Coordination Chemistry of Uranyl Ions with Surface-Immobilized Peptides: An XPS Study.
The coordination chemistry of uranyl ions with surface immobilized peptides was studied using X-ray photoemission spectroscopy (XPS). All the peptides in the study were modified using a six-carbon alkanethiol as a linker on a gold substrate with methylene blue as the redox label. The X-ray photoemission spectra reveal that each modified peptide interacts differently with the uranyl ion. For all the modified peptides, the XPS spectra were taken in both the absence and presence of the uranium, and their comparison reveals that the interaction depends on the chemical group present in the peptides. The XPS results show that, among all the modified peptides in the current study, the (arginine)9 (R9) modified peptide showed the largest response to uranium. In the order of response to uranium, the second largest response was shown by the modified (arginine)6 (R6) peptide followed by the modified (lysine)6 (K6) peptide. Other modified peptides, (alanine)6 (A6), (glutamic acid)6 (E6) and (serine)6 (S6), did not show any response to uranium.


Minimally Displaced Humeral Lateral Condyle Fractures: Immobilize or Operate When Stability Is Unclear?
Either casting or in situ fixation (to prevent displacement) are recommended for minimally displaced pediatric lateral condyle fractures of indeterminate stability with ≤2 mm lateral displacement and narrowed fracture extension to the epiphyseal articular cartilage. This study compares casting only, acute prophylactic in situ pinning, and surgery if casting fails due to displacement. In total, 738 fractures at a level 1 trauma center between 2008 and 2014 were reviewed. All fractures were assigned a Song classification and Song 2 fractures followed to union were analyzed. Worsening displacement was defined as an increase in Song stage. Patients were grouped per treatment: (1) cast only; (2) in situ pinning; or (3) closed or open reduction percutaneous pinning after displacement during attempted cast treatment. In total, 139 fractures were included and 45 (32%) underwent surgery. Among 114 fractures intended for casting, only 20 (18%) displaced and needed surgery. This implies 82% of fractures prophylactically pinned in situ may have remained stable in a cast. On average, displaced fractures were noted 6.5 (2 to 13) days after presentation and required 1 extra clinic visit and week of immobilization without increased complications. Surgeons chose open reduction percutaneous pinning more often for displaced fractures. Our data estimate 82% of Song 2 fractures never meaningfully displace in a cast. Meaningful displacements occur in <2 weeks. Benefits of prophylactic pinning include 1 less x-ray and clinic visit in exchange for a clinically insignificant lateral cortex reduction and inherent surgical risks. Compliance, surgical scheduling, and a higher rate of open reduction after displacement should influence early treatment decisions. Level III.


Toxicokinetics of perfluorooctanoate (PFOA) in rainbow trout (Oncorhynchus mykiss).
Rainbow trout (Oncorhynchus mykiss) confined to respirometer-metabolism chambers were dosed with perfluorooctanoate (PFOA) by intra-arterial (i.a.) injection and sampled to obtain concentration time-course data for plasma, urine, and expired water. The data were then analyzed by compartmental modeling to estimate rates of renal and branchial clearance. Averaged across all animals, the renal clearance rate (1.35mL/h/kg) was more than ten times greater than the branchial clearance rate (0.12mL/h/kg). The average whole-body elimination half-life was 12.6d, which is somewhat longer than values obtained in previous studies with smaller trout. The tissue distribution of PFOA was assessed by collecting tissues at the end of chambered exposures and in a separate tissue time-course experiment. From the time-course study it appeared that an internal steady-state was established within 24h of i.a. injection. Consistent with previous studies, the rank order of PFOA concentration in tissues at steady state was: plasma>liver>kidney>muscle. In a second set of chambered experiments, fish were exposed to PFOA in water to determine the rate of branchial uptake. Branchial uptake rates were too low to assess directly by measuring PFOA concentrations in inspired and expired water. Uptake rate constants (mean 0.19L/d/kg; 0.1% uptake efficiency) were therefore estimated by compartmental modeling using plasma concentration time-course data and model parameters derived from the elimination experiments. It is clear from this effort that elimination of PFOA by trout occurs primarily via the renal route. This finding is consistent with numerous studies of mammals and suggests that trout possess membrane transporters that facilitate the movement of PFOA from plasma to urine.


Gel-free mass spectrometry-based high throughput proteomics: tools for studying biological response of proteins and proteomes.
Revolutionary advances in biological mass spectrometry (MS) have provided a basic tool to make possible comprehensive proteomic analysis. Traditionally, two-dimensional gel electrophoresis has been used as a separation method coupled with MS to facilitate analysis of complex protein mixtures. Despite the utility of this method, the many challenges of comprehensive proteomic analysis has motivated the development of gel-free MS-based strategies to obtain information not accessible using two-dimensional gel separations. These advanced strategies have enabled researchers to dig deeper into complex proteomes, gaining insights into the composition, quantitative response, covalent modifications and macromolecular interactions of proteins that collectively drive cellular function. This review describes the current state of gel-free, high throughput proteomic strategies using MS, including (i) the separation approaches commonly used for complex mixture analysis; (ii) strategies for large-scale quantitative analysis; (iii) analysis of post-translational modifications; and (iv) recent advances and future directions. The use of these strategies to make new discoveries at the proteome level into the effects of disease or other cellular perturbations is discussed in a variety of contexts, providing information on the potential of these tools in electromagnetic field research.


Identification of Mytilus edulis genetic regulators during early development.
Understanding the mechanisms that enable growth and survival of an organism while driving it to the full range of its adaptation is fundamental to the issues of biodiversity and evolution, particularly regarding global climatic changes. Here we report the Illumina RNA-sequencing (RNA-seq) and de novo assembly of the blue mussel Mytilus edulis transcriptome during early development. This study is based on high-throughput data, which associates genome-wide differentially expressed transcript (DET) patterns with early activation of developmental processes. Approximately 50,383 high-quality contigs were assembled. Over 8000 transcripts were associated with functional proteins from public databases. Coding and non-coding genes served to design customized microarrays targeting every developmental stage, which encompass major transitions in tissue organization. Consequently, multi-processing pattern exploration protocols applied to 3633 DETs helped discover 12 unique coordinated eigengenes supposedly implicated in various physiological and morphological changes that larvae undergo during early development. Moreover, dynamic Bayesian networks (DBNs) provided key insights to understand stage-specific molecular mechanisms activated throughout ontogeny. In addition, delayed and contemporaneous interactions between DETs were coerced with 16 relevant regulators that interrelated in non-random genetic regulatory networks (GRNs). Genes associated with mechanisms of neural and muscular development have been characterized and further included in dynamic networks necessary in growth and functional morphology. This is the first large-scale study being dedicated to M. edulis throughout early ontogeny. Integration between RNA-seq and microarray data enabled a high-throughput exploration of hidden processes essential in growth and survival of microscopic mussel larvae. Our integrative approach will support a holistic understanding of systems biology and will help establish new links between environmental assessment and functional development of marine bivalves.


Successful treatment of maternal septicemia due to Listeria monocytogenes at 26 weeks' gestation.
A case of successful therapy with ampicillin of maternal septicemia due to Listeria monocytogenes at 26 weeks' gestation with resultant delivery at term of a normal neonate is reported. The ability to positively influence the outcome of hematogenously acquired maternal-fetal infection is stressed.


[Fluorescence diagnosis and photodynamic therapy in urology].
Urology is a preferential domain of endoscopy and as such an important research field for photodynamic procedures. An important milestone in the long-lasting and successful history of "photodynamics" in urology is the European approval of hexaminolevulinate (HAL, Hexvix) for fluorescence cystoscopy. All clinical studies carried out so far have demonstrated a significant increase in sensitivity of fluorescence versus standard cystoscopy for the detection of bladder cancer, especially concerning carcinoma in situ. The majority of the randomised, two-armed studies additionally show significantly reduced rates of residual tumour and recurrences. Tumor-selective fluorescence can also be observed in the kidney and prostate. Intraoperative fluorescence detection might thus simplify the achievement of high rates of R0 resections. Apart from the diagnostic potential of "photodynamics", also some possible therapeutic indications will be mentioned, including photodynamic therapy of bladder cancer and prostate cancer. Whereas initial clinical experience has been obtained for photodynamic therapy of bladder cancer, clinical studies for other indications are currently being designed. By providing an overview over methods and procedures as well as hitherto the available clinical results, we hope to provide reader with a basis for obtaining his/her own judgement.


Development of depression during placebo-controlled trials of bupropion for smoking cessation: case reports.
Recent attention has focused on the relationship between depression and smoking cessation. This article describes 5 cases of severe depression that occurred during 2 multicenter trials using bupropion for smoking cessation. Subjects were participants in 2 randomized, double-blind, placebo-controlled studies investigating the efficacy of bupropion for smoking cessation. Data from both trials were restricted to subjects at the Rochester, Minn., site in order to have access to the medical records for information on depression diagnosis, treatment, and follow-up. The first trial involved 205 smokers who received active bupropion or placebo for 7 weeks. In the second trial, 252 smokers received open-label bupropion therapy for 7 weeks. Those abstinent from smoking at the end of week 7 (N = 148) were randomly assigned to a 45-week, double-blind, relapse-prevention phase. In the first trial, 1 of the 205 participants (0.49%) experienced major depression during the 7-week treatment phase. In the second trial, none of the 252 subjects developed major depression during the 7-week, open-label phase. When results of both trials across the 7-week treatment phase (study 1, N = 205; study 2, N = 252) are combined, the rate of developing major depression was 0.22% (1 of 457). Of the 457 subjects, none of the 51 who received placebo and 1 (0.25%) of the 406 who received active bupropion developed major depression. In the second trial, 4 (2.7%) of the 148 subjects randomly assigned to the 45-week, relapse-prevention phase developed depression. Overall, 4 of the 5 cases from the 2 trials had a past history of major depression prior to study entry, but none had current major depression. Major depression may occur in some individuals during smoking cessation treatment with bupropion.


