Peripheral blood DNA methylation and neuroanatomical responses to HDACi treatment that rescues neurological deficits in a Kabuki syndrome mouse model.
Recent findings from studies of mouse models of Mendelian disorders of epigenetic machinery strongly support the potential for postnatal therapies to improve neurobehavioral and cognitive deficits. As several of these therapies move into human clinical trials, the search for biomarkers of treatment efficacy is a priority. A potential postnatal treatment of Kabuki syndrome type 1 (KS1), caused by pathogenic variants in KMT2D encoding a histone-lysine methyltransferase, has emerged using a mouse model of KS1 (Kmt2d+/βGeo). In this mouse model, hippocampal memory deficits are ameliorated following treatment with the histone deacetylase inhibitor (HDACi), AR-42. Here, we investigate the effect of both Kmt2d+/βGeo genotype and AR-42 treatment on neuroanatomy and on DNA methylation (DNAm) in peripheral blood. While peripheral blood may not be considered a "primary tissue" with respect to understanding the pathophysiology of neurodevelopmental disorders, it has the potential to serve as an accessible biomarker of disease- and treatment-related changes in the brain. Half of the KS1 and wildtype mice were treated with 14 days of AR-42. Following treatment, fixed brain samples were imaged using MRI to calculate regional volumes. Blood was assayed for genome-wide DNAm at over 285,000 CpG sites using the Illumina Infinium Mouse Methylation array. DNAm patterns and brain volumes were analyzed in the four groups of animals: wildtype untreated, wildtype AR-42 treated, KS1 untreated and KS1 AR-42 treated. We defined a DNAm signature in the blood of KS1 mice, that overlapped with the human KS1 DNAm signature. We also found a striking 10% decrease in total brain volume in untreated KS1 mice compared to untreated wildtype, which correlated with DNAm levels in a subset KS1 signature sites, suggesting that disease severity may be reflected in blood DNAm. Treatment with AR-42 ameliorated DNAm aberrations in KS1 mice at a small number of signature sites. As this treatment impacts both neurological deficits and blood DNAm in mice, future KS clinical trials in humans could be used to assess blood DNAm as an early biomarker of therapeutic efficacy.


Transient congenital hypothyroidism due to thyroid-stimulating hormone receptor blocking antibodies: a case series.
We describe seven infants with transient congenital hypothyroidism (CH) due to maternal thyroid-stimulating hormone receptor (TSH-R) blocking antibodies (TRAb) identified over three decades of newborn screening for CH in Wales, UK that represents a minimum incidence of 1.6% of CH cases. Infants with transient CH due to maternal TRAb presented with a spectrum of clinical and biochemical hypothyroidism. Blood spot TSH concentrations ranged 60.5-332 mIU/L. CH was confirmed by plasma thyroid function tests in all cases (plasma TSH ranged 21-752 mIU/L). The seven infants belonged to five different families. On examination, four infants were clinically hypothyroid. Five infants had a thyroid ultrasound, of which three were abnormal. All infants were treated with thyroxine, which was subsequently withdrawn from three. Following thyroxine withdrawal, one infant resumed normal thyroid function and two developed compensated hypothyroidism. Of the five mothers, two had undiagnosed hypothyroidism and three were receiving thyroxine for longstanding hypothyroidism. Thyroid peroxidase antibody (aTPO) was measured in four and was negative in two, borderline positive in one and strongly positive in another. TRAb was measured in all five women and was strongly positive in all of them. This case series highlights the importance of identifying CH due to TRAb by investigating both the infant and the mother following a raised TSH found on newborn screening. The identification of those infants with transient CH caused by maternal transfer of TRAb is essential for optimizing management during childhood (including potential withdrawal of thyroxine replacement in the longer term) and in any subsequent pregnancy.


LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions.
UL18 is a human CMV (HCMV) MHC class I (MHCI) homolog that efficiently inhibits leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1)+ NK cells. We found an association of LILRB1 polymorphisms in the regulatory regions and ligand-binding domains with control of HCMV in transplant patients. Naturally occurring LILRB1 variants expressed in model NK cells showed functional differences with UL18 and classical MHCI, but not with HLA-G. The altered functional recognition was recapitulated in binding assays with the binding domains of LILRB1. Each of 4 nonsynonymous substitutions in the first 2 LILRB1 immunoglobulin domains contributed to binding with UL18, classical MHCI, and HLA-G. One of the polymorphisms controlled addition of an N-linked glycan, and that mutation of the glycosylation site altered binding to all ligands tested, including enhancing binding to UL18. Together, these findings indicate that specific LILRB1 alleles that allow for superior immune evasion by HCMV are restricted by mutations that limit LILRB1 expression selectively on NK cells. The polymorphisms also maintained an appropriate interaction with HLA-G, fitting with a principal role of LILRB1 in fetal tolerance.


Slit2 signaling stimulates Ewing sarcoma growth.
Ewing sarcoma is a cancer of bone and soft tissue in children driven by EWS::ETS fusion, most commonly EWS::FLI1. Because current cytotoxic chemotherapies are not improving the survival of those with metastatic or recurrent Ewing sarcoma cases, there is a need for novel and more effective targeted therapies. While EWS::FLI1 is the major driver of Ewing sarcoma, EWS::FLI1 has been difficult to target. A promising alternative approach is to identify and target the molecular vulnerabilities created by EWS::FLI1. Here we report that EWS::FLI1 induces the expression of Slit2, the ligand of Roundabout (Robo) receptors implicated in axon guidance and multiple other developmental processes. EWS::FLI1 binds to the Slit2 gene promoter and stimulates the expression of Slit2. Slit2 inactivates cdc42 and stabilizes the BAF chromatin remodeling complexes, enhancing EWS::FLI1 transcriptional output. Silencing of Slit2 strongly inhibited anchorage-dependent and anchorage-independent growth of Ewing sarcoma cells. Silencing of Slit2 receptors, Robo1 and Robo2, inhibited Ewing sarcoma growth as well. These results uncover a new role for Slit2 signaling in stimulating Ewing sarcoma growth and suggest that this pathway can be targeted therapeutically.


Efficacy and Safety of Immuno-Magnetically Sorted Smooth Muscle Progenitor Cells Derived from Human-Induced Pluripotent Stem Cells for Restoring Urethral Sphincter Function.
Human-induced pluripotent stem cells (hiPSCs)-based cell therapy holds promise for treating stress urinary incontinence (SUI). However, safety concerns, especially tumorgenic potential of residual undifferentiated cells in hiPSC derivatives, are major barriers for its clinical translation. An efficient, fast and clinical-scale strategy for purifying committed cells is also required. Our previous studies demonstrated the regenerative effects of hiPSC-derived smooