Genome-Transcriptome-Functional Connectivity-Cognition Link Differentiates Schizophrenia From Bipolar Disorder.
Schizophrenia (SZ) and bipolar disorder (BD) share genetic risk factors, yet patients display differential levels of cognitive impairment. We hypothesized a genome-transcriptome-functional connectivity (frontoparietal)-cognition pathway linked to SZ-versus-BD differences, and conducted a multiscale study to delineate this pathway. Large genome-wide studies provided single nucleotide polymorphisms (SNPs) conferring more risk for SZ than BD, and we identified their regulated genes, namely SZ-biased SNPs and genes. We then (a) computed the polygenic risk score for SZ (PRSSZ) of SZ-biased SNPs and examined its associations with imaging-based frontoparietal functional connectivity (FC) and cognitive performances; (b) examined the spatial correlation between ex vivo postmortem expressions of SZ-biased genes and in vivo, SZ-related FC disruptions across frontoparietal regions; (c) investigated SZ-versus-BD differences in frontoparietal FC; and (d) assessed the associations of frontoparietal FC with cognitive performances. PRSSZ of SZ-biased SNPs was significantly associated with frontoparietal FC and working memory test scores. SZ-biased genes' expressions significantly correlated with SZ-versus-BD differences in FC across frontoparietal regions. SZ patients showed more reductions in frontoparietal FC than BD patients compared to controls. Frontoparietal FC was significantly associated with test scores of multiple cognitive domains including working memory, and with the composite scores of all cognitive domains. Collectively, these multiscale findings support the hypothesis that SZ-biased genetic risk, through transcriptome regulation, is linked to frontoparietal dysconnectivity, which in turn contributes to differential cognitive deficits in SZ-versus BD, suggesting that potential biomarkers for more precise patient stratification and treatment.


Air force takes aim at a big bird.
Early this year, the U.S. land-based force of nuclear missiles became vulnerable to destruction in a preemptive attack by the Soviet Union. The Air Force has worried about this situation for a long time, searching high and low for a better place to put both the existing silo-based missiles and a new missile, the MX. The first article in this series examined the reasons that U.S. officials became alarmed about missile vulberability, and the second examined the short-term plan to put missiles into silos. This article explores the Ait Force's least favourite long-term basing mode. Subsequent articles will explore the alternatives.


Effects of a standardized extract of Withania somnifera (Ashwagandha) on depression and anxiety symptoms in persons with schizophrenia participating in a randomized, placebo-controlled clinical trial.
Extracts of Withania somnifera (WSE), or Ashwagandha, has traditionally been used as an adaptogen in Ayurvedic medicine, and evidence suggests that it may have efficacy in the treatment of psychiatric disorders, including schizophrenia. This secondary analysis reviewed change in depression and anxiety symptoms in a study using WSE as an adjunctive treatment in patients with schizophrenia experiencing an exacerbation of positive symptoms. We enrolled patients with schizophrenia in a 12-week, randomized, placebo-controlled, double-blind study. Active treatment was with 1,000 mg of standardized WSE. This analysis reviewed outcomes for 66 patients with depression and anxiety symptoms by examining the singleitem depression and anxiety-depression cluster subscores extracted from the Positive and Negative Syndrome Scale. Medium effect sizes of 0.683 (95% confidence interval [CI], 0.16 to 1.21) and 0.686 (95% CI, 0.16 to 1.21) favoring WSE over placebo were observed for depression single-item and anxiety-depression cluster scores, respectively. Adverse events were mild and transient. Our findings suggest that WSE may hold promise in the treatment of depression and anxiety symptoms in schizophrenia. While the mechanism of its clinical efficacy requires more exploration, the data suggest.


Interactive effects of cumulative stress and impulsivity on alcohol consumption.
Alcohol addiction may reflect adaptations to stress, reward, and regulatory brain systems. While extensive research has identified both stress and impulsivity as independent risk factors for drinking, few studies have assessed the interactive relationship between stress and impulsivity in terms of hazardous drinking within a community sample of regular drinkers. One hundred and thirty regular drinkers (56M/74F) from the local community were assessed for hazardous and harmful patterns of alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT). All participants were also administered the Barratt Impulsiveness Scale (BIS-11) as a measure of trait impulsivity and the Cumulative Stress/Adversity Checklist (CSC) as a comprehensive measure of cumulative adverse life events. Standard multiple regression models were used to ascertain the independent and interactive nature of both overall stress and impulsivity as well as specific types of stress and impulsivity on hazardous and harmful drinking. Recent life stress, cumulative traumatic stress, overall impulsivity, and nonplanning-related impulsivity as well as cognitive and motor-related impulsivity were all independently predictive of AUDIT scores. However, the interaction between cumulative stress and total impulsivity scores accounted for a significant amount of the variance, indicating that a high to moderate number of adverse events and a high trait impulsivity rating interacted to affect greater AUDIT scores. The subscale of cumulative life trauma accounted for the most variance in AUDIT scores among the stress and impulsivity subscales. Findings highlight the interactive relationship between stress and impulsivity with regard to hazardous drinking. The specific importance of cumulative traumatic stress as a marker for problem drinking is also discussed.


Superior wear resistance and low friction in hybrid ultrathin silicon nitride/carbon films: synergy of the interfacial chemistry and carbon microstructure.
Amorphous carbon-based films are commonly investigated as protective nanocoatings in macro- to nano-scale devices due to their exceptional tribological and mechanical properties. However, with further device miniaturization where even thinner coatings are required, the wear durability of the nanocoating rapidly degrades at the expense of lower thickness. Here we discover that for sub-10 nm coating thicknesses, a hybrid bi-layer film structure, comprising a high sp3-bonded amorphous carbon top layer and a silicon nitride (SiNx) bottom layer, consistently outperforms its single-layer amorphous carbon counterpart in terms of wear durability on a commercial tape drive head, while exhibiting low, stable friction and excellent wear resistance on a flat ceramic substrate. The superior performance of the hybrid film is attributed to the constructive synergy of the sp3-rich carbon microstructure and an enhanced interfacial chemistry arising from additional interfacial bonding. Moreover, a high energy C+ ion treatment step, introduced either directly to the substrate or to the SiNx layer before carbon deposition, also aids in increasing atomic mixing that contributes to further improvement in the wear resistance. This study highlights the importance of both the carbon microstructure and interfacial chemistry in the design of wear-durable nanocoatings at few-nanometer thicknesses, particularly for aggressive wear conditions.


Development of naturally selected and molecularly engineered intrachain and competitive FRET-aptamers and aptamer beacons.
Several different approaches have been taken to development of homogeneous fluorescent aptamer assays including end-labeled beacons and signaling aptamers which are intrinsically quenched by nucleotides. Two new strategies dubbed "intrachain" and "competitive" FRET-aptamer assays are summarized in this review. Intrachain and competitive FRET-aptamers can be engineered on the molecular level through a series exploratory experiments involving prior knowledge of aptamer secondary or tertiary structures and hypotheses about aptamer conformational changes. However, there is an intrinsic risk of altering aptamer affinity or specificity associated with chemical modifications of an aptamer. Natural selection methods for FRET-aptamers have also been devised to potentially obviate the chemical modification problem. The naturally selected aptamers are subjected to fluorophore (F)- and or quencher (Q)-conjugated nucleotide triphosphate (NTP) incorporation by polymerase chain reaction (PCR) with permissive polymerases such as Deep Vent exo-, but still demonstrate sensitive and specific assay performance despite modified bases, because they are ultimately selected after decoration with F and Q. This paper summarizes work in this area and presents some new examples of the engineered and naturally selected FRET-aptamers for detection of vitamin D.


Polydimethylsiloxane thin film characterization using all-optical photoacoustic mechanism.
This paper presents a nondestructive ultrasound testing method for characterization of the resonant frequencies of polydimethylsiloxane (PDMS) thin film by using a miniature fiber optic photoacoustic (PA) probe. The PA probe was fabricated with an optical fiber and a synthesized gold nanocomposite. During the experiment, a cured PDMS thin film with a thickness of 220 μm was immersed into a water medium using a custom-designed holder to clamp the film. An acoustic pulse was generated by the PA probe and propagated through the water media to excite the fixed film. A fiber optic pressure sensor based on the Fabry-Perot principle was used to collect the excited acoustic signals on the other side of the film. The acquired response of the acoustic pulse was used to compute the resonant frequencies of the PDMS thin film based on a deconvolution method.


Validation of the Rotterdam Elderly Pain Observation Scale in the Hospital Setting.
The Rotterdam Elderly Pain Observation Scale (REPOS) has been proven useful to assess pain in noncommunicative and cognitively impaired nursing home residents. We evaluated whether the REPOS is also reliable and valid for pain assessment in the hospital setting. In this prospective multicenter observational study, surgical patients were observed perioperatively at bedside and internal medicine patients were filmed during a possible painful moment and at rest. Pain behavior was assessed from the video recordings with the REPOS and the Pain Assessment Checklist for seniors with Severe Dementia-Dutch language (PACSLAC-D). Longitudinal associations between REPOS score and numeric rating scale pain ratings from observers and nurses (NRSobs and NRSproxy ) corrected for patients' gender were assessed with linear mixed models. In total, 72 patients were included; 118 observations of surgical and 68 observations of internal medicine patients were analyzed. Interobserver reliability between the researcher and 2 other observers was good, with Cohen's kappa values of 0.71 (confidence interval [CI] 0.59 to 0.83) and 0.84 (CI 0.74 to 0.94), respectively. The intraobserver reliability of the principal investigator was good, with Cohen's kappa 0.82 (CI 0.67 to 0.91). Linear mixed modeling revealed correlation values between the REPOS and NRSobs of 0.67 and the REPOS and NRSproxy of 0.73. Optimal sensitivity (78%) and specificity (90%) for the detection of pain were found with a REPOS cutoff score of ≥3, using an NRS score of ≥4 as the reference value. The REPOS is reliable and valid for the assessment of postoperative and chronic pain in hospital patients who cannot self-report pain.


Azide-Modified Membrane Lipids: Synthesis, Properties, and Reactivity.
In the present work, we describe the synthesis and the temperature-dependent behavior of photoreactive membrane lipids as well as their capability to study peptide/lipid interactions. The modified phospholipids contain an azide group either in the middle part or at the end of an alkyl chain and also differ in the linkage (ester vs ether) of the second alkyl chain. The temperature-dependent aggregation behavior of the azidolipids was studied using differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and small-angle X-ray scattering (SAXS). Aggregate structures were visualized by stain and cryo transmission electron microscopy (TEM) and were further characterized by dynamic light scattering (DLS). We show that the position of the azide group and the type of linkage of the alkyl chain at the sn-2 position of the glycerol influences the type of aggregates formed as well as their long-term stability: P10AzSPC and r12AzSHPC show the formation of extrudable liposomes, which are stable in size during storage. In contrast, azidolipids that carry a terminal azido moiety either form extrudable liposomes, which show time-dependent vesicle fusion (P15AzPdPC), or self-assemble in large sheet-like, nonextrudable aggregates (r15AzPdHPC) where the lipid molecules are arranged in an interdigitated orientation at temperatures below Tm (LβI phase). Finally, a P10AzSPC:DMPC mixture was used for photochemically induced cross-linking experiments with a transmembrane peptide (WAL-peptide) to demonstrate the applicability of the azidolipids for the analysis of peptide/lipid interactions. The efficiency of photo-cross-linking was monitored by attenuated total reflection infrared (ATR-IR) spectroscopy and mass spectrometry (MS).


Eye-tracking patterns in schizophrenia. An analysis based on the incidence of saccades.
Saccades occurring when tracking a sine-wave target and when fixating a stationary target were studied in the following three groups: schizophrenics, other psychiatric inpatients, and normal controls. The frequency of saccades when tracking and when fixating was significantly greater among schizophrenics than among the two comparison groups. The pattern of occurrence of saccades within cycles of the sine movement was similar in the three groups; the greatest occurrence was at the highest target velocity and the lowest occurrence was at reversal points. The data are interpreted as consistent with the hypothesis of a failure on inhibiting mechanisms.


Epidermoid of the quadrigeminal cistern--case report.
The authors report a case of an epidermoid in the quadrigeminal cistern in a 40-year-old female who presented with headache and nausea. According to the literature, epidermoids are rarely found in the quadrigeminal cistern. Additional unusual features in this case were the absence of a capsule and T1-weighted magnetic resonance images suggestive of both solid (less intense) and fluid (more intense) components.


Protective effect of melatonin against hippocampal injury of rats with intermittent hypoxia.
Obstructive sleep apnea (OSA) patients suffer from intermittent hypoxia (IH) and neuropsychologic impairments. Oxidative stress is involved in the pathogenesis of OSA, so the application of an antioxidant may be useful. We evaluated the hypothesis that melatonin would reduce IH-induced hippocampal injury via an increased expression of antioxidant enzymes. Adult Sprague-Dawley rats that had received a daily injection of melatonin or vehicle were exposed to IH for 8 hr/day for 7 or 14 days. The serum and hippocampus were harvested for the measurement of malondialdehyde (MDA). Apoptotic cell death was studied histologically in hippocampal sections. The mRNA expression of inflammatory mediators including tumor necrosis factor-alpha, inducible nitric oxide synthase, cyclooxygenase-2 and antioxidant enzymes including glutathione peroxidase, catalase and copper/zinc superoxide dismutase were examined in the hippocampus by RT-PCR. The results show significant increases in levels of serum and hippocampal MDA, apoptotic cell death and mRNA levels of inflammatory mediators in hypoxic rats when compared with the normoxic controls. Also, mRNA levels of the antioxidant enzymes were decreased in hypoxic animals. In the melatonin-treated hypoxic rats, serum MDA levels were comparable with those in normoxic control rats. Also, melatonin treatment significantly reduced hippocampal MDA levels and totally prevented apoptosis. Moreover, there were a decreased expression of the inflammatory mediators and an elevated expression of antioxidant enzymes in the melatonin injected rats when compared with vehicle-treated animals. These results indicate that melatonin mitigates oxidative stress and the pathogenesis of IH-induced hippocampal injury via its antioxidant and anti-inflammatory properties which includes stimulation of transcriptional regulation of antioxidant enzymes.


Expression of HIV-1 antigens in plants as potential subunit vaccines.
Human immunodeficiency virus type 1 (HIV-1) has infected more than 40 million people worldwide, mainly in sub-Saharan Africa. The high prevalence of HIV-1 subtype C in southern Africa necessitates the development of cheap, effective vaccines. One means of production is the use of plants, for which a number of different techniques have been successfully developed. HIV-1 Pr55Gag is a promising HIV-1 vaccine candidate: we compared the expression of this and a truncated Gag (p17/p24) and the p24 capsid subunit in Nicotiana spp. using transgenic plants and transient expression via Agrobacterium tumefaciens and recombinant tobamovirus vectors. We also investigated the influence of subcellular localisation of recombinant protein to the chloroplast and the endoplasmic reticulum (ER) on protein yield. We partially purified a selected vaccine candidate and tested its stimulation of a humoral and cellular immune response in mice. Both transient and transgenic expression of the HIV antigens were successful, although expression of Pr55Gag was low in all systems; however, the Agrobacterium-mediated transient expression of p24 and p17/p24 yielded best, to more than 1 mg p24/kg fresh weight. Chloroplast targeted protein levels were highest in transient and transgenic expression of p24 and p17/p24. The transiently-expressed p17/p24 was not immunogenic in mice as a homologous vaccine, but it significantly boosted a humoral and T cell immune response primed by a gag DNA vaccine, pTHGagC. Transient agroinfiltration was best for expression of all of the recombinant proteins tested, and p24 and p17/p24 were expressed at much higher levels than Pr55Gag. Our results highlight the usefulness of plastid signal peptides in enhancing the production of recombinant proteins meant for use as vaccines. The p17/p24 protein effectively boosted T cell and humoral responses in mice primed by the DNA vaccine pTHGagC, showing that this plant-produced protein has potential for use as a vaccine.


Coarse-Grained Parameterization of Nucleotide Cofactors and Metabolites: Protonation Constants, Partition Coefficients, and Model Topologies.
Nucleotides are structural units relevant not only in nucleic acids but also as substrates or cofactors in key biochemical reactions. The size- and timescales of such nucleotide-protein interactions fall well within the scope of coarse-grained molecular dynamics, which holds promise of important mechanistic insight. However, the lack of specific parameters has prevented accurate coarse-grained simulations of protein interactions with most nucleotide compounds. In this work, we comprehensively develop coarse-grained parameters for key metabolites/cofactors (FAD, FMN, riboflavin, NAD, NADP, ATP, ADP, AMP, and thiamine pyrophosphate) in different oxidation and protonation states as well as for smaller molecules derived from them (among others, nicotinamide, adenosine, adenine, ribose, thiamine, and lumiflavin), summing up a total of 79 different molecules. In line with the Martini parameterization methodology, parameters were tuned to reproduce octanol-water partition coefficients. Given the lack of existing data, we set out to experimentally determine these partition coefficients, developing two methodological approaches, based on 31P-NMR and fluorescence spectroscopy, specifically tailored to the strong hydrophilicity of most of the parameterized compounds. To distinguish the partition of each relevant protonation species, we further potentiometrically characterized the protonation constants of key molecules. This work successfully builds a comprehensive and relevant set of computational models that will boost the biochemical application of coarse-grained simulations. It does so based on the measurement of partition and acid-base physicochemical data that, in turn, covers important gaps in nucleotide characterization.


[A simple renal cyst, the origin of Wunderlich's syndrome].
An additional case of Wunderlich syndrome arising from a ruptured simple renal cyst is presented. A 50-year-old female presented with pain, a mass in the left renal fossa and hypovolemia that could not be managed conservatively. The imaging techniques disclosed a large collection of blood in the left perirenal area. Surgical drainage of the hematoma and nephrectomy were performed. A simple cyst containing blood was found in the lower pole of the kidney. Its wall had been ruptured and had caused the hemorrhage. If surgical management of hemorrhage is decided in a patient with Wunderlich's syndrome, a conservative procedure should be performed and nephrectomy avoided if the underlying condition is benign.


Effects of Dietary Intervention on Gut Microbiota and Metabolic-Nutritional Profile of Outpatients with Non-Alcoholic Steatohepatitis: a Randomized Clinical Trial.
Modulation of the gut microbiota emerges as a therapeutic possibility to improve health. Our objective was to compare the impact of three months of intervention with diet plus nutritional orientation versus only nutritional orientation on the gut microbiota and metabolic-nutritional profile of outpatients with non-alcoholic steatohepatitis. It was a randomized clinical trial with 40 outpatients (49.48 ± 10.3 years), allocated in two groups: DIET group (n=20), who received diet (1.651.34 ± 263.25 kcal; 47% carbohydrates, 28% lipids, 25% proteins, 30 g fibers) and nutritional orientation, and control group (n = 20), which received only nutritional orientation. The DIET group, in relation to baseline, presented a reduction in body weight (p<0.001), BMI (p<0.001), waist circumference (p=0.001), percentage of fat (p=0.002), serum aspartate aminotransferase (p<0.001), alanine aminotransferase (p<0.001), γ-glutamyltransferase (p=0.001), glycemia (p=0.003), homeostasis model assessment of insulin resistance (p=0.017), total cholesterol (p=0.014), and triacylglycerols (p=0.008), whereas the control group did not present changes. After intervention, the small intestinal bacterial overgrowth frequency was 30% in the DIET group and 45% in the control group (p=0.327). In the DIET group, an increase in the density of total microorganisms (3.76 ± 7.17 x 10 8 cells g -1 ; p=0.048) was detected, while in the control group reduced Bacteroidetes (-0.77 ± 2.01 x 10 8 cells g -1 , p=0.044) and Verrucomicrobiales (-0.46 ± 0.75 x 10 8 cells g -1 ; p=0.022) were observed. The results suggest that exclusively dietary modifications contribute to health promotion in non-alcoholic steatohepatitis and should be the basis of nutritional treatment for this condition.


Muscle force output and electromyographic activity in squats with various unstable surfaces.
The purpose of the study was to compare force output and muscle activity of leg and trunk muscles in isometric squats executed on stable surface (i.e., floor), power board, BOSU ball, and balance cone. Fifteen healthy men (23.3 ± 2.7 years, mass: 80.5 ± 8.5 kg, height: 1.81 ± 0.09 m) volunteered. The force output and electromyographic (EMG) activities of the rectus femoris, vastus medialis, vastus lateralis, biceps femoris, soleus, rectus abdominis, oblique external, and erector spinae were assessed. The order of the surfaces was randomized. One familiarization session was executed before the experimental test. Compared with stable surface (749 ± 222 N), the force output using power board was similar (-7%, p = 0.320) but lower for BOSU ball (-19%, p = 0.003) and balance cone (-24%, p ≤ 0.001). The force output using BOSU ball and balance cone was approximately 13% (p = 0.037) and approximately 18% (p = 0.001) less than the power board. There were similar EMG activities between the surfaces in all muscles except for rectus femoris, in which stable squat provided greater EMG activity than did the other exercises (p = 0.004-0.030). Lower EMG activity was observed in the rectus femoris using balance cone compared with the BOSU ball (p = 0.030). In conclusion, increasing the instability of the surface during maximum effort isometric squats usually maintains the muscle activity of lower-limb and superficial trunk muscles although the force output is reduced. This suggests that unstable surfaces in the squat may be beneficial in rehabilitation and as a part of periodized training programs, because similar muscle activity can be achieved with reduced loads.


Development and Evaluation of Amorphous Solid Dispersion of Riluzole with PBPK Model to Simulate the Pharmacokinetic Profile.
In the current work, screening of polymers viz. polyacrylic acid (PAA), polyvinyl pyrrolidone vinyl acetate (PVP VA), and hydroxypropyl methyl cellulose acetate succinate (HPMC AS) based on drug-polymer interaction and wetting property was done for the production of a stable amorphous solid dispersion (ASD) of a poorly water-soluble drug Riluzole (RLZ). PAA showed maximum interaction and wetting property hence, was selected for further studies. Solid state characterization studies confirmed the formation of ASD with PAA. Saturation solubility, dissolution profile, and in vivo pharmacokinetic data of the ASD formulation were generated in rats against its marketed tablet Rilutor. The RLZ:PAA ASD showed exponential enhancement in the dissolution of RLZ. Predicted and observed pharmacokinetic data in rats showed enhanced area under curve (AUC) and Cmax in plasma and brain with respect to Rilutor. Furthermore, a physiologically based pharmacokinetic (PBPK) model of rats for Rilutor and RLZ ASD was developed and then extrapolated to humans where physiological parameters were changed along with a biochemical parameter. The partition coefficient was kept similar in both species. The model was used to predict different exposure scenarios, and the simulated data was compared with observed data points. The PBPK model simulated Cmax and AUC was within two times the experimental data for plasma and brain. The Cmax and AUC in the brain increased with ASD compared to Rilutor for humans showing its potential in improving its biopharmaceutical performance and hence enhanced therapeutic efficacy. The model can predict the RLZ concentration in multiple compartments including plasma and liver.


What landscape elements are needed for hospital healing spaces? Evidence from an empirical study of 10 compact hospitals.
Modern medical research shows that a rationally planned landscape environment helps patients recover. With the growing number of hospital patients and the tightening of per capita medical landscape land, the use of limited landscape resources to serve patients has become challenging. This study focused on the landscape environment of 10 hospitals in Guangdong Province, China. Based on the KANO theoretical model, a survey questionnaire was designed and administered to 410 participants. The data were analyzed based on demand attributes, importance, sensitivity, and group differences. The maintenance requirements were the most important item in the sensitivity ranking. Furthermore, the analysis revealed that the users need a safe, quiet, and private environment, owing to their higher requirements, including visual healing, rehabilitation activities, shading and heat preservation, and medical escort. Moreover, adolescents and older adult patients have common and contradictory environmental needs. For example, the landscape environment should provide both an active space and a quiet rehabilitation environment. This study evaluates how landscape resources can be better utilized from the perspective of the user and expands the theory of healing landscapes, which has practical implications for hospital renovation and landscape environment strategies.


Supracricoid hemilaryngopharyngectomy. Analysis of 240 cases.
The supracricoid hemilaryngopharyngectomy consists of resection of the supracricoid hemilarynx and ipsilateral pyriform sinus. Two hundred forty patients underwent this procedure from 1964 through 1983. Two hundred twenty-two patients had no airway impairment, and 204 recovered normal deglutition. The local recurrence rate was 5.2%. Indications for the procedure are carcinoma of the supracricoid upper part of the pyriform sinus and carcinoma of the lateral laryngeal margin with normal vocal cord mobility.


CD19 and CD22 expression reciprocally regulates tyrosine phosphorylation of Vav protein during B lymphocyte signaling.
B cell development and humoral immune responses are controlled by signaling thresholds established through the B lymphocyte antigen receptor (BCR) complex. BCR signaling thresholds are differentially regulated by the CD22 and CD19 cell surface receptors in vivo. B cells from CD22-deficient mice exhibit characteristics of chronic stimulation and are hyper-responsive to BCR crosslinking with augmented intracellular Ca2+ responses. By contrast, B cells from CD19-deficient mice are hypo-responsive to transmembrane signals. To identify signaling molecules involved in the positive and negative regulation of signaling thresholds, the signal transduction pathways activated after BCR crosslinking were examined in CD22- and CD19-deficient B cells. These comparisons revealed that tyrosine phosphorylation of Vav protein was uniquely augmented after BCR or CD19 crosslinking in CD22-deficient B cells, yet was modest and transient after BCR crosslinking in CD19-deficient B cells. Ligation of CD19 and CD22 in vivo is likely to positively and negatively regulate BCR signaling, respectively, because CD19 crosslinking was more efficient than BCR crosslinking at inducing Vav phosphorylation. However, simultaneous crosslinking of CD19 with the BCR resulted in a substantial decrease in Vav phosphorylation when CD22 was expressed. Thus, the differential regulation of Vav tyrosine phosphorylation by CD19 and CD22 may provide a molecular mechanism for adjusting BCR signaling thresholds.


Long-term follow-up and characteristics of cancer negative cases after endoscopic resection and gastrectomy for early gastric cancer.
Endoscopic resection (ER) and gastrectomy are widely used for early gastric cancer (EGC). However, unexpected cases, which show no cancer after treatment, have occurred. The present study was designed to characterize cancer negative cases after ER and gastrectomy, and determine their long term prognosis. Patients with EGC who underwent ER from January 2004 to October 2012 and gastrectomy from January 2000 to December 2007 were analyzed. There were 13 CFG from 1508 EGC cases after ER (0.9%) and 13 CFG from 4,101 gastrectomy (0.3%), respectively. The tumor size of the CFG group after ER was smaller than the control group (median value of tumor area of CFG vs. control groups, 48.0 mm2 vs. 146.0 mm2, respectively, P = 0.008). However, the CFG group, after gastrectomy, showed marginal differences in size and biopsy number when compared with the control group. There was no mortality in the all CFG. The small diameter and area of EGC are factors which determine if the lesion can be completely removed by forcep biopsy. A final pathology report of "No cancer was detected" after ER and surgery of EGC is not detrimental to the patient.


Technique and timing of two-stage exchange for infection in TKA.
Infection in total knee arthroplasty is a devastating complication. The two-stage exchange procedure has evolved as an effective treatment option. The classification and alternatives to a two-stage procedure are presented. Current diagnosis and monitoring of infection in total knee arthroplasty with laboratory, aspiration, and imaging techniques are reviewed. The timing, technique, and results of a two-stage procedure are discussed. A knee aspiration with synovial fluid cell count and culture may be a useful adjunct. The use of antibiotic-impregnated cement spacers may be considered at the first-stage surgery. Spacers may be static or articulating, intramedullary dowels, preformed or constructed in the operating room, and provide single- or multiple-agent antibiotic (and antifungal) joint space delivery. Proper technique, antibiotic dosing, and indications with these devices will avoid complications between stages. The most common complications encountered with the use of spacers include dislocation/instability, implant extrusion, overstuffing of the patellofemoral and tibiofemoral joints, and implant or periprosthetic fracture. At the second stage of the procedure, surgical exposure, intraoperative frozen sections, assessment of bone and soft tissue defects, the integrity of the extensor mechanism, and implant selection are important factors to consider in the second-stage reimplantation revision total knee arthroplasty. Level V, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.


Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma.
The Notch signaling pathway is required for the expansion of undifferentiated pancreatic progenitor cells during embryonic development and has been implicated in the progression of pancreatic ductal adenocarcinoma (PDAC). The interaction of Notch ligands with their receptors promotes a gamma-secretase-dependent cleavage of the Notch receptor and release of the Notch intracellular domain, which translocates to the nucleus and activates transcription. We investigated the role of this pathway in PDAC progression. We tested the effects of a gamma-secretase inhibitor (GSI) that blocks Notch signaling in PDAC cell lines and a genetically engineered mouse model of PDAC (Kras p53 L/+ mice). Notch signaling was activated in PDAC precursors and advanced tumors. The GSI inhibited the growth of premalignant pancreatic duct-derived cells in a Notch-dependent manner. Additionally, in a panel of over 400 human solid tumor-derived cell lines, PDAC cells, as a group, were more sensitive to the GSI than any other tumor type. Finally, the GSI completely inhibited tumor development in the genetically engineered model of invasive PDAC (P < .005, chi2 test; compared with mice exposed to vehicle). These results suggest that Notch signaling is required for PDAC progression. Pharmacologic targeting of this pathway offers therapeutic potential in this treatment-refractory malignancy.


Biochemical characterization and mass spectrometric disulfide bond mapping of periplasmic alpha-amylase MalS of Escherichia coli.
Periplasmic alpha-amylase of Escherichia coli, the malS gene product, hydrolyzes linear maltodextrins. The purified enzyme exhibited a Km of 49 microM and a Vmax of 0.36 micromol of p-nitrophenylhexaoside hydrolyzed per min per mg of protein. Amylase activity was optimal at pH 8 and was dependent on divalent cations such as Ca2+. MalS exhibited altered migration on SDS-polyacrylamide gel electrophoresis under nonreducing conditions. Analytical ultracentrifugation and electrospray mass spectrometry indicated that MalS is monomeric. The four cysteine residues are involved in intramolecular disulfide bonds. To map disulfide bonds, MalS was proteolytically digested. The resulting peptides were separated by reverse phase-high performance liquid chromatography, and matrix-assisted laser desorption/ionization mass spectrometry analysis indicated the presence of two disulfide bonds, i.e. Cys40-58 and Cys104-520. The disulfide bond at Cys40-58 is located in an N-terminal extension of about 160 amino acids which has no homology to other amylases but to the proposed peptide binding domain of GroEL, the Hsp60 of E. coli. The N-terminal extension is linked to the C-terminal amylase domain via disulfide bond Cys104-520. Reduction of disulfide bonds by dithiothreitol treatment led to aggregation suggesting that the N terminus of MalS may represent an internal chaperone domain.


Recent Advances on the Possible Neuroprotective Activities of Epstein-Barr Virus Oncogene BARF1 Protein in Chronic Inflammatory Disorders of Central Nervous System.
Multiple sclerosis and neurodegenerative diseases in which cells of the central nervous system (CNS) are lost or damaged are rapidly increasing in frequency, and there is neither effective treatment nor cure to impede or arrest their destructive course. The Epstein-Barr virus is a human gamma-herpesvirus that infects more than 90% of the human population worldwide and persisting for the lifetime of the host. It is associated with numerous epithelial cancers, principally undifferentiated nasopharyngeal carcinoma and gastric carcinoma. Individuals with a history of symptomatic primary EBV infection, called infectious mononucleosis, carry a moderately higher risk of developing multiple sclerosis (MS). It is not known how EBV infection potentially promotes autoimmunity and central nervous system (CNS) tissue damage in MS. Recently it has been found that EBV isolates from different geographic regions have highly conserved BARF1 epitopes. BARF1 protein has the neuroprotective and mitogenic activity, thus may be useful to combat and overcome neurodegenerative disease. BARF1 protein therapy can potentially be used to enhance the neuroprotective activities by combinational treatment with anti-inflammatory antagonists and neuroprotectors in neural disorders.


Synonymous codon usage variation among Giardia lamblia genes and isolates.
The pattern of codon usage in the amitochondriate diplomonad Giardia lamblia has been investigated. Very extensive heterogeneity was evident among a sample of 65 genes. A discrete group of genes featured unusual codon usage due to the amino acid composition of their products: these variant surface proteins (VSPs) are unusually rich in Cys and, to a lesser extent, Gly and Thr. Among the remaining 50 genes, correspondence analysis revealed a single major source of variation in synonymous codon usage. This trend was related to the extent of use of a particular subset of 21 codons which are inferred to be those which are optimal for translation; at one end of this trend were genes expected to be expressed at low levels with near random codon usage, while at the other extreme were genes expressed at high levels in which these optimal codons are used almost exclusively. These optimal codons all end in C or G so G + C content at silent sites varies enormously among genes, from values around 40%, expected to reflect the background level of the genome, up to nearly 100%. Although VSP genes are occasionally extremely highly expressed, they do not, in general, have high frequencies of optimal codons, presumably because their high expression is only intermittent. These results indicate that natural selection has been very effective in shaping codon usage in G. lamblia. These analyses focused on sequences from strains placed within G. lamblia "assemblage A"; a few sequences from other strains revealed extensive divergence at silent sites, including some divergence in the pattern of codon usage.


Postoperative Regression of Retro-odontoid Pseudotumor After Atlantoaxial Posterior Fixation: 11 Years of Experience in Patients With Atlantoaxial Instability.
Case series study. The aim was to investigate the incidence of retro-odontoid pseudotumor in patients with atlantoaxial instability (AAI) and evaluate pseudotumor regression after posterior fixation. The incidence of retro-odontoid pseudotumor in atlantoaxial instability patients remains uncertain. Moreover, the regression of retro-odontoid pseudotumor after posterior fixation in patients with various underlying diseases needs to be further investigated. From July 2004 to August 2015, 175 patients with AAI underwent posterior fixation operations at our institution. After excluding 11 patients (previous operation, n = 4; history of tumor, n = 7), the final study population comprised 164 patients. The final study population was categorized according to their underlying diseases (rheumatoid arthritis [RA], os odontoideum, atlanto-occipital assimilation, dens fracture, AAI of unknown cause, etc.) and age (adult and pediatric groups). The incidence of retro-odontoid pseudotumor in each group was analyzed. Pre- and postoperative magnetic resonance or computed tomography images were reviewed to assess its regression following surgery. Of the 164 patients included, 38 had retro-odontoid pseudotumor (23.2%). Three were diagnosed with RA and the rest were non-RA patients including os odontoideum (n = 12), dens fracture (n = 6), atlanto-occipital assimilation (n = 4), Morquio syndrome (n = 1), and AAI of unknown cause (n = 12). Pseudotumor size regressed in all 38 patients after atlantoaxial posterior fixation. There was a statistically significant decrease in pseudotumor size (the length between the anterior border of the odontoid process to the posterior border of the pseudotumor) from a mean length of 17.7 to 14.9 mm (P < 0.001). The patients had various underlying diseases and the overall incidence of retro-odontoid pseudotumor in patients with symptomatic AAI was 23.2% at our institution during the past 11 years. All patients who underwent posterior fixation for AAI showed a statistically significant decrease in pseudotumor size. 4.


Nasal High Flow Versus Conventional Oxygen Therapy for Postoperative Cardiothoracic Surgery Patients.
Reintubation and complications in postoperative cardiothoracic patients remain high despite medical advancements. A 2-year retrospective, observational study was conducted in postextubated cardiothoracic patients to assess the effectiveness of the current standard-conventional oxygen therapy (COT) compared with a nasal high flow (NHF) therapy. The objective of this study was to understand whether NHF therapy would reduce the need for reintubation and improve clinical outcomes after surgery. All consecutive postoperative patients who had same-day elective cardiothoracic surgery in a tertiary hospital were included. The 2013 data were from patients' charts who received COT, and the 2014 data were from patients' charts after the implementation of NHF therapy post extubation as a standard of care. A total of 400 patient charts were analyzed: 221 and 179 patients in the COT and NHF, respectively. No significant difference was seen in the frequency of reintubation (P = .48). Despite both cohorts having the same length of stay (P = .10), patients treated with NHF required less time on supplemental oxygen (P = .001). Day 1 postoperative chest x-ray results did not show any significant differences between groups, whereas day 2 x-rays showed worsening results in the COT cohort (P < .001). Furthermore, the incidence of ventilator-associated pneumonia (VAP) post extubation was significantly higher in the COT cohort, with zero VAP episodes reported in the NHF cohort (P = .02). Although this study was not able to demonstrate the reduction in reintubation between groups, the use of NHF compared with COT seems to reduce the time spent on oxygen therapy and decrease the rate of VAP. Further evidence including randomized controlled trials is required to determine the impact of NHF on reintubation and complications in postoperative cardiothoracic surgery.


SIRT-1 is required for release of enveloped enteroviruses.
Enterovirus D68 (EV-D68) is a re-emerging enterovirus that causes acute respiratory illness in infants and has recently been linked to Acute Flaccid Myelitis. Here, we show that the histone deacetylase, SIRT-1, is essential for autophagy and EV-D68 infection. Knockdown of SIRT-1 inhibits autophagy and reduces EV-D68 extracellular titers. The proviral activity of SIRT-1 does not require its deacetylase activity or functional autophagy. SIRT-1's proviral activity is, we demonstrate, mediated through the repression of endoplasmic reticulum stress (ER stress). Inducing ER stress through thapsigargin treatment or SERCA2A knockdown in SIRT-1 knockdown cells had no additional effect on EV-D68 extracellular titers. Knockdown of SIRT-1 also decreases poliovirus and SARS-CoV-2 titers but not coxsackievirus B3. In non-lytic conditions, EV-D68 is primarily released in an enveloped form, and SIRT-1 is required for this process. Our data show that SIRT-1, through its translocation to the cytosol, is critical to promote the release of enveloped EV-D68 viral particles.


Knee Arthroscopy Simulation: A Randomized Controlled Trial Evaluating the Effectiveness of the Imperial Knee Arthroscopy Cognitive Task Analysis (IKACTA) Tool.
Virtual-reality and cadaveric simulations are expensive and not readily accessible. Innovative and accessible training adjuncts are required to help to meet training needs. Cognitive task analysis has been used extensively to train pilots and in other surgical specialties. However, the use of cognitive task analyses within orthopaedics is in its infancy. The purpose of this study was to evaluate the effectiveness of a novel cognitive task analysis tool to train novice surgeons in diagnostic knee arthroscopy in high-fidelity, phantom-limb simulation. Three expert knee surgeons were interviewed independently to generate a list of technical steps, decision points, and errors for diagnostic knee arthroscopy. A modified Delphi technique was used to generate the final cognitive task analysis. A video and a voiceover were recorded for each phase of this procedure. These were combined to produce the Imperial Knee Arthroscopy Cognitive Task Analysis (IKACTA) tool that utilizes written and audiovisual stimuli to describe each phase of a diagnostic knee arthroscopy. In this double-blinded, randomized controlled trial, a power calculation was performed prior to recruitment. Sixteen novice orthopaedic trainees who performed ≤10 diagnostic knee arthroscopies were randomized into 2 equal groups. The intervention group (IKACTA group) was given the IKACTA tool and the control group had no additional learning material. They were assessed objectively (validated Arthroscopic Surgical Skill Evaluation Tool [ASSET] global rating scale) on a high-fidelity, phantom-knee simulator. All participants, using the Likert rating scale, subjectively rated the tool. The mean ASSET score (and standard deviation) was 19.5 ± 3.7 points in the IKACTA group and 10.6 ± 2.3 points in the control group, resulting in an improvement of 8.9 points (95% confidence interval, 7.6 to 10.1 points; p = 0.002); the score was determined as 51.3% (19.5 of 38) for the IKACTA group, 27.9% (10.6 of 38) for the control group, and 23.4% (8.9 of 38) for the improvement. All participants agreed that the cognitive task analysis learning tool was a useful training adjunct to learning in the operating room. To our knowledge, this is the first cognitive task analysis in diagnostic knee arthroscopy that is user-friendly and inexpensive and has demonstrated significant benefits in training. The IKACTA will provide trainees with a demonstrably strong foundation in diagnostic knee arthroscopy that will flatten learning curves in both technical skills and decision-making.


