked to a collagen tail that associates with the basal lamina. Genomic clones of acetylcholinesterase from T. californica revealed that individual enzyme forms are encoded within a single gene that yields multiple mRNAs. Each enzyme form is encoded in three exons: the first two exons, bases -22 to 1502 and 1503 to 1669, encode sequence common to both forms, while alternative third exons encode a hydrophobic C-terminal region, to which a glycophospholipid is added upon processing, and a nonprocessed C-terminus, yielding a catalytic subunit that disulfide-links with a collagen-like structural unit. The 3' untranslated region of each alternative exon contains tandem repeat sequences that are inverted with respect to the other exon. This may either dictate alternative exon usage by formation of cis stem-loops or affect the abundance of translatable mRNA by trans-hybridization between the alternative spliced mRNA species.


Arterial flow reduces oxidative stress via an antioxidant response element and Oct-1 binding site within the NADPH oxidase 4 promoter in endothelial cells.
The main sources of oxidative stress in the vessel wall are nicotine adenine dinucleotide phosphate (NADPH) oxidase (Nox) complexes. The endothelium mainly expresses the Nox4-containing complex; however, the mechanism by which shear stress in endothelial cells regulates Nox4 is not well understood. This study demonstrates that long-term application of arterial laminar shear stress using a cone-and-plate viscometer reduces endothelial superoxide anion formation and Nox4 expression. In primary human endothelial cells, we identified a 47 bp 5'-untranslated region of Nox4 mRNA by 5'-rapid amplification of cDNA ends (5'-RACE) PCR. Cloning and functional analysis of human Nox4 promoter revealed a range between -1,490 and -1,310 bp responsible for flow-dependent downregulation. Mutation of an overlapping antioxidative response element (ARE)-like and Oct-1 binding site at -1,376 bp eliminated shear stress-dependent Nox4 downregulation. Consistent with these observations, electrophoretic mobility shift assays (EMSA) demonstrated an enhanced shear stress-dependent binding of Nox4 oligonucleotide containing the ARE-like/Oct-1 binding site, which could be inhibited by specific antibodies against the transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2) and octamer transcription factor 1 (Oct-1). Furthermore, shear stress caused the translocation of Nrf2 and Oct-1 from the cytoplasm to the nucleus. Knockdown of Nrf2 by short hairpin RNA (shRNA) increased Nox4 expression twofold, indicating a direct cross-talk between Nrf2 and Nox4. In conclusion, an ARE-like/Oct-1 binding site was noticed to be essential for shear stress-dependent downregulation of Nox4. This novel mechanism may be involved in the flow-dependent downregulation of endothelial superoxide anion formation.


How is the loss of a parent in youth related to attachment and adult separation anxiety among women?
This study aimed to examine attachment and adult separation anxiety (ASA) among women who lost a parent in their youth. We hypothesized that insecure attachment and increased ASA from a romantic partner would be found among women who have lost a parent in youth, compared to women whose parents were both alive. Sixty women who lost one or both parents in their youth and 60 who had living parents participated in the study (mean age: 32.3, range: 18-62 years). Participants filled out the ASA and Short Attachment questionnaires. Women who lost a parent reported higher levels of anxious attachment and ASA from partner; the two groups did not differ, however, in terms of avoidant attachment. Additionally, similar effects on ASA and attachment were found among adult women who lost a father or a mother in their youth. In conclusion, the loss of a parent early in life may be associated with an insecure attachment style and increased ASA.


Birth weight, current body mass index, and insulin sensitivity and secretion in young adults in two Latin American populations.
Although studies have shown association of birth weight (BW) and adult body mass index (BMI) with insulin sensitivity in adults, there is limited evidence that BW is associated with insulin secretion. We assessed the associations between BW and current BMI with insulin sensitivity and secretion in young Latin American adults. Two birth cohorts, one from Ribeirao Preto, Brazil, based on 1984 participants aged 23-25 years, and another from Limache, Chile, based on 965 participants aged 22-28 years were studied. Weight and height at birth, and current fasting plasma glucose and insulin levels were measured. Insulin sensitivity (HOMA%S) and secretion (HOMA%β) were estimated using the Homeostatic Model Assessment (HOMA2). Multiple linear regression analyses were carried out to test the associations between BW and adult BMI z-scores on log HOMA%S and log HOMA%β. BW z-score was associated with HOMA%S in the two populations and HOMA%β in Ribeirao Preto when adult BMI z-score was included in the model. BW z-score was associated with decreasing insulin secretion even without adjusting for adult BMI, but only in Ribeirao Preto. BMI z-score was associated with low HOMA%S and high HOMA%β. No interactions between BW and BMI z-scores on insulin sensitivity were shown. This study supports the finding that BW may affect insulin sensitivity and secretion in young adults. The effect size of BW on insulin status is small in comparison to current BMI.


Prevalence of hospital-acquired infections and antibiotic use in two tertiary Mongolian hospitals.
Health statistics of Mongolia indicate that hospital-acquired infections (HAIs) occur in 0.01-0.05% of all hospital admissions. This is considerably lower than internationally reported rates. A one-day survey was conducted in two tertiary hospitals of Ulaanbaatar in September 2008 to estimate HAI prevalence, associated risk factors and patterns of antibiotic usage. Among 933 patients surveyed, 50 (5.4%) were diagnosed with HAI. Prevalence of surgical site infection was 1.1% (3.9% among surgical patients), bloodstream infection 0.3%, respiratory tract infection 1.3%, urinary tract infection 1.3%, and other HAI 1.4%. Microbiological investigations were only documented for 18.9% of all patients. A total of 558 patients (59.8%) were taking 902 courses of antibiotics; 92.1% of patients were prescribed antibiotics without a sensitivity test. Multiple logistic regression analysis revealed that HAI was significantly associated with the admission source, the hospital, length of hospital stay, surgical and other invasive procedures, urinary catheters and other indwelling devices. The study results were comparable with reports from some other developing countries and confirm that official statistics underestimate the true frequency of HAI in Mongolia.


[Presence of antibodies against gangliosides among patients with Lyme borreliosis--preliminary study].
THE AIM of the study was the evaluation of autoantibody reaction against endogenous gangliosides in the course of Lyme borreliosis. Antibodies against profile of gangliosides composed of GM1, GM2, GM3, GD1a,GD1b,GT1b, GQ1b were evaluated in serum patients with early disseminated (neuroborreliosis) Lyme disease (n = 16), patients with long lasting serologic response against Borrelia burgdorferi (n = 32) and in healthy subjects (n = 16). Immunoblot test for IgG was used. Antibodies were detected in all evaluated groups. In group of neuroborreliosis (lymphocytic meningitis with cranial nerve invoIvement) there was no essential difference with control group. It was stated in group of forestry workers with serological features of infection B. burgdorferi lasting for years. Results of the study do not support the thesis of participation of IgG autoantibodies against gangliosides in pathogenesis early disseminated Lyme borreliosis in form of lymphocytic meningitis with cranial nerves paresis. Antibodies against endogenous glicosfingolipides in Lyme borreliosis probably can lead to affecting nervous system (demielinisation and polineuropathy) but probably require long-term immunization, what is suggested by results of examined group of patients with the multi-annual serological features of infection.


Airports, highways and COVID-19: An analysis of spatial dynamics in Brazil.
The high transmissibility and infectivity of the new coronavirus, the high proportion of asymptomatic transmitters and the rapid and continuous spatial displacement of people, by the different mechanisms of locomotion, are elements that can contribute to the dissemination of COVID-19. This study aims to describe the geographical dispersion of COVID-19 in the state of Bahia and the importance of major airports and highways in the dynamics of disease transmission. This is an ecological study involving all cases of COVID-19 registered in the state of Bahia between March 6, date of the first registered case and May 16, 2020. After collection, an exploratory spatial analysis was performed, considering the cases accumulated on the last day of each epidemiological week. The first cases of COVID-19 were concentrated in areas served by three important airport complexes in the state, located in Salvador, Ilhéus and Porto Seguro. From week 16-20, there was a more intense expansion of COVID-19 to the interior of the state. A global spatial autocorrelation was observed (I Moran 0.2323; p = 0.01), with the influence of distance: positive correlation at distances less than 205.8 km (I Moran 0.040; p = 0.01) and greater than 800 km (I Moran 0.080; p = 0.01). Based on the spatial dispersion pattern of COVID-19 in the state of Bahia, airports and highways that cross the state were responsible for the interiorization of the disease.


[Unusual stromal corneal deposits].
We describe the case of a 70-year-old woman who presented with slowly progressive vision deterioration in both eyes and an increase in glare sensitivity. A slit-lamp examination showed stromal corneal deposits that were atypical for a dystrophy. Protein electrophoresis with immunofixation and bone marrow aspiration led to the diagnosis of an IgG-kappa myeloma. Chemotherapy relieved systemic disease and improved the patient's visual symptoms.


REPRODUCTIVE CHARACTER DISPLACEMENT IN PHLOX.
Plants of the red- and pink-flowered P. drummondii were introduced into a natural population of P. cuspidata. Their seeds were progeny-tested, and the percentage hybrid seed determined for each variant. Thirty-eight percent of the seed from the pink variant were hybrid compared to 13% of the red. The difference in hybrid production is best explained by corolla color. The self- and cross-compatibility of nine sympatric and nine allopatric populations were studied in the greenhouse. On the average, sympatric populations are more self-compatible than allopatric populations. Pollen germination is 13.7% vs. 7.3%, the difference being statistically significant. The self-compatibility differential was accompanied by a self seedset differential. On the average, sympatric populations are more cross-compatible with P. cuspidata than are allopatric populations. The germination of P. cuspidata pollen on sympatric P. drummondii stigmas was 13.3% vs. 9.8% on allopatric stigmas. However, the difference is not statistically significant. The presence of P. cuspidata has promoted reproductive character divergence in P. drummondii. The shift in corolla color and the increase in self-compatibility reduce the potential for gametic wastage and interspecific hybridization.


A large pelvic mass in a 39-year-old man.
Schwannomas are encapsulated, usually benign, tumors composed of well-differentiated Schwann cells, arising from the neural sheath of peripheral nerves. The most common type of benign schwannoma is the acoustic neuroma arising from the eighth cranial nerve. Retroperitoneal schwannomas account for 0.5-3% of the retroperitoneal tumors in most series. We present a case of a 39-year-old man with a pelvic mass, arising from a sacral nerve root, diagnosed as a schwannoma.


Oxidative stress and the deleterious consequences to the rat cochlea after prenatal chronic mild exposure to carbon monoxide in air.
Pregnant rats (starting on E5) were exposed chronically to carbon monoxide (CO) from gestational days 5-20. In the postnatal period, rat pups were grouped as follows: group A: prenatal exposure to CO only; group B: prenatal exposure to CO then exposed to CO from postnatal day (P) 5 to P20; group C, control (air without CO). Groups A and B showed similar deleterious effects after CO exposure. At P3, rat pup cochlea from group A showed a normal organization of the organ of Corti. There was no morphological deterioration, or loss of inner or outer hair cells. At P20, animals from group A and B showed vacuolization on the afferent terminals at the basal portion of the cochlea. We found synapsin-1 immunoreactivity (IR) to be decreased in efferent nerve terminals in CO-exposed pups at P3. From P12 to P20, synapsin-1-IR is low in efferent terminals. At P20, type I spiral ganglia neurons and afferent nerve fibers showed decreased neurofilament-IR in CO-exposed groups when compared with controls. Heme oxygenase-1 and superoxide dismutase-1-IR were elevated in the stria vascularis and blood vessels from CO-exposed rat pups at P12 and P20 in group B; in contrast group A showed a comparable expression to controls. Inducible nitric oxide synthase (iNOS) and nitrotyrosine-IR were increased in blood vessels of the cochlea in CO-exposed groups, from P3 to P20. iNOS up-regulation and the presence of nitrotyrosine in blood vessels of the cochlea indicated that CO exposure activates the production of nitric oxide via increased iNOS activity. Prenatal chronic CO exposure promotes oxidative stress in the cochlea blood vessels that in turn is reflected in damage to spiral ganglia neurons and inner hair cells, suggesting for the first time that prenatal exposure to CO at concentrations expected in poorly ventilated environments impairs the development of the inner ear.


Congenital lipoid adrenal hyperplasia: Immunohistochemical study of testosterone synthesis in Leydig cells.
Congenital lipoid adrenal hyperplasia is a rare disease that causes disorders of sex development. The 46,XY patient presents with female external genitalia and inguinal testes. We describe the case of a patient with congenital lipoid adrenal hyperplasia and investigated the testes of this patient in detail. A 15-day-old 46,XY neonate presented with severe adrenal insufficiency. Congenital lipoid adrenal hyperplasia was diagnosed after detection of steroidogenic acute regulatory gene mutations. At 2 years and 5 months, she underwent bilateral gonadectomy. Leydig cells were observed both with and without lipid droplets in the testes of this patient. We also demonstrated immunohistochemically that some testosterone-synthesizing enzymes were maintained in this patient. The results indicated transcription of testosterone-synthesizing enzymes remained despite lipid accumulation in this patient. The pattern of expression of testosterone-synthesizing enzymes suggested fetal Leydig cells may have remained after birth in the testes of this patient.


Primer on medical decision analysis: Part 2--Building a tree.
This part of a five-part series covering practical issues in the performance of decision analysis outlines the basic strategies for building decision trees. The authors offer six recommendations for building and programming decision trees. Following these six recommendations will facilitate performance of the sensitivity analyses required to achieve two goals. The first is to find modeling or programming errors, a process known as "debugging" the tree. The second is to determine the robustness of the qualitative conclusions drawn from the analysis.


Risk Factors for Disability Pension among Young Adults Diagnosed with Attention-deficit Hyperactivity Disorder (ADHD) in Adulthood.
To investigate risk factors of disability pension (DP) in young adults diagnosed with ADHD in Sweden. In total, 9718 individuals diagnosed with incident ADHD in young adult age (19-29 years) 2006 to 2011, were identified through national registers. They were followed for 5 years and Cox regression models were applied to analyze the DP risk (overall and by sex), associated with socio-demographics, work-related factors, and comorbid disorders. Twenty-one percent of all received DP. Being younger at diagnosis (hazard ratio [HR] = 1.54; 95%confidence interval [CI] 1.39-1.71); low educational level (HR = 1.97; 95%CI 1.60-2.43 for <10 years); work-related factors at baseline (no income from work [HR = 2.64; 95%CI 2.35-2.98] and sickness absence >90 days [HR = 2.48; 95%CI2.17-2.83]); and schizophrenia/psychoses (HR = 2.16; 95%CI 1.66-2.80), autism (HR = 1.87; 95%CI 1.42-2.46), anxiety (HR = 1.34; 95%CI 1.22-1.49) were significantly associated with an increased risk of DP. Similar risk patterns were found in men and women. Work-related factors and comorbid mental disorders need to be highlighted in early vocational rehabilitation for individuals with ADHD.


Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer.
Cisplatin-based neoadjuvant chemotherapy (NAC) is recommended prior to radical cystectomy for muscle-invasive bladder cancer (MIBC) patients. Despite a 5-10% survival benefit, some patients do not respond and experience substantial toxicity and delay in surgery. To date, there are no clinically approved biomarkers predictive of response to NAC and their identification is urgently required for more precise delivery of care. To address this issue, a multi-methods analysis approach of machine learning and differential gene expression analysis was undertaken on a cohort of 30 MIBC cases highly selected for an exquisitely strong response to NAC or marked resistance and/or progression (discovery cohort). RGIFE (ranked guided iterative feature elimination) machine learning algorithm, previously demonstrated to have the ability to select biomarkers with high predictive power, identified a 9-gene signature (CNGB1, GGH, HIST1H4F, IDO1, KIF5A, MRPL4, NCDN, PRRT3, SLC35B3) able to select responders from non-responders with 100% predictive accuracy. This novel signature correlated with overall survival in meta-analysis performed using published NAC treated-MIBC microarray data (validation cohort 1, n = 26, Log rank test, p = 0.02). Corroboration with differential gene expression analysis revealed cyclic nucleotide-gated channel, CNGB1, as the top ranked upregulated gene in non-responders to NAC. A higher CNGB1 immunostaining score was seen in non-responders in tissue microarray analysis of the discovery cohort (n = 30, p = 0.02). Kaplan-Meier analysis of a further cohort of MIBC patients (validation cohort 2, n = 99) demonstrated that a high level of CNGB1 expression associated with shorter cancer specific survival (p < 0.001). Finally, in vitro studies showed siRNA-mediated CNGB1 knockdown enhanced cisplatin sensitivity of MIBC cell lines, J82 and 253JB-V. Overall, these data reveal a novel signature gene set and CNGB1 as a simpler proxy as a promising biomarker to predict chemoresponsiveness of MIBC patients.