Rethinking vulnerability analysis and governance with emphasis on a participatory approach.
This article draws on vulnerability analysis as it emerged as a complement to classical risk analysis, and it aims at exploring its ability for nurturing risk and vulnerability governance actions. An analysis of the literature on vulnerability analysis allows us to formulate a three-fold critique: first, vulnerability analysis has been treated separately in the natural and the technological hazards fields. This separation prevents vulnerability from unleashing the full range of its potential, as it constrains appraisals into artificial categories and thus already closes down the outcomes of the analysis. Second, vulnerability analysis focused on assessment tools that are mainly quantitative, whereas qualitative appraisal is a key to assessing vulnerability in a comprehensive way and to informing policy making. Third, a systematic literature review of case studies reporting on participatory approaches to vulnerability analysis allows us to argue that participation has been important to address the above, but it remains too closed down in its approach and would benefit from embracing a more open, encompassing perspective. Therefore, we suggest rethinking vulnerability analysis as one part of a dynamic process between opening-up and closing-down strategies, in order to support a vulnerability governance framework.


Decoupling of bowtie and object effects for beam hardening and scatter artefact reduction in iterative cone-beam CT.
Cone-beam computed tomography (CBCT) is an important imaging modality for image-guided radiotherapy and adaptive radiotherapy. Feldkamp-Davis-Kress (FDK) method is widely adopted in clinical CBCT reconstructions due to its fast and robust application. While iterative algorithms have been shown to outperform FDK techniques in reducing noise and imaging dose, they are unable to correct projection-domain artefacts such as beam hardening and scatter. Empirical correction techniques require a holistic approach as beam hardening and scatter coexist in the measurement data. This multi-part proof of concept study conducted in MATLAB presents a novel approach to artefact reduction for CBCT image reconstruction. Firstly, we decoupled the beam hardening and scatter contributions originating from the imaging object and the bowtie filter. Next, a model was constructed to apply pixel-wise corrections to separately account for artefacts induced by the imaging object and the bowtie filter, in order to produce mono-energetic equivalent and scatter-compensated projections. Finally, the effectiveness of the correction model was tested on an offset phantom scan as well as a clinical brain scan. A conjugate-gradient least-squares algorithm was implemented over five iterations using FDK result as the initial input. Our proposed correction model was shown to effectively reduce cupping and shading artefacts in both phantom and clinical studies. This simple yet effective correction model could be readily implemented by physicists seeking to explore the benefits of iterative reconstruction.


Two types of Drosophila R7 photoreceptor cells are arranged randomly: a model for stochastic cell-fate determination.
The R7 photoreceptor cells of the Drosophila retina are ultraviolet sensitive and are thought to mediate color discrimination and polarized light detection. In addition, there is growing evidence that the color sensitivity of the R8 cell within an individual ommatidium is regulated by a genetic switch that depends on the type of R7 cell adjacent to it. Here we examine the organization of the two major types of R7 cells by three different rigorous statistical methods and present evidence that they are arranged randomly and independently. First, we performed L-function analyses to test whether the organization of R7 cells (and the relationship between them) is regular, clustered, or completely spatially random. Next, we used generalized linear mixed models to test whether the proportion of R7 cell neighbors differs from their prevalence within the eye as a whole. Finally, we conducted a series of simulations to test whether the proportion of R7 cell neighbors differs from that in a random simulation. In each case, we found evidence that the organization of the two types of R7 cells is random and independent, suggesting that R7 cells in neighboring ommatidia are unlikely to interact and influence each other's identity and may be determined stochastically in a cell-autonomous manner. Compared with traditional lineage or inductive mechanisms, this may represent a novel mechanism of cell fate determination based on noisy or stochastic gene expression in which the differentiation of an individual R7 cell is a random event but the proportions of R7 cell subtypes are regulated.


Cardiovascular risk in vasculitis.
The present review summarizes the burden, risk factors, biomarkers of and therapeutic consideration for cardiovascular disease in systemic vasculitis. Ischemic heart disease (IHD) and stroke are intrinsic features of Kawasaki disease, Takayasu arteritis, Giant Cell Arteritis (GCA), and Behcet's disease. The risk of IHD and stroke is increased in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and cryoglobulinemic vasculitis. Behcet's disease could present with venous thromboembolism. The risk of venous thromboembolism is increased in AAV, polyarteritis nodosa, and GCA. The risk of cardiovascular events is greatest at or immediately after the diagnosis of AAV or GCA, therefore, controlling vasculitis disease activity is of utmost importance. Traditional as well as disease-related risk factors drive the heightened cardiovascular risk in vasculitis. Aspirin or statins reduce the risk of IHD or stroke in GCA or the risk of IHD in Kawasaki Disease. Venous thromboembolism in Behcet's disease should be treated with immunosuppressive therapy rather than with anticoagulation.


Combination of calcipotriol and clobetasol propionate as a premixed ointment for the treatment of psoriasis.
The treatment of psoriasis requires good compliance, efficacy and low toxicity because of its long-term course and wide distribution. The aim of the study was to compare the efficacy of a once daily application of calcipotriol alone or calcipotriol and a superpotent steroid in a premixed form in patients with psoriasis. The monotherapy group of 32 patients with stable plaque psoriasis received 0.005% calcipotriol alone once daily. The combination group of 29 patients was treated once per day with 0.004% calcipotriol/0.01% clobetasol propionate as a premixed ointment. Eruption score of truncal involvement was evaluated. The combination regimen was more efficacious than the monotherapy as evidenced by (1) more patients with at least 50% reduction in the eruption score after 2 weeks, (2) lower eruption score after 6 weeks and later, and (3) less adverse effects. The combined once-per-day application of 0.004% calcipotriol/0.01% clobetasol propionate as a premixed ointment is a promising regimen for psoriasis.


Delineation of the intronless nature of the genes for the human and hamster beta 2-adrenergic receptor and their putative promoter regions.
The beta 2-adrenergic receptor is the first adenylate cyclase-coupled receptor to be cloned. We provide here a detailed characterization of its complete gene in both the human and hamster which reveals several unusual and provocative features. The genes are present in a single copy, are intronless, and are bounded by homologous 18-bp (base pair) direct repeats. These findings suggest that the beta 2-adrenergic receptor may have arisen as a processed gene for another related gene. Genomic Southern blots done at reduced stringency in fact reveal additional weak signals. The human and hamster gene sequences 5' to the principal site of transcription initiation are highly homologous and share many characteristics of promoters for housekeeping genes. Moreover, there is present in the human genome a long (777 bp) open reading frame which is in frame with the beta-adrenergic receptor coding block and which ends only 234 bp 5' to the initiator methionine of the receptor. An unusual cDNA has been found, transcribed from a putative second more 5' promoter which contains the 5' half of the beta-adrenergic receptor as well as 1065-bp 5' to the receptor coding region, including the entire upstream long open reading frame (sufficient to encode a putative protein of Mr approximately 28,000).


The causality between systemic inflammatory regulators and chronic respiratory diseases: A bidirectional Mendelian-randomization study.
Accumulative evidence suggests the associations between systemic inflammatory regulators and chronic respiratory diseases (CRDs). However, the intrinsic causation remains implicit. Therefore, this study aimed to examine causative associations by mendelian randomization (MR) and to identify valuable active factors. Based on data from the GWAS database, we performed MR analyses of 41 serum cytokines from 8,293 Finnish and European descent cohorts from GBMI and UKBB for five major CRDs. We mainly applied inverse variance weighted regression, supplemented by MR-Egger regression, weighted median, maximum likelihood, weighted mode, and simple mode algorithms. Moreover, sensitivity analyses were conducted using Cochrane's Q test, MR-Egger intercept, MR-PRESSO Global test and MR-Steiger filtering. Eventually, the consistency of MR results was assessed by leave-one-out. Our results suggest that 12 genetically predicted systemic inflammatory regulators probably participate in the progression of CRDs, including four risk factors (IL-1RA, IL-4, MIP-1A, PDGF-BB) and one protective factor (IL-6) in IPF, two protective factors (SCF, SDF-1A) in COPD, and two protective factors (SCF, SDF-1A) in asthma, two protective factors (GROA, IL-2RA) were also included in asthma, whereas only one factor (HGF) was protective against bronchiectasis. Additionally, two protective factors (FGF-BASIC, G-CSF) were identified in sarcoidosis. Sensitivity analyses showed no horizontal pleiotropy and significant heterogeneity. Finally, based on the findings of inverse MR analysis, no inverse causal association was uncovered, confirming the robustness of results. Our study unearths potential associations between systemic inflammatory modulators and common CRDs, providing new insights for inflammation-mediated CRD prevention and therapeutic approaches.


Realistic modeling of the illumination point spread function in confocal scanning optical microscopy.
In this paper we present a rigorous and general theoretical model for the illumination point spread function of a confocal microscope that correctly reproduces the optical setup. The model uses vectorial theory and assumes that monochromatic light with a Gaussian intensity distribution (such as from a laser or a single-mode fiber) is focused by a microscope objective with high numerical aperture and passes through stratified media on its way to the sample. This covers the important practical case of illumination through up to three layers, which is the situation most commonly encountered in biological microscopy (immersion oil, glass coverslip, aqueous sample medium). It also accounts for objectives that are corrected for a certain coverslip thickness and refractive index but operated under non-design conditions. Furthermore, illumination with linearly, circularly, or elliptically polarized light is covered by introducing a Babinet-Soleil compensator into the beam path. The model leads to a set of analytical equations that are readily evaluated. Two-dimensional intensity distributions for particular cases of interest are presented and discussed.


Serum biochemical markers of central nerve system damage in children with acute elemental mercury intoxicatıon.
Acute mercury intoxication among children can occur through unintentional exposure, and neurotoxicity is one of the main findings in acute exposures. In this study, we aimed to study the central nerve system markers, namely neuron-specific enolase (NSE), S100B, and glutamate receptor (GRIA 1) levels and discuss the mechanisms of central nerve system damage and whether these parameters could be used as markers of acute elemental mercury intoxication neurotoxicity. This is a case-control study which includes 169 children with acute elemental mercury intoxication, who were exposed to mercury in the school laboratory from a broken jar, and 45 sex- and age-matched controls without mercury exposure. Patient group were divided into three subgroups according to the neurological examination performed during the admission. Neuropathy Group included the children with neurological symptoms including peripheral neuropathy and decreased muscle strength (n = 39) (with or without dilated pupils). Dilated Pupil Group included the children who had mid-dilated/dilated pupils (n = 52). Asymptomatic Exposure Group included the children who did not have any neurological symptoms (n = 78). Serum NSE, S100B, GRIA 1, blood, and urine mercury levels were determined. NSE, S100B, GRIA 1, and blood mercury levels were significantly higher in exposed group than the nonexposed subjects (Median values NSE 22.4 ng/mL, 17.2 ng/mL; S100B 0.09 ng/mL, 0.08 ng/mL; GRIA 1 70.6 pg/mL, 54.1 pg/mL, and blood mercury 15.2 μg/L, 0.23 μg/L for exposed and nonexposed groups, respectively). GRIA 1 levels found to differ between exposed and nonexposed groups and it has also been found to be increased in the subgroups with positive neurological findings compared to that in neurological finding negative groups. S100B levels were found to be increased in exposed and having neurological symptom groups. There was not a significant difference between exposed-not having neurological symptom patients and control group. NSE levels were found to be higher in all subgroups when compared to those in controls, however there was not a significant difference between the subgroups. Serum NSE, GRIA 1, and S100B were increased with mercury exposure. GRIA 1 and S100B levels were observed to have the power to discriminate neurological symptom positive and negative groups. The increase in S100B levels are thought to be protecting the neurons and preventing further NSE elevations.


The Effect of Glycemic Control on Endothelial and Cardiac Dysfunction Induced by Red Blood Cells in Type 2 Diabetes.
Red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM) induce endothelial dysfunction and impair cardiac function following ischemia via increase in RBC arginase and oxidative stress. Here, we aimed to elucidate whether the effect of RBC-mediated cardiac impairment following ischemia and endothelial dysfunction in T2DM is dependent on glycemic control. Patients with T2DM at poor glycemic control (T2DM PGC) and at improvement in glycemic control (T2DM IGC) and healthy subjects were recruited. Isolated RBCs from subjects were incubated with aortic rings from healthy wild-type rats with subsequent evaluation of endothelium-dependent relaxation (EDR) using wire myograph. Moreover, RBCs were administered to isolated wild-type rat hearts with subsequent evaluation of left ventricular developed pressure (LVDP) during reperfusion using Langendorff setup. In separate experiments, RBCs were preincubated with an arginase inhibitor before perfusion. Blood glucose and glycated hemoglobin were 33 and 26%, respectively, lower in T2DM IGC compared with those in T2DM PGC. RBCs from T2DM PGC and T2DM IGC impaired EDR to a similar magnitude compared with RBCs from healthy subjects. LVDP was significantly impaired in hearts given RBCs from T2DM PGC as compared with those from healthy subjects. The impairment of LVDP induced by T2DM PGC was attenuated by RBCs from T2DM IGC. Arginase inhibition improved LVDP to a similar extent between T2DM PGC and IGC groups. These observations indicate that glycemic control abrogate the impairment in postischemic recovery but not endothelial dysfunction induced by RBCs from T2DM. Moreover, inhibition of RBC arginase improves cardiac function irrespective of glycemic control.


The comparison of the graft patency after coronary artery bypass grafting using coronary angiography and multi-slice computed tomography.
Coronary angiography (CAG) is the gold standard method in evaluating graft patency following coronary artery bypass grafting (CABG), even though there are several kinds of non-invasive methods. Recently developed multi-slice CT (m-CT), having effective scan times up to 0.25 s and multi-row detector array systems, enable rapid imaging of cardiac structures, including coronary arteries during one breath-hold. We compared m-CT with CAG for the evaluation of graft patency following CABG. Forty-two patients having undergone m-CT and CAG within 3 months of CABG were studied. Twenty-three patients underwent conventional CABG and 19 off-pump CABG. A total of 125 grafts were used, including 42 left internal mammary arteries (LIMA), 25 radial arteries (RA), 3 right internal mammary arteries (RIMA) and 55 vein grafts. CAG showed a 96% (120/125) patency rate (1 LIMA, 2 RA and 2 vein grafts were occluded). m-CT showed a 98% (122/125) correct positive ratio with a sensitivity and specificity of 98 and 100%, respectively. The sensitivity in LIMA, RA, RIMA and vein grafts was 98, 91, 100 and 100%, respectively, with 100% specificity for all. There was an equivocal result in the competitive grafts with native coronary artery that were patent in the CAG, but faint opacification with no significant flow in the m-CT. This study showed that m-CT was very simple, useful and accurate in evaluating graft patency during the early post-operative period following CABG, even though there was an equivocal result in the competitive grafts with a native coronary artery.


Food Insecurity and Adolescent Psychosocial Adjustment: Indirect Pathways through Caregiver Adjustment and Caregiver-Adolescent Relationship Quality.
Household food insecurity is associated with youth behavioral problems, yet few studies have examined potential mechanisms that underline this association, particularly among adolescents. The Family Stress Model (FSM) states that food insecurity potentially impacts adolescent psychosocial adjustment indirectly through its effects on parental psychological functioning and parenting. The current study examined data from the Children, Welfare, and Families study (N = 687, 53% female, Mage of child at baseline = 11.74 years, SD = 1.39) to determine whether household food insecurity at the beginning of adolescence predicts later behavioral outcomes and whether that association is mediated through caregiver depression and caregiver-adolescent relationship quality. Caregivers completed measures of past-year household food insecurity, current self-reported depressive symptoms and adolescent behavior problems, while adolescents completed a measure of current caregiver-adolescent relationship quality. A serial multiple mediator model, controlling for baseline values of mediators, outcomes, and relevant demographic covariates, indicated a significant total indirect effect, whereas the total direct effect was not significant. Significant indirect effects through both caregiver depression and caregiver-adolescent relationship quality were also found. These results are the first to explicitly examine the FSM with respect to household food insecurity and to demonstrate the indirect effects of food insecurity on adolescent adjustment. The findings indicate the need to improve food security and address subsequent intra- and inter-personal difficulties among low-income families that contribute to behavioral problems among adolescents facing household food insecurity.


Cloning and expression of genes encoding pheromone-inducible antigens of Enterococcus (Streptococcus) faecalis.
Fragments, generated by restriction enzyme digestion, of the 58-kilobase Enterococcus (Streptococcus) faecalis tetracycline resistance plasmid pCF10 were cloned and introduced into Escherichia coli and E. faecalis to characterize the pheromone-inducible conjugation system encoded by this plasmid. Western blot (immunoblot) analyses revealed that a 130-kilodalton (kDa) antigen, identical to the Tra130 antigen shown previously to be involved in pCF10-mediated pheromone-inducible surface exclusion, was produced by both bacterial hosts carrying the recombinant plasmid pINY1825 (cloned EcoRI C fragment). Both bacterial hosts carrying pINY1825 also produced various amounts of immunologically related 118- to 125-kDa antigens (designated pre-Tra130) that resembled antigens produced by E. faecalis cells carrying pCF10. An additional 150-kDa antigen, Tra150, probably involved in pheromone-induced cellular aggregation, was produced by Escherichia coli and E. faecalis hosts carrying pINY1801 (cloned EcoRI C and E fragments). The coding sequences for the Tra150 and Tra130 antigens were further localized in the TRA region of pCF10 by transposon insertion mutagenesis. Western blot analyses of the recombinant strains, and of strains carrying derivatives of pCF10 or various recombinant plasmids containing Tn5 or Tn917 insertions, suggested that the portion of pCF10 comprising the tra3 through -6 segments (previously defined by Tn917 insertional mutagenesis) contained several genes that are involved in regulating the synthesis of Tra130 and Tra150.


Identification of a conserved neutralizing epitope in Seneca Valley virus VP2 protein: new insight for epitope vaccine designment.
Seneca Valley virus (SVV) is a picornavirus that causes vesicular disease in swine. Clinical characteristics of the disease are similar to common viral diseases such as foot-and-mouth disease virus, porcine vesicular disease virus, and vesicular stomatitis virus, which can cause vesicles in the nose or hoof of pigs. Therefore, developing tools for detecting SVV infection is critical and urgent. The neutralizing antibodies were produced to detect the neutralizing epitope. Five SVV neutralizing monoclonal antibodies (mAb), named 2C8, 3E4, 4C3, 6D7, and 7C11, were generated by immunizing mouses with ultra-purified SVV-LNSY01-2017. All five monoclonal antibodies exhibited high neutralizing titers to SVV. The epitopes targeted by these mAbs were further identified by peptide scanning using GST fusion peptides. The peptide 153QELNEE158 is defined as the smallest linear neutralizing epitope. The antibodies showed no reactivity to VP2 single mutants E157A. Furthermore, the antibodies showed no neutralizing activity with the recombinant virus (SVV-E157A). The five monoclonal antibodies and identified epitopes may contribute to further research on the structure and function of VP2 and the development of diagnostic methods for detecting different SVV strains. Additionally, the epitope recognized by monoclonal antibodies against VP2 protein may provide insights for novel SVV vaccines and oncolytic viruses development.


Prejunctional and postjunctional effects of neuropeptide Y at the noradrenergic neuroeffector junction of the perfused mesenteric arterial bed of the rat.
The effect of neuropeptide Y (NPY) on periarterial nerve stimulation-induced release of norepinephrine (NE) and increase in perfusion pressure in the perfused mesenteric arterial bed of the rat was examined. Perfusate effluents were continuously collected and assayed for endogenous NE by high-pressure liquid chromatography (HPLC) coupled to electrochemical detection. Perfusion pressure was continuously monitored by means of a pressure transducer. Periarterial nerve stimulation (8 or 16 Hz, 60 V, 2-ms duration for 30 s) resulted in a readily detectable increase in NE release and perfusion pressure that was attenuated by the prior administration of tetrodotoxin (TTX) (10(-5) M) or guanethidine (5 X 10(-5) M). NPY exerted both prejunctional and postjunctional effects on noradrenergic neurotransmission in this preparation. The peptide produced a concentration-dependent reduction in the release of NE over a concentration range of 10(-10) - 10(-7) M. A similar inhibition effect occurred at 8, 10, and 16 Hz. In contrast, low concentrations (10(-10) and 10(-9) M) decreased the effect of nerve stimulation on perfusion pressure, whereas higher concentrations (10(-7) M) produced a marked potentiation. The alpha 2-adrenoceptor antagonist, yohimbine, did not alter the inhibitory effect of NPY on evoked NE release or the effect on perfusion pressure. Prazosin similarly did not alter the inhibitory effect of NPY on NE release but prevented the increase in perfusion pressure. We conclude that NPY modulates noradrenergic neurotransmission in the mesenteric arterial bed by decreasing the evoked release of NE and producing a concentration-dependent biphasic response on vascular smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)