A Canadian Massage Therapy Education Environmental Scan.
Massage therapists have been a part of Canadian's health care since 1919. The profession has gone through great change over the past 100 years including adjustments to entry-to-practice education. An important recent change was the implementation of massage therapy (MT) education program accreditation. In light of the likely disruption as a result of programs becoming accredited, a scan of the current state of MT education in Canada was undertaken. An environmental scan informed by seminal medical education efforts was used to describe the thoughts and opinions of MT education stakeholders in Canada. Specifically, stakeholders were interviewed regarding the current state of MT education and their comments were analyzed for common themes. Twenty-one stakeholders participated. Four themes were constructed: variation, isolation, stagnation, and accreditation. Variation is described as the impact of differences in content and quality of the education provided in MT colleges. Isolation is described as the feeling of the participant being separated, or disconnected, from the regulator, accreditor, or colleagues due, at least in part, to a lack of communication or networking opportunities. Stagnation is described as a lack of activity, growth, or development within MT education. Participants talked about accreditation, both as a solution for some of the challenges previously mentioned, and as a potential challenge in itself. Several challenges to MT education were described by stakeholders that they hoped would be remedied by national MT program accreditation. Despite some limitations, this environmental scan forms a baseline for stakeholder views on massage education in Canada upon which future comparisons can be made. While the environmental scan results are most useful when applied to the MT in Canada context, stakeholders in other countries may also find them interesting and valuable when considering challenges facing their own education programs.


Asymptomatic right atrial myxoma originating from the inferior vena cava and right atrium junction in a patient with breast ductal adenocarcinoma.
We present asymptomatic right atrial myxoma in a patient with breast ductal adenocarcinoma. A 58-year-old female was referred to our clinic for the evaluation of the potential cardiotoxic side effects of anthracycline-based chemotherapy. She had a 10-month history of modified radical mastectomy for ductal adenocarcinoma of the breast, followed by adjuvant chemotherapy. To evaluate potential side effects of anthracycline-based regimen, transthoracic echocardiography was performed, which showed a highly mobile, cystic, and heterogeneous mass, 20 x 25 mm in size, located in the right atrium. Transesophageal echocardiography confirmed the highly mobile mass originating from the inferior vena cava and extending to the right atrium. Surgery was planned. Upon exposure, the tumor had a broad base, with attachment to the lower dorsal free wall, interatrial septum of the right atrial cavity, and upper border of the inferior vena cava. The tumor was completely excised and histopathologic diagnosis was myxoma. Localization of right atrial myxoma at the junction of the inferior vena cava and right atrium is a rare condition, and its coexistence with breast carcinoma has only been reported once.


Statistical Validation of An Automated Method for Calculating Time Domain Heart Rate Variability on The QT Dataset.
Heart rate variability measures calculated from electrocardiography recordings reflect social competence. Clinical assessments of social skills have found that reduced heart rate variability is related to differences in the development of social skills in children and increase the risk of mental disorders. Limited by widespread manual signal processing and R-peak detection in current clinical assessments, most literature reports only short-term baseline studies, with fewer studies reporting social interaction settings with prolonged recording. There is an urgent need for an automated physiological signal processing toolbox to detect R-peaks and perform heart rate variability measurements in social settings. This paper proposes a modified automated Neurokit2 toolbox with signal processing procedures similar to the MindWare software that requires manual inspection of R-peak locations. We calculate time domain heart rate variability metrics from the publicly available QT database by PhysioNet collected at resting states and under stress tests, mimicking social interaction stress scenarios. Statistical analysis conveys that heart rate variability metrics calculation applying both signal processing approaches using the Neurokit2 toolbox are statistically equivalent in comparison to the hand-labelled R-peaks from the QT database (n= 10 in the normal sinus rhythm group, and n= 6 in the ST Change group). Such validation results are crucial for the adoption of automated toolboxes for heart rate variability measures in social interaction assessments, where more movement and mood changes of participants are expected.Clinical Relevance- This contributes to the body of evidence of the reliability of the Neurokit2 toolbox for automatic cleaning of prolonged cardiac electrophysiological signals and calculation of heart rate variability in time-domain characterization in social interaction stress assessment.


Plastics recycling: challenges and opportunities.
Plastics are inexpensive, lightweight and durable materials, which can readily be moulded into a variety of products that find use in a wide range of applications. As a consequence, the production of plastics has increased markedly over the last 60 years. However, current levels of their usage and disposal generate several environmental problems. Around 4 per cent of world oil and gas production, a non-renewable resource, is used as feedstock for plastics and a further 3-4% is expended to provide energy for their manufacture. A major portion of plastic produced each year is used to make disposable items of packaging or other short-lived products that are discarded within a year of manufacture. These two observations alone indicate that our current use of plastics is not sustainable. In addition, because of the durability of the polymers involved, substantial quantities of discarded end-of-life plastics are accumulating as debris in landfills and in natural habitats worldwide. Recycling is one of the most important actions currently available to reduce these impacts and represents one of the most dynamic areas in the plastics industry today. Recycling provides opportunities to reduce oil usage, carbon dioxide emissions and the quantities of waste requiring disposal. Here, we briefly set recycling into context against other waste-reduction strategies, namely reduction in material use through downgauging or product reuse, the use of alternative biodegradable materials and energy recovery as fuel. While plastics have been recycled since the 1970s, the quantities that are recycled vary geographically, according to plastic type and application. Recycling of packaging materials has seen rapid expansion over the last decades in a number of countries. Advances in technologies and systems for the collection, sorting and reprocessing of recyclable plastics are creating new opportunities for recycling, and with the combined actions of the public, industry and governments it may be possible to divert the majority of plastic waste from landfills to recycling over the next decades.


Inhaled porcine pancreatic elastase causes bronchoconstriction via a bradykinin-mediated mechanism.
Neutrophil elastase has been linked to inflammatory lung diseases such as chronic obstructive pulmonary disease, adult respiratory distress syndrome, emphysema, and cystic fibrosis. In guinea pigs, aerosol challenge with human neutrophil elastase causes bronchoconstriction, but the mechanism by which this occurs is not completely understood. Our laboratory previously showed that human neutrophil elastase releases tissue kallikrein (TK) from cultured tracheal gland cells. TK has been identified as the major kininogenase of the airway and cleaves both high- and low-molecular weight kininogen to yield lysyl-bradykinin. Because inhaled bradykinin causes bronchoconstriction and airway hyperresponsiveness in asthmatic patients and allergic sheep, we hypothesized that elastase-induced bronchoconstriction could be mediated by bradykinin. To test this hypothesis, we measured lung resistance (RL) in sheep before and after inhalation of porcine pancreatic elastase (PPE) alone and after pretreatment with a bradykinin B(2) antagonist (NPC-567), the specific human elastase inhibitor ICI 200,355, the histamine H(1)-antagonist diphenhydramine hydrochloride, the cysteinyl leukotriene 1 receptor antagonist montelukast, or the cyclooxygenase inhibitor indomethacin. Inhaled PPE (125-1,000 microg) caused a dose-dependent increase in RL. Aerosol challenge with a single 500 microg dose of PPE increased RL by 132 +/- 8% over baseline. This response was blocked by pretreatment with NPC-567 and ICI-200,355 (n = 6; P < 0.001), whereas treatment with diphenhydramine hydrochloride, montelukast, or indomethacin failed to block the PPE-induced bronchoconstriction. Consistent with pharmacological data, TK activity in bronchial lavage fluid increased 134 +/- 57% over baseline (n = 5; P < 0.02). We conclude that, in sheep, PPE-induced bronchoconstriction is in part mediated by the generation of bradykinin. Our findings suggest that elastase-kinin interactions may contribute to changes in bronchial tone during inflammatory diseases of the airways.


Mechanism of gamma sigma T-cell-mediated inhibition of stem cell differentiation in vitro: possible relevance for myelosuppression in HIV-infected individuals.
We investigated whether gamma delta T cells contribute to the suppression of myelopoiesis in HIV infection. Freshly isolated gamma delta T cells from HIV seropositive patients suppressed CFU-GM growth in vitro. Preactivation of gamma delta T cells with IL-2 and/or IL-15 further reduced the number of CFU-GM. Natural killer cells and to a lower extent CD4+ and CD8+ cells also inhibited CFU-GM growth. In contrast to gamma delta T cells, this effect was not dependent on IL-15 or IL-2 preactivation. Moreover, no enhanced inhibitory effect of CD56+ and CD4+ cells was observed in HIV+ subjects compared to HIV- donors. The myelosuppressive effect of supernatants of gamma delta T cells could be inhibited by antibodies against IFN-gamma or TNF-alpha. Accordingly, we found increased numbers of TNF-alpha or IFN-gamma-secreting CD8+ gamma delta T cells in HIV+ patients. We conclude that the increased fraction of activated gamma delta T cells producing myelosuppressive cytokines might contribute to the dyshematopoiesis frequently observed in HIV-infected individuals.


Latexin regulation by HMGB2 is required for hematopoietic stem cell maintenance.
Hematopoietic stem cells provide life-long production of blood cells and undergo self-renewal division in order to sustain the stem cell pool. Homeostatic maintenance of hematopoietic stem cell pool and blood cell production is vital for the organism to survive. We previously reported that latexin is a negative regulator of hematopoietic stem cells in mice. Its natural variation in the expression is inversely correlated with hematopoietic stem cell number. However, the molecular mechanisms regulating latexin transcription remain largely unknown, and the genetic factors contributing to its natural variation are not clearly defined. Here we discovered a chromatin protein, high-mobility group protein B2, as a novel transcriptional suppressor of latexin by using DNA pull-down and mass spectrometry. High-mobility group protein B2 knockdown increases latexin expression at transcript and protein levels, and decreases hematopoietic stem cell number and regeneration capacity in vivo Concomitant blockage of latexin activation significantly reverses these phenotypic changes, suggesting that latexin is one of the downstream targets and functional mediators of high-mobility group protein B2. We further identified a functional single nucleotide polymorphism, rs31528793, in the latexin promoter that binds to high-mobility group protein B2 and affects the promoter activity. G allelic variation in rs31528793 associates with the higher latexin expression and lower hematopoietic stem cell number, whereas C allele indicates the lower latexin expression and higher stem cell number. This study reveals for the first time that latexin transcription is regulated by both transacting (high-mobility group protein B2) and cis-acting (single nucleotide polymorphism rs31528793) factors. It uncovers the functional role of naturally occurring genetic variants, in combination with epigenetic regulator, in determining differential gene expression and phenotypic diversity in the hematopoietic stem cell population.


The ameliorative effect of cerium oxide nanoparticles on chlorpyrifos induced hepatotoxicity in a rat model: Biochemical, molecular and immunohistochemical study.
Chlorpyrifos (CPF) is a widely used insecticide that causes toxicity to living organisms through the production of free radicals. Cerium oxide nanoparticles (CeO2NPs) are a new antioxidant agent that has proved therapeutic effects. We evaluated the effect of CeO2NPs on CPF hepatotoxicity. Forty rats were randomized into four groups. Group I: rats received 1 ml corn oil by gastric tube once daily and 0.5 ml PBS by intra-peritoneal injection twice a week for 4 weeks. Group II: received CeO2NPs 0.5 mg/kg in PBS by i.p. injection, twice weekly for four weeks. Group III: were treated with oral administration of CPF 13.5 mg/kg in corn oil daily for 4 weeks. Group IV: received CPF as in group III, then each animal received CeO2NPs twice weekly for four weeks as in group II. Twenty-four hours after the last dose, rats were anesthetized and sera were collected for liver enzymes assessment. Afterwards, rats were sacrificed, livers were excised, the right lobe of each liver was fixed for immunohistochemical studies, and the left lobe was homogenized for oxidative profile assessment and molecular analysis. CPF group showed significant increase in liver transaminases, disturbance of the oxidative profile with up-regulation of BAX expression and down-regulation in the Bcl-2, Gadd45 and NFE2L2. CPF caused severe histopathological liver damage as well as significant increase in anti-Caspase 3 and TNF immunostaining. The CeO2NPs treated group revealed significant improvement of all previous parameters. CeO2NPs could alleviate CPF hepatoxicity through decreasing expression of the inflammatory and apoptotic proteins and increasing the activity of antioxidant enzymes.


Long-term evaluation of the efficacy and safety of Nd:YAG laser vitreolysis for symptomatic vitreous foaters.
This study aimed to evaluate the long-term safety and efficacy of neodymium-doped yttrium aluminum garnet (Nd:YAG) vitreolysis for symptomatic vitreous floaters as it remains a controversial procedure due to insufficient robust evidence in the literature for the maintenance of the results and absence of adverse effects. This is an observational extension to the previously presented prospective, randomized, double-blind clinical trial. Eight of thirteen subjects who underwent vitreolysis with YAG laser returned for a late reevaluation, 18 months after the procedure, to evaluate the efficacy and safety of the procedure. All patients maintained the improvement in symptomatology noted after the procedure, with 25% showing complete improvement and a similar proportion (37.5%) reporting significant or partial improvement. Objective improvement in opacity was similar to that found at 6 months follow-up. The NEI-VFQ 25 quality of life questionnaire showed no statistically significant difference in responses between the 6th and 18th month. No adverse effects were noted on clinical examination or reported by patients. Vitreolysis efficacy observed at 6 months of follow-up was maintained until the eighteenth month, with all patients reporting improvement from the pre-procedure state. No late adverse effects were noted. A larger randomized clinical trial is needed to confirm the safety of the procedure.


[Repeatability of insulin sensitivity estimation using the Minimal Model and comparison with a modified short low-dose insulin tolerance test].
Hyperinsulinemia and insulin-resistance are metabolic disturbances associated with obesity, essential hypertension, hypertriglyceridemia, glucose intolerance, overt non-insulin dependent diabetes mellitus, polymetabolic syndrome and atherosclerotic disease. The assessment of in vivo insulin sensitivity (SAI in vivo) changes achieved by life style modifications or drug interventions require a reproducible technique. To evaluate the day-to-day intra-individual repeatability of SAI-in vivo, we determined the variation in the SI index (calculated from the Minimal Model of Bergman modified by insulin or MMins) in 11 subjects with a wide range of insulin-resistance. SI (first study) varied from 0.82 to 8.48 x 10(-4) min-1/microU.mL (4.43 +/- 2.85 x 10(-4) min-1/microU.mL mean +/- SD) and highly correlated with SI (second study) (r = 0.89; p = 0.0002). The average interday coefficient of variation was 20.9 +/- 13.9% and was similar in subjects with low or high SI values. We also measured SAI in vivo by assessing the rate of serum glucose decline induced by human cristalline insulin 0.025 U/kg IV dose after a 12-14 hours fasting period (a modified Bonora's method or BBD) in 11 subjects. No subject presented biochemical or symptomatic hypoglycemia. SAI in vivo values determined by BBD varied from 21 a 234 mumol/ml/min (134 +/- 64.8 mumol/ml/min, mean +/- SD). We found a highly significant correlation between SI values obtained from MMins and SAI in vivo assessed by the BBD (r = 0.89, p = 0.0002). Our results suggest that the Mmins is a fairly reproducible procedure and that a BBD is an acceptable option to quantify SAI in vivo, mainly when a fast-execution practice is necessary or cost restrictions are required.


[Current outcome quality in the care of preterm infants with birth weight less than 1 500 g as a basis for regionalisation of risk pregnancies].
For preterm infants an association between patient volume and mortality has been described. Outcome variables were evaluated for 28 hospitals in Baden-Württemberg for the years 2004-2008. Hospitals with high patient volume were compared to hospitals with a lower patient volume. Outcomes for 1 164 infants in 2008 and for 4 775 infants in 2004-2008 were analysed. In 2008, mortality of preterm infants less than 32 weeks gestational age (GA) was 9.2% (n=402) in the 5 major hospitals compared to 6.5% (n=520) in the other hospitals (combined mortality 7.7%, n. s., chi-square test). In the years 2004-2008, mortality showed a greater variation in hospitals with a patient volume below 50 and mean mortality was 21.1% higher for infants less than 500 g BW. Hospitals with a patient volume >or= 50 had a lower mortality for infants with BW below 500 g and between 500 g and 749 g (18% and 11%, chi-square test: p<0.05 and <0.01, respectively). For preterm infants with GA below 24 weeks and between 24 and 25 weeks, patient volume and mortality were negatively correlated (p<0.01 and <0.0001, respectively). For infants with a BW >or= 750 g or a GA >or= 26 weeks patient volume had no effect on outcome. Regionalisation of preterm infants with BW less than 750 g and a GA less than 26 weeks may contribute to reduce mortality. Infants with BW >or= 750 g and a GA >or= 26 weeks may not benefit from indirect quality indicators such as patient volume.


Extracellular vesicles and co-isolated endogenous retroviruses from murine cancer cells differentially affect dendritic cells.
Cells secrete extracellular vesicles (EVs) and non-vesicular extracellular (nano)particles (NVEPs or ENPs) that may play a role in intercellular communication. Tumor-derived EVs have been proposed to induce immune priming of antigen presenting cells or to be immuno-suppressive agents. We suspect that such disparate functions are due to variable compositions in EV subtypes and ENPs. We aimed to characterize the array of secreted EVs and ENPs of murine tumor cell lines. Unexpectedly, we identified virus-like particles (VLPs) from endogenous murine leukemia virus in preparations of EVs produced by many tumor cells. We established a protocol to separate small EVs from VLPs and ENPs. We compared their protein composition and analyzed their functional interaction with target dendritic cells. ENPs were poorly captured and did not affect dendritic cells. Small EVs specifically induced dendritic cell death. A mixed large/dense EV/VLP preparation was most efficient to induce dendritic cell maturation and antigen presentation. Our results call for systematic re-evaluation of the respective proportions and functions of non-viral EVs and VLPs produced by murine tumors and their contribution to tumor progression.


The Baby's First Bites RCT: Evaluating a Vegetable-Exposure and a Sensitive-Feeding Intervention in Terms of Child Health Outcomes and Maternal Feeding Behavior During Toddlerhood.
Parenting interventions during the first years of life on what and/or how to feed infants during complementary feeding can promote healthy eating habits. An intervention promoting repeated exposure to a variety of vegetables [repeated vegetable exposure (RVE); what] and an intervention promoting responding sensitively to child signals during mealtime [video-feedback intervention to promote positive parenting-feeding infants (VIPP-FI); how] were compared, separately and combined (COMBI), with an attention control condition (AC). Primary outcomes were vegetable consumption and self-regulation of energy intake; secondary outcomes were child anthropometrics and maternal feeding practices (sensitive feeding, pressure to eat). Our 4-arm randomized controlled trial included 246 first-time Dutch mothers and their infants. Interventions started when infants were 4-6 mo old and ended at age 16 mo. The present study evaluated effects at 18 (t18) and 24 (t24) mo of age. Vegetable acceptance was assessed using three 24-h dietary recalls, self-regulation of energy intake by an eating-in-the-absence-of-hunger experiment and mother-report, and maternal feeding behavior by observation and mother-report. Linear mixed model and ANOVA analyses revealed no follow-up group differences regarding child vegetable intake or self-regulatory behavior. The proportion of children with overweight was significantly lower in the COMBI group, compared with the VIPP-FI group at t18 (2% compared with 16%), and with the AC group at t24 (7% compared with 20%), although this finding needs to be interpreted cautiously due to the small number of infants with overweight and nonsignificant effects on the continuous BMI z-score measure (P values: 0.29-0.82). Finally, more sensitive feeding behavior and less pressure to eat was found in the VIPP-FI and COMBI groups, compared with the RVE and AC groups, mostly at t18 (significant effect sizes: d = 0.23-0.64). Interventions were not effective in increasing vegetable intake or self-regulation of energy intake. Future research might usefully focus on risk groups such as families who already experience problems around feeding.This trial is registered at clinicaltrials.gov as NCT03348176.


Electronic-resonance-enhanced coherent anti-Stokes Raman scattering of nitric oxide: saturation and Stark effects.
A theoretical analysis of electronic-resonance-enhanced (ERE) coherent anti-Stokes Raman scattering (CARS) of NO is described. The time-dependent density-matrix equations for the nonlinear ERE-CARS process are derived and manipulated into a form suitable for direct numerical integration. In the ERE-CARS configuration considered in this paper, the pump and Stokes beams are far from electronic-resonance. The visible 532 and 591 nm laser beams are used to excite Q-branch Raman resonances in the vibrational bands of the X (2)Pi electronic state of NO. An ultraviolet probe beam at 236 nm is used to excite P-, Q-, or R-branch transitions in the (v'=0, v"=1) band of the A (2)Sigma(+)-X (2)Pi electronic system of NO molecule. Experimental spectra are obtained either by scanning the ultraviolet probe beam while keeping the Stokes frequency fixed (probe scans) or by scanning the Stokes frequency while keeping the probe frequency fixed (Stokes scans). The calculated NO ERE-CARS spectra are compared with experimental spectra, and good agreement is observed between theory and experiment in terms of spectral peak locations and relative intensities. The effects of saturation of the two-photon Raman-resonant Q-branch transitions, the saturation of a one-photon electronic-resonant P-, Q-, or R-branch transitions in the A (2)Sigma(+)-X (2)Pi electronic system, and the coupling of these saturation processes are investigated. The coupling of the saturation processes for the probe and Raman transitions is complex and exhibits behavior similar to that observed in the electromagnetic induced transparency process. The probe scan spectra are significantly affected by Stark broadening due to the interaction of the pump and Stokes radiation with single-photon resonances between the upper vibration-rotation probe level in the A (2)Sigma(+) electronic levels and vibration-rotation levels in higher lying electronic levels. The ERE-CARS signal intensity is found to be much less sensitive to variations in the collisional dephasing rates under saturation conditions.


