Effect of phlebotomy on lipid metabolism in subjects with hereditary hemochromatosis.
Genetic predisposition to hereditary hemochromatosis (HH) is associated with primary hypertriglyceridemia (HTG). If iron overload influences the development of HTG, the management of these patients could be different. However, the metabolic syndrome in primary HTG is frequent; and it could partially confuse the association. The objective was to determine whether periodic bloodletting could decrease triglyceride concentrations in subjects with HH and iron overload. We retrospectively studied 155 genetically defined HH patients (C282Y homozygotes and compound heterozygotes C282Y/H63D) with iron overload and under periodic therapeutic phlebotomy. Hypertriglyceridemia (triglycerides ≥150 mg/dL) was present in 49 subjects at baseline (31.6%). Phlebotomies significantly decreased triglycerides, especially in subjects with basal HTG (from 287 mg/dL at baseline to 133 mg/dL after phlebotomies, P < .001). Blood glucose and total cholesterol did not change with phlebotomies. The triglyceride-lowering effect was obtained until ferritin concentration decreased to less than 200 μg/L and transferrin saturation to less than 40%. The triglyceride-lowering effect was obtained for glucose levels both less than and greater than 100 mg/dL. In summary, HH subjects frequently have HTG that improves after therapeutic phlebotomy, independently of basal blood glucose. Our results suggest that therapeutic phlebotomy could be a useful therapeutic approach in patients with HTG and iron overload.


Evaluating Country Performance After Transitioning From Gavi Assistance: An Applied Synthetic Control Analysis.
Over the past decade, international development assistance for health has slowed. As donors seek to increase domestic cofinancing and ultimately transition countries from donor aid dependence, COVID-19 has severely constrained public budgets. The evaluation of sustainability and longer-term impacts of donor withdrawal is increasingly important. We assess vaccination coverage and post-neonatal mortality to estimate country performance of these outcomes among countries that no longer received assistance from Gavi, the Vaccine Alliance (Gavi) between 2000 and 2018. Using data from all countries receiving Gavi support between 2000 and 2020, we employed a synthetic control method to generate a pre-transition counterfactual with the same characteristics as the observation of interest to predict a future that empirically never existed. The synthetic unit is constructed from the weighted average of other units with good fit to the unit of interest before transition but did not transition. We found substantial heterogeneity after transitioning from Gavi assistance. China, Guyana, and Turkmenistan overperformed their expected coverage rates; Albania, Bhutan, China, Guyana, and Turkmenistan maintained coverage over 90%; and Bosnia and Herzegovina and Ukraine reported precipitous drop-offs that fell well below their synthetic controls. We also observed a vaccination coverage decline in 2020 for several countries after transitioning and most synthetic controls, which we attribute to COVID-19-related service disruptions. We recommend that Gavi adjust its transition model to systematically assess contextual externalities and risk. In addition, countries that no longer receive Gavi assistance can leverage technical assistance and communities of practice to mutually assist each other and other countries advancing toward transition. This could also foster intracountry accountability after transition. We also recommend that Gavi systematize post-transition assessments and evaluations that leverage the expertise and experience of graduated countries to encourage cross-learning.


Measurement of hydrolysis kinetics of galactose-substituted fluorescein by beta-galactosidase at the toluene-water interface by spinning microtube fluorometry.
A new analytical technique, spinning microtube fluorometry (SMF), was developed and applied to the study of interfacial hydrolysis of 5-dodecanoylaminofluorescein di-beta-D: -galactopyranoside (C12FDG) by beta-galactosidase (beta-gal) in the toluene-water system. The nonfluorescent lactone form of C12FDG in the toluene phase was converted at the interface to 5-dodecanoylaminofluorescein (C12F), which was fluorescent in the aqueous phase as a dianion at pH 7.3, though some part of C12F was extracted into the toluene phase as its nonfluorescent lactone form. The distribution ratios of C12FDG and C12F at pH 7.3 were determined as 1.4 x 10(2) and 1.97, respectively. The interfacial adsorption constants from the toluene phase to the interface at pH 7.3 were 4.8 x 10(-4) and 1.7 x 10(-2) dm for C12FDG and C12F, respectively. The kinetic experiments with the SMF method concluded that the rate-determining step of the enzymatic hydrolysis at the interface and in the aqueous phase was the 1:1 reaction of C12FDG and beta-gal and that the hydrolysis reaction rate constant at the interface at pH 7.3 was 1.84 x 10(3) M(-1)s(-1), almost equal to that in the aqueous solution, 1.76 x 10(3) M(-1)s(-1). Finally, the SMF method revealed that the contribution of the interfacial reaction to the overall hydrolysis reaction rate of the toluene-water system was as high as 97%.


A Case of Intrathoracic Carotid Bifurcation Without Klippel-Feil Syndrome.
Intrathoracic carotid bifurcation is a rare vascular anomaly, with only 8 cases reported. This vascular anomaly was recently correlated with Klippel-Feil syndrome, a rare congenital disorder involving fusion of the cervical vertebrae. A 70-year-old deaf mute man was admitted to our department because of right hemiparesis and right sensory disturbance. He displayed no abnormalities associated with Klippel-Feil syndrome. Diffusion-weighted imaging revealed acute multiple infarcts in bilateral hemispheres. Computed tomography angiography showed that the left common carotid artery bifurcated at the T2 vertebral level. No significant stenosis was seen in the carotid arteries. Transesophageal echocardiography confirmed a complicated atheromatous lesion at the aortic arch. This case was diagnosed with aortogenic brain embolism, incidentally accompanied by left intrathoracic carotid bifurcation without Klippel-Feil syndrome. Intrathoracic carotid bifurcation can occur in cases without Klippel-Feil syndrome. The knowledge of this anatomic variation is important in evaluating vascular lesions of the carotid arteries in patients with stroke.


Diabetes mellitus and colorectal carcinoma outcomes: a meta-analysis.
The impact of diabetes mellitus (DM) on colorectal cancer (CRC) outcomes remains unknown. We studied this by conducting a meta-analysis to evaluate (1) CRC outcomes with and without DM and (2) treatment patterns. We searched PubMed, EMBASE, Google Scholar, and CINAHL for full-text English studies from 1970 to 12/31/2017. We searched keywords, subject headings, and MESH terms to locate studies of CRC outcomes/treatment and DM. Studies were evaluated by two oncologists. Of 14,332, 48 met inclusion criteria. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method, we extracted study location, design, DM definition, covariates, comparison groups, outcomes, and relative risks and/or hazard ratios. We utilized a random-effects model to pool adjusted risk estimates. Primary outcomes were all-cause mortality (ACM), disease-free survival (DFS), relapse-free survival (RFS), and cancer-specific survival (CSS). The secondary outcome was treatment patterns. Forty-eight studies were included, 42 in the meta-analysis, and 6 in the descriptive analysis, totaling > 240,000 patients. ACM was 21% worse (OR 1.21, 95% CI 1.15-1.28) and DFS was 75% worse (OR 1.75, 95% CI: 1.33-2.31) in patients with DM. No differences were detected in CSS (OR 1.10, 95% CI 0.98-1.23) or RFS (OR 1.12, 95% CI 0.91-1.38). Descriptive analysis of treatment patterns in CRC and DM suggested potentially less adjuvant therapy use in cases with DM and CRC. Our meta-analysis suggests that patients with CRC and DM have worse ACM and DFS than patients without DM, suggesting that non-cancer causes of death in may account for worse outcomes.


[Compensation of gait disorders after left-sided removal of a portion of the motor cortex in the white rat].
Spatial quantitative aspects of walking are described prior to and after partial extirpation of left motor cortex in rats. Symmetry of the gait returned to normalcy within over three months after the operation. Length and width of the steps did not return to the prior-to-operation level within 12 months.


Persistent lymphadenopathy associated with hypertransfusion in sickle-cell disease.
We report the results of an immunologic evaluation of two hypertransfused (HT) patients with sickle-cell disease (SCD) who have developed persistent generalized lymphadenopathy. In order to interpret the results of this evaluation, we studied seven other HT patients with SCD and seven nonhypertransfused patients with SCD. Patients with SCD had decreased percentages of T-lymphocytes to include both helper and suppressor subsets in their peripheral blood. These decreases resulted in T helper/suppressor ratios not different from those of healthy normal control subjects. Lymphocyte proliferative responses to mitogen were decreased in the nonhypertransfused group, whereas mononuclear cell populations from both patient groups had higher levels of spontaneous suppressor cell activity than did control subjects. The patients with lymphadenopathy were distinguished from other HT sickle-cell anemia patients by immunologic abnormalities that included decreased percentages of T4+ lymphocytes, decreased T helper/suppressor ratios, and decreased lymphocyte responses to mitogen. Furthermore, the serum of these patients contained antibody specific for human T cell lymphotropic virus type III (HTLV-III). We believe that these two patients have developed acquired immunodeficiency syndrome-related lymphadenopathy as the result of transfusion-acquired HTLV-III. We propose that hypertransfusion treatment in SCD, possibly in association with phenytoin administration, places individuals at risk for HTLV-III-associated syndromes.


Endorphins and the central inhibition of urinary bladder motility.
The involvement of endogenous opioid mechanisms in the central neurogenic control of urinary bladder function has been examined in anesthetized rats. Intracerebroventricular (ICV) microinjections of beta-endorphin (0.5-2.0 micrograms) produced powerful inhibition of rhythmic bladder contractions initiated by central reflex activity. The peptide fragments gamma-endorphin and alpha-endorphin (4-16 micrograms), formed by the processing of beta-endorphin by membrane homogenates of brain, were less active than the parent compound. The inhibitory effects of beta-endorphin was reversed by ICV naloxone (1-2 micrograms) but higher doses were required to reverse gamma- or alpha-endorphin effects. ICV naloxone administered alone increased intravesicular pressure and bladder contraction frequency. These observations support the hypothesis that the endorphins have a physiological role in the central regulation of urinary bladder activity.


Triterpenes derived from hydrolyzate of total Gynostemma pentaphyllum saponins with anti-hepatic fibrosis and protective activity against H2O2-induced injury.
Gynostemma pentaphyllum is a popular functional food, and it is also used as a traditional medicine in Asia. In this study, five previously undescribed triterpenes, gypensapogenin M, gypensapogenin N, gypensapogenin O, gypensapogenin P, and gypensapogenin Q, together with five known compounds were isolated from the hydrolyzate of total G. pentaphyllum saponins. The bioassay data showed that all the triterpenes exhibited significant protective activity against H2O2-induced myocardial cell injury and anti-hepatic fibrosis activity. Taken together, the discovery of these triterpenes from the hydrolyzate of total G. pentaphyllum saponins expands its use as a functional food for preventing myocardial injury and liver fibrosis.


Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments.
Although enhancers are central regulators of mammalian gene expression, the mechanisms underlying enhancer-promoter (E-P) interactions remain unclear. Chromosome conformation capture (3C) methods effectively capture large-scale three-dimensional (3D) genome structure but struggle to achieve the depth necessary to resolve fine-scale E-P interactions. Here, we develop Region Capture Micro-C (RCMC) by combining micrococcal nuclease (MNase)-based 3C with a tiling region-capture approach and generate the deepest 3D genome maps reported with only modest sequencing. By applying RCMC in mouse embryonic stem cells and reaching the genome-wide equivalent of ~317 billion unique contacts, RCMC reveals previously unresolvable patterns of highly nested and focal 3D interactions, which we term microcompartments. Microcompartments frequently connect enhancers and promoters, and although loss of loop extrusion and inhibition of transcription disrupts some microcompartments, most are largely unaffected. We therefore propose that many E-P interactions form through a compartmentalization mechanism, which may partially explain why acute cohesin depletion only modestly affects global gene expression.


Community detection for directional neural networks inferred from EEG data.
One major challenge in neuroscience is to identify the functional modules from multichannel, multiple subjects recordings. Most research on community detection has focused on finding the association matrix based on functional connectivity, instead of effective connectivity, thus not capturing the causality in the network. In this paper, we propose a community detection algorithm suitable for weighted and asymmetric (directed) networks representing effective connectivity, and apply the algorithm to multichannel electroencephalogram (EEG) data. In addition, we extend the algorithm to find one common community structure from multiple subjects.


Polymorphism of the follicle stimulating hormone receptor does not impact reproductive performance or in-vitro embryo production in beef heifers.
Assisted reproductive technologies are used to propagate desirable genetics in a shortened timeframe. Selected females undergo ovarian stimulation with the use of follicle stimulating hormone (FSH) to increase embryo recovery for subsequent transfer programs. The FSH receptor (FSHR) c.337 C > G variant was reported to have a reduction in viable embryo numbers in an ovarian stimulation protocol. We, therefore, hypothesized that FSHR c.337 C > G would result in reduced in-vitro blastocyst development. Beef heifers were genotyped and selected based on the c.337 C > G FSHR genotype (CC, CG, GG; n = 15-16/genotype). Estrus was synchronized with a Select Synch protocol and heifers were slaughtered 5 days after induced ovulation. Anterior pituitaries, serum and reproductive tracts were collected at slaughter for analysis. Cumulus oocyte complexes (COCs) were collected and pooled within genotype for in-vitro fertilization (IVF) and subsequent blastocyst development. No differences were observed in carcass weights, anterior pituitary weights, serum progesterone, corpus lutea weight, surface follicle counts, histological follicle counts or follicular fluid estradiol concentration (P > 0.1) due to FSHR genotype. Differences were observed for ovulation rates in the GG FSHR genotype group (P < 0.01). However, cleavage and blastocyst rates were not affected due to FSHR genotype (P > 0.1), following standard IVF protocols. The FSHR variant does not influence antral follicle counts, estradiol production, or in-vitro blastocyst development in beef heifers. The GG FSHR genotype had an increased ovulation rate, which may indicate a greater potential for twinning, but research with a larger population is warranted to support this hypothesis.


Pain coping skills training un-locks patient-centered pain care during the COVID- 19 lockdown.
In 2020, the COVID-19 virus sparked a crisis constituting a nationwide public health emergency that rapidly altered the provision of healthcare services for all Americans. Infectious disease mitigation led to widespread lockdowns of perceived nonessential services, programs, and non-emergent healthcare interventions. This lockdown exacerbated the public health dyad of uncontrolled pain and the opioid epidemic, which was already in a crisis state. Current literature supports the management of uncontrolled pain with a biopsychosocial approach, empowering patients to explore self-care to enhance activities of daily living. Pain Coping Skills Training (PCST) delivers real-life strategies that improve quality of life and strengthen self-efficacy. Self-efficacy has been identified as a patient outcome measure that demonstrates improved patient-perceived function and quality of life despite pain intensity. Studies have shown that nurse practitioners (APRN) are well-positioned to provide PCST to chronic pain sufferers. A pretest-posttest design was utilized for this project to enhance pain self- efficacy through an APRN-led community-based intervention. Community-dwelling adults treated in a specialty pain management practice were self-selected to participate in a 6-week telehealth delivered PCST Program. This APRN delivered program presented basic pain education and a broad range of evidence-based nonpharmacologic pain management self-care tools. The primary outcome was improved Pain Self-efficacy measured with the pain self-efficacy questionnaire (PSEQ), with secondary outcomes of improved perceived pain intensity and function measured with the pain, enjoyment, and general activity (PEG) scale tracked weekly. Baseline PSEQ and weekly PEG scores were obtained and compared to scores after the program. Collateral data points included confidence in using complementary and alternative nonpharmacologic interventions, satisfaction with the program, and a qualitative patient statement regarding pre-and post-intervention participation. This project concluded that a Nurse Practitioner delivered PCST program via telehealth technology could provide community-dwelling adults with an intervention that improves pain self-efficacy, enhances self-reported PEG measures, and meets the social distancing requirements that continue to impact patients during the COVID-19 pandemic.


Ewing tumor biology: perspectives for innovative treatment approaches.
The Ewing's sarcoma family of tumors (EFT) is a group of malignancies affecting bone and soft tissue in adolescents. It is characterized by a unique gene rearrangement between the EWS gene and an ets transcription factor gene. EFT can be cured with conventional multi modal treatment, however, about 40% of patients still succumb to the disease. Relapses can be observed more than 5 years after the end of primary treatment suggesting persistence of minimal residual disease (MRD). Due to the still enigmatic nature of EFT histogenesis the phenotype of EFT stem cells and of dormant tumor cells remains unknown. The most frequent fusion product associated with EFT, EWS-FLI1, is the founding member of a whole class of similarly structured chimeric proteins associated with a variety of human sarcomas and also specific leukemias. The corresponding gene rearrangement constitutes a rate limiting step in oncogenesis as implied by the high association of EFT with EWS-ETS fusions, strong selective pressure for maintenance of a correct reading frame in the tumors, and by experimental data confirming the transforming and tumorigenic potential of EWS-FLI1. Understanding the biology of EWS-ETS gene fusions and its interplay with essential cellular pathways regulating cell growth, apoptosis, differentiation, genomic integrity, and treatment resistance may unravel specifically vulnerable sites for therapeutic targeting. This review summarizes the current knowledge about the EWS-FLI1 pathway in EFT and provides some ideas as to how this knowledge may be translated into innovative treatment approaches.


The effects of parents' vaccine hesitancy and COVID-19 vaccine literacy on attitudes toward vaccinating their children during the pandemic.
The study was conducted to examine the effects of parents' vaccine hesitancy and COVID-19 vaccine literacy on their attitudes toward vaccinating their children during the COVID-19 pandemic. The study was descriptive, cross-sectional, and comparative. The data were collected from 199 parents with children aged 0-18 using a Google Form on social media. In the study, the Parent Introductory Information Form, the Vaccine Hesitancy Scale in Pandemics, and the COVID-19 Vaccine Literacy Scale were used. In the analysis of the data, numbers, percentages, and means were calculated, and the significance test of the difference between the two means and the logistic regression analysis were used. Parents' vaccination hesitancy scale sub-dimensions and COVID-19 vaccine literacy scale sub-dimensions together explain 25.4% of their attitudes toward having their children vaccinated against COVID-19. When the variables were examined individually, it was determined that the sub-dimensions of the Vaccine Hesitancy Scale in Pandemics alone significantly affected their attitudes during the pandemic period (p < 0.001). Parents are hesitant about getting their children vaccinated against COVID-19. Improving vaccine literacy can increase vaccination rates in special groups to overcome vaccine hesitancy.


Effects of amperozide on psychostimulant-induced hyperlocomotion and dopamine release in the nucleus accumbens.
N-Ethyl-4-[4',4'-bis(p-fluorophenyl)-butyl]-1-piperazine carboxamide [amperozide (APZ)] is a novel atypical neuroleptic that appears to selectively act on the limbic system. The present study investigated behavioral and biochemical effects of APZ on either d-amphetamine (AMPH)- or cocaine (COC)-treated rats. Behavior was assessed by locomotor activity measurements. Compared to saline controls, APZ (5 and 10 mg/kg, SC) decreased spontaneous locomotion. AMPH (1.0 mg/kg, SC)- or COC (10 mg/kg, IP)-induced hyperlocomotion was markedly reduced by APZ administered 20 min earlier. Biochemical data were obtained by in vivo microdialysis in freely moving animals. APZ dose dependently increased interstitial concentrations of dopamine (DA, +25%) and its metabolite, homovanillic acid (HVA, +20%), in the nucleus accumbens (NAC). While either AMPH or COC alone increased DA levels (450 and 270%, respectively), pretreatment with APZ had no effect on these increases. In contrast, APZ pretreatment dose dependently attenuated the reduction of DA metabolites induced by both AMPH and COC. Thus, APZ blocked hyperlocomotion induced by psychostimulants without producing correlative changes in DA concentrations in the NAC.


Weighted single-step GWAS and RNA sequencing reveals key candidate genes associated with physiological indicators of heat stress in Holstein cattle.
The study of molecular processes regulating heat stress response in dairy cattle is paramount for developing mitigation strategies to improve heat tolerance and animal welfare. Therefore, we aimed to identify quantitative trait loci (QTL) regions associated with three physiological indicators of heat stress response in Holstein cattle, including rectal temperature (RT), respiration rate score (RS), and drooling score (DS). We estimated genetic parameters for all three traits. Subsequently, a weighted single-step genome-wide association study (WssGWAS) was performed based on 3200 genotypes, 151,486 phenotypic records, and 38,101 animals in the pedigree file. The candidate genes located within the identified QTL regions were further investigated through RNA sequencing (RNA-seq) analyses of blood samples for four cows collected in April (non-heat stress group) and four cows collected in July (heat stress group). The heritability estimates for RT, RS, and DS were 0.06, 0.04, and 0.03, respectively. Fourteen, 19, and 20 genomic regions explained 2.94%, 3.74%, and 4.01% of the total additive genetic variance of RT, RS, and DS, respectively. Most of these genomic regions are located in the Bos taurus autosome (BTA) BTA3, BTA6, BTA8, BTA12, BTA14, BTA21, and BTA24. No genomic regions overlapped between the three indicators of heat stress, indicating the polygenic nature of heat tolerance and the complementary mechanisms involved in heat stress response. For the RNA-seq analyses, 2627 genes were significantly upregulated and 369 downregulated in the heat stress group in comparison to the control group. When integrating the WssGWAS, RNA-seq results, and existing literature, the key candidate genes associated with physiological indicators of heat stress in Holstein cattle are: PMAIP1, SBK1, TMEM33, GATB, CHORDC1, RTN4IP1, and BTBD7. Physiological indicators of heat stress are heritable and can be improved through direct selection. Fifty-three QTL regions associated with heat stress indicators confirm the polygenic nature and complex genetic determinism of heat tolerance in dairy cattle. The identified candidate genes will contribute for optimizing genomic evaluation models by assigning higher weights to genetic markers located in these regions as well as to the design of SNP panels containing polymorphisms located within these candidate genes.


Improvement of perfusion flow in the isolated rat liver under the influence of streptase. Autohistoradiographic aspects of 125I-labelled fibrinogen deposition.
The dynamics of the fibrinoplastic process were studied in rat isolated liver, perfused in normothermia with a synthetical medium. For the autohistoradiographical study, 125I-labelled fibrinogen was added to the perfusing medium. The historadiograms obtained suggest that the main link in the rise of trans-hepatic vascular resistance is thickening of the fibrin muff of the sinusoids. Consequent reduction of the capillary permeability determines favourable conditions for stasis and massive precipitation of fibrinogen under the form of fibrin thrombi into the intrahepatic vessels. Streptase addition to the perfusion medium prevents the intervention of these mechanisms during the studied period.


Low-molecular-weight or unfractionated heparin in venous thromboembolism: the influence of renal function.
In patients with acute venous thromboembolism and renal insufficiency, initial therapy with unfractionated heparin may have some advantages over low-molecular-weight heparin. We used the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) Registry data to evaluate the 15-day outcome in 38,531 recruited patients. We used propensity score matching to compare patients treated with unfractionated heparin with those treated with low-molecular-weight heparin in 3 groups stratified by creatinine clearance levels at baseline: >60 mL/min, 30 to 60 mL/min, or <30 mL/min. Patients initially receiving unfractionated heparin therapy (n = 2167) more likely had underlying diseases than those receiving low-molecular-weight heparin (n = 34,665). Propensity score-matched groups of patients with creatinine clearance levels >60 mL/min (n = 1598 matched pairs), 30 to 60 mL/min (n = 277 matched pairs), and <30 mL/min (n = 210 matched pairs) showed an increased 15-day mortality for unfractionated heparin compared with low-molecular-weight heparin (4.5% vs 2.4% [P = .001], 5.4% vs 5.8% [P = not significant], and 15% vs 8.1% [P = .02], respectively), an increased rate of fatal pulmonary embolism (2.8% vs 1.2% [P = .001], 3.2% vs 2.5% [P = not significant], and 5.7% vs 2.4% [P = .02], respectively), and a similar rate of fatal bleeding (0.3% vs 0.3%, 0.7% vs 0.7%, and 0.5% vs 0.0%, respectively). Multivariate analysis confirmed that patients treated with unfractionated heparin were at increased risk for all-cause death (odds ratio, 1.8; 95% confidence interval, 1.3-2.4) and fatal pulmonary embolism (odds ratio, 2.3; 95% confidence interval, 1.5-3.6). In comparison with low-molecular-weight heparin, initial therapy with unfractionated heparin was associated with a higher mortality and higher rate of fatal pulmonary embolism in patients with creatinine clearance levels >60 mL/min or <30 mL/min, but not in those with levels between 30 and 60 mL/min.


Diethylpyrocarbonate inhibition of sodium-glucose cotransport in kidney brush-border membrane vesicles.
Exposure of kidney brush-border membrane vesicles to the acylating reagent diethylpyrocarbonate resulted in inactivation of the glucose transporter, as demonstrated by inhibition of sodium-coupled D-glucose transport and phlorizin binding. The transport site(s) was protected against inactivation by the simultaneous presence of sodium ions and D-glucose, and were partially protected by phlorizin. Transport activity was not restored by hydroxylamine; this rules out the possibility of diethylpyrocarbonate interaction with histidine, serine or tyrosine transporter residues. Dithiothreitol, a thiol protector, slightly prevented diethylpyrocarbonate inactivation. It is therefore suggested that (an) amino group(s) in the translocation complex is involved, at the level of the sugar transport site and the preferential protection of D-glucose against diethylpyrocarbonate inactivation related to a conformation change caused by the simultaneous binding of sodium and D-glucose to the cotransporter.


Plasma membrane-focused proteomics: dramatic changes in surface expression during the maturation of human dendritic cells.
The differential expression of surface molecules on dendritic cells (DC) reflects their functional differences as immature and mature subsets. It is difficult, however, to characterize differences in surface expression by standard proteomic approaches, due mainly to the hydrophobic nature and low abundance of the individual proteins in question. We have established a method for obtaining high-yield plasmalemma preparations which contain surface molecules enriched more than 200-fold by coating cells with beads conjugated with antibody against a cell type-specific cell-surface molecule, followed by nitrogen cavitated disruption, magnetic separation, and density gradient ultracentrifugation. We identified and quantified 339 human monocyte-derived DC transmembrane proteins, including 33 previously uncharacterized molecules. Whereas 106 proteins were selectively expressed in immature cells or down-regulated after maturation, 191 proteins were selectively expressed in mature cells or up-regulated after maturation.


Inhibition and deficiency of the immunoproteasome subunit LMP7 attenuates LCMV-induced meningitis.
In addition to antigen processing, immunoproteasomes were recently shown to exert functions influencing cytokine production by monocytes and T cells, T-helper cell differentiation, and T-cell survival. Moreover, selective inhibition of the immunoproteasome subunit LMP7 ameliorated symptoms of autoimmune diseases including CD4(+) T-cell mediated EAE. In this study, we show that LMP7 also plays a crucial role in the pathogenesis of lymphocytic choriomeningitis virus (LCMV)-induced meningitis mediated by CTLs. Mice lacking functional LMP7 display delayed and reduced clinical signs of disease accompanied by a strongly decreased inflammatory infiltration into the brain. Interestingly, we found that selective inhibition and genetic deficiency of LMP7 affect the pathogenesis of LCMV-induced meningitis in a distinct manner. Our findings support the important role of LMP7 in inflammatory disorders and suggest immunoproteasome inhibition as a novel strategy against inflammation-induced neuropathology in the CNS.


Modification by steroids of pulmonary oedema and prostaglandin E2 pharmacokinetics induced by endotoxin in rats.
1. A single i.p. injection of bacterial endotoxin in rats (3.5 mg kg-1) caused lung injury assessed as changes in lung dry:wet weight ratio and leukopaenia over the subsequent 28 h. 2. This treatment also slowed the efflux of 14C from [14C]-prostaglandin E2 (PGE2), i.e., increased t1/2 and increased the survival of PGE2 in isolated perfused lungs over the same period. 3. These effects of endotoxin were reversed by methylprednisolone (30 mg kg-1), given 30 min after the endotoxin. 4. Another synthetic corticosteroid, budesonide (1.2 mg kg-1) given 1 h before endotoxin partially prevented the lung injury and leukopaenia but did not affect the increased t1/2 for PGE2 nor its survival. 5. The reversal by methylprednisolone of both the physical signs of lung injury and the changes in PGE2 pharmacokinetics caused by endotoxin suggests that changes in PGE2 pharmacokinetics could serve as an index of acute lung injury following sepsis.


A comparison between parents of children with cochlear implants and parents of children with hearing aids regarding parental distress and treatment expectations.
The aim of the present study was to compare the parents of children with a hearing aid (HA) and children with a cochlear implant (CI) regarding their psychological distress, their expectations from treatment, their family climate, and the way they first obtained information on HA/CI. 154 parents (return quota 41%; 81 mothers and 73 fathers) of 90 children with a HA and 103 parents (return quota 59%; 57 mothers and 46 fathers) of 57 children with a CI were interviewed by means of a questionnaire. Both groups of parents felt distressed, particularly at the time of diagnosis. Their psychological well-being was gradually stabilized in the further course of rehabilitation. Due to the operation associated with it, fitting with a CI brought on a phase of heightened parental psychological distress compared with less invasive treatment with a HA. Regarding family climate, more distress was found in parents of CI children than in parents of HA children. Expectations from therapy appeared realistic in both parental groups; however, after CI fitting, the parents of the CI children showed heightened expectations by comparison with the parents of the HA children. The results of our study suggest that the parents of hearing impaired children fitted with a HA or a CI may be divided into two subgroups with divergent psychosocial parameters. For the counseling of the parents of hearing impaired children in clinical practice, it would seem important to take these specific differences into consideration.


Tacrolimus as a risk factor for tuberculosis and outcome of treatment with rifampicin in solid organ transplant recipients.
The purpose of this study was to investigate the incidence, risk factors, and treatment outcome of tuberculosis (TB) in solid organ transplant (SOT) recipients treated with rifampicin. The incidence density of TB was calculated by a retrospective cohort study. Risk factors for TB were analyzed by a nested case-control study. Treatment outcome and effects of anti-TB drugs on immunosuppressants and allograft were compared between patients whose initial 2-month intensive regimen included rifampicin and those whose intensive regimen did not. Among the 2144 SOT recipients over 16 years, 40 cases of TB were found (1.7%). The incidence density was 372 cases per 10(5) patient years (95% confidence interval [CI], 270-503), which was 4 times higher than for the general Korean population (90 cases per 10(5) person years). The median time to the development of TB was 234 days (range, 33-3940 days). The use of tacrolimus (odds ratio [OR] 4.90; 95% CI, 1.74-13.80; P = 0.003) and cytomegalovirus (CMV) infection within the prior 3 months (OR 4.62; 95% CI, 1.44-14.87; P = 0.01) were found to be risk factors for TB. Patients whose intensive regimen included rifampicin were more likely to have an increased dose of calcineurin inhibitors than patients whose intensive regimen did not include rifampicin (13/15 [86.7%] vs. 3/14 [21.4%], P = 0.001). Graft rejection and mortality did not differ between the 2 groups. Use of tacrolimus and CMV infection were major risk factors for TB in SOT recipients. The graft outcome and mortality did not differ whether rifampicin was used or not during the first 2-month intensive phase.


The X-ray crystal structure of PA1374 from Pseudomonas aeruginosa, a putative oxidative-stress sensing transcriptional regulator.
Members of the multiple antibiotic resistance regulator (MarR) family regulate the expression of genes related to antibiotic resistance, oxidative stress, and virulence in bacteria and Archaea. Here, we determined the structure of PA1374 from Pseudomonas aeruginosa at 2.3Å resolution. PA1374 belonged to the MarR family and its structure revealed a tightly bound dimer with each subunit containing a winged helix-turn-helix (wHTH) DNA-binding motif. Conserved arginine residues, Arg55, Arg74, and Arg77, were located in the wHTH region, which might be important to DNA binding. Furthermore, each monomer contained a pocket made of conserved hydrophobic residues. A highly conserved Cys11 located at one end of this pocket may undergo oxidation by organic hydroperoxide molecules, as shown in other MarR family proteins acting as redox-sensing regulators. These results provide insights about the role of PA1374 as a putative oxidative-stress sensing transcriptional regulator.


Teaching yourself about structural racism will improve your machine learning.
In this commentary, we put forth the following argument: Anyone conducting machine learning in a health-related domain should educate themselves about structural racism. We argue that structural racism is a critical body of knowledge needed for generalizability in almost all domains of health research.


Medial rectus plication for consecutive exotropia in a patient with stretched scar syndrome.
We report a case of stretched scar syndrome in a 12-year-old girl with consecutive exotropia who had previously been treated with bilateral medial rectus muscle recessions. Stretched scar syndrome was confirmed intraoperatively, and bilateral medial rectus muscle plication was performed, successfully restoring normal alignment. Use of plication rather than resection of rectus muscles (stretched scar) can reduce the risk of a lost or slipped muscle and reduce surgical trauma and bleeding.


Mitochondrial control region and 12S rRNA variation in Przewalski's horse (Equus przewalskii).
Variation in the control region and the 12S rRNA gene of all surviving mitochondrial lineages of Przewalski's horse was investigated. Variation is low despite the present day population being descended from 13 individuals probably representing animals from three different regions of its range. Phylogenetic comparison of these sequences, with sequences for the domestic horse, does not resolve the ancestral status of either horse.


Suitability of infrared microspectroscopic imaging for histopathology of the uterine cervix.
Infrared microspectroscopy (IR-MSP) has been proposed for automated histological tissue differentiation of unstained specimens based on chemical analysis of cell and extracellular constituents. This study aimed to determine the accuracy of IR-MSP-based histopathology of cervical carcinoma sections with complex tissue architecture under practically relevant testing conditions. In total, 46 regions of interest, covering an area of almost 50 mm(2) on sections derived from paraffin-embedded tissue of radical hysterectomy specimens, were analysed by IR-MSP (nominal resolution ~4.2 μm). More than 2.8 million pixel spectra that were processed using fuzzy c-means clustering followed by hierarchical cluster analysis permitted image segmentation regarding different biochemical properties. Linear image registration was applied to compare these segmentation results with manual labelling on haematoxylin and eosin-stained references (resolution ~0.7 μm). For recognition of nine tissue types, sensitivities were 42-91% and specificities were 79-100%, mostly being affected by peritumoral inflammatory responses. Algorithmic variation of the outline of dysplasia and carcinoma revealed a spatial preference of false values in tissue transition areas. This imaging technique has potential as a new method for tissue characterization; however, the recognition accuracy does not justify a pathologist-independent tissue analysis, and the application is only possible in combination with concomitant conventional histopathology.


Value of high spatial and high temporal resolution magnetic resonance angiography for differentiation between idiopathic and thromboembolic pulmonary hypertension: initial results.
Differentiation between different forms of pulmonary hypertension (PH) is essential for correct disease management. The goal of this study was to elucidate the clinical impact of high spatial resolution MR angiography (SR-MRA) and time-resolved MRA (TR-MRA) to differentiate between patients with chronic thromboembolic PH (CTEPH) and idiopathic pulmonary arterial hypertension (IPAH). Ten PH patients and five volunteers were examined. Twenty TR-MRA data sets (TA 1.5 s) and SR-MRA (TA 23 s) were acquired. TR-MRA data sets were subtracted as angiography and perfusion images. Evaluation comprised analysis of vascular pathologies on a segmental basis, detection of perfusion defects, and bronchial arteries by two readers in consensus. Technical evaluation comprised evaluation of image quality, signal-to-noise ratio (SNR) measurements, and contrast-media passage time. Visualization of the pulmonary arteries was possible down to a subsegmental (SR-MRA) and to a segmental (TR-MRA) level. SR-MRA outperformed TR-MRA in direct visualization of intravascular changes. Patients with IPAH predominantly showed tortuous pulmonary arteries while in CTEPH wall irregularities and abnormal proximal-to-distal tapering was found. Perfusion images showed a diffuse pattern in IPAH and focal defects in CTEPH. TR-MRA and SR-MRA resulted in the same final diagnosis. Both MRA techniques allowed for differentiation between IPAH and CTEPH. Therefore, TR-MRA can be used in the clinical setting, especially in dyspneic patients.


Ependymoma: Evaluation and Management Updates.
To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults. Ependymomas may occur either in the brain or in the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. The new WHO classification of CNS tumors of 2021 has subdivided ependymomas into different histomolecular subgroups with different outcome. The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors. Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy. Standard treatments are still the mainstay of treatment: the discovery of new druggable pathways will hopefully increase the therapeutic armamentarium in the near future.


New perspectives for targeting therapy in ALK-positive human cancers.
Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor protein-tyrosine kinase superfamily and was first discovered in anaplastic large-cell lymphoma (ALCL). ALK alterations, including fusions, over-expression and mutations, are highly associated with cancer initiation and progression. This kinase plays an important role in different cancers, from very rare to the more prevalent non-small cell lung cancers. Several ALK inhibitors have been developed and received Food and Drug Administration (FDA) approval. However, like other drugs used in targeted therapies, ALK inhibitors inevitably encounter cancer cell resistance. Therefore, monoclonal antibody screening based on extracellular domain or combination therapies may provide viable alternatives for treating ALK-positive tumors. In this review, we discuss the current understanding of wild-type ALK and fusion protein structures, the pathological functions of ALK, ALK target therapy, drug resistance and future therapeutic directions.


Model-based assessment of combination therapies - ranking of radiosensitizing agents in oncology.
To increase the chances of finding efficacious anticancer drugs, improve development times and reduce costs, it is of interest to rank test compounds based on their potential for human use as early as possible in the drug development process. In this paper, we present a method for ranking radiosensitizers using preclinical data. We used data from three xenograft mice studies to calibrate a model that accounts for radiation treatment combined with radiosensitizers. A nonlinear mixed effects approach was utilized where between-subject variability and inter-study variability were considered. Using the calibrated model, we ranked three different Ataxia telangiectasia-mutated inhibitors in terms of anticancer activity. The ranking was based on the Tumor Static Exposure (TSE) concept and primarily illustrated through TSE-curves. The model described data well and the predicted number of eradicated tumors was in good agreement with experimental data. The efficacy of the radiosensitizers was evaluated for the median individual and the 95% population percentile. Simulations predicted that a total dose of 220 Gy (5 radiation sessions a week for 6 weeks) was required for 95% of tumors to be eradicated when radiation was given alone. When radiation was combined with doses that achieved at least 8 [Formula: see text] of each radiosensitizer in mouse blood, it was predicted that the radiation dose could be decreased to 50, 65, and 100 Gy, respectively, while maintaining 95% eradication. A simulation-based method for calculating TSE-curves was developed, which provides more accurate predictions of tumor eradication than earlier, analytically derived, TSE-curves. The tool we present can potentially be used for radiosensitizer selection before proceeding to subsequent phases of the drug discovery and development process.


Inhibitory effects of Bifidobacterium spp. isolated from a healthy Korean on harmful enzymes of human intestinal microflora.
Five hundreds of bifidobacteria were isolated from a healthy Korean and the inhibitory effects of these isolated bacteria on harmful enzymes of human intestinal microflora were examined by cocultivation of the isolated bifidobacteria with E. coli or total human intestinal microflora. In comparison with the results of E. coli or intestinal microflora cultivation, Bifidobacterium breve K-110, B. breve K-111 and B. infantis K-525 effectively inhibited harmful enzymes (beta-glucuronidase and tryptophanase) of E. coli and lowered the pH of the culture media. Also they inhibited the harmful enzymes (beta-glucosidase, beta-glucuronidase, tryptophanase and urease) and ammonia production of intestinal microflora, and lowered pH of the culture media by increasing lactic acid bacteria of intestinal microflora. When these isolated bifidobacteria were administered on mice, fecal harmful enzymes were also inhibited. Among tested bifidobacteria, B. breve K-110 had the highest inhibitory effect of fecal harmful enzymes.


Extracellular potassium dynamics in the border zone during acute myocardial ischemia in a canine model.
Bifunctional intramyocardial potassium ion (K+)-sensitive and bipolar wire electrodes were used to evaluate extracellular K+ dynamics and electrophysiologic changes during acute myocardial ischemia in the border zone, ischemic zone (5 to 7 mm from the border), central ischemic zone (15 to 25 mm from the border) and normal myocardium in 11 open chest dogs during a 30 min ligation of the left anterior descending coronary artery. At the end of this period, the hearts were injected with rhodamine dye and quickly frozen. Ultraviolet NADH (nicotinamide adenine dinucleotide) rhodamine fluorescence photography was used to localize the border between normally perfused and ischemic tissue and determine the site of electrodes in relation to this border. Before coronary ligation, extracellular K+ ranged from 4.0 +/- 0.3 to 4.3 +/- 0.3 mM in these four zones. After ligation, extracellular K+ accumulated in the ischemic and central ischemic zones in a pattern characterized by an initial rapid increase for approximately 5 min, followed by a slowly rising plateau phase, reaching maximal levels of 9.8 +/- 2.0 and 14.4 +/- 4.4 mM, respectively. In contrast, K+ dynamics in the border zone showed a biphasic response, with an initial rapid increase to a maximal level of 7.5 +/- 2.4 mM at approximately 9 min after coronary ligation, followed by a gradual decrease to a level of 5.3 +/- 1.2 mM by the end of the 30 min ligation period. No significant changes in K+ occurred in the normal zone throughout the ischemic period. The correlation of K+ electrode, electrophysiologic and postmortem NADH-rhodamine fluorescence data indicated the existence of a well defined border zone.(ABSTRACT TRUNCATED AT 250 WORDS)


Use of interventional procedures for peripheral arterial occlusive disease in Ontario between 1991 and 1998: a population-based study.
Although peripheral arterial occlusive disease (PAOD) is a public health issue in the elderly population, limited population-based data are available on use of interventional procedures in Canada. We describe trends in use of interventional procedures to treat PAOD in Ontario over the past decade. A retrospective population-based cohort study was conducted for fiscal years 1991 to 1998 with Ontario administrative databases to identify all arterial bypass surgeries, angioplasty procedures, and amputations performed. A total of 19,332 bypass operations, 16,334 angioplasty procedures, and 17,534 amputations were identified. Population-based rates showed that angioplasty use peaked at about 110 per 100,000 at age 65 to 74 years, arterial bypass surgery use peaked at 129 per 100,000 at age 75 to 84 years, and amputation use peaked at 138 per 100,000 at age 85 years or older. All types of interventional procedures to treat PAOD were performed more frequently in men than in women. Age-adjusted and sex-adjusted rate of arterial bypass surgery decreased significantly, from 77 to 61 per 100,000 population aged 45 years or older (P =.0002, linear regression analysis), whereas rate for PTA increased significantly, from 59 to 75 per 100,000 population aged 45 years or older (P =.0005). The overall major amputation rate declined slightly over the study period, influenced by the decreased rate in patients aged 85 years or older. The revascularization rate in patients aged 85 years or older increased (P =.055). Reduced use of arterial bypass surgery and increased use of angioplasty procedures has occurred over the past decade and may reflect a change in the practice pattern of vascular surgeons in Ontario, who have become more conservative in treating localized disease and reserve surgical interventions for more severe forms of PAOD. The slight reduction in overall major amputation rate, driven by decreased rate in patients aged 85 years or older, may reflect a trend toward a more aggressive revascularization approach in this age group.


Visual field testing with reduced sets of test points. A computerized analysis.
A computerized analysis of visual fields is described. In a second step these results are condensed into a 'reduced' set of test points so constructed that if testing is limited to 6-8 points nearly all defective visual fields would have been spotted with at least one defective point. The 'reduced' set involves the testing of few points several times in a session rather than spending very few trials on a great number of points. This is a new approach which merits further investigation.


Expansion, Exploitation and Extinction: Niche Construction in Ephemeral Landscapes.
We aim to understand general consequences of niche construction on metapopulation dynamics in ephemeral landscapes. To this effect, a contact process-like stochastic spatial model is introduced where local populations colonize and go extinct on a dynamic landscape of habitable and destroyed patches. In contrast to previous models, where the extinction threshold is a consequence of available niche rendered by global rates of patch destruction/renewal, here we investigate how the metapopulation persists when they are the sole generators of their own niche. Niche construction is full-filled by localized populations through the transformation of destroyed patches in their neighborhood to viable habitat for future colonization. With this theoretical framework we are able to address the dual nature of niche construction by investigating the ephemerality of the landscape (destruction rate) and the continuum of population level strategies, where construction comes at a cost to colonization. Using mean field theory and Monte Carlo simulations of the model, we are able to quantify optimal population level strategies in a wide range of ephemeral landscapes. Interestingly, we observe qualitative differences at the extinction threshold between analytic and numeric results. Investigating this discrepancy further, we find that increasing niche construction neighborhood in the spatial model leads to two interrelated effects i) an increased rate in range expansion ii) a loss in resiliency and return of the discontinuous transition at the extinction threshold. Furthermore, in the discontinuous regime of the model, spatial clustering prior to a critical transition disappears. This is a significant finding as spatial clustering has been considered to be an early warning signal before ecosystems reach their 'tipping point'. In addition to maintaining stability, we find local niche construction strategies have an advantage when in scramble competition with an exploiter strategy because of their ability to monopolize the constructed niche due to spatial adjacency. As the niche construction neighborhood expands this advantage disappears and the exploiter strategy out-competes the niche constructor. In some cases the exploiter pushes the niche constructor to extinction, thus a tragedy of the commons ensues leading to 'ecological suicide' and a collapse of the niche.


Balancing the benefit and risk of oral antiplatelet agents in coronary artery bypass surgery.
Concern about possible hemorrhagic complications arising from use of oral antiplatelet agents in immediate proximity to coronary artery bypass graft (CABG) surgery leads many clinicians to avoid or discontinue these agents preoperatively. Recent evidence suggests that aspirin and clopidogrel can be used with relative safety in the preoperative period; dual antiplatelet therapy in the 5 days immediately preceding CABG surgery results in a moderate and variable increase in the risk of procedural bleeding. This modest hemorrhagic risk may be acceptable, given the clinical benefits of sustained antiplatelet therapy in preventing graft occlusion and ischemic complications pre- and post-CABG. Because the bleeding risk with aspirin is dose dependent, use of a low dose is preferred post-CABG.


Analyzing the Metabolic Phenotype of Bone Marrow-Derived Dendritic Cells by Assessing Their Oxygen Consumption and Extracellular Acidification.
Dendritic cells (DCs) are the bridge between innate and T cell-dependent adaptive immunity, and are promising therapeutic targets for cancer and immune-mediated disorders. In the recent past, DCs have gained significant interest to manipulate them for the treatment of cancer and immune-mediated disorders. This can be achieved by differentiating them into either immunogenic or tolerogenic DCs (TolDCs), by modulating their metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid metabolism, to orchestrate their desired function. For immunogenic DCs, this maturation shifts the metabolic profile to a glycolytic metabolic state and leads to the use of glucose as a carbon source, whereas TolDCs prefer oxidative phosphorylation (OXPHOS) and fatty acid oxidation for their energy resource.Understanding the metabolic regulation of DC subsets and functions at large not only will improve our understanding of DC biology and immune regulation, but can also open up opportunities for treating immune-mediated ailments and cancers by tweaking endogenous T-cell responses through DC-based immunotherapies. Here we describe a method to analyze this dichotomous metabolic reprogramming of the DCs for generating reliable and effective DC cell therapy products. We, hereby, report how to measure the OXPHOS and glycolysis level of DCs. We focus on the metabolic reprogramming of TolDCs using a pharmacological nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2) activator as an example to illustrate the metabolic profile of TolDCs.


Evaluating the effectiveness of a social and emotional learning program among preschool children in Japan: an experimental cohort study.
Research on school maladjustment has increasingly focused on social skills, such as the ability to control emotions, collaborate with others, and achieve goals. Social and emotional learning (SEL) is one approach to nurturing social skills. However, few preventive interventions to promote SEL have been conducted among young children, particularly in Asian countries, including Japan. Therefore, this study examined the effectiveness of an SEL program-Fun FRIENDS-among children in Japan. In mid-2022, the Fun FRIENDS program was administered to 115 children aged 4-5 years, who were enrolled in two kindergartens. The program was administered to the entire class as part of their kindergarten activities. The control group included 93 children in three kindergartens. This study included 94 participants (81.7%) in the intervention group and 66 (71.0%) in the control group, whose parents agreed with the assessment of their skills. Fun FRIENDS is a support program based on a cognitive-behavioral approach. The program aims to teach children how to cope with anxiety and stress and develop resilience and confidence to face difficulties. The program includes 10 sessions, each lasting approximately 1 h and conducted once per week. To examine the program's effectiveness, teachers evaluated these children's social skills before and after program implementation using the Social Skill Scale. Results showed significant post-intervention improvements in self-control and cooperation scores among children in the intervention group, compared with pre-intervention. Further, post-intervention self-control and cooperation scores were significantly higher among children in the intervention group than the control group. SEL implemented on a class-wide basis could be effective in early childhood. An early approach targeting preschool-aged children is necessary to prevent school maladjustment. A universal approach implemented on a whole-class basis could contribute to improving children's social skills.


Cervix carcinoma: treatment with combination cisplatin and bleomycin.
Thirty patients with metastatic carcinoma of the cervix were treated with a combination of cisplatin and bleomycin. Thirty patients were evaluable for toxicity and 24 were evaluable for response. Thirteen patients achieved a partial remission for an objective response rate of 54% with a median duration of 3.5 months. The response rate for extrapelvic disease without prior radiation was 57% while the response rate for disease recurring in the previously irradiated pelvic area was only 36%. Response rates were higher in tumors with nonsquamous histology. Survival times for responders and nonresponders were not significantly different. Significant toxicity was observed. It is concluded that the combination of high-dose cisplatin and bleomycin infusion in patients with recurrent cervix cancer has an improved response rate. However, these responses are of short duration and drug toxicity is significant. The role of this combination for adjuvant studies is discussed.


Identification and characterization of Δ12 and Δ12/Δ15 bifunctional fatty acid desaturases in the oleaginous yeast Lipomyces starkeyi.
Fatty acid desaturases play vital roles in the synthesis of unsaturated fatty acids. In this study, Δ12 and Δ12/Δ15 fatty acid desaturases of the oleaginous yeast Lipomyces starkeyi, termed LsFad2 and LsFad3, respectively, were identified and characterized. Saccharomyces cerevisiae expressing LsFAD2 converted oleic acid (C18:1) to linoleic acid (C18:2), while a strain of LsFAD3-expressing S. cerevisiae converted oleic acid to linoleic acid, and linoleic acid to α-linolenic acid (C18:3), indicating that LsFad2 and LsFad3 were Δ12 and bifunctional Δ12/Δ15 fatty acid desaturases, respectively. The overexpression of LsFAD2 in L. starkeyi caused an accumulation of linoleic acid and a reduction in oleic acid levels. In contrast, overexpression of LsFAD3 induced the production of α-linolenic acid. Deletion of LsFAD2 and LsFAD3 induced the accumulation of oleic acid and linoleic acid, respectively. Our findings are significant for the commercial production of polyunsaturated fatty acids, such as ω-3 polyunsaturated fatty acids, in L. starkeyi.