The Impact of Antidepressants on the Risk of Developing Obstructive Sleep Apnea in Posttraumatic Stress Disorder: A Nationwide Cohort Study in Taiwan.
The association between posttraumatic stress disorder (PTSD) and obstructive sleep apnea (OSA) has been reported inconsistently, and the association between antidepressant use and the risk of developing OSA in patients with PTSD has not been previously studied. Therefore, we used the Longitudinal National Health Insurance Database (LHID) to investigate the impact of PTSD and antidepressant use on the risk of OSA development. Identified from the LHID, 2,316 individuals aged ≥ 18 years with PTSD, but with no history of OSA, and 23,160 control individuals matched for age, sex, obesity and index date were enrolled between 2000 and 2015 and followed up until the end of 2015 to identify the development of OSA. A two-tailed Bonferroni-corrected P < .00038 (.05/13) was considered statistically significant as we examined 13 antidepressants. Individuals with PTSD had increased risk of developing OSA (adjusted hazard ratio 4.672, 95% confidence interval 2.246-9.787, P < .001) after adjusting for demographic data, medical comorbidities, and medication. Treatment with antidepressants was not significantly associated with an increased risk of developing OSA compared to no antidepressant treatment. Asian patients with PTSD had increased risk of developing OSA, and treatment with antidepressants did not play a key role in increasing the risk of OSA development. Further studies are required to investigate the underlying mechanisms of PTSD and the roles of antidepressants on the risk of developing OSA. Lin C-E, Chung C-H, Chen L-F, Chien W-C, Chou P-H. The impact of antidepressants on the risk of developing obstructive sleep apnea in posttraumatic stress disorder: a nationwide cohort study in taiwan. J Clin Sleep Med. 2019;15(9):1233-1241.


Functional-morphological studies on in vitro cardionatrin release.
Atrial natriuretic peptides (ANP) are hormones produced by the heart atrial cardiocytes in mammals. The main function of these peptides appears to be that of modulating the actions of the renin-angiotensin-aldosterone system. In the rat ANP are stored within specific atrial granules, mainly as a 126-amino acid peptide (cardionatrin IV) which is processed to a 28-amino acid peptide (cardionatrin I) just prior to or during release from cardiocytes. Development of an isolated perifused rat atria preparation has allowed quantitative and qualitative studies on ANP release. Increasing mechanical load in this preparation gives an increased rate of release of immunoreactive cardionatrin. This finding suggests that there is an intrinsic 'stretch-secretion coupling' in the atria.


Emergent burn care.
The estimated 32,600,000 fires that occur annually in the United States produce over 300,000 injuries and 7,500 deaths. Ten percent of hospitalized burn victims die as a direct result of the burn. Initial evaluation and management of the burn patient are critical. The history should include the burn source, time of injury, burn environment, and combustible products. The burn size is best estimated by the Lund and Browder chart, and the burn depth is determined by clinical criteria. Pulmonary involvement and circumferential thoracic or extremity burns require detection and aggressive treatment to maintain organ viability. Hospitalization is usually necessary for adults with burns larger than 10% of the total body surface area (TBSA) or children with burns larger than 5% of TBSA. Major burns, those of 25% or more of TBSA or of 10% or more of full thickness, should be considered for treatment at a burn center, as well as children or elderly victims with burns of greater than 10% TBSA. Lactated Ringer's solution, infused at 4 ml/kg/% TBSA, is generally advocated for initial fluid restoration. After the acute phase (48 hours), replacement of evaporative and hypermetabolic fluid loss is necessary. These losses may constitute 3 to 5 liters per day for a 40% to 70% TBSA burn. Blood transfusion is often required because of persistent loss of red blood cells (8% per day for about ten days). Many electrolyte abnormalities may occur in the first two weeks. Pulmonary injury commonly is lethal. Circumoral burns, oropharyngeal burns, and carbonaceous sputum are indicative of inhalation injury, but arterial blood gas determinations, fiberoptic bronchoscopy, and xenon lung scans are useful for confirming the diagnosis. Humidified oxygen, intubation, positive-pressure ventilation, and pulmonary toilet are the mainstays of therapy for inhalation injury. Wound care is initially directed at preservation of vital function by escharotomy, if restrictive eschar impairs ventilatory or circulatory function. Antibacterial agents may be applied to the burn, but invasive sepsis, defined as greater than 10(5) organisms per gram of tissue with invasion of subjacent viable tissue, requires systemic antibiotic therapy. Wound debridement is done by daily hydrotherapy, tangential excision, chemicals, primary excision, and grafting, tailoring the technique to the individual burn.(ABSTRACT TRUNCATED AT 400 WORDS)


[Frequency of recurrence and repeated development of ovarian tumors after conservative operations].
Study on the late results of 330 preserving operations for benign ovarian tumors has indicated that the recurrence and redevelopment of the tumor occurs in 13.8% of female patients. In a group of females primarily operated at the age under 45 the development of cancer in a retained ovary was noted in 0.78% of cases, while in the operated patients aged over 45--in 5.2%. It was found that the frequency of recurrences and redevelopment of ovarian tumor is dependent on the extent of surgical intervention and histological structure of the resected neoplasm. The data obtained enabled bilateral ovariectomy to be recommended in menopausal women operated for benign ovarian tumors. The females who underwent resection of the ovary or unilateral ovariectomy should be kept under a dispensary supervision.


Serotonin transporter production and degradation rates: studies with RTI-76.
The objective of this study was to examine the turnover of the serotonin transporter (SERT) by determining its production rate (r), degradation rate constant (k) and half-life of recovery (t1/2). The turnover of SERT was determined from the rate of recovery of binding after administration of RTI-76, an irreversible inhibitor of ligand binding. In preliminary studies, in vitro incubation of rat cerebral cortex with RTI-76 produced a wash and temperature resistant inhibition of SERT binding densities (Bmax). Citalopram protected against the RTI-76-induced inhibition of SERT binding. Following 6 h of in vivo intracerebroventricular injections of 100 nmol of RTI-76, there was a dose- and time-dependent reduction (- 60%) of SERT binding in hippocampus and striatum, without a change in the Kd. SERT binding densities recovered over several days, reaching control levels by day 14. The recovery curve fit the standard model of protein synthesis and degradation. The turnover parameters of SERT were determined in hippocampus and striatum, regions that receive serotonergic innervation from the dorsal and median midbrain raphe nuclei, respectively. In the hippocampus, the production rate constant was 2.36 fmol mg protein (-1)h(-1); the degradation rate constant was 0.0077 h(-1); and the half-life of the SERT recovery was 3.4 days. The values in the striatum were similar. The decrease and recovery of [3H]-5-HT uptake correlated highly (r = 0.93) with the recovery of SERT binding.


A powerful DNA extraction method and PCR for detection of microsporidia in clinical stool specimens.
The diagnosis of intestinal microsporidiosis has traditionally depended on direct visualization of the parasite in stool specimens or intestinal biopsy samples by light and/or electron microscopy. Limited information about the specificity and sensitivity of PCR for the detection microsporidia in clinical stool specimens is available. To establish a sensitive and specific method for the detection of microsporidia in clinical samples, we studied clinical stool specimens of 104 randomly selected human immunodeficiency virus-infected patients with diarrhea to compare light microscopy and PCR. Fluorochrome Uvitex 2B staining was used for light microscopy. To raise the sensitivity of PCR, we used a powerful and fast DNA extraction method including stool sedimentation, glass bead disruption, and proteinase K and chitinase digestion. PCR was performed with primer pairs V1-PMP2, V1-EB450, and V1-SI500, and the nature of the PCR products was confirmed by Southern blot hybridization. Microsporidiosis was diagnosed by light microscopy in eight patients. Ten patients tested positive for microsporidiosis by PCR. Enterocytozoon bieneusi was found in seven cases, and Encephalitozoon intestinalis was found in four cases. In one case a double infection with E. bieneusi and E. intestinalis was diagnosed by PCR, whereas light microscopy showed only E. bieneusi infection. PCR testing of stool specimens is useful for diagnosis and species differentiation of intestinal microsporidiosis in HIV patients.


Speech acts: sampling the social construction of mental retardation in everyday life.
A sample of speech acts in everyday discourse referring to persons or events having to do with the term mental retardation was analyzed in order to investigate the belief that language use both constructs and reflects cultural norms that define the social roles of persons reduced to object status through categorical membership. Speech acts gathered suggest four emergent themes: the discourse of category membership, the dichotomy of normal and abnormal, issues of place and space, and fear. These themes were explicated from a social constructionist perspective, displaying the way speech acts construct mental retardation and subvert individuals with the label into demeaned and ridiculed objects of cultural fear.


DNA damage response: three levels of DNA repair regulation.
Genome integrity is challenged by DNA damage from both endogenous and environmental sources. This damage must be repaired to allow both RNA and DNA polymerases to accurately read and duplicate the information in the genome. Multiple repair enzymes scan the DNA for problems, remove the offending damage, and restore the DNA duplex. These repair mechanisms are regulated by DNA damage response kinases including DNA-PKcs, ATM, and ATR that are activated at DNA lesions. These kinases improve the efficiency of DNA repair by phosphorylating repair proteins to modify their activities, by initiating a complex series of changes in the local chromatin structure near the damage site, and by altering the overall cellular environment to make it more conducive to repair. In this review, we focus on these three levels of regulation to illustrate how the DNA damage kinases promote efficient repair to maintain genome integrity and prevent disease.


Calibration-less sizing and quantitation of polymeric nanoparticles and viruses with quartz nanopipets.
The feasibility of using quartz nanopipets as simple and cost-effective Coulter counters for calibration-less quantitation and sizing of nanoparticles by resistive pulsing sensing (RPS) was investigated. A refined theory was implemented to calculate the size distribution of nanoparticles based on the amplitude of resistive pulses caused by their translocation through nanopipets of known geometry. The RPS provided diameters of monodisperse latex nanoparticles agreed within the experimental error with those measured by using scanning electron microscopy (SEM), dynamic light scattering (DLS), and nanoparticle tracking analysis (NTA). The nanopipet-based counter, by detecting individual nanoparticles, could resolve with similar resolution as SEM mixtures of monodisperse nanoparticles having partially overlapping size distributions, which could not be discriminated by DLS or NTA. Furthermore, by calculating the hydrodynamic resistance of the nanopipets and consequently the volume flow through the tip enabled for the first time the calibration-less determination of nanoparticle concentrations with nanopipets. The calibration-less methodology is applied to sizing and quantitation of inactivated poliovirus of ~26 nm diameter, which is the smallest size spherical shape virus ever measured by resistive pulse sensing.


Voice recognition software can be used for scientific articles.
Dictation of scientific articles has been recognised as an efficient method for producing high-quality, first article drafts. However, standardised transcription service by a secretary may not be available for all researchers and voice recognition software (VRS) may therefore be an alternative. The purpose of this study was to evaluate the out-of-the-box accuracy of VRS. Eleven young researchers without dictation experience dictated the first draft of their own scientific article after thorough preparation according to a pre-defined schedule. The dictate transcribed by VRS was compared with the same dictate transcribed by an experienced research secretary, and the effect of adding words to the vocabulary of the VRS was investigated. The number of errors per hundred words was used as outcome. Furthermore, three experienced researchers assessed the subjective readability using a Likert scale (0-10). Dragon Nuance Premium version 12.5 was used as VRS. The median number of errors per hundred words was 18 (range: 8.5-24.3), which improved when 15,000 words were added to the vocabulary. Subjective readability assessment showed that the texts were understandable with a median score of five (range: 3-9), which was improved with the addition of 5,000 words. The out-of-the-box performance of VRS was acceptable and improved after additional words were added. Further studies are needed to investigate the effect of additional software accuracy training.


Sexual and Reproductive Health Outcomes among Incarcerated Women in Canada: A Scoping Review.
Women are the fastest growing population in Canadian prisons. Incarceration can limit access to essential health services, increase health risks and disrupt treatment and supports. Despite legal requirements to provide care at professionally accepted standards, evidence suggests imprisonment undermines sexual and reproductive health. This scoping review asks, "What is known about the sexual and reproductive health of people incarcerated in prisons for women in Canada?" We use the Joanna Briggs Institute methodology for systematic scoping reviews. Databases searched include MEDLINE, CINAHL, PsycINFO, Gender Studies Abstracts, Google Scholar and Proquest Dissertations and grey literature. The search yielded 1424 titles and abstracts of which 15 met the criteria for inclusion. Conducted from 1994-2020, in provincial facilities in Ontario, British Columbia, Alberta and Quebec as well as federal prisons, the 15 studies included qualitative, quantitative and mixed methods. The most common outcomes of interest were related to HIV. Other outcomes studied included Papanicolaou (Pap) and sexually transmitted infection (STI) testing, contraception, pregnancy, birth/neonatal outcomes, and sexual assault. Incarceration results in lack of access to basic services including contraception and prenatal care. Legal obligations to provide sexual and reproductive health services at professionally acceptable standards appear unmet. Incarceration impedes rights of incarcerated people to sexual and reproductive health.


Anterolateral thigh free flaps for the reconstruction of scalp angiosarcoma - 18-year experience in Chang Gung memorial hospital.
Scalp angiosarcoma is a rare and highly aggressive cutaneous malignancy with poor prognosis and high recurrence rate. Multimodality approach is currently the treatment protocol for resectable angiosarcoma, including wide local excision and postoperative radiation. This single-institution study reviews the 18-year experience of the surgical treatment of scalp angiosarcomas. A retrospective chart review was performed on patients with scalp angiosarcoma who received wide local excision and free flap reconstruction from 2001 to 2018. The type of free flap, safety margin, outer cortex burring, and dose for radiation were recorded. Kaplan-Meier plots were computed. Eight male patients (mean age of 74.4 years old) were enrolled in the series. Tumor sizes ranged from 3 × 3 to 8 × 13 cm. All patients underwent wide local excision and outer cortex burring (cortical curettage). Seven (87.5%) scalp defects were reconstructed with anterolateral thigh free flap. All patients received adjuvant radiation therapy for tumor bed and margins. Chemotherapy was adopted for the management of local recurrence (37.5%) or distant metastasis (37.5%). The 2-year and 5-year survival rates are 72.9% and 38.9%, respectively, and 1-year and 2-year disease-free rates are 37.5% each. Scalp angiosarcoma is a rare and highly aggressive cutaneous malignancy with poor prognosis. Anterolateral thigh free flap is a good reconstructive option due to its ability to cover large cutaneous defects with minimal need for skin grafting. Multimodal treatment protocol, including wide local excision with cortical curettage, and adjuvant radiation (regular basis) and chemotherapy (local recurrence or distant metastasis) may offer improved 1-year survival rate (100%).


Development of a nurse-led primary healthcare service for injecting drug users in inner-city Sydney.
Injecting drug users (IDUs) experience numerous health problems, but report barriers to utilising general practitioners (GPs). A nurse-led Harm Minimisation-based Primary Healthcare (HMPH) service for IDUs was established within a needle and syringe program in inner-city Sydney with Area Health Service medical support and clinical governance. This paper aimed to describe the HMPH service, review service utilisation and assess nurses' perceptions of their work with IDUs. A review of the most recent 200 clinic files was undertaken. Service utilisation, GP and other health service use and access were extracted and analysed using SPSS. A semi-structured qualitative interview with clinic nurses regarding their experience working with IDUs and local GPs was conducted and analysed. Since its inception in mid-2006, the service has been utilised by 417 clients. Of the most recent 200 files, blood-borne virus and sexually transmitted infection screening were the primary reason for presentation (64.5%). At least one follow-up visit was attended by 90% of clients. A total of 62% of clients reported consulting a GP in the last 12 months. The service provided 102 referrals. Nurses believed that IDUs tend to utilise GPs ineffectively and that self-care is a low priority, but that they can support IDUs to overcome some barriers to GPs and facilitate access. Targeted primary health care services led by nurses with focussed medical support and co-located with needle and syringe programs can fill an important gap in delivering and facilitating health care to IDUs.


Stavudine or zidovudine in three-drug combination therapy for initial treatment of HIV infection in antiretroviral-naïve individuals.
The introduction of highly active antiretroviral therapy (ART) as treatment for HIV infection has greatly improved mortality and morbidity for adults and children living with HIV around the world. Two common medications given in first-line antiretroviral therapy are the nucleoside reverse transcriptase inhibitors (NRTI) stavudine (d4T) or zidovudine (AZT). To assess the efficacy of d4T compared to AZT in combination with one NRTI and one non-nucleoside reverse transcriptase inhibitor (NNRTI), two additional NNRTIs, or one NRTI and one protease inhibitor (PI), as part of first-line ART for HIV-infected people in low-resource settings. Standard Cochrane methods were used to search electronic databases and conference proceedings with relevant search terms without limits to language. Randomised controlled trials of HIV-infected patients 5 years of age and older were included. Primary outcomes of interest included mortality, severe adverse events, virologic response to ART, and adherence/tolerance/retention. Secondary outcomes included immunologic response to ART, development of ART drug resistance, and prevention of sexual transmission of HIV. Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form. Nine randomised controlled trials were identified as meeting the inclusion criteria. The nine trials enrolled 2,159 participants but looked at a multiplicity of drug combinations. Despite this, a reasonably robust literature suggests no statistically significant difference between the two drug combinations, including severe adverse events and adherence/tolerance/retention. The quality of the literature was found overall to be low to very low for all key outcomes. Only one study reported on drug resistance, and no studies reported on sexual transmission of HIV. The length of follow-up time and study settings varied greatly. While ideally future research would focus on direct comparison of standard therapeutic combinations of d4T+3TC+an NNRTI and AZT+3TC+an NNRTI to compare these regimens more directly, it is unlikely that additional trials will be mounted. Observational studies should focus on understanding outcomes, including toxicity and tolerability, in low- and middle-income countries.


Edible Plant Sprouts: Health Benefits, Trends, and Opportunities for Novel Exploration.
The consumption of plant sprouts as part of human day-to-day diets is gradually increasing, and their health benefit is attracting interest across multiple disciplines. The purpose of this review was to (a) critically evaluate the phytochemicals in selected sprouts (alfalfa, buckwheat, broccoli, and red cabbage), (b) describe the health benefits of sprouts, (c) assess the recent advances in sprout production, (d) rigorously evaluate their safety, and (e) suggest directions that merit special consideration for further novel research on sprouts. Young shoots are characterized by high levels of health-benefitting phytochemicals. Their utility as functional ingredients have been extensively described. Tremendous advances in the production and safety of sprouts have been made over the recent past and numerous reports have appeared in mainstream scientific journals describing their nutritional and medicinal properties. However, subjects such as application of sprouted seed flours in processed products, utilizing sprouts as leads in the synthesis of nanoparticles, and assessing the dynamics of a relationship between sprouts and gut health require special attention for future clinical exploration. Sprouting is an effective strategy allowing manipulation of phytochemicals in seeds to improve their health benefits.


Crosstalk between alternative polyadenylation and miRNAs in the regulation of protein translational efficiency.
3' UTRs play important roles in the gene regulation network via their influence on mRNA stability, translational efficiency, and subcellular localization. For a given gene, 3' UTRs of different lengths generated by alternative polyadenylation (APA) may result in functional differences in regulation. The mechanistic details of how length changes of 3' UTRs alter gene function remain unclear. By combining APA sequencing and polysome profiling, we observed that mRNA isoforms with shorter 3' UTRs were bound with more polysomes in six cell lines but not in NIH3T3 cells, suggesting that changing 3' UTRs to shorter isoforms may lead to a higher gene translational efficiency. By interfering with the expression of TNRC6A and analyzing AGO2-PAR-CLIP data, we revealed that the APA effect on translational efficiency was mainly regulated by miRNAs, and this regulation was cell cycle dependent. The discrepancy between NIH3T3 and other cell lines was due to contact inhibition of NIH3T3. Thus, the crosstalk between APA and miRNAs may be needed for the regulation of protein translational efficiency.