Performance, stability and operation voltage optimization of screen-printed aqueous supercapacitors.
Harvesting micropower energy from the ambient environment requires an intermediate energy storage, for which printed aqueous supercapacitors are well suited due to their low cost and environmental friendliness. In this work, a systematic study of a large set of devices is used to investigate the effect of process variability and operating voltage on the performance and stability of screen printed aqueous supercapacitors. The current collectors and active layers are printed with graphite and activated carbon inks, respectively, and aqueous NaCl used as the electrolyte. The devices are characterized through galvanostatic discharge measurements for quantitative determination of capacitance and equivalent series resistance (ESR), as well as impedance spectroscopy for a detailed study of the factors contributing to ESR. The capacitances are 200-360 mF and the ESRs 7.9-12.7 Ω, depending on the layer thicknesses. The ESR is found to be dominated by the resistance of the graphite current collectors and is compatible with applications in low-power distributed electronics. The effects of different operating voltages on the capacitance, leakage and aging rate of the supercapacitors are tested, and 1.0 V found to be the optimal choice for using the devices in energy harvesting applications.


Formation and secretion of induced penicillinase in protoplasts of Staphylococcus aureus.
Conditions suitable for induced formation and secretion of penicillinase (EC 18.104.22.168) in protoplasts of Staphylococcus aureus were determined. No requirement was found for cells to be exposed to inducer prior to formation of protoplasts. Neither cell wall components nor mesosomes appeared to be necessary for induction or secretion. In medium containing 1.1 M sucrose about half of the formed enzyme was soluble, whereas in medium containing 0.37 M sodium succinate only about 10% of the penicillinase remained protoplast-bound. Low concentrations of polyanions (dextran sulfate and potassium polyvinyl-sulfonate) inhibited the formation of induced penicillinase, as did 4-acetamido-4'-isothiocyano-stilbene 2,2'-disulfonic acid. None of these compounds inhibited the activity of native penicillinase, and none would be expected to pass through the protoplast membrane. Penicillinase, denatured in 4 M urea, could be renatured by dilution in the presence of benzylpenicillin, and the above three inhibitors interfered strongly with this process. The results are taken as evidence that penicillinase may be secreted through the protoplast membrane in an incompletely folded form.


Long-term outcome of iliosacral resection without reconstruction for primary bone tumours.
Iliac wing (Type I) and iliosacral (Type I/IV) pelvic resections for a primary bone tumour create a large segmental defect in the pelvic ring. The management of this defect is controversial as the surgeon may choose to reconstruct it or not. When no reconstruction is undertaken, the residual ilium collapses back onto the remaining sacrum forming an iliosacral pseudarthrosis. The aim of this study was to evaluate the long-term oncological outcome, complications, and functional outcome after pelvic resection without reconstruction. Between 1989 and 2015, 32 patients underwent a Type I or Type I/IV pelvic resection without reconstruction for a primary bone tumour. There were 21 men and 11 women with a mean age of 35 years (15 to 85). The most common diagnosis was chondrosarcoma (50%, n = 16). Local recurrence-free, metastasis-free, and overall survival were assessed using the Kaplan-Meier method. Patient function was evaluated using the Musculoskeletal Tumour Society (MSTS) and Toronto Extremity Salvage Score (TESS). At a mean follow-up of 159 months (1 to 207), 23 patients were alive without disease, one was alive with lung metastases, one was alive following local recurrence, four were dead of disease, and three had died from other causes. The overall ten-year survival was 77%. There was only one (3%) local recurrence, which occurred at 26 months. There were 18 complications in 17 patients; 13 wound healing complications/infections, three fractures, one pulmonary embolism, and one dislocation of the hip. Most complications occurred early. The mean functional scores were 21.1 (SD 8.1) for MSTS-87, 67.3 (SD 23.9) for MSTS-93 and 76.2 (SD 20.6) for TESS. Patients requiring Type I or Type I/IV pelvic resections can expect a good oncological outcome and a high rate of local control. Complications are generally acute in nature and are easily manageable. These patients achieved a good functional outcome without the need for bony reconstruction. Cite this article: Bone Joint J 2020;102-B(6):779-787.


In Vivo Inhibition of miR-34a Modestly Limits Cardiac Enlargement and Fibrosis in a Mouse Model with Established Type 1 Diabetes-Induced Cardiomyopathy, but Does Not Improve Diastolic Function.
MicroRNA 34a (miR-34a) is elevated in the heart in a setting of cardiac stress or pathology, and we previously reported that inhibition of miR-34a in vivo provided protection in a setting of pressure overload-induced pathological cardiac hypertrophy and dilated cardiomyopathy. Prior work had also shown that circulating or cardiac miR-34a was elevated in a setting of diabetes. However, the therapeutic potential of inhibiting miR-34a in vivo in the diabetic heart had not been assessed. In the current study, type 1 diabetes was induced in adult male mice with 5 daily injections of streptozotocin (STZ). At 8 weeks post-STZ, when mice had established type 1 diabetes and diastolic dysfunction, mice were administered locked nucleic acid (LNA)-antimiR-34a or saline-control with an eight-week follow-up. Cardiac function, cardiac morphology, cardiac fibrosis, capillary density and gene expression were assessed. Diabetic mice presented with high blood glucose, elevated liver and kidney weights, diastolic dysfunction, mild cardiac enlargement, cardiac fibrosis and reduced myocardial capillary density. miR-34a was elevated in the heart of diabetic mice in comparison to non-diabetic mice. Inhibition of miR-34a had no significant effect on diastolic function or atrial enlargement, but had a mild effect on preventing an elevation in cardiac enlargement, fibrosis and ventricular gene expression of B-type natriuretic peptide (BNP) and the anti-angiogenic miRNA (miR-92a). A miR-34a target, vinculin, was inversely correlated with miR-34a expression, but other miR-34a targets were unchanged. In summary, inhibition of miR-34a provided limited protection in a mouse model with established type 1 diabetes-induced cardiomyopathy and failed to improve diastolic function. Given diabetes represents a systemic disorder with numerous miRNAs dysregulated in the diabetic heart, as well as other organs, strategies targeting multiple miRNAs and/or earlier intervention is likely to be required.


Depression and Anxiety in Mothers Who Were Pregnant During the COVID-19 Outbreak in Northern Italy: The Role of Pandemic-Related Emotional Stress and Perceived Social Support.
The COVID-19 pandemic is a collective trauma that is threatening citizens' mental health resulting in increased emotional stress, reduced social support, and heightened risk for affective symptoms. The present study aimed to investigate the effects of antenatal pandemic-related emotional stress and perceived social support on the symptoms of depression and anxiety of mothers who were pregnant during the initial COVID-19 outbreak in northern Italy. A sample of 281 mothers was enrolled at eight maternity units in the first hotspot region of the COVID-19 outbreak in northern Italy. Participants filled out online questionnaires assessing the direct or indirect exposure to the SARS-CoV-2 virus, pandemic-related stress, perceived social support, as well as symptoms of depression and anxiety. Depressive and anxious symptomatology was above clinical concern, respectively, in 26 and 32% of the respondents. Mothers who reported no exposure to SARS-CoV-2 during pregnancy and those who reported at least one direct or indirect exposure did not differ in terms of affective symptoms. Continuous scores and risk for severe depression and anxiety were positively associated with prenatal pandemic-related emotional stress and negatively linked with perceived social support during pregnancy. Women who become mothers during the COVID-19 emergency may be at high risk for affective problems. Dedicated preventive programs are needed to provide adequate preventive support and care for maternal mental health during and after the COVID-19 pandemic.


Blunt renal trauma in children: experience with conservative management at a pediatric trauma center.
The authors reviewed the outcome for children with blunt renal injury managed with a nonoperative protocol at their pediatric trauma center. Fifty-five consecutive children aged 0.5 to 17 years with blunt renal injury managed over a 14-year period were reviewed. All patients were evaluated with computed tomographic scanning. Injuries were graded according to the American Association for the Surgery of Trauma Organ Injury Scale. Forty-eight of 55 children (87%) were successfully managed nonoperatively. Overall, there were 5 grade I, 13 grade II, 18 grade III, 14 grade IV, and 5 grade V injuries. All children with grades I and III injuries were successfully managed nonoperatively. Two (6%) of these children required transfusion. Only four (29%) children with grade IV and three (60%) with grade V injuries required surgical interventions (one nephrostomy, six nephrectomies). Excluding patients with continuing hemorrhage, only 2 (14%) of 14 with high-grade injuries required surgical intervention (1 nephrostomy, 1 nephrectomy). Clearance of gross hematuria correlated with severity of injury and was prolonged in grade IV and V compared with grade I to III injuries (6.8 +/- 2.7 vs. 3.2 +/- 2.1 days, respectively; p < 0.05). Fifty-one children (93%) available for follow-up were normotensive with normal renal function. These data support the use of conservative management for all grades in stable children with blunt renal injury. Transfusion requirements, operative rates, and outcome are consistent with other pediatric solid organ injuries.


Emphysematous cystitis: a review of the literature.
Emphysematous cystitis (EC) is a rare form of complicated urinary tract infection, its characteristic feature being gas within the bladder wall and lumen. Patients with EC present with variable clinical manifestations ranging from asymptomatic to severe sepsis. EC is typically observed in elderly women with severe diabetes mellitus. Escherichia coli and Klebsiella pneumoniae are often isolated from urine cultures. Imaging methods, such as plain conventional abdominal radiography and computed tomography, are pivotal for obtaining a definitive diagnosis of EC. Most cases can be treated with a combination of antibiotics, bladder drainage and glycemic control. EC is potentially life-threatening, with a mortality rate of 7%. Early medical intervention can contribute to achieving a favorable prognosis without the need for surgical intervention. In this review, we provide a comprehensive description of the clinical characteristics of EC.