SCN5A compound heterozygosity mutation in Brugada syndrome: Functional consequences and the implication for pharmacological treatment.
SCN5A gene encodes the α-subunit of Nav1.5, mainly found in the human heart. SCN5A variants are the most common genetic alterations associated with Brugada syndrome (BrS). In rare cases, compound heterozygosity is observed; however, its functional consequences are poorly understood. We aimed to analyze the functional impact of de novo Nav1.5 mutations in compound heterozygosity in distinct alleles (G400R and T1461S positions) previously found in a patient with BrS. Moreover, we evaluated the potential benefits of quinidine to improve the phenotype of mutant Na+ channels in vitro. The functional properties of human wild-type and Nav1.5 variants were evaluated using whole-cell patch-clamp and immunofluorescence techniques in transiently expressed human embryonic kidney (HEK293) cells. Both variants occur in the highly conservative positions of SCN5A. Although all variants were expressed in the cell membrane, a significant reduction in the Na+ current density (except for G400R alone, which was undetected) was observed along with abnormal biophysical properties, once the variants were expressed in homozygosis and heterozygosis. Interestingly, the incubation of transfected cells with quinidine partially rescued the biophysical properties of the mutant Na+ channel. De novo compound heterozygosis mutations in SNC5A disrupt the Na+ macroscopic current. Quinidine could partially reverse the in vitro loss-of-function phenotype of Na+ current. Thus, our data provide, for the first time, a detailed biophysical characterization of dysfunctional Na+ channels linked to compound heterozygosity in BrS as well as the benefits of the pharmacological treatment using quinidine on the biophysical properties of Nav1.5.


In vitro and in vivo toxicological studies of V nerve agents: molecular and stereoselective aspects.
In vitro inhibition data of cholinesterases (ChEs) and reactivation with HI 6 are presented for separated VX and VR enantiomers with high purity (enantiomer excess >99.999%). Inhibition rate constants for (-)-VR were fourfold higher than for (-)-VX. Marked higher stereoselectivity of ChEs inhibition was observed for VR compared with VX enantiomers. Low/no reactivation was determined for respective (+)-enantiomers. Results were related to orientation of (-)- and (+)-enantiomers in ChEs active sites. In vivo in swine, absorption rate constants were practically identical for VX and VR enantiomers after percutaneous application of 3xLD₅₀ underlining relevance of amine group and postulated equilibria shifts between charged, uncharged, open and cyclic form (skin depot). In vivo toxicokinetics of VX and VR enantiomers differed markedly after 4h. Elimination of VX was much slower compared with VR. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in vivo differed for VX and VR. In vivo spontaneous reactivation was not observed for VX-inhibited AChE while VR-inhibited AChE was much faster spontaneously reactivated than expected and AChE inhibition by VR was slower than expected. Progredient BChE inhibition was detected after VX application while VR inhibited BChE weakly. Possible explanation may be impact of the agents on hemodynamics and different metabolisms. Thus, due to increase of the V agents' blood concentration after atropine administration (depot release) the present standard therapy should be thoroughly reconsidered.


Electrodeposition-based construction of random arrays of Pt nanoparticles on glassy carbon electrode (GCE) towards methanol oxidation application.
An eletrodeposition of random arrays of Pt nanoparticles, supported on glassy carbon electrode (GCE), is reported. It has been shown that such arrays exhibited good catalytic activity with respect to methanol oxidation in an acidic medium and longer deposition time produced more Pt nanoparticles on GCE leading to larger effective catalytic area and higher catalytic current. It was found that the process of methanol oxidation was controlled by the diffusion of methanol and the Pt nanoparticles formed stable film on GCE surface and also exhibited stable catalytic performance towards methanol oxidation.


Characterization of the inhibition of Escherichia coli pyruvate dehydrogenase complex by pyruvate.
The E. coli pyruvate dehydrogenase complex was inhibited by pyruvate in absence of its cofactor, NAD+. The inhibition was found to increase with pH and phosphate concentration of the buffer and decrease with its ionic strength. The inhibition profile was different with MOPS buffer. No radioactivity was found in the enzyme, when the latter was incubated with 2-14C-pyruvate. The results suggest that covalent adduct formation is not necessary for the observed inhibition.


Mycorrhizal root colonization in maize fields is more affected by soil management and climate conditions than by plant genotype.
This work aims to characterize the arbuscular mycorrhizal association between maize genotypes and the effects of soil physical-chemical attributes on the symbiosis. A preliminary greenhouse assay evaluated five maize landraces and five conventional modern genotypes in non-sterile, low-P soil. Sixty days after sowing, we measured plant height, stem diameter, shoot and root dry biomass, root colonization structures, and shoot P concentration and total accumulation. In a second stage, a 2-year on-farm study evaluated how soil physical-chemical attributes in fields with three plant genotype groups affected the arbuscular mycorrhizal fungal symbiosis in a maize diversity microcenter in Southern Brazil. We collected soil and plant material in farms growing landrace, conventional modern genotypes, or genetically modified (GM) maize. There were five collection points at each group, and we measured mycorrhizal colonization, soil physicochemical attributes, and shoot phosphorus concentration. The greenhouse study showed that genotypes have different growth strategies for root production and shoot growth. No differences in mycorrhizal colonization rates occurred among landraces and modern maize genotypes in the low-P soil. The field study showed that soil and climate conditions had a more marked effect on mycorrhizal root colonization than plant genotype groups (landrace, conventional modern genotypes, or GM maize).


Roof runoff contamination: Establishing material-pollutant relationships and material benchmarking based on laboratory leaching tests.
Because roofs represent a major part of the urban impervious surface, it is hypothesized that roof runoff is an important source of urban stormwater contamination. However, the contribution of different roofing materials to this contamination has only been examined to a limited extent. In this study, a resource and time efficient methodology, which uses some of the principles of a standardized leaching test (CEN/TS16637-2), was developed to identify material-pollutant relationships for sixteen commonly used roofing materials (EPDM, PVC, TPO, EVA, PU and bitumen membranes). Metals were detected in concentrations ranging from several μg/L in the leachate of synthetic materials up to 2.5 mg/L for Zn in the leachate of EPDM materials. Cd and Cr were not detected in any of the leachates. Furthermore, polycyclic aromatic hydrocarbons were detected in most leachates, with phenanthrene and naphthalene being most frequently detected in concentrations up to 4.5 μg/L for naphthalene. Further insights on organic pollutants' leaching from the tested materials were obtained by a non-target GC-MS screening of the leachates. Several commonly used additives such as flame retardants and light stabilizers were detected. Although no information on long-term leaching and material behavior under outdoor conditions could be obtained by the developed methodology, the laboratory test results could be used to benchmark the materials for their potential impact on roof runoff quality by the calculation of material indexes (which summarize the material-pollutant relationships). EPDM and PU roofing materials were identified as the materials having the highest potential to affect roof runoff quality.


Automatic Remasking of Digital Subtraction Angiography Images in Pulmonary Angiography.
In pulmonary angiography, the heartbeat creates artifacts that hinder extraction of blood vessel images in digital subtraction angiography. Remasking according to the cardiac phase of the angiogram may be effective but has yet to be automated. Here, automatic remasking was developed and assessed according to the cardiac phase from electrocardiographic information collected simultaneously with imaging. Manual remasking, fixed remasking, and our proposed automatic remasking were applied to 14 pulmonary angiography series from five participants with either chronic thromboembolic pulmonary hypertension or pulmonary arteriovenous malformation. The processing time and extent of artifacts from the heartbeat were compared. In addition, the peak signal-to-noise ratio (PSNR) was measured from differential images between mask image groups before the injection of the contrast medium to investigate optimal mask images. The mean time required for automatic remasking was 4.7 s/series, a significant reduction in processing time compared with the mean of 266 s/series for conventional manual processing. A visual comparison of the different approaches showed virtually no misregistration artifacts from the heartbeat in manual or automatic remasking according to cardiac phase. The results from measuring the PSNR for differential images between mask image groups also showed that smaller cardiac phase difference and time difference between two images ensure higher PSNR (p < 0.01). Automatic remasking according to the cardiac phase was fast and easy to implement and reduced misregistration artifacts from heartbeat.