Nicotine Gateway Effects on Adolescent Substance Use.
Given the rise in teenage use of electronic nicotine delivery systems ("vaping") in congruence with the increasing numbers of drug-related emergencies, it is critical to expand the knowledge of the physical and behavioral risks associated with developmental nicotine exposure. A further understanding of the molecular and neurochemical underpinnings of nicotine's gateway effects allows emergency clinicians to advise patients and families and adjust treatment accordingly, which may minimize the use of tobacco, nicotine, and future substances. Currently, the growing use of tobacco products and electronic cigarettes among teenagers represents a major public health concern. Adolescent exposure to tobacco or nicotine can lead to subsequent abuse of nicotine and other substances, which is known as the gateway hypothesis. Adolescence is a developmentally sensitive time period when risk-taking behaviors, such as sensation seeking and drug experimentation, often begin. These hallmark behaviors of adolescence are largely due to maturational changes in the brain. The developing brain is particularly vulnerable to the harmful effects of drugs of abuse, including tobacco and nicotine products, which activate nicotinic acetylcholine receptors (nAChRs). Disruption of nAChR development with early nicotine use may influence the function and pharmacology of the receptor subunits and alter the release of reward-related neurotransmitters, including acetylcholine, dopamine, GABA, serotonin, and glutamate. In this review, we emphasize that the effects of nicotine are highly dependent on timing of exposure, with a dynamic interaction of nAChRs with dopaminergic, endocannabinoid, and opioidergic systems to enhance general drug reward and reinforcement. We analyzed available literature regarding adolescent substance use and nicotine's impact on the developing brain and behavior using the electronic databases of PubMed and Google Scholar for articles published in English between January 1968 and November 2018. We present a large collection of clinical and preclinical evidence that adolescent nicotine exposure influences long-term molecular, biochemical, and functional changes in the brain that encourage subsequent drug abuse.


A PCA Based Artifact Removal Algorithm for Neural Signal Acquisition with kS/s Sampling Rate.
The contamination of stimulus artifacts during Deep Brain Stimulation (DBS) brings challenges to the signal processing, especially when the ratio of the kS/s sampling rate to the stimulation frequency is not an integer. In this work we study to deal with this problem. A transfer function is built to describe the relationship between the stimulation signal and the artifact at the acquisition site. A principal component analysis (PCA) based linear regression algorithm for eliminating the artifact is proposed. The algorithm can be used for the artifact removal with low sampling rate of the neural signal. Higher than 60% correlation coefficient of the artifact-free signal and the predetermined self-generated signal is achieved when the artifact is 60dB larger than the predetermined signal. The numerical recipe for the critical algorithm is also proposed, lowering the complexity from cubic degree to square degree.


Pelvic exenteration for vaginal embryonal rhabdomyosarcoma: a review.
The English language literature for the years 1935-1972 was reviewed to assess the effect of pelvic exenteration on vaginal embryonal rhabdomyosarcoma. Twenty-one cases were determined eligible for review. Tumor was confined to the vagina in 8 cases and extended beyond the vagina in 13 cases. Treatment by pelvic exenteration was found to be relatively ineffective means of curing patients with tumor extending beyond the limits of the vagina. Recent evidence from the literature indicates that better results can be obtained by coordinated treatment, ie, surgery, radiation therapy, and/or chemotherapy, than by surgery alone.


[Differentiation of serous and purulent fluids in vitro and in vivo by means of diffusion-weighted MRI].
The aim of this study was to test the feasibility for differentiation of serous fluid collections and abscess fluid with diffusion-weighted imaging and to compare three different diffusion sequences. Thirteen puncture samples (6 serous, 7 purulent) and 19 patients with either serous fluid collections (n = 12) or abscesses (n = 7) were examined with diffusion-weighted spin-echo (SE), stimulated-echo (STE), and fatsuppressed SE (SE-SPIR) sequences. For in vitro studies 4 different b-factors (0, 87, 355, 798 s/mm2 in SE and SE-SPIR and 0, 51, 204, 460 s/mm2 in STE) were chosen and the apparent diffusion coefficient (ADC) was calculated. For in vivo measurements identical sequences with two b-factors (0.598 s/mm2 in SE and SE-SPIR and 0.360 s/mm2 in STE) were applied and the normalized signal attenuation was calculated. A navigator-echo technique and peripheral pulse triggering was used for motion artifact reduction. The in vitro study yielded an ADC of serous fluid, which was close to that of free water, whereas for purulent fluid a significantly lower ADC was calculated. During in vivo examinations, serous fluids showed a strong signal attenuation (down to 22-32% of basic value) compared to a minor signal attenuation in purulent fluids (down to 86-94% of basic value) (p < 0.05). In summary, with all three investigated diffusion schemes serous and purulent fluids can be clearly differentiated.


Relationship of ocular accommodation and motor skills performance in developmental coordination disorder.
Ocular accommodation provides a well-focussed image, feedback for accurate eye movement control, and cues for depth perception. To accurately perform visually guided motor tasks, integration of ocular motor systems is essential. Children with motor coordination impairment are established to be at higher risk of accommodation anomalies. The aim of the present study was to examine the relationship between ocular accommodation and motor tasks, which are often overlooked, in order to better understand the problems experienced by children with motor coordination impairment. Visual function, gross and fine motor skills were assessed in children with developmental coordination disorder (DCD) and typically developing control children. Children with DCD had significantly poorer accommodation facility and amplitude dynamics compared to controls. Results indicate a relationship between impaired accommodation and motor skills. Specifically, accommodation anomalies correlated with visual motor, upper limb and fine dexterity task performance. Consequently, we argue accommodation anomalies influence the ineffective coordination of action and perception in DCD. Furthermore, reading disabilities were related to poorer motor performance. We postulate the role of the fastigial nucleus as a common pathway for accommodation and motor deficits. Implications of the findings and recommended visual screening protocols are discussed.


The control of synthesis of bacterial cell walls. Interaction in the synthesis of nucleotide precursors.
Phosphoenolpyruvate-UDP-N-acetylglucosamine enolpyruvyltransferase, UDP-N-acetylglucosamine pyrophosphorylase and CDP-glycerol pyrophosphorylase activities were demonstrated in soluble extracts from Bacillus licheniformis A.T.C.C. 9945. The effect of various nucleotides, sugar nucleotides and sugar phosphates on the nucleotide pyrophosphorylases was investigated. UDP-N-acetylglucosamine pyrophosphorylase was inhibited by UDP-MurAc-pentapeptide (UDP-N-acetylmuramyl-l-alanyl-d-glutamyl- meso-diaminopimelyl-d-alanyl -d-alanine) and CDP-glycerol. CDP-glycerol pyrophosphorylase was inhibited by UDP-MurAc-pentapeptide and stimulated by UDP-N-acetylglucosamine. Interaction between a precursor of one cell-wall polymer and an enzyme involved in the synthesis of a precursor of a second polymer has therefore been demonstrated. The possible role of such interaction in the control of bacterial cell-wall synthesis is discussed. Of the other compounds investigated mono- and di-nucleotides were shown to be inhibitory, indicating that nucleotide pyrophosphorylase activities may be influenced by the energy charge of the cell.


The small-molecule CDK inhibitor, SNS-032, enhances cellular radiosensitivity in quiescent and hypoxic non-small cell lung cancer cells.
In solid tumors, including non-small cell lung carcinomas (NSCLC) the existence of radioresistant subpopulations, such as quiescent or hypoxic tumor cells, is well established, thus posing a critical therapeutic problem. Although small-molecule inhibitors targeting cyclin-dependent kinases (CDK) were demonstrated to enhance cellular radiosensitivity preferentially in proliferating tumor cells, cell cycle-independent activities of these substances were recently suggested. In this study, the potential of a newer generation small-molecule CDK inhibitor, SNS-032, to sensitize radioresistant tumor cells to ionizing radiation was tested in vitro using two NSCLC cell lines (NCI-H460 and A549). Exposure of quiescent and hypoxic lung tumor cells to SNS-032 at a clinically achievable concentration (500 nM) prior to irradiation resulted in a significant increase in cellular radiosensitivity indicating cell cycle-unrelated mechanisms. The effect of SNS-032 on non-cycling cells was not attributed to an enhanced toxicity of the drug. A SNS-032 mediated delay in the resolution of radiation-induced gammaH2AX foci a surrogate for DNA double-strand breaks was determined in non-cycling cells, suggesting a modulation of DNA double-strand break repair. These results indicate a modulation of DNA double-strand break repair to be partially attributed to the radiosensitization effects of SNS-032 observed in hypoxic and quiescent lung tumor cells. Considering the importance of therapy resistance for the radiocurability of solid tumors, our findings may provide the basis for an improvement of the well-established treatment regimens in clinical oncology.


Effects of fluoride on structure and function of canine gastric mucosa.
These studies were done to determine the effects of fluoride (F) on the structure and function of the canine gastric mucosa and the possible protective effects of 16,16-dimethyl-prostaglandin E2 (dmPGE2). A portion of the stomach with its vascular supply intact was mounted in a two-compartment chamber, one side of which contained a control solution. Minor effects were caused by exposure to 1 mmol/liter F. Both 5 and 10 mmol/liter F caused marked increases in the fluxes of water and Na, K, and H ions; mucus secretion; and tissue swelling and redness. The extent of these changes did not increase appreciably upon exposure to 50 or 100 mmol/liter F. Histological findings included marked thinning of the surface cell layer, reduced uptake of PAS stain, localized exfoliation and necrosis of surface cells, acute gastritis, and edema. It was concluded that: (1) the threshold F concentration for effects on the structure and function of the gastric mucosa was approximately 1 mmol/liter; (2) the maximum or near-maximum effects were caused by 10 mmol/liter F; (3) the effects persisted for at least 6 hr after the exposure; and (4) dmPGE2 (0.5 microg/ml) did not attenuate the effects induced by F.


Acute alcohol consumption and injury: risk associations and attributable fractions for different injury mechanisms.
Most studies on alcohol as a risk factor for injuries have been mechanism specific, and few have considered several mechanisms simultaneously or reported alcohol-attributable fractions (AAFs)-which was the aim of the current study. Data from 3,592 injured and 3,489 noninjured patients collected between January 2003 and June 2004 in the surgical ward of the emergency department of the Lausanne University Hospital (Switzerland) were analyzed. Four injury mechanisms derived from the International Classification of Diseases, 10th Revision, were considered: transportation-related injuries, falls, exposure to forces and other events, and interpersonal violence. Multinomial logistic regression models were calculated to estimate the risk relationships of different levels of alcohol consumption, using noninjured patients as quasi-controls. The AAFs were then calculated. Risk relationships between injury and acute consumption were found across all mechanisms, commonly resulting in dose-response relationships. Marked differences between mechanisms were observed for relative risks and AAFs, which varied between 15.2% and 33.1% and between 10.1% and 35.9%, depending on the time window of consumption (either 6 hours or 24 hours before injury, respectively). Low and medium levels of alcohol consumption generally were associated with the most AAFs. This study underscores the implications of even low levels of alcohol consumption on the risk of sustaining injuries through any of the mechanisms considered. Substantial AAFs are reported for each mechanism, particularly for injuries resulting from interpersonal violence. Observation of a so-called preventive paradox phenomenon is discussed, and prevention or intervention measures are described.