Quality of life in NIDDM patients assessed with the SF-20 questionnaire.
The health-related quality of life (HRQOL) was studied in non-insulin-dependent diabetic (NIDDM) patients aged under 65 years, compared with age- and gender-matched controls, with the Medical Outcomes Study short-form (SF-20) general measure. Of 260 NIDDM patients and their 260 controls, 254 (98%) and 177 (68%), respectively, completed the SF-20. Among NIDDM patients, mean age was 56.3 (SD 6.9) years, BMI 30.4 (SD 5.5) kg/m2 and HbA1c 8.6% (SD 2.0%). The mean scores of six SF-20 dimensions were 11-27% lower in the NIDDM patients than in the controls (P < 0.01). Obesity, longer duration of diabetes, insulin treatment and impaired visual acuity were associated with poor HRQOL. In logistic regression analysis with the entire study population, existence of diabetes, coronary heart disease (CHD) and other macrovascular diseases were associated with impaired physical (OR 3.8-7.4), role (OR 2.2-2.8) and social (OR 2.2-2.8) functioning and health perception (OR 2.4-3.7). Diabetes was also associated with impaired mental health (OR 2.8). No associations were found between HRQOL and gender, age or marital status. NIDDM patients had significant and major impairments in HRQOL compared with non-diabetic controls, which were mainly due to macrovascular diseases.


[Voltammetric detection of extracellular 5-hydroxyindole compounds at the level of cell bodies and the terminals of the raphe system: variations during the wake-sleep cycle in the rat in chronic experiments].
In rats, chronically implanted for measurements of both voltammetric and polygraphic parameters, variations of the electrochemical signal corresponding to extracellular 5-hydroxyindole compounds (peak 3) were measured during the sleep-waking cycle. The higher amplitude of this signal is always measured during waking. It decreases during slow-wave sleep (20 to 30%) and reaches its lower value during paradoxical sleep (30 to 40%). This phenomenon has been found in all structures investigated, cerebral cortex, caudate nuclei, dorsal hippocampus, suprachiasmatic nuclei, cerebellum, nuclei raphe dorsalis, centralis, pontis and magnus.


Impact of the Admission Pathway on the Gender-Related Mortality of Patients With ST-Elevation Myocardial Infarction.
The mortality of women with ST-elevation myocardial infarction (STEMI) exceeds that of men, supposedly the result of older age and co-morbidities. Patients with STEMI can be transported directly to the catherization lab by the emergency medical service (EMS) or to the emergency department (ED) by the EMS, a regular ambulance, or independently. This raises the question whether gender disparity in the transport of patients with STEMI may affect time to therapy and consequently explain the disparate outcome in men and women with STEMI. We analyzed a large nationwide registry of prospectively-recorded patients with acute coronary syndromes in order to determine if there is a survival gap between men and women with STEMI, and to assess the gender-related effect of admission pathway on time intervals and 5-year mortality. Study population included 2,740 patients with STEMI who underwent primary percutaneous coronary interventions, comprising 464 women (17%, median-70 years) and 2,276 men (83%, median-58 years). The unadjusted 5-year mortality of women was higher compared with men (26.4% vs 15.6%, p = 0.001) but adjustment abrogated this survival difference. Regardless of adjustment, the 5-year mortality of patients with STEMI admitted directly to the catherization lab or to the ED by EMS was similar for men and women but significantly lower in the directly admitted patients (p <0.028). In contrast, admission to the ED by non-EMS was associated with markedly worse survival among women. These results indicate that women suspected of STEMI benefit from transportation by the EMS and should use this pathway exclusively to reach the hospital.


Test-retest reliability of pelvic floor muscle contraction measured by 4D ultrasound.
The aim of the present study was to evaluate test-retest measurements of functional aspects of pelvic floor muscle (PFM) contraction using four dimensional (4D) ultrasound. Seventeen females preformed three maximal PFM contractions in standing, recorded by 4D real time ultrasound, on two separate occasions. Very good and good reliability was fond for measurement of: Levator hiatus (LH) area, LH antero-posterior dimension, LH transverse dimension, puborectal muscle length and LH narrowing. Shortening of LH transverse distance and muscle length during contraction showed poor and fair reliability, respectively. In the mid sagittal plane the displacement of bladder neck, rectal ampulla and back sling of the poborectal muscle measured with on screen vector assessment demonstrated good reliability. During contraction the LH area was reduced 25% from resting area of 19.7 cm(2) (95% CI = 16.8-22.7) to 14.70 cm(2) (95% CI = 12.82-16.58). The muscle length shortened 21%, from 12.5 cm (95% CI = 11.1-13.8) to 9.70 cm (95% CI = 8.73-10.67). The mid urethra moved 1.1 mm (95% CI = 0.1-2.2) towards the pubic bone during contraction. The back sling of the puborectal muscle and the rectal ampulla had a greater displacement than the bladder neck (P > .004). The displacement of the pelvic organs was two times, or more, greater in the cranial versus anterior direction. 4D ultrasound can reliable assess muscle length, narrowing of LH area, reduction of LH antero-posterior dimension and lift of BN, rectal ampulla and back sling of the puborectal muscle. Hence, both squeeze and lift can be quantified during PFM contraction.


A prospective validation of Sepsis-3 guidelines in acute hepatobiliary sepsis: qSOFA lacks sensitivity and SIRS criteria lacks specificity (Cohort Study).
Since its introduction in 2016, the Sepsis-3 guidelines, with emphasis on the quick Sequential Organ Failure Assessment (qSOFA) score, have generated much debate and controversy. It is recognised that the new definitions require validation in specific clinical settings and have yet to be universally adopted. We aim to validate new Sepsis-3 guidelines in acute hepatobiliary infection. A prospective cohort of patients admitted with acute hepatobiliary infection from the emergency department from July 2016 to June 2017 was studied. The Systemic Inflammatory Response Syndrome (SIRS) criteria, SOFA and qSOFA scores were calculated and predictive performance evaluated with area under the receiver operating characteristic (AUROC) curves for predictive ability of these indices for critical care unit admission and morbidity. 124 patients with a median age of 64.5 years and majority males (n = 75, 60.5%) were admitted with acute hepatobiliary infection during the study period. Acute cholecystitis was the most common admission diagnosis (n = 83, 66.9%) and most patients were managed in general ward (n = 91, 73.3%) with median length of stay of 6 days (range 1-40). On multivariate analysis, diabetes mellitus (p = 0.003) predicted high dependency unit (HDU) admission, while age (p = 0.001), positive blood culture (p = 0.012), positive fluid culture (p = 0.015) and SOFA score (p = 0.002) predicted length of hospital stay. The sensitivity of SIRS in predicting HDU admission (60% vs. 4%), intensive care unit (ICU) admission (62.5% vs. 0%) and morbidity (66.7% vs. 0%) was higher than qSOFA score. The specificity of qSOFA in predicting HDU admission (100% vs. 49.5%), ICU admission (99.1% vs. 53.3%) and morbidity (99.2% vs. 47.9%) was higher than SIRS criteria. The SIRS criteria has high sensitivity and the qSOFA score has high specificity in predicting outcomes of patients with acute hepatobiliary infection.


A visual ethnographic study on nurse lecturers' enactment of compassionate care within the adult pre-registration nursing curriculum.
Nurse lecturers make a valuable contribution to developing the future nursing workforce. However, how this is nurtured within nurse education requires further exploration. There is limited research exploring the experiences of nurse lecturers providing compassionate care within the adult pre-registration nursing curriculum. This study explores how nurse lecturers enact compassionate care within the adult pre-registration nursing curriculum. To elicit shared patterns of behaviours and use creative methods to promote a critical dialogue. A visual ethnographic approach was used to explore nurse lecturers' experiences at a University in England. Using purposive sampling, nine auto-driven photo-elicitation interviews took place, and five participants attended a focus group to develop individual and collaborative concept maps. A thematic approach to data analysis was employed. Five themes were identified, illustrating compassionate care as the human condition involving appropriate behaviours and competent action. Compassionate care is threaded through the curriculum using different teaching and learning approaches, requiring a culture of shared human relationships. The combination of photographs, maps and descriptions provide a unique perspective of how nurse lecturers nurture and role model compassionate care to their students. There are many ways compassionate care is experienced, enacted and enhanced by nurse lecturers within the adult pre-registration nurse curriculum. The five main themes act as a framework to guide nursing education and nursing practice. Future research should aim to understand better how compassionate care can be nurtured within different fields of nursing.


Prevalence of hypercalcemia among cancer patients in the United States.
Hypercalcemia of malignancy (HCM) is a serious metabolic complication whose population-based prevalence has not been quantified. Rates of HCM differ by tumor type, with highest rates reported in multiple myeloma and lowest among colorectal and prostate cancer patients. This analysis estimates HCM prevalence in the US. This retrospective study used the Oncology Services Comprehensive Electronic Records (OSCER) warehouse of electronic health records (EHR) including laboratory values from 569000 patients treated at 565 oncology outpatient sites. OSCER data were projected to the national level by linking EHR to claims data. Cancer patients included were ≥18 years, and had serum calcium (Ca) and albumin (for corrected serum Ca [CSC]) records. Period prevalence was estimated by HCM CTCAE grade, tumor type, and year (2009-2013). Estimates were adjusted to capture patients diagnosed with HCM outside oncology practices based on a subset of patients linkable to office and hospital data. The analysis included 68023 (2009) to 121482 (2013) cancer patients. In 2013, patients with HCM had a median of six Ca tests, 69.7% had chemotherapy, and 34% received bone modifying agents. HCM rates were highest for multiple myeloma patients (7.5% [2012]-10.2% [2010]), lowest for prostate cancer (1.4% [2012]-2.1% [2011]).The estimated adjusted annual prevalence of HCM from 2009 to 2013 was 95441, 96281, 89797, 70158, and 71744, respectively. HCM affected 2.0-2.8% of all cancer patients. EHR data from oncology clinics were critical for this study because these data contain results from laboratory studies (i.e., serum calcium values) that are routinely ordered in that setting. We estimated that the prevalence of HCM in the US in 2013 is 71744, affecting approximately 2% of cancer patients overall. This percentage differs by tumor type and appears to have decreased over the five-year study period.


Facile and cost-effective technique to control europium oxidation states in glassy fluorophosphate matrices with tunable photoluminescence.
Inorganic fluorophosphate glasses doped with Eu[Formula: see text]/Eu[Formula: see text] are potential candidates for phosphors for commercial white LEDs. This report presents a fast, inexpensive and effective method of controlling the relative concentrations of Eu[Formula: see text]/Eu[Formula: see text] photoluminescent centers in these glasses. The technique consists of a fast quenching of the melt of initial reagents under appropriate conditions. Eu[Formula: see text]/Eu[Formula: see text] ratio was controlled by carrying out the melting under a reducing atmosphere at a temperature between 1000 and 1200 [Formula: see text]C for periods of 5 to 15 minutes. The reducing atmosphere was provided by a 'double crucible' technique and did not require special gas lines during the synthesis. The samples were studied by several complementary experimental methods (X-ray diffractometry-XRD, X-ray photoelectron spectroscopy-XPS, photoluminescence-PL-and photoluminescence excitation-PLE-spectroscopies as well as optical transmission spectroscopy). It was shown that the syntheses resulted in amorphous materials with different relative Eu[Formula: see text]/Eu[Formula: see text] concentration ratios, strongly dependent on the preparation conditions: the temperature and the time of melting in a reducing atmosphere. Moreover, changes in these ratios strongly affected the materials' PL and PLE spectra. Demonstration of reproducible smooth transition from amaranth to blue luminescence color, with white in between, was the most spectacular result of this work.


Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies.
Azole antifungal drugs are commonly used in antifungal chemotherapy. Antibacterial effects of some topical antifungals, such as miconazole and econazole, have lately been revealed, which suggests a promising venue in antimicrobial chemotherapy. In this study, we tested an in-house azole collection with antifungal properties for their antibacterial activity to identify dual-acting hits using the broth microdilution method. The in vitro screen yielded a number of potent derivatives against gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. Compound 73's minimum inhibitory concentration (MIC) value less than 1 μg/ml against S. aureus; however, none of the compounds showed noteworthy activity against methicillin-resistant S. aureus (MRSA). All the active compounds were found safe at their MIC values against the healthy fibroblast cells in the in vitro cytotoxicity test. Molecular docking studies of the most active compounds using a set of docking programs with flavohemoglobin (flavoHb) structure, the proposed target of the azole antifungals with antibacterial activity, presented striking similarities regarding the binding modes and interactions between the tested compounds and the antifungal drugs with crystallographic data. In addition to being noncytotoxic, the library was predicted to be drug-like and free of pan-assay interference compounds (PAINS). As a result, the current study revealed several potential azole derivatives with both antifungal and antibacterial activities. Inhibition of bacterial flavoHb was suggested as a possible mechanism of action for the title compounds.


Myofiber damage precedes macrophage infiltration after in vivo injury in dysferlin-deficient A/J mouse skeletal muscle.
Mutations in the dysferlin gene (DYSF) lead to human muscular dystrophies known as dysferlinopathies. The dysferlin-deficient A/J mouse develops a mild myopathy after 6 months of age, and when younger models the subclinical phase of the human disease. We subjected the tibialis anterior muscle of 3- to 4-month-old A/J mice to in vivo large-strain injury (LSI) from lengthening contractions and studied the progression of torque loss, myofiber damage, and inflammation afterward. We report that myofiber damage in A/J mice occurs before inflammatory cell infiltration. Peak edema and inflammation, monitored by magnetic resonance imaging and by immunofluorescence labeling of neutrophils and macrophages, respectively, develop 24 to 72 hours after LSI, well after the appearance of damaged myofibers. Cytokine profiles 72 hours after injury are consistent with extensive macrophage infiltration. Dysferlin-sufficient A/WySnJ mice show much less myofiber damage and inflammation and lesser cytokine levels after LSI than do A/J mice. Partial suppression of macrophage infiltration by systemic administration of clodronate-incorporated liposomes fails to suppress LSI-induced damage or to accelerate torque recovery in A/J mice. The findings from our studies suggest that, although macrophage infiltration is prominent in dysferlin-deficient A/J muscle after LSI, it is the consequence and not the cause of progressive myofiber damage.


Ocular cicatricial pemphigoid.
This review offers recommendations for monitoring disease status in ocular cicatricial pemphigoid as well therapeutic options including local and systemic therapies. A negative biopsy on direct immunofluorescence does not preclude a diagnosis of OCP. If a patient's cicatrization is active and/or progressive, systemic immunosuppression should be commenced. OCP is a chronic systemic autoimmune disease that requires systemic immunosuppression.


A network meta-analysis comparing perioperative outcomes of interventions aiming to decrease ischemia reperfusion injury during elective liver resection.
This study sought to compare the perioperative outcomes of interventions aiming to decrease ischemia-reperfusion (IR) injury during elective liver resection. A comprehensive literature search was performed to identify randomized controlled trials. A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method in WinBUGS following the guidelines of the National Institute for Health and Clinical Excellence Decision Support Unit. Odds ratios for binary outcomes and mean differences for continuous outcomes were calculated using a fixed effect model or a random effects model according to model fit. Forty-four trials with 2,457 patients having undergone liver resection were included and were divided into 8 classes of interventions aimed at decreasing IR injury and a control group, which was hepatectomy alone. There was no difference between the different interventions in mortality, quantity of blood transfusion, and durations of stay in an intensive therapy unit between any pairwise comparisons. Patients treated with ischemic preconditioning, cardiovascular modulators, and miscellaneous interventions had significantly fewer serious adverse events compared with patients undergoing liver resection alone. Ischemic preconditioning patients had significantly fewer transfusion proportions and shorter operative time than patients treated with steroids. Ischemic preconditioning had significantly less operative blood loss compared with all other interventions, and a lesser duration of hospital stay than hepatectomy alone. Sensitivity analysis showed that the drugs sevoflurane (a volatile anesthetic), verapamil (a calcium channel blocker), and gabexate mesilate (a thrombin inhibitor) produced fewer serious adverse events compared with hepatectomy alone. Ischemic preconditioning resulted in multiple beneficial clinical endpoints and further RCTs seem to be needed to confirm its clinical benefits.


Physiology of invertebrate oxytocin and vasopressin neuropeptides.
Neuropeptides and regulatory peptide hormones control many developmental, physiological and behavioural processes in animals, including humans. The nonapeptides oxytocin and arginine vasopressin are produced and released by the pituitary gland and have actions on many organs and tissues. Receptive cells possess particular receptors to which the peptides bind as ligands, leading to activation of G-protein-coupled receptors, hence cellular responses. In humans and other mammalian species, oxytocin and vasopressin mediate a range of peripheral and central physiological functions that are important for osmoregulation, reproduction, complex social behaviours, memory and learning. The origin of the oxytocin/vasopressin signalling system is thought to date back more than 600 million years. All vertebrate oxytocin- and vasopressin-like peptides have presumably evolved from the ancestral nonapeptide vasotocin by gene duplication and today are present in vertebrates, including mammals, birds, reptiles, amphibians and fish. Oxytocin- and vasopressin-like peptides have been identified in several invertebrate species, including molluscs, annelids, nematodes and arthropods. Members of this peptide family share high sequence similarity, and it is possible that they are functionally related across the entire animal kingdom. However, it is evident that not all animals express oxytocin/vasopressin neuropeptides and that there is little information available about the biology and physiology of this signalling system of invertebrates and, in particular, of insects, which represent more than half of all known living organisms. This report describes the discovery of novel oxytocin- and vasopressin-like peptides in arthropods and summarizes the status quo of the functional relevance of this neuropeptide signalling system in invertebrates, which will have beneficial implications for the design of selective and potent ligands to human oxytocin and vasopressin receptors.


Prognostic significance of independent auras in temporal lobe seizures.
We performed a retrospective study of auras that occurred independently of complex partial seizures in patients undergoing continuous EEG monitoring with stereotactically implanted depth electrodes placed in mesiotemporal structures. Forty of 54 patients had a history of independent auras, and 32 of these individuals had independent auras while being monitored. Two hundred ninety-two independent auras were recorded, and EEG characteristics and subjective symptoms were analyzed with regard to surgical outcome. Most patients had ictal EEG changes with all or some of their auras. Four patients had nonlocalized or multifocal complex partial seizures despite the presence of well-localized auras, indicating that if intracranial ictal recording is used as a gold standard for localization, complex partial seizures must be recorded. Presence or absence of EEG change with auras did not affect prognosis nor did variability of ictal EEG pattern, spatial extent of initial field potential, aura duration, or character of symptoms correlate with prognosis or postoperative persistence of auras.


Proteolytic cleavage of factor VIII heavy chain is required to expose the binding-site for low-density lipoprotein receptor-related protein within the A2 domain.
Low-density lipoprotein receptor-related protein (LRP) is an endocytic receptor that contributes to the clearance of coagulation factor (F) VIII from the circulation. Previously, we have demonstrated that region Glu(1811)-Lys(1818) within FVIII light chain constitutes an important binding region for this receptor. We have further found that FVIII light chain and intact FVIII are indistinguishable in their LRP-binding affinities. In apparent contrast to these observations, a second LRP-binding region has been identified within A2 domain region Arg(484)-Phe(509) of FVIII heavy chain. In this study, we addressed the relative contribution of FVIII heavy chain in binding LRP. Surface plasmon resonance analysis unexpectedly showed that FVIII heavy chain poorly associated to the receptor. The binding to LRP was, however, markedly enhanced upon cleavage of the heavy chain by thrombin. The A2 domain, purified from thrombin-activated FVIII, also showed efficient binding to LRP. Competition studies employing a recombinant antibody fragment demonstrated that region Arg(484)-Phe(509) mediates the enhanced LRP binding after thrombin cleavage. We propose that LRP binding of non-activated FVIII is mediated via the FVIII light chain while in activated FVIII both the heavy and light chain contribute to LRP binding.


Cl transport in the frog cornea: an electron-microprobe analysis.
The intracellular electrolyte concentrations of the bullfrog corneal epithelium have been determined in thin freeze-dried cryosections using the technique of electron-microprobe analysis. Under control conditions, transepithelial potential short-circuited and either side of the cornea incubated in Conway's solution, the mean intracellular concentrations (in mmol/kg wet weight) were 8.0 for Na, 18.4 for Cl and 117.3 for K. These values are in good agreement with ion activities previously obtained by Reuss et al. (Am. J. Physiol. 244:C336-C347, 1983) under open-circuit conditions. From a comparison of the chemical concentrations and activities of Na and K a mean intracellular activity coefficient of 0.75 is calculated. For small ions no significant differences between nuclear and cytoplasmic concentration values were detectable. The Cl concentrations in the different epithelial layers were virtually identical and showed parallel changes at varying states of Cl secretion, suggesting that the epithelium represents a functional syncytium. For Na a concentration gradient between the outer and inner epithelial layer was observed, which can be accounted for by two different models of epithelial cooperation. The behavior of the intracellular Na and Cl concentrations after removal of Na, Cl or K from the outer or inner bathing medium provides support for a passive electrodiffusive Cl efflux across the apical membrane and a Na-coupled Cl uptake across the basolateral membrane. The results are inconclusive with regard to the exact mechanism of Cl uptake, indicating either a variable stoichiometry of the symporter or the presence of more than one transport system. Furthermore, a dependence of intracellular Cl on HCO3 and CO2 was observed. Extracellular measurements in corneal stroma demonstrated that ion concentrations in this space are in free equilibrium with the inner bath.