Imaginal disc development in a non-pupariating lethal mutant inDrosophila melanogaster.
Imaginal disc development in the non-pupariating lethall(1)npr-1, a mutant that maps to an ecdysone early puff site, is studied in situ, in vitro and in transplanted discs. Disc development is slightly abnormal from the middle of the third instar with severe abnormalities appearing after the rise in 20-hydroxyecdysone that triggers metamorphosis. The mutant discs only partly evaginate and do not undergo any of the detailed morphological changes characteristic of metamorphosis. Treatment of the mutant dises in vitro with colcemid and trypsin facilitates evagination but the appendages remain morphologically abnormal. A number of differentiative processes occur in mutant discs in situ and in discs transplanted into wild type hosts in spite of the absence of normal morphogenesis. Implications of the observations for normal disc development are discussed. Possible modes of action of thel(1)npr-1 gene are also discussed in light of the observation that the mutant gene maps to a locus which is thought to have a regulatory function in development.


Local preoptic/anterior hypothalamic warming alters spontaneous and evoked neuronal activity in the magno-cellular basal forebrain.
Local warming of the medial preoptic/anterior hypothalamus (POAH) promotes sleep, enhances EEG slow-wave activity during sleep, and suppresses arousal-related discharge in neurons of the midbrain reticular formation (MRF) and the posterior lateral hypothalamic area (PLHa). Another important site of sleep and arousal regulation, and a potential site of POAH thermal modulation, is the magnocellular basal forebrain (BF). We examined the ability of local POAH warming during wakefulness to influence the spontaneous and evoked discharge of neurons recorded in the BF of unanesthetized, unrestrained cats. Seventy of 174 BF neurons responded to 60-90 s periods of POAH warming with either increases or decreases in discharge rate. Forty-one of the 70 responsive cells displayed suppression of waking discharge during warming. Discharge rate in these cells declined by an average of 26.04 +/- 2.76%/degrees C of POAH temperature increase. The majority of warming-suppressed BF cells (73%) displayed higher rates of discharge during periods of wakefulness compared to periods of sleep. Twenty-nine of 70 responsive cells responded to POAH warming with an average increase in discharge rate of 43.81 +/- 6.26%/degrees C. A majority of these neurons (62%) exhibited higher spontaneous discharge rates during sleep compared to waking. Orthodromic excitatory responses were evoked in 29 BF cells by electrical stimulation of the MRF or PLHa. Thirteen of 29 cells displayed a waking-related discharge pattern, and responded to POAH warming with a significant suppression of evoked excitation. For a group of 15 behavioral state-indifferent cells (i.e., cells displaying no modulation of spontaneous discharge rate across the sleep-waking cycle), POAH warming had no effect on evoked excitatory responses. These results support the hypothesis that thermosensitive neurons of the POAH exert control of sleep-waking state, in part, via modulation of arousal- and sleep-regulating cell types within the magnocellular BF.


An improved and reproducible protocol for the extraction of high quality fungal RNA from plant biomass substrates.
Isolation of high quantity and quality RNA is a crucial step in the detection of meaningful gene expression data. Obtaining intact fungal RNA from complex lignocellulosic substrates is often difficult, producing low integrity RNA which perform poorly in downstream applications. In this study we developed an RNA extraction method using CsCl centrifugation procedure, modified from previous reports and adapted for isolation of RNA from plant biomass. This method provided high level of integrity and good quantity of RNA which were suitable for reliable analyses of gene expression and produced consistent and reproducible results.


NF-κB is a critical mediator of post-mitotic senescence in oligodendrocytes and subsequent white matter loss.
Inflammaging represents an accepted concept where the immune system shifts to a low-grade chronic pro-inflammatory state without overt infection upon aging. In the CNS, inflammaging is mainly driven by glia cells and associated with neurodegenerative processes. White matter degeneration (WMD), a well-known process in the aging brain, manifests in myelin loss finally resulting in motor, sensory and cognitive impairments. Oligodendrocytes (OL) are responsible for homeostasis and maintenance of the myelin sheaths, which is a complex and highly energy demanding process sensitizing these cells to metabolic, oxidative and other forms of stress. Yet, the immediate impact of chronic inflammatory stress like inflammaging on OL homeostasis, myelin maintenance and WMD remains open. To functionally analyze the role of IKK/NF-κB signaling in the regulation of myelin homeostasis and maintenance in the adult CNS, we established a conditional mouse model allowing NF-κB activation in mature myelinating oligodendrocytes. IKK2-CAPLP-CreERT2 mice were characterized by biochemical, immunohistochemical, ultrastructural and behavioral analyses. Transcriptome data from isolated, primary OLs and microglia cells were explored by in silico pathway analysis and validated by complementary molecular approaches. Chronic NF-κB activation in mature OLs leads to aggravated neuroinflammatory conditions phenocopying brain inflammaging. As a consequence, IKK2-CAPLP-CreERT2 mice showed specific neurological deficits and impaired motoric learning. Upon aging, persistent NF-κB signaling promotes WMD in these mice as ultrastructural analysis revealed myelination deficits in the corpus callosum accompanied by impaired myelin protein expression. RNA-Seq analysis of primary oligodendrocytes and microglia cells uncovers gene expression signatures associated with activated stress responses and increased post mitotic cellular senescence (PoMiCS) which was confirmed by elevated senescence-associated β-galactosidase activity and SASP gene expression profile. We identified an elevated integrated stress response (ISR) characterized by phosphorylation of eIF2α as a relevant molecular mechanism which is able to affect translation of myelin proteins. Our findings demonstrate an essential role of IKK/NF-κB signaling in mature, post-mitotic OLs in regulating stress-induced senescence in these cells. Moreover, our study identifies PoMICS as an important driving force of age-dependent WMD as well as of traumatic brain injury induced myelin defects.


Increased frequency of goitre in epileptic patients on long-term phenytoin or carbamazepine treatment.
Thyroid function, the clinical occurrence of goitre and ultrasonically determined thyroid gland volume were investigated in 23 patients with phenytoin- and 28 patients with carbamazepine-treated convulsive disorders and compared with matched healthy controls. In the phenytoin treated group median thyroid volume was 26 ml (range 14-57 ml) compared to 17 ml (range 8-41 ml) in the controls (P less than 0.01). Ten patients and four controls had a goitre (NS). Median serum T4 and FT4I levels were reduced, serum TSH level increased and serum T3, T3RU, FT3I and thyroglobulin levels unaltered compared with the controls. In the carbamazepine treated group median thyroid volume was 25 ml (range 13-66 ml) compared to 16 ml (range 9-44 ml) in the controls (P less than 0.01). Thirteen patients and three controls had a goitre (P less than 0.02). Median serum T4, FT4I and FT3I levels were reduced, serum thyroglobulin increased and serum T3, T3RU and TSH levels unaltered compared with the controls. The increase in thyroid size is probably a compensatory mechanism due to the low free thyroid hormones in serum caused by an increased hepatic degradation of thyroid hormones by phenytoin and carbamazepine.


On-line determination of aliphatic amines in water using in-tube solid-phase microextraction-assisted derivatisation in in-valve mode for processing large sample volumes in LC.
This paper describes a cost-effective procedure for the analysis of short-chain aliphatic amines in water samples using a solid-phase microextraction device. Analyte preconcentration and derivatisation were effected into a capillary column coated with 95% polydimethylsiloxane-5% polydiphenylsiloxane, which was used as the injection loop of a Rheodyne injection valve. The coating was previously loaded with the derivatisation reagent, 9-fluorenylmethyl chloroformate. A volume of 1 mL of samples was then drawn into the capillary column, and the extracted analytes were left to react on the capillary coating for 5 min. Next, the capillary column was cleaned by passing water. Finally, the injection valve was rotated, and the derivatives formed were dynamically desorbed and transferred to the analytical column into the mobile phase. Methylamine, ethylamine, propylamine, n-butylamine and n-pentylamine were selected as model compounds. Excellent sensitivity was achieved, being the limits of detection of 15-200 microg/L when using UV detection and of 0.1-0.4 microg/L by fluorescence.


Practitioners beware: regional differences in beliefs about nutrition during pregnancy.
We surveyed 1,771 members of The American Dietetic Association, who worked in general nutrition, pediatrics, and public health nutrition, about their clients' beliefs about nutrition during pregnancy. The practitioners were chosen because they likely served pregnant women and/or women with young children. Items for the belief inventory were generated by surveying the beliefs of pregnant and nonpregnant adolescents and their families, teachers, and peers as well as by collecting beliefs heard from clients of social workers, nurses, and dietitians residing in the state of Tennessee. Using a modified q-sort, 26 statements were developed to survey dietitians practicing nationwide. Results indicate that beliefs about physiological needs during pregnancy, practices related to a healthy baby, and beverage recommendations were not significantly different across the regions designated by US Public Health Services (Standard Federal Administrative Regions). However, beliefs about cravings and folklore showed strong regional differences, with the Southeast regions and adjacent states differing significantly from other regions. The majority of beliefs are not supported by scientific information, and results support the need for each region to identify beliefs that could influence dietary patterns (eg, eating for two, eating only a few selected foods, restricting salt, taking vitamins to overcome an inadequate diet, and deciding pregnancy is a good time to lose weight). We recommend that dietetic practitioners become aware of clients' beliefs, support beliefs that are accurate according to current recommendations for pregnancy, and counsel clients about beliefs that are potentially detrimental to good nutrition during pregnancy.