Histiocytic sarcoma of the scrotum in a rat.
A 225-day-old male fourth generation rat from a developing recombinant inbred line (Lewis x Brown Norway) had a bilaterally symmetrical enlargement of the scrotum. Palpation indicated the presence of a firm lobulated mass extending from the tip of the scrotum to the abdominal wall. Bilateral nodular masses totally occupied the scrotal sacs, surrounded the testicles, and extended along the spermatic cords into the abdominal cavity. Tumor nodules also were present in the intestinal mesentery, omentum, mesenteric lymph nodes, pancreas, and lung. Histologically, the neoplasm presented a spectrum of characteristics varying from that of a granuloma with giant cells to a diffuse proliferation of spindle-shaped mononuclear cells.


Total synthesis of the fumiquinazoline alkaloids: solid-phase studies.
We have previously described an efficient four-step synthesis of the fumiquinazoline alkaloids (Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432-2433). Here, we demonstrate that this route is readily adaptable to combinatorial synthesis on solid phase. Linear tripeptides containing a central anthranilate unit were assembled on the Wang resin and subjected to dehydration and cyclative release to yield the pyrazino[2,1-b]quinazoline-3,6-diones in high purity. To demonstrate the scope of this protocol, a small library [ca. 20 compounds] of unnatural analogues was prepared by parallel synthesis.


Origins of agriculture in eastern north america.
As a result of research carried out over the past decade, eastern North America now provides one of the most detailed records of the origins of agriculture available. Spanning a filll three millennia, the transition from forager to farmer in eastern North America involved the domestication of four North American seed plants during the second millennium B.C., the initial emergence of food production economies based on local crop plants between 250 B.C. and A.D. 200, and the rapid and broad-scale shift to maize-centered agriculture during the three centuries from A.D. 800 to 1100.


Evaluation of the impact of a scanner prototype on proton CT and helium CT image quality and dose efficiency with Monte Carlo simulation.
Objective.The use of ion computed tomography (CT) promises to yield improved relative stopping power (RSP) estimation as input to particle therapy treatment planning. Recently, proton CT (pCT) has been shown to yield RSP accuracy on par with state-of-the-art x-ray dual energy CT. There are however concerns that the lower spatial resolution of pCT compared to x-ray CT may limit its potential, which has spurred interest in the use of helium ion CT (HeCT). The goal of this study was to investigate image quality of pCT and HeCT in terms of noise, spatial resolution, RSP accuracy and imaging dose using a detailed Monte Carlo (MC) model of an existing ion CT prototype.Approach.Three phantoms were used in simulated pCT and HeCT scans allowing estimation of noise, spatial resolution and the scoring of dose. An additional phantom was used to evaluate RSP accuracy. The imaging dose required to achieve the same image noise in a water and a head phantom was estimated at both native spatial resolution, and in a scenario where the HeCT spatial resolution was reduced and matched to that of pCT using Hann windowing of the reconstruction filter. A variance reconstruction formalism was adapted to account for Hann windowing.Main results.We confirmed that the scanner prototype would produce higher spatial resolution for HeCT than pCT by a factor 1.8 (0.86 lp mm-1versus 0.48 lp mm-1at the center of a 20 cm water phantom). At native resolution, HeCT required a factor 2.9 more dose than pCT to achieve the same noise, while at matched resolution, HeCT required only 38% of the pCT dose. Finally, RSP mean absolute percent error (MAPE) was found to be 0.59% for pCT and 0.67% for HeCT.Significance.This work compared the imaging performance of pCT and HeCT when using an existing scanner prototype, with the spatial resolution advantage of HeCT coming at the cost of increased dose. When matching spatial resolution via Hann windowing, HeCT had a substantial dose advantage. Both modalities provided state-of-the-art RSP MAPE. HeCT might therefore help reduce the dose exposure of patients with comparable image noise to pCT, enhanced spatial resolution and acceptable RSP accuracy at the same time.


A genetic analysis of primary products of bacteriophage lambda recombination.
Primary products of bacteriophage lambda recombination that display heterozygosity as a consequence of the presence of regions of heteroduplex DNA are rare in standard lambda crosses. Phage manifesting heterozygosity at a given allele are evident when recombinants, emerging from a cross, are selected for an exchange in a neighboring interval. We show that the abundance of such heterozygotes can be increased 10- to 20-fold by selection on an E. coli indicator that is defective in methyl-directed mismatch repair (mutL). Thus, the activity of the methyl-directed mismatch repair system is, at least in part, responsible for the low frequency of detectably heterozygous phage emerging from a standard cross. In a mutL indicator, many primary products of recombination are replicated without the intervention of mismatch repair.--The products of a six-factor phage cross have been plated on a mutL indicator allowing visual detection of those phage products heterozygous for one of the allelic pairs, cI. By genetic analysis, we show that the heteroduplex regions of these primary products of recombination are on the average about 4 kb in length and can include as much as half of the lambda genome.


Persistent ICT malaria P.f/P.v panmalarial and HRP2 antigen reactivity after treatment of Plasmodium falciparum malaria is associated with gametocytemia and results in false-positive diagnoses of Plasmodium vivax in convalescence.
A problem with rapid Plasmodium falciparum-specific antigen histidine-rich protein 2 (HRP2) detection tests for malaria is the persistence of antigen in blood after the disappearance of asexual-stage parasitemia and clinical symptoms, resulting in false-positive (FP) test results following treatment. The ICT P.f/P.v immunochromatographic test detects both HRP2 and a panmalarial antigen (PMA) found in both P. falciparum and Plasmodium vivax. To examine posttreatment antigen persistence with this test and whether persistent sexual-stage forms (gametocytes) are a cause of FP tests after treatment, we compared serial antigen test results with microscopy results from patients symptomatic with P. falciparum malaria in Indonesia for 28 days following treatment with chloroquine (CQ; n = 66), sulfadoxine-pyrimethamine (SP; n = 36), and artesunate plus sulfadoxine-pyrimethamine (ART + SP; n = 15). Persistent FP antigenemia following SP treatment occurred in 29% (HRP2) and 42% (PMA) of the patients on day 7 and in 10% (HRP2) and 23% (PMA) on day 14. The high rates of persistent HRP2 and PMA antigenemia following CQ and SP treatment were strongly associated with the presence of gametocytemia, with the proportion with gametocytes on day 7 posttreatment being significantly greater in those with FP results than in those with true-negative PMA and HRP2 results. Gametocyte frequency on day 14 post-SP treatment was also greater in those with FP PMA results. Following SP treatment, PMA persisted longer than HRP2, giving an FP diagnosis of P. vivax in up to 16% of patients on day 14, with all FP P. vivax diagnoses having gametocytemia. In contrast, PMA was rapidly cleared following ART + SP treatment in association with rapid clearance of gametocytemia. Gametocytes appear to be an important cause of persistent posttreatment panmalarial antigenemia in areas of endemicity and may also contribute in part to persistent HRP2 antigenemia following treatment.


Evaluation of Demineralized Bone Matrix Particles Delivered by Alginate Hydrogel for a Bone Graft Substitute: An Animal Experimental Study.
BACKGROUND Our objective was to explore a synthetic alginate hydrogel delivery system for the delivery of demineralized bone matrix (DBM) particles for bone graft substitutes. MATERIAL AND METHODS The physiochemical properties of surface morphology, porosity measurements, in vitro degradation, equilibrium swelling, and mechanical testing of combined DBM powder and alginate in amounts of 0 mg/1 mL, 25 mg/1 mL, 50 mg/1 mL, and 100 mg/1 mL were detected. In vitro cell culture and in vivo studies using Sprague-Dawley rats were performed to evaluate the biocompatibility and osteoinductivity of DBM-alginate (ADBM) composites. RESULTS DBM particles were uniformly scattered in all composites, and macro-scale pores were omnipresent. All composites showed a similar low degradation rate, with approximately 85% of weight remaining after 15 days. As the concentration of DBM particles in composites increased, degradation in collagenase and elastic modulus increased and the pore area and swelling ratio significantly decreased. No cytotoxicity of ADBM or alginate on mesenchymal stem cells (MSCs) was observed. Cell cultivation with ADBM showed greater osteogenic potential, evidenced by the upregulation of alkaline phosphatase and alizarin red staining activity and the mRNA expression level of marker genes RUNX2, OCN, OPN, and collagen I compared with the cells grown in alginate. Evaluation of ectopic bone formation revealed the osteoinductivity of the ADBM composites was significantly greater than that of DBM particles. Osteoinduction of the composites was demonstrated by a cranial defect model study. CONCLUSIONS The delivery of DBM particles using a synthetic alginate hydrogel carrier may be a promising approach in bone tissue engineering for bone defects.


The role of matrix metalloproteinase-2 promoter polymorphisms in coronary artery disease and myocardial infarction.
The matrix metalloproteinase (MMP) family are key enzymes involved in the breakdown of the extracellular matrix in normal physiological processes, including tissue remodeling, and disease processes, such as arthritis and metastasis. The promoter polymorphism in the MMP2 gene may be responsible for multiple diseases related to extracellular matrix degradation. Therefore, we aimed to investigate the relationship between genotypes or haplotypes of -1575 G/A, -1306 C/T, -790 T/G, and -735 C/T promoter polymorphisms and coronary artery disease (CAD) with or without myocardial infarction (MI) history. This study included 298 patients with angiographically confirmed CAD and 299 age matched controls. Genomic DNA was isolated from whole blood and genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. No significant associations were found between -1575 G/A, -1306 C/T, and -790 T/G polymorphisms and CAD with or without MI history. However, the frequency of the -735 TT genotype was significantly lower in the controls than in the patients with MI alone when compared with the CC genotype (p=0.021). Only the distribution of the ACGC haplotype in CAD patients exhibited a significant difference than that in controls (p<0.05). The distribution of other haplotypes did not differ between CAD patients and controls. The present investigation is the first report to detect an association between MMP2 promoter polymorphisms and CAD with or without MI history in the Turkish population. Further case-control studies in CAD development might be contributed to clarify the role of these polymorphisms.


Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II.
The convenient synthesis of a focused library (forty molecules) of novel 6,6,5-tricyclic thiazolo[5,4-f]quinazolines was realized mainly under microwave irradiation. A novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (1) was used as a versatile molecular platform for the synthesis of various derivatives. Kinase inhibition, of the obtained final compounds, was evaluated on a panel of two kinases (DYRK1A/1B) together with some known reference DYRK1A and DYRK1B inhibitors (harmine, TG003, NCGC-00189310 and leucettine L41). Compound IC50 values were obtained and compared. Five of the novel thiazolo[5,4-f]quinazoline derivatives prepared, EHT 5372 (8c), EHT 6840 (8h), EHT 1610 (8i), EHT 9851 (8k) and EHT 3356 (9b) displayed single-digit nanomolar or subnanomolar IC50 values and are among the most potent DYRK1A/1B inhibitors disclosed to date. DYRK1A/1B kinases are known to be involved in the regulation of various molecular pathways associated with oncology, neurodegenerative diseases (such as Alzheimer disease, AD, or other tauopathies), genetic diseases (such as Down Syndrome, DS), as well as diseases involved in abnormal pre-mRNA splicing. The compounds described in this communication constitute a highly potent set of novel molecular probes to evaluate the biology/pharmacology of DYR1A/1B in such diseases.


[Cryoplasma-anti-enzyme combination in the treatment of acute pancreatitis].
Results of treatment of 397 patients with acute pancreatitis are analyzed. Use of fresh-frozen and cryosupernatant plasma, heparin and protease inhibitors provide more effective elimination of disseminated intravascular blood coagulation syndrome, disorders of microcirculation that permits to improve results of treatment.


Participatory scenario development for environmental management: a methodological framework illustrated with experience from the UK uplands.
A methodological framework is proposed for participatory scenario development on the basis of evidence from the literature, and is tested and refined through the development of scenarios for the future of UK uplands. The paper uses a review of previous work to justify a framework based around the following steps: i) define context and establish whether there is a basis for stakeholder engagement in scenario development; ii) systematically identify and represent relevant stakeholders in the process; iii) define clear objectives for scenario development with stakeholders including spatial and temporal boundaries; iv) select relevant participatory methods for scenario development, during initial scenario construction, evaluation and to support decision-making based on scenarios; and v) integrate local and scientific knowledge throughout the process. The application of this framework in case study research suggests that participatory scenario development has the potential to: i) make scenarios more relevant to stakeholder needs and priorities; ii) extend the range of scenarios developed; iii) develop more detailed and precise scenarios through the integration of local and scientific knowledge; and iv) move beyond scenario development to facilitate adaptation to future change. It is argued that participatory scenario development can empower stakeholders and lead to more consistent and robust scenarios that can help people prepare more effectively for future change.


SERPINE2 (protease nexin I) promotes extracellular matrix production and local invasion of pancreatic tumors in vivo.
In large-scale expression profiling analyses, we have previously identified genes differentially expressed between subclones of the pancreatic cancer cell line SUIT-2. One of the genes most strongly overrepresented in the highly metastatic subclone S2-007 as compared with the rarely metastatic subclone S2-028 was the serine proteinase inhibitor SERPINE2 (protease nexin I), suggesting that this protein may play an important part in the process of metastasis. The aim of this study was to functionally characterize SERPINE2 for its potential to influence the invasive and metastatic phenotype of cancer cells in vitro and in vivo. SERPINE2 expression was weak or absent in all normal pancreas and chronic pancreatitis tissue samples examined. In contrast, it was strongly overexpressed in the majority of pancreatic carcinoma as well as gastric and colorectal cancer samples. [(3)H]Thymidine incorporation, soft agar, two chamber migration, Matrigel invasion, and zymography assays of SERPINE2-transfected S2-028 cells revealed no significant effects on metastasis-related cellular characteristics of isolated cancer cells. Although overall metastatic activity of the transfected cells in vivo was also unaltered, SERPINE2 overexpression greatly enhanced the local invasiveness of the s.c. xenograft tumors, accompanied by a massive increase in extracellular matrix (ECM) production in the invasive tumors. ECM deposits were positive for type I collagen, fibronectin, and laminin, thus resembling the desmoplastic reaction commonly observed in pancreatic cancer. Moreover, cancer cells in invasive SERPINE2-expressing tumors tended to adopt a spindle-shaped morphology and strongly expressed the mesenchymal intermediate filament marker vimentin. We propose that SERPINE2 overexpression enhances the invasive potential of pancreatic cancer cells in nude mouse xenografts by altering ECM production and organization within the tumors. Thus, our experimental system for the first time provides the opportunity to effectively model the desmoplastic reaction of pancreatic cancer and represents a valuable new tool for the study of tumor-stroma interactions.


Deletion diagnostics for alternating logistic regressions.
Deletion diagnostics are introduced for the regression analysis of clustered binary outcomes estimated with alternating logistic regressions, an implementation of generalized estimating equations (GEE) that estimates regression coefficients in a marginal mean model and in a model for the intracluster association given by the log odds ratio. The diagnostics are developed within an estimating equations framework that recasts the estimating functions for association parameters based upon conditional residuals into equivalent functions based upon marginal residuals. Extensions of earlier work on GEE diagnostics follow directly, including computational formulae for one-step deletion diagnostics that measure the influence of a cluster of observations on the estimated regression parameters and on the overall marginal mean or association model fit. The diagnostic formulae are evaluated with simulations studies and with an application concerning an assessment of factors associated with health maintenance visits in primary care medical practices. The application and the simulations demonstrate that the proposed cluster-deletion diagnostics for alternating logistic regressions are good approximations of their exact fully iterated counterparts.


DTaP-IPV-HB-Hib vaccine (Hexaxim): an update 10 years after first licensure.
Hexaxim® is fully liquid, hexavalent, combination vaccine that provides immunization against diphtheria, tetanus, pertussis (whooping cough), polio, hepatitis B, and invasive diseases caused by Haemophilus influenzae type b. Combination vaccines such as Hexaxim reduce the number of injections needed, improving both vaccination compliance and operational efficiency. Safety and immunogenicity data were reviewed from >25 clinical trials involving approximately 7200 infants/toddlers, identified using PubMed searches to April 2023. These trials have evaluated a diverse range of primary series and booster schedules, including antibody persistence, co-administration of Hexaxim with other routine pediatric vaccines, and specific populations (born to Tdap-vaccinated women, preterm, and immunocompromised infants). Lastly, post-marketing surveillance and real-world effectiveness data were assessed. An extensive program of clinical development prior to licensure demonstrated favorable vaccine safety and good immunogenicity of each antigen, and Hexaxim was first approved for use in 2012. In the 10 years since licensure, Hexaxim has been adopted widely, with more than 180 million doses distributed worldwide. The widespread use of this hexavalent vaccine is a crucial tool in the ongoing and future control of six pediatric infectious diseases globally.


Exploring the link between innate immune activation and thymic function by measuring sCD14 and TRECs in HIV patients living in Belgium.
Microbial translocation is now viewed as a central event in the pathogenesis of chronic inflammation during HIV infection. Thymic function failure is another crucial factor involved in HIV disease progression. The goal of this study was to explore the hypothesis of potential links between microbial translocation and thymic function in HIV-1 patients living in Belgium. The extent of microbial translocation was assessed through the measurement of soluble CD14 (sCD14). T-cell receptor excision circles (sjTRECs and dβTRECs) were used as a measure of thymic function. Data were collected from 75 HIV-infected patients. Simple and complex linear regressions were done to analyze the link between these two processes. We found a statistically relevant negative correlation between thymopoiesis (sjTREC) and sCD14 level (p = 0.004). These results suggest a link between thymic function failure, microbial translocation and innate immune activation.


Temperature response of photosynthesis in C3, C4, and CAM plants: temperature acclimation and temperature adaptation.
Most plants show considerable capacity to adjust their photosynthetic characteristics to their growth temperatures (temperature acclimation). The most typical case is a shift in the optimum temperature for photosynthesis, which can maximize the photosynthetic rate at the growth temperature. These plastic adjustments can allow plants to photosynthesize more efficiently at their new growth temperatures. In this review article, we summarize the basic differences in photosynthetic reactions in C3, C4, and CAM plants. We review the current understanding of the temperature responses of C3, C4, and CAM photosynthesis, and then discuss the underlying physiological and biochemical mechanisms for temperature acclimation of photosynthesis in each photosynthetic type. Finally, we use the published data to evaluate the extent of photosynthetic temperature acclimation in higher plants, and analyze which plant groups (i.e., photosynthetic types and functional types) have a greater inherent ability for photosynthetic acclimation to temperature than others, since there have been reported interspecific variations in this ability. We found that the inherent ability for temperature acclimation of photosynthesis was different: (1) among C3, C4, and CAM species; and (2) among functional types within C3 plants. C3 plants generally had a greater ability for temperature acclimation of photosynthesis across a broad temperature range, CAM plants acclimated day and night photosynthetic process differentially to temperature, and C4 plants was adapted to warm environments. Moreover, within C3 species, evergreen woody plants and perennial herbaceous plants showed greater temperature homeostasis of photosynthesis (i.e., the photosynthetic rate at high-growth temperature divided by that at low-growth temperature was close to 1.0) than deciduous woody plants and annual herbaceous plants, indicating that photosynthetic acclimation would be particularly important in perennial, long-lived species that would experience a rise in growing season temperatures over their lifespan. Interestingly, across growth temperatures, the extent of temperature homeostasis of photosynthesis was maintained irrespective of the extent of the change in the optimum temperature for photosynthesis (T opt), indicating that some plants achieve greater photosynthesis at the growth temperature by shifting T opt, whereas others can also achieve greater photosynthesis at the growth temperature by changing the shape of the photosynthesis-temperature curve without shifting T opt. It is considered that these differences in the inherent stability of temperature acclimation of photosynthesis would be reflected by differences in the limiting steps of photosynthetic rate.