The response of aged mice to primary infection and re-infection with pneumonia virus of mice depends on their genetic background.
The pneumonia virus of mice (PVM) model is used to study respiratory syncytial virus (RSV) pathogenesis. The outcome of PVM infection varies in different inbred mouse strains, BALB/c being highly susceptible and C57BL/6 more resistant. As the disease symptoms induced by RSV infection can become more severe as people age, we examined the primary and secondary immune responses to infection with PVM in aged BALB/c and C57BL/6 mice. Based on clinical parameters, aged C57BL/6 mice displayed less severe disease than young adult mice when infected with 3000pfu of PVM-15, while BALB/c mice were equally susceptible at both ages showing significant weight loss and high levels of virus replication. Furthermore, after primary infection the CD4(+) T cell numbers in the lungs were higher in young adult mice, while the CD8(+) T cell numbers were comparable in both age groups and strains. When either C57BL/6 or BALB/c mice were infected with PVM as young adults and then re-infected as aged mice, they were protected from clinical disease, while virus replication was reduced. In contrast to mice with a primary PVM-infection, re-infected mice did not have infiltration of neutrophils or inflammatory mediators in the lung. BALB/c mice had higher virus neutralizing antibody levels in the serum and lung than C57BL/6 mice upon re-infection. Re-infection with PVM led to significant influx of effector CD4(+) T cells into the lungs when compared to aged mice with a primary infection, while this cell population was decreased in the lung draining lymph nodes in both mouse strains. After re-infection the effector CD8(+) T cell population was also decreased in the lung draining lymph nodes in both mouse strain when compared to aged mice after primary infection. However, the central memory CD4(+) and CD8(+) T cells were significantly enhanced in numbers in the lungs and draining lymph nodes of both mouse strains after re-infection, and these numbers were higher for C57BL/6 mice.


Insulin resistance and impaired glucose metabolism in a predominantly Maori community.
We sought to identify lifestyle behaviours which influence risk of impaired glucose metabolism, IGM (newly diagnosed type 2 diabetes, impaired glucose tolerance [IGT] or impaired fasting glycemia [IFG]) or insulin resistance (IR) in a predominantly Maori community, and applied the McAuley formula to determine whether it predicts high risk individuals amongst this community. Three hundred and seventy one participants completed a lifestyle and dietary behaviour questionnaire and oral glucose tolerance test. Clinical variables, microalbuminuria, fasting glucose, insulin and lipids were measured. Diabetes, IFG and IGT were defined according to WHO criteria. IR was defined using the McAuley formula. Those with IGM and those with IR showed similar risk factor attributes. Odds ratios (95% CI) for development of IGM and IR were 0.43 (0.21-0.88) and 0.51 (0.33-0.80), respectively, for regular physical activity, and 0.55 (0.26-1.15) and 0.59 (0.37-0.96), respectively, for two or more dietary behaviours characterized by a high intake of fibre. Regular physical activity and a diet characterized by a high intake of dietary fibre were found to reduce risk of newly diagnosed IGM or IR. The McAuley formula appears to predict high-risk individuals in a predominantly Maori population as it does in European populations.


Long-term psychosocial and health economy consequences of ADHD, autism, and reading-writing disorder: a prospective service evaluation project.
The study aims to evaluate psychosocial, societal, and family cost consequences of a psychoeducational intervention program. Sixty boys with ADHD, Asperger syndrome/high-functioning autism (AS/HFA), and reading and writing disorder (RD/WD) were allocated to participate in a service evaluation project. Every other boy in each diagnostic group was randomly allocated to receive either (a) a special education program (clinical index group) or (b) follow-up without the special education program (clinical comparison group). Nine years after initial assessments the stability of the psychosocial and economic resource consequences over time was studied. ADHD, AS/HFA, and RD/WD all had severe impact on family life quality. The societal costs were high, but no significant differences in resource use or in total costs were found between the clinical index and the comparison groups. The results underscore the very long-term need for support including individually tailored reevaluations and carefully monitored intervention programs adapted to family needs and severity of child disorder.


Src is Implicated in Hepatic Ischemia Reperfusion-Induced Hippocampus Injury and Long-Term Cognitive Impairment in Young Mice via NMDA Receptor Subunit 2A Activation.
Hepatic ischemia reperfusion (HIR) has been found to induce hippocampus injury and cognitive dysfunction. The N-methyl-d-aspartate (NMDA) receptor subunit 2A (NR2A) is an important factor mediating excitotoxicity and neurons injury, and autophosphorylation of Src can up-regulate tyrosine phosphorylation of NR2A to improve its activity. However, the role of Src and NR2A in HIR-induced hippocampus injury in young mice remains unknown. In this study, we found that serum biomarkers of brain injury (S100β and NSE) increased significantly and reached highest after reperfusion of 3 days which had the same trend with the levels of p-Src and p-NR2A. Interactions between Src and NR2A or PSD95 were increased after HIR. Hippocampal neuron apoptosis was increased, and long-term cognitive impairment was found after reperfusion of 1 month. Inhibition of Src and NR2A with PP2 and NVP-AAM077 respectively not only down-regulated the levels of p-Src and p-NR2A, but also ameliorated hippocampal neurons apoptosis and long-term cognitive impairment after HIR. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-6 were increased after reperfusion of 3 days, while PP2 and NVP-AAM077 treatment didn't attenuate the changes. And no difference was found in serum TNF-α, IFN-γ, IL-6 concentrations as well as the levels of Src, p-Src, NR2A, p-NR2A, PSD95 among the four groups after reperfusion of 1 month. In summary, HIR can lead to hippocampus injury and long-term cognitive dysfunction, and Src-PSD95-NR2A pathway plays an important role in the process.


Temperature mainly determines the temporal succession of the photosynthetic picoeukaryote community in Lake Chaohu, a highly eutrophic shallow lake.
Photosynthetic picoeukaryotes (PPEs) are key players in aquatic systems, while their diversity and community composition dynamics remain poorly understood. The monthly composition of PPEs in Lake Chaohu was investigated using a combination of flow cytometry sorting and high throughput sequencing. Results indicated that temperature is the most important factor shaping PPEs community structure. The PPEs community can be categorized into three groups that are dominant at different temperature ranges: high temperature (>21.8 °C), intermediate temperature (between 9.8 °C and 21.8 °C) and low temperature (<9.8 °C). At the supergroup level, Cryptophyta were dominant at the intermediate temperature level, and Bacillariophyta were prevalent at low temperatures. In comparison, Chlorophyta PPEs were sensitive to temperature at the order level. Molecular network analysis using 18S rDNA sequencing results from sorted samples revealed that the Operational Taxonomic Units (OTUs) of PPE from the same taxonomic groups were predominantly positive, implying that they were occupying similar niches. The cooccurrence patterns between PPEs and fungi were mostly negative. In particular, OTU101, which was associated with Chytridiomycota, was negatively related to many OTUs belonging to Chlorophyta and Diatom, indicating that their potential parasitic associations may be not species-specific.


Creating an Inexpensive PVC Shoulder Model for the Training of Ultrasound-Guided Posterior Glenohumeral Joint Injections.
Ultrasound-guided injections are used to treat common shoulder pathologies and have been shown to be more accurate and effective than traditional landmark-guided procedures. Currently, there exists no inexpensive shoulder model that accurately simulates the anatomical structures of the shoulder while also facilitating glenohumeral joint (GHJ) injection. Our model is an alternative to the traditional bedside training and provides a low-risk training environment. We created this model from easily accessible materials. Polyvinyl chloride pipe was used to create the skeletal infrastructure pectoral girdle. A detergent pod was used to represent the GHJ space. Steaks were used to simulate the infraspinatus and deltoid muscles, with meat glue as a fascial layer between the two simulated muscles. Total cost of materials for the model was $19.71. Our model successfully replicates known anatomical features of the GHJ. Additionally, the model facilitates injection into a GHJ space, representing a GHJ injection. Our model was replicated to train medical student practitioners during five different educational sessions. The model was validated through comparison to standardized educational ultrasound training videos. It was further validated by ultrasound experts. The shoulder model we created is effective in simulating GHJ injections under ultrasound guidance. It simulates realistic muscle and bony landmarks both for ultrasound imaging and injection feel. Importantly, it is inexpensive and easy to replicate allowing more access to medical practitioners and students to be educated on the procedure.


Risk factors associated with post-hemorrhagic hydrocephalus among very low birth weight infants of 24-28 weeks gestation.
Post-hemorrhagic hydrocephalus (PHH) is associated with morbidity and mortality among very low birth weight (VLBW) infants. This study aimed to determine risk factors for PHH among VLBW infants with peri-intraventricular hemorrhage (PIVH). This is a population-based cohort of VLBW infants of 24 to 28 weeks gestation, born in Israel from 1995 to 2012. Infants in whom a brain ultrasound was not performed before 28 days or with major congenital malformations were excluded. Univariate and multivariable analyses identified risk factors associated with PHH. The final study cohort comprised 2811 infants with grade 2 or higher PIVH, of whom 610 (21.7%) developed PHH. PHH was independently associated with PIVH severity, with bilateral grade 3 PIVH and PIVH grade 3 and contralateral grade 4 having the highest risks (odds ratio (OR) 12.2, 95% confidence interval (CI) 8.56 to 17.4 and OR 13.7, 95% CI 9.4 to 20.1, respectively). Unilateral grade 3 or 4 PIVH's had moderately increased risks of PHH (OR 3.50, 95% CI 2.26 to 5.42 and OR 3.79, 95% CI 2.35 to 6.12, respectively). PHH was independently associated with increasing gestational age (GA) and with neonatal morbidities including patent ductus arteriosus (OR 1.47, 95% CI 1.15 to 1.88 if medically treated and OR 3.01, 95% CI 2.11 to 4.29 if surgically treated), sepsis (OR 1.79, 95% CI 1.44 to 2.22) and necrotizing enterocolitis (OR 1.60, 95% CI 1.18 to 2.17). Among VLBW infants with PIVH, PHH was independently associated with PIVH severity group, increasing GA and acute neonatal morbidities. Unilateral grade 3 or 4 PIVH was associated with a moderate risk of developing PHH compared with bilateral severe hemorrhages.