Prognostic implications of PD-L1 expression in patients with angiosarcoma.
There are limited data on the feasibility of programmed death ligand-1 (PD-L1) expression as a prognostic biomarker in metastatic angiosarcoma. We retrospectively collected and analyzed the data on PD-L1 expression in 70 angiosarcoma patients who were diagnosed at our center between 2005 and 2019. Thirteen (19%) patients had PD-L1 expression. Metastatic angiosarcoma patients who were PD-L1-negative (n = 24) showed longer median progression-free survival (4.9 vs 1.6 months; p = 0.04) and median overall survival (OS; 10.9 vs 5.4 months; p = 0.01) than those who were PD-L1-positive (n = 4). PD-L1 status proved to be a significant factor for OS. Metastatic angiosarcoma patients with PD-L1 expression showed shorter survival. PD-L1 status is an independent prognostic factor for OS in metastatic angiosarcoma patients.


Elastocapillarity: stress transfer through fibrous probes in wicking experiments.
Current advances in the manufacture of nanoporous and nanofibrous materials with high absorption capacity open up new opportunities for the development of fiber-based probes and sensors. Pore structures of these materials can be designed to provide high suction pressure and fast wicking. During wicking, due to the strong capillary action, liquids exert stresses on the fiber network. In this paper, we discuss the effect of stress transfer in the direction of propagation of the wetting front. As an illustration, we first consider a single capillary and demonstrate the effect of a moving meniscus on stress distribution along capillary walls. We then analyze similar effects in yarns. We consider a yarn that can capture an aerosol droplet as a promising sensing element that could monitor the stresses caused by wetting fronts. We also discuss the elastocapillary effects occurring during upward and downward wicking. The distributions of stresses in these two cases are shown to differ significantly. We discuss how these effects might be exploited for designing fiber-based sensors that can probe very small amounts of liquids.


High avoidance and low approach motivation affect cognitive reappraisal generation in the face of anger.
This study investigates the link between the revised reinforcement sensitivity theory (RST) and individuals' capacity to spontaneously invent alternate appraisals for aversive events. Eighty-two women completed the Reappraisal Inventiveness Test for anger-eliciting situations, and quantity and quality of reappraisal ideas were correlated with BIS, BAS, and FFFS sensitivity (RST-Personality Questionnaire). Results revealed that high BIS and high FFFS reduced the total number of reappraisal ideas, indicating that combined heightened sensitivity of the two avoidance systems may deplete individuals' repertoire of potential reappraisals. RST effects on the quality of generated reappraisals were also found. High BIS and low BAS lowered individuals' propensity to produce positive re-interpretations, which are considered a more adaptive reappraisal tactic. High FFFS sensitivity was linked to a lower preference for problem-oriented reappraisals. This study underlines that certain interactions of motivational subsystems may be particularly detrimental for successful reappraisal of anger-eliciting events. Our findings reveal potential links between revised RST effects and adaptive emotion regulation.


Species-specific defence responses facilitate conspecifics and inhibit heterospecifics in above-belowground herbivore interactions.
Conspecific and heterospecific aboveground and belowground herbivores often occur together in nature and their interactions may determine community structure. Here we show how aboveground adults and belowground larvae of the tallow tree specialist beetle Bikasha collaris and multiple heterospecific aboveground species interact to determine herbivore performance. Conspecific aboveground adults facilitate belowground larvae, but other aboveground damage inhibits larvae or has no effect. Belowground larvae increase conspecific adult feeding, but decrease heterospecific aboveground insect feeding and abundance. Chemical analyses and experiments with plant populations varying in phenolics show that all these positive and negative effects on insects are closely related to root and shoot tannin concentrations. Our results show that specific plant herbivore responses allow herbivore facilitation and inhibition to co-occur, likely shaping diverse aboveground and belowground communities. Considering species-specific responses of plants is critical for teasing apart inter- and intraspecific interactions in aboveground and belowground compartments.


Unilateral acute posterior multifocal placoid pigment epitheliopathy in a convalescent COVID-19 patient.
To report a case of unilateral acute posterior multifocal placoid pigment epitheliopathy (APMPPE) in a Hispanic convalescent COVID-19 female patient. Case presentation A 35-year-old Hispanic female with exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was evaluated due to unilateral visual loss. Ophthalmic examination and diagnostic tests were consistent with APMPPE. Ocular changes can be observed in patients with COVID-19. A complete ophthalmic evaluation must be performed in patients with low vision after SARS-CoV-2 infection.


Genomic analysis of Pseudomonas putida: genes in a genome island are crucial for nicotine degradation.
Nicotine is an important chemical compound in nature that has been regarded as an environmental toxicant causing various preventable diseases. Several bacterial species are adapted to decompose this heterocyclic compound, including Pseudomonas and Arthrobacter. Pseudomonas putida S16 is a bacterium that degrades nicotine through the pyrrolidine pathway, similar to that present in animals. The corresponding late steps of the nicotine degradation pathway in P. putida S16 was first proposed and demonstrated to be from 2,5-dihydroxy-pyridine through the intermediates N-formylmaleamic acid, maleamic acid, maleic acid, and fumaric acid. Genomics of strain S16 revealed that genes located in the largest genome island play a major role in nicotine degradation and may originate from other strains, as suggested by the constructed phylogenetic tree and the results of comparative genomic analysis. The deletion of gene hpo showed that this gene is essential for nicotine degradation. This study defines the mechanism of nicotine degradation.


Sequence analysis for the complete proviral genome of reticuloendotheliosis virus Chinese strain HA9901.
The genomic DNA extracted from chicken embryo fibroblast (CEF) infected with a Chinese field isolate HA9901 of reticuloendotheliosis virus (REV) was used as the template to amplify the REV proviral genomic cDNA by PCR with 6 pairs of primers according to published sequences. Six overlapping fragments were amplified, cloned into the TA vector and sequenced, including a fragment which was amplified from the circular proviral cDNA and covering both 5'- and 3'-ends. The complete sequence of the whole genome was established and analyzed with a DNAstar software. Comparisons of the sequence with two other strains demonstrated that the genomes of REV were relatively conservative, the homogenecity for all genes or LTR fragments of the 3 strains was over 92%, no matter whether they were isolated from different species and regions in different years. But, the homology of Chinese strain HA9901 to a fowl pox virus-associated strain from Chickens was higher than that to strain SNV isolated from ducks.


Early Lifestyle Determinants of Adiposity Trajectories from Childhood into Late Adolescence.
Objective: The aim of this study was to examine associations of childhood physical activity, sedentary behavior, and dietary intake with adiposity trajectories from childhood to adolescence. Methods: Quebec Adipose and Lifestyle Investigation in Youth (QUALITY) cohort (n = 630) data from 3 time points (8-10, 10-12, and 15-17 years) for 377 Caucasian children with parental obesity were analyzed. Height and weight, physical activity and sedentary behavior (7-day accelerometry), screen time (self-reported), and dietary intake (three 24-hour diet recalls) were measured. Group-based trajectory modeling identified longitudinal trajectories of body-mass index z-scores (zBMIs). Inverse probability of exposure-weighted multinomial logistic regressions examined associations between baseline lifestyles and zBMI trajectory groups. Results: Six trajectory groups were identified: Stable-Low-Normal-Weight (two groups, 5.7% and 33.0%, which were combined), Stable-High-Normal-Weight (24.8%), Stable-Overweight (19.8%), Stable-Obesity (8.8%), and Overweight-Decreasers (7.9%). For every additional portion of fruits and vegetables, the likelihood of being in the group of Overweight-Decreasers increased by 29% (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.09-1.55) compared with the reference group (Stable-Low-Normal-Weight). For every additional hour of sedentary behavior, the likelihood of belonging to the group of Overweight-Decreasers increased 2-fold (OR: 1.99, 95% CI: 1.28-3.21) and Stable-Obesity increased 1.5-fold (OR: 1.56, 95% CI: 1.08-2.23), compared with the reference. Every additional 10 minutes of moderate-to-vigorous physical activity was associated with a lower likelihood of belonging to the Stable-Obesity group (OR: 0.75, 95% CI: 0.61-0.89) and to the group of Overweight-Decreasers (OR: 0.79, 95% CI: 0.64-0.95) compared with the reference. Finally, children were more likely to belong to the Stable-Obesity group with each additional hour/day of screen time (OR: 1.23, 95% CI: 1.01-1.58). Conclusions: Trajectories of zBMIs from childhood to late adolescence were stable, except for one group which decreased from overweight in childhood to normal weight in adolescence. The latter had more favorable baseline dietary intake of fruits and vegetables. ClinicalTrials.org no. NCT03356262.