Use of vaginal pressure measurements in urodynamic testing.
A study of 50 women using vaginal pressure measurements in urodynamic testing was performed. In the majority of patients, the vaginal pressure accurately reflects events occurring in the abdominal cavity. The elimination of abdominal pressure artifacts assists the physician in identifying patients with unstable bladders and assessing the voiding mechanisms. Vaginal placement of the pressure transducer is easier than rectal placement and better tolerated by patients.


Probability estimation in arithmetic and adaptive-Huffman entropy coders.
Entropy coders, such as Huffman and arithmetic coders, achieve compression by exploiting nonuniformity in the probabilities under which a random variable to be coded takes on its possible values. Practical realizations generally require running adaptive estimates of these probabilities. An analysis of the relationship between estimation quality and the resulting coding efficiency suggests a particular scheme, dubbed scaled-count, for obtaining such estimates. It can optimally balance estimation accuracy against a need for rapid response to changing underlying statistics. When the symbols being coded are from a binary alphabet, simple hardware and software implementations requiring almost no computation are possible. A scaled-count adaptive probability estimator of the type described in this paper is used in the arithmetic coder of the JBIG and JPEG image coding standards.


Influence of premium vs masked cigarette brand names on the experienced taste of a cigarette after tobacco plain packaging in Australia: an experimental study.
Few studies have experimentally assessed the contribution of branding to the experience of smoking a cigarette, compared with the inherent properties of the product. This study examined the influence of cigarette brand name on the sensory experience of smoking a cigarette. Seventy-five Australian smokers aged 18-39 years smoked two 'premium' cigarettes, one with the brand variant name shown and one with the brand variant name masked (which provided 'objective' ratings). Unknown to participants, the two cigarettes were identical. At recruitment, participants rated their expected enjoyment, quality and harshness of several premium cigarette brands. Branded cigarettes were rated as having a significantly more favorable taste (M(SE) = 64.14(2.21)) than masked cigarettes (M(SE) = 58.53(2.26), p = .031). Branded cigarettes were also rated as being less stale (M(SE) = 36.04(2.62)) than masked cigarettes (M(SE) = 43.90(2.60), p = .011). Purchase intent tended to be higher among those shown the branded cigarette compared to the masked cigarette (χ2 (1) = 3.00, p = .083). Expected enjoyment and quality of the brand variant (enjoyment: b = 0.31, 95%CI = 0.11, 0.51, p < .01; quality: b = 0.46, 95%CI = 0.21, 0.72, p < .01) contributed to the perceived smoking experience more than the objective enjoyment and quality of the cigarette (enjoyment: b = 0.23, 95%CI = 0.05, 0.41, p < .05; quality: b = 0.08, 95%CI = - 0.13, 0.30, p > .05). This pattern was not observed for cigarette harshness. A premium brand variant name can enhance the subjective experience of a cigarette. Further, smokers' expectations of such brand variants contribute to the smoking experience as much, if not more than, the actual qualities of the product.


The Application of Machine Perfusion as an Enhanced ex vivo Model for Optical Imaging.
Optical imaging techniques such as spectral imaging show promise for the assessment of tissue health during surgery; however, the validation and translation of such techniques into clinical practise is limited by the lack of representative tissue models. In this paper, we demonstrate the application of an organ perfusion machine as an ex vivo tissue model for optical imaging. Three porcine livers are perfused at stepped blood oxygen saturations. Over the duration of each perfusion, spectral data of the tissue are captured via diffuse optical spectroscopy and multispectral imaging. These data are synchronised with blood oxygen saturation measurements recorded by the perfusion machine. Shifts in the optical properties of the tissue are demonstrated over the duration of the each perfusion, as the tissue becomes reperfused and as the oxygen saturation is varied.


A comparative analysis of the osteogenic effects of BMP-2, FGF-2, and VEGFA in a calvarial defect model.
The utilization of growth factors for bone regeneration is a widely studied field. Since the approval of bone morphogenetic protein-2 (BMP-2) for therapeutic use in humans, the concept of utilizing growth factors for bone regeneration in translational medicine has become even more attractive. Despite many studies published on individual growth factors in various bone models, comparative analysis is largely lacking. The aim of our study was to compare three different proosteogenic factors under identical in vivo conditions. Thus, we tested the bone regeneration capacity of the three different growth factors BMP-2, fibroblast growth factor-2 (FGF-2), and vascular endothelial growth factor A (VEGFA) in a calvarial defect model. We demonstrated that BMP-2 and VEGFA had similar bone healing capacities, resulting in complete calvarial healing as early as week 3. FGF-2 also showed a significantly higher bone regeneration capacity; however, the healing rate was lower than with BMP-2 and VEGFA. Interestingly, these findings were paralleled by an increased angiogenic response upon healing in BMP-2- and VEGFA-treated calvarial defects as compared with FGF-2. Immunohistochemistry for proliferating and osteoprogenitor cells revealed activity at different points after surgery among the groups. In conclusion, we demonstrated an efficient bone regeneration capacity of both BMP-2 and VEGFA, which was superior to FGF-2. Moreover, this study highlights the efficient bone regeneration of VEGFA, which was comparable with BMP-2. These data provide a valuable comparative analysis, which can be used to further optimize growth factor-based strategies in skeletal tissue engineering.


Soy food and isoflavone intake and endometrial cancer risk: the Japan Public Health Center-based prospective study.
Compared with western populations, the consumption of soy foods among Japanese is very high and the incidence of endometrial cancer very low. We evaluated the association of soy food and isoflavone intake with endometrial cancer risk in Japanese women. Prospective cohort study. Ten public health centre areas in Japan. Forty nine thousand one hundred and twenty-one women of age 45-74 years who responded to a 5-year follow-up survey questionnaire. Intakes of soy foods as well as other covariates were assessed in 1995-1998 by a self-administered food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Incidence of endometrial cancer. During an average of 12.1 years of follow up, 112 newly diagnosed endometrial cancer cases were identified. Energy-adjusted intakes of soy food and isoflavone were not associated with the risk of endometrial cancer. The multivariate-adjusted HR per 25 g/day increase in the intake of soy food was 1.02 (95% CI 0.94-1.10), and the corresponding value for isoflavone intake per 15 mg/day was 1.01 (95% CI 0.84-1.22). In this population-based prospective cohort study of Japanese women, we observed no evidence of a protective association between soy food or isoflavone intake and endometrial cancer risk.


Snapshots in ants? New interpretations of paradigmatic experiments.
Ants can use visual information to guide long idiosyncratic routes and accurately pinpoint locations in complex natural environments. It has often been assumed that the world knowledge of these foragers consists of multiple discrete views that are retrieved sequentially for breaking routes into sections controlling approaches to a goal. Here we challenge this idea using a model of visual navigation that does not store and use discrete views to replicate the results from paradigmatic experiments that have been taken as evidence that ants navigate using such discrete snapshots. Instead of sequentially retrieving views, the proposed architecture gathers information from all experienced views into a single memory network, and uses this network all along the route to determine the most familiar heading at a given location. This algorithm is consistent with the navigation of ants in both laboratory and natural environments, and provides a parsimonious solution to deal with visual information from multiple locations.


Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors.
Subgroups of patients with chronic lymphocytic leukemia (CLL) have distinct expression profiles of Toll-like receptor (TLR) pathway-associated genes. To test the hypothesis that signaling through innate immunity receptors may influence the behavior of the malignant clone, we investigated the functional response triggered by the stimulation of TLRs and NOD2 in 67 CLL cases assigned to different subgroups on the basis of immunoglobulin heavy variable (IGHV ) gene usage, IGHV gene mutational status or B-cell receptor (BcR) stereotypy. Differences in the induction of costimulatory molecules and/or apoptosis were observed in mutated versus unmutated CLL. Different responses were also identified in subsets with stereotyped BcRs, underscoring the idea that "subset-biased" innate immunity responses may occur independently of mutational status. Additionally, differential modulation of kinase activities was induced by TLR stimulation of different CLL subgroups, revealing a TLR7-tolerant state for cases belonging to stereotyped subset #4. The distinct patterns of TLR/NOD2 functional activity in cells from CLL subgroups defined by the molecular features of the clonotypic BcRs might prove relevant for elucidating the immune mechanisms underlying CLL natural history and for defining subgroups of patients who might benefit from treatment with specific TLR ligands.


Electrophilic bis-fluorophosphonium dications: Lewis acid catalysts from diphosphines.
Stepwise oxidation of 1,8-bis(diphenylphosphino)naphthalene and a series of (oligo)methylene-linked diphosphines with XeF2 followed by fluoride abstraction yields a family of compounds featuring phosphine, phosphonium and phosphorane moieties in close proximity. The bisphosphonium ions [(C10H6)(Ph2PF)2]2+ (5) and [CH2(Ph2PF)2]2+ (9a) exhibit remarkable Lewis acidity arising from the proximity of the phosphonium centers. The effectiveness of bisphosphonium dications (5, 9a-e) is examined in a series of Lewis acid catalysed transformations.


CD4+ CD25+ regulatory T cells control T helper cell type 1 responses to foreign antigens induced by mature dendritic cells in vivo.
Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II-restricted interferon gamma-producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.


Impedance-based viscoelastic flow cytometry.
Elastic nature of the viscoelastic fluids induces lateral migration of particles into a single streamline and can be used by microfluidic based flow cytometry devices. In this study, we investigated focusing efficiency of polyethylene oxide based viscoelastic solutions at varying ionic concentration to demonstrate their use in impedimetric particle characterization systems. Rheological properties of the viscoelastic fluid and particle focusing performance are not affected by ionic concentration. We investigated the viscoelastic focusing dynamics using polystyrene (PS) beads and human red blood cells (RBCs) suspended in the viscoelastic fluid. Elasto-inertial focusing of PS beads was achieved with the combination of inertial and viscoelastic effects. RBCs were aligned along the channel centerline in parachute shape which yielded consistent impedimetric signals. We compared our impedance-based microfluidic flow cytometry results for RBCs and PS beads by analyzing particle transit time and peak amplitude at varying viscoelastic focusing conditions obtained at different flow rates. We showed that single orientation, single train focusing of nonspherical RBCs can be achieved with polyethylene oxide based viscoelastic solution that has been shown to be a good candidate as a carrier fluid for impedance cytometry.