Mycobacterium tuberculosis attenuated by multiple deletions of rpf genes effectively protects mice against TB infection.
In this study, we investigated the residual virulence of mutants of Mycobacterium tuberculosis that are defective in 4 of the 5 rpf-like genes, their capacity to persist in the murine host and the utility present in these mutants to serve as novel vaccine candidates. Our data indicate that the two quadruple rpf deletion mutants, ΔACBD and ΔACDE, both display significant attenuation in the mouse lungs after aerosol infection, with no observable increase in bacillary loads upon aminoguanidine-induced immune suppression. However, after subcutaneous injection these strains were able to persist at the low level, similar to that of BCG, in the mouse lungs and lymphoid organs. Furthermore, both rpf quadruple mutants were able to enhance the numbers of IFN-γ-producing T-cells in spleens to a level comparable to that of BCG, and conferred protection upon subsequent challenge with virulent M. tuberculosis in terms of mycobacterial multiplication in organs and survival time. The reduction in organ bacillary loads after vaccination with ΔACDE was comparable to that of BCG, while ΔACBD displayed a small but statistically significant enhancement in protection compared to BCG. Collectively, these data suggest that rpf deletion mutants show potential for further development as novel vaccine candidates for tuberculosis.


Resolution of severe obsessive--compulsive disorder after a small unilateral nondominant frontoparietal infarct.
Obsessive--compulsive disorder (OCD) is a disabling neuropsychiatric disorder, which rarely spontaneously remits. We present a case of a patient suffering with severe OCD whose symptoms disappeared immediately following a small right posterior frontoparietal infarct. We speculate that the lesion modulated the cortical-subcortical circuits, likely through a change in input into in the dorsolateral prefrontal cortex. This could have implications regarding surgical targeting in OCD.


Current trends in research and clinical issues in the study of personality and its disorders: a survey of the presentations at the ISSPD anniversary congress.
The International Society for the Study of Personality Disorders (ISSPD) celebrated its 25th anniversary in September 2013 in Copenhagen and commemorated the First International Congress at the same site. The overall theme of the congress was "Bridging Personality and Psychopathology: The Person Behind the Illness." More than 400 abstracts were submitted, and the program included 8 keynote presentations, 18 invited symposia, a debate on current controversial issues in the classification of personality disorders (Fossati, Tyrer, Livesley, and Krueger), an ISSPD award lecture (Silk), a jubilee lecture (Simonsen), a young researchers' symposium (Hopwood, Sharp, and Kaess), and special lectures on the Danish philosopher Soeren Kierkegaard and the poet Hans Christian Andersen. In this article we will survey the presentations and highlight the important issues in order to underline the current trends in research and clinical interests in personality disorders. The keynote video presentations, invited symposia, and slide presentations are freely available at www.isspd2013.com.


Malawer limb salvage surgery for the treatment of scapular chondrosarcoma.
Chondrosarcoma is a common malignant bone tumor, which accounts for 20% of all malignant bone tumors. It often occurs in the long bones, but the incidence of scapular chondrosarcoma is rare. Here, we describe a case of a large chondrosarcoma occurring in the scapula which was treated with Malawer limb salvage surgery. The patient retained considerable limb function after complete removal of the tumor tissue as assessed at the follow-up visit two years and ten months following surgery.


Repetitive behavior in 12-month-olds later classified with autism spectrum disorder.
As compared to the utility of early emerging social communicative risk markers for predicting a later diagnosis of autism spectrum disorder (ASD), less is known about the relevance of early patterns of restricted and repetitive behaviors. We examined patterns of stereotyped motor mannerisms and repetitive manipulation of objects in 12-month-olds at high and low risk for developing ASD, all of whom were assessed for ASD at 24 months. Observational coding of repetitive object manipulation and stereotyped motor behaviors in digital recordings of the Communication and Symbolic Behavior Scales was conducted using the Repetitive and Stereotyped Movement Scales for 3 groups of 12-month-olds: low-risk infants (LR, n = 53); high-familial-risk infants who did not meet diagnostic criteria for ASD at 24 months (HR-negative, n = 75); and high-familial-risk infants who met diagnostic criteria for ASD at 24 months (HR-ASD, n = 30). The HR-ASD group showed significantly more stereotyped motor mannerisms than both the HR-negative group (p = .025) and the LR group (p = .001). The HR-ASD and HR-negative groups demonstrated statistically equivalent repetitive object manipulation scores (p = .431), and both groups showed significantly more repetitive object manipulation than the LR group (p < .040). Combining the motor and object stereotypy scores into a Repetitive and Stereotyped Movement Scales (RSMS) composite yielded a disorder-continuum effect such that each group was significantly different from one another (LR < HR-negative < HR-ASD). These results suggest that targeted assessment of repetitive behavior during infancy may augment early ASD identification efforts.


Dipyridamole reverses peripheral ischemia and induces angiogenesis in the Db/Db diabetic mouse hind-limb model by decreasing oxidative stress.
Dipyridamole anti-platelet therapy has previously been suggested to ameliorate chronic tissue ischemia in healthy animals. However, it is not known if dipyridamole therapy represents a viable approach to alleviating chronic peripheral tissue ischemia associated with type 2 diabetes. Here we examine the hypothesis that dipyridamole treatment restores reperfusion of chronic hind-limb ischemia in the murine B6.BKS-Lepr(db/db) diabetic model. Dipyridamole therapy quickly rectified ischemic hind-limb blood flow to near preligation levels within 3 days of the start of therapy. Restoration of ischemic tissue blood flow was associated with increased vascular density and endothelial cell proliferation observed only in ischemic limbs. Dipyridamole significantly increased total nitric oxide metabolite levels in tissue, which were not associated with changes in endothelial NO synthase expression or phosphorylation. Interestingly, dipyridamole therapy significantly decreased ischemic tissue superoxide and protein carbonyl levels, identifying a dominant antioxidant mechanistic response. Dipyridamole therapy also moderately reduced diabetic hyperglycemia and attenuated development of dyslipidemia over time. Together, these data reveal that dipyridamole therapy is an effective modality for the treatment of chronic tissue ischemia during diabetes and highlights the importance of dipyridamole antioxidant activity in restoring tissue NO bioavailability during diabetes.


Epidemiological studies on Salmonella in a certain area ("Walcheren Project"). IV. The incidence of Salmonella in the sewage system, in the faeces of man and pets as well as in shops, kitchens and lavatories in the village of Aagtekerke.
As part of the epidemiological investigations on Salmonella ion the former island of Walcheren, the contamination of sewage water in the village of Aagtekerke was studied over a prolonged period of time. These studies showed that this sewage water was frequently contaminated by large numbers of Salmonella. In the present study efforts were made to find the source of this contamination and for this purpose the incidence of Salmonella in the sewage system, in the faeces of man and pets as well as in shops, kitchens and lavatories in the village of Aagtekerke was studied for a period of three weeks in June 1977. Salmonella was only isolated from a few samples of faecal material of human and animal origin, and from the sewage system (including the inlet water and effluents of the sewage works). Serotyping showed that the strains isolated from human faeces were similar to those found to be present in the sewage system. This fact taken in conjunction with the results of the bacterial counts, suggests that the sewage system was only contaminated by a small number of carriers. The reduction of contamination observed in the sewage system during the period of investigation could be evidence that Salmonella organisms cannot survive by themselves in an environment of this type, at least not at the temperatures recorded when collecting samples from the sewage water. Growth of organisms under more favourable conditions cannot be ruled out. A questionnaire about the dietary habits and kitchen hygiene of the local population showed that contamination within households, originating with the food, is a real possibility.


Development of Transition-Metal-Free Lewis Acid-Initiated Double Arylation of Aldehyde: A Facile Approach Towards the Total Synthesis of Anti-Breast-Cancer Agent.
This work describes a mild and robust double hydroarylation strategy for the synthesis of symmetrical /unsymmetrical diaryl- and triarylmethanes in excellent yields using Lambert salt (0.2-1.0 mol%). Despite the anticipated challenges associated with controlling selective product formation, unsymmetrical diaryl- and triarylmethanes products are obtained unprecedentedly. A highly efficient gram scale reaction has also been reported (TON for symmetrical product=475 and for unsymmetrical product=390). The synthetic utility of the methodology is demonstrated by the preparation of several unexplored diaryl- and triarylmethane-based biologically relevant molecules, such as arundine, vibrindole A, turbomycin B, and certain anti-inflammatory agents. A total synthesis of an anti-breast-cancer agent is also demonstrated. Control experiments, Hammett analysis, HRMS and GC-MS studies reveal the reaction intermediates and reaction mechanism.


Prospects for the Use of Gold Nanoparticles to Increase the Sensitivity of an Acoustic Sensor in the Detection of Microbial Cells.
The interaction of microbial cells with antibody-gold nanoparticle conjugates in conductive suspensions was experimentally studied by using an acoustic slot-mode sensor. The sensor consisted of a piezoelectric plate with a propagating acoustic wave and a liquid container located above this plate with a given gap. An analysis of the measured parameters of the sensor revealed that the specific interaction of bacterial cells with the conjugates led to a stronger change in the sensor output signal than the specific interaction of bacterial cells with antibodies. The measurements were made for Azospirillum brasilense Sp7 cells in buffer with an initial conductivity of 5-30 μS/cm. The limit of cell detection with the conjugates was 103 cells/mL, and the analysis took about 4 min. The advantage of the sensor is the possibility of repeated use and cleaning of the liquid container without damaging the sensor's elements. These results are promising for use in rapid test systems for the direct detection of microbial cells in actual samples of liquids in medical diagnostics.


Seasonal dynamics of nitrate and ammonium ion concentrations in soil solutions collected using MacroRhizon suction cups.
The aims of the study were to analyse the concentration of nitrate and ammonium ions in soil solutions obtained using MacroRhizon miniaturized composite suction cups under field conditions and to determine potential nitrogen leaching from soil fertilized with three types of fertilizers (standard urea, slow-release urea, and ammonium nitrate) at the doses of 90 and 180 kg ha-1, applied once or divided into two rates. During a 3-year growing experiment with sugar sorghum, the concentration of nitrate and ammonium ions in soil solutions was the highest with standard urea fertilization and the lowest in variants fertilized with slow-release urea for most of the months of the growing season. Higher concentrations of both nitrogen forms were noted at the fertilizer dose of 180 kg ha-1. One-time fertilization, at both doses, resulted in higher nitrate concentrations in June and July, while dividing the dose into two rates resulted in higher nitrate concentrations between August and November. The highest potential for nitrate leaching during the growing season was in July. The tests confirmed that the miniaturized suction cups MacroRhizon are highly useful for routine monitoring the concentration of nitrate and ammonium ions in soil solutions under field conditions.


Computer-aided dosage form design. III. Feasibility assessment for an oral prolonged-release phenytoin product.
Previous publications described computer-aided methodology for assessing the feasibility of designing prolonged release oral dosage forms containing linear-disposition drugs. Those methods determined all useful release rates and examined those rates to decide whether product development was warranted. The present study developed software to obtain similar information for phenytoin, which exhibits Michaelis-Menten disposition. The values for Vmax, Km, and Vd in 27 patients were employed to assess the ability of prolonged absorption to maintain steady-state plasma concentrations between 10 and 20 mg/liter following oral administration at 8-, 12-, and 24-hr intervals. Phenytoin steady-state plasma concentrations in this range were controlled by elimination and were not extended by prolonged absorption. Furthermore, single i.v. bolus doses resulting in an initial plasma level of 20 mg/liter provided concentrations above 10 mg/liter for approximately 1 to 3 days. When an oral multiple-dose regimen was found to maintain steady-state concentrations between 10 and 20 mg/liter, that dose and interval produced concentrations within that range regardless of the absorption rate. While absorption rate was not important, each patient's dose ranges were extremely narrow, emphasizing that dose size was the dominant factor in the control of phenytoin levels.


Evaluation of marginal adaptation of Co-Cr-Mo metal crowns fabricated by traditional method and computer-aided technologies.
The purpose of this study was to evaluate the marginal gaps of dental restorations manufactured using conventional loss wax and casting, computer-aided design/computer-aided manufacturing (CAD/CAM), and 3D printing methods. A zirconia master die model with an upper right first molar resin crown was prepared as a standardized model. A total of 30 resin master die models were duplicated from this standard model. Simultaneously, 10 Co-Cr-Mo metal crowns were individually obtained using the conventional loss wax and casting method (Group A), selective laser sintering (Group B), and CAD/CAM (Group C), respectively. The marginal gaps between the crowns fabricated conventional and digital methods with master die models were calculated using a 3D replica and mapping technique. Statistical analyses revealed there were significant differences in the marginal gaps in the group A with group B and C (p < 0.05). The mean marginal gaps between dental crowns with die models were 76 ± 61 μm, 116 ± 92 μm, and 121 ± 98 μm for groups A, B, and C, respectively. Within the limitations of this study, the marginal gaps were clinical acceptable in conventional and digital techniques.


Echinococcal cysts in the common bile duct: an uncommon cause of obstruction.
Obstruction of the biliary system due to intraductal echinococcal cysts is a rare but serious presentation of hepatic echinococcal disease. Four cases are described. There was a 50% mortality rate and morbidity was high. The clinical presentation is difficult to differentiate from other disease processes. Careful preoperative sonograms should be taken to detect echogenic cyst material in the biliary system in all patients with hepatic echinococcal cysts. If biliary pigments are seen in the cyst during surgical removal, or if the patient has a recent history of jaundice or cholangitis, intraoperative cholangiography should be done to rule out intraductal cysts, which may cause obstruction.


Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice.
The extensive and unpredictable biliary excretion of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G) may contribute to the wide interpatient variability reported in the disposition and gastrointestinal toxicity of CPT-11. We studied the role of P-glycoprotein (P-gp) in in vivo biliary excretion of CPT-11, SN-38 and SN-38G in mice lacking mdr1-type P-gp [ mdr1a/1b(-/-)] in the presence of the multidrug resistance (MDR) reversal agent, PSC833. Wild-type (Wt) and mdr1a/1b(-/-) mice ( n=3 or 4) were treated intragastrically with PSC833 (50 mg/kg) or vehicle 2 h prior to i.v. CPT-11 dosing (10 mg/kg), and bile samples were collected. P-gp was found to play an important role in CPT-11 biliary excretion, as there was a significant (40%, P<0.05) decrease in its biliary recovery in 90 min in mdr1a/1b(-/-) mice (6.6+/-0.6% dose) compared with Wt mice (11+/-1.2%). This also implied a major role of other undetermined non-P-gp-mediated mechanism(s) for hepatic transport of CPT-11, which was inhibited by PSC833 (1.8+/-0.8% with PSC833, 6.6+/-0.6% without PSC833) in mdr1a/1b(-/-) mice. SN-38 and SN-38G biliary transport was unchanged in mice lacking P-gp after vehicle treatment, indicating a lack of P-gp mediation in their transport. PSC833 significantly reduced (56-89%) SN-38 and SN-38G biliary transport in Wt and mdr1a/1b(-/-) mice, suggesting that PSC833 may be a candidate to modulate biliary excretion of SN-38 with potential use in reducing CPT-11 toxicity.


An unusual presentation of diffuse large B-cell lymphoma with ureteric involvement: A case report.
Non-Hodgkin's lymphomas are a heterogeneous group of malignancies in the lymphoid system and ureteric involvement by non-Hodgkin's lymphoma is very rare. We present a 37-year-old male, presenting with lower urinary tract symptoms and right flank pain. Initially, he presented with lower urinary tract symptoms without having any evidence of urinary tract infection and was managed for nonspecific cystitis. His ureteral histopathology report indicated a diffused infiltration by malignant lymphoid cells and the final diagnosis revealed diffuse large B-cell lymphoma. His positron-emission tomography scan indicated stage 4 disease with skeletal involvement and he was then treated by rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and methylprednisolone chemotherapy. Later, he was also diagnosed with central nervous system lymphoma and died during his stay in the hospital. Primary diffuse large B-cell lymphoma of the ureter is extremely rare; however, it should be considered in the differential diagnosis for patients presenting with obstructive uropathy as its early detection is crucial for diagnostic and therapeutic treatment.


Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity.
As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4(+) T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.


MiR-29b expression is altered in crescent formation of HSPN and accelerates Ang II-induced mesangial cell activation.
MicroRNA-29b (miR-29b) has been suggested to possess pro-inflammatory activity, which can partially be explained by the repression of tumor necrosis factor alpha protein three antibody (TNFAIP3). Meanwhile, it also promotes thyroid cell proliferation via Smad signaling pathways. The present study aimed to elucidate the role of miR-29b in Henoch Schönlein purpura nephritis (HSPN) and its underlying molecular mechanism in angiotensin II (Ang II)-induced human glomerular mesangial cell (HGMC) activation. We evaluated miR-29b expression in 35 HSPN renal tissues based on crescent formation, glomerular sclerosis, interstitial fibrosis, thrombosis formation and capillary loop necrosis. Meanwhile, HGMCs were cultured, treated with Ang II and then transfected with LV-hsa-miR-29b-1 to induce miR-29b overexpression or LV-hsa-miR-29b-3p-inhibition to inhibit miR-29b expression. Finally, we examined the effects of miR-29b on cell proliferation and release of inflammatory mediators. We observed that miR-29b expression was significantly higher in the crescent group than in the no crescent group. MiR-29b overexpression induced the release of intercellular adhesion molecule-1, interleukin-1β (IL-1β), IL-6, IL-8, the increase of CyclinA2, CyclinD1, and cell proliferation. It also could inhibit the expressions of TNFAIP3 and NF-kappa-B-repressing factor (NKRF). Correspondingly, miR-29b inhibition produced the opposite effects and increased the expression of TNFAIP3 and NKRF. MiR-29b expression is altered in crescent formation of HSPN and accelerates Ang II-induced mesangial cell proliferation and release of inflammatory mediators.


Outcome and effect of endovascular treatment in stroke associated with acute extracranial internal carotid artery occlusion: Single-center experience in Japan.
Positive data from several randomized controlled trials (RCTs) of endovascular treatment (EVT) for acute ischemic stroke (AIS) patients with anterior circulation large vessel occlusion (ACLVO) have emerged. However, little evidence exists on EVT for acute extracranial internal carotid artery (EC-ICA) occlusion. We therefore analysed the outcome and effect of EVT on AIS due to ACLVO caused by EC-ICA occlusion, including tandem occlusion compared with that caused by pure intracranial artery occlusion. A total of 135 consecutive AIS patients with ACLVO between July 2014 and December 2017 were identified. We retrospectively analysed the efficacy of EVT for ACLVO after introducing a stent retriever (SR). We classified ACLVO into the following categories: group A, intracranial artery occlusion without EC-ICA occlusion (pure intracranial artery occlusion), and group B, ipsilateral EC-ICA occlusion with/without intracranial artery occlusion. In total, 65 patients were enrolled. Group A comprised 71% (46/65) of all cases. No difference was observed in terms of age, National Institute of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early Computed Tomography Score-Diffusion Weighted imaging (ASPECTS-DWI), several clinical time intervals, rate of successful revascularization (74% versus 84%), and rate of functional independence (42% versus 39%) between groups A and B. In all patients, an ASPECTS-DWI ≥6 and an onset-to-door time ≤6 h were associated with good outcome, whereas intracranial artery occlusion without EC-ICA occlusion (pure intracranial artery occlusion) was not. The outcomes support the efficacy of EVT in stroke associated with acute EC-ICA occlusion. In the EVT of AIS due to ACLVO, there was no significant difference in the results between ipsilateral EC-ICA occlusion with/without intracranial artery occlusion and intracranial artery occlusion without EC-ICA occlusion (pure intracranial artery occlusion).


[Diffusion-weighted imaging for assessment of lung cancer response to chemotherapy].
DWI-MRI could detect the microscopic motion of water molecules which is sensitive to microcirculation change of many kinds of tumors after therapy. The aim of this study is to investigate the value of diffusion-weighted imaging (DWI) in monitoring and predicting lung cancer response to chemotherapy. Nineteen patients pathologically diagnosed as lung cancer were included in this study, all of whom received both conventional MRI and DWI examinations one week before and one month after the initiation of chemotherapy. The response of lung cancers to therapy were classified into four groups: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) based on the change of lesion diameter measured on axial T₂-weighted MR imaging. Apparent diffusion coefficients (ADCs) were measured for each lesion at pre- and post-chemotherapy and were compared with t-test. The correlations between the percentage changes of ADCs and the percentage changes of diameters (long, short, and mean) were further evaluated with Pearson correlation coefficient, as well as that between pre-chemotherapy ADCs and the percentage changes of diameters. The mean pre-chemotherapy ADCs was significantly higher than that of the post-chemotherapy ADCs (1.482 ± 0.456 vs 1.675±0.485, P=0.004). A positive correlation was found between the percentage changes of ADCs and the percentage changes of the long, short, and the mean diameter, respectively (r=0.635, r=0.612, r=0.539, P < 0.05). A negative correlation was found between pre-chemotherapy ADCs and the percentage change of the long diameter after chemotherapy in PR and SD group (r=-0.806, r=-0.632, P < 0.05). The change of ADCs can sensitively reflect the early change of lung cancer response to chemotherapy and has the potential ability to dynamically monitor the lung cancer response to chemotherapy combined with the morphological measurement.


In vitro characterization of proliferation and differentiation of pig satellite cells.
Skeletal muscle contains various muscle fiber types exhibiting different contractile properties based on the myosin heavy chain (MyHC) isoform profile. Muscle fiber type composition is highly variable and influences growth performance and meat quality, but underlying mechanisms regulating fiber type composition remain poorly understood. The aim of the present work was to develop a model based on muscle satellite cell culture to further investigate the regulation of adult MyHC isoforms expression in pig skeletal muscle. Satellite cells were harvested from the mostly fast-twitch glycolytic longissimus (LM) and predominantly slow-twitch oxidative rhomboideus (RM) muscles of 6-week-old piglets. Satellite cells were allowed to proliferate up to 80% confluence, reached after 7 day of proliferation (D7), and then induced to differentiate. Kinetics of proliferation and differentiation were similar between muscles and more than 95% of the cells were myogenic (desmin positive) at D7 with a fusion index reaching 65 ± 9% after 4 day of differentiation. One-dimensional SDS polyacrylamide gel electrophoresis revealed that satellite cells from both muscles only expressed the embryonic and fetal MyHC isoforms in culture, without any of the adult MyHC isoforms that were expressed in vivo. Interestingly, triiodothyronine (T3) induced de novo expression of adult fast and α-cardiac MyHC in vitro making our culture system a valuable tool to study de novo expression of adult MyHC isoforms and its regulation by intrinsic and/or extrinsic factors.


Functional comparison of bone marrow-derived macrophages obtained by cultivation in serum-free or serum-supplemented medium.
Bone marrow-derived macrophages obtained by cultivation in a serum-free or in a serum-supplemented medium were compared in terms of the activation of the respiratory burst and the activation of tumor cytotoxicity. Serum-free-cultured macrophages responded to interferon-gamma (IFN-gamma) and to lipopolysaccharide (LPS) by an enhancement of the respiratory burst. Macrophages obtained in a serum-supplemented medium are characterized by a diminished capacity to release O2-. These cells did not respond to IFN-gamma unless the stimulation was performed in a serum-containing medium. In terms of activation of tumor cell cytotoxicity, serum-supplemented macrophage cultures seem to be primed by unknown serum constituents because they only need one signal (IFN-gamma or LPS) to become fully cytotoxic. Serum-free cultivated macrophages can be rendered cytotoxic only after exposure to combinations of IFN-gamma and LPS.


Otorhinolaryngologic manifestations of Hartsfield syndrome: Case series and review of literature.
Diagnosis of Hartsfield syndrome includes recognition of three distinct clinical anomalies: holoprosencephaly, ectrodactyly, and bilateral cleft-lip and palate syndrome. A family including three male siblings all affected by Hartsfield syndrome presented to our institution for care. An autosomal dominant variant in Fibroblast Growth Factor Receptor 1 (FGFR1) was identified. This report focuses on otorhinolaryngologic manifestationsof Hartsfield syndrome, previously undescribed, including midline defects of holoprosencephaly, bilateral cleft-lip and palate, retrognathia, gastroesophageal reflux disease, external ear anomalies, eustachian tube dysfunction, and midface abnormalities, in addition to multidisciplinary, long-term management strategies. Multidisciplinary management is imperative in the care of these children with modification of approach based on their medical complexity.


Management of patients with motor neurone disease.
After reviewing the nature of motor neurone disease (MND) and its clinical features, course, prognosis, and aetiology, this paper discusses both specific and symptomatic therapy and then the major challenges for rehabilitation in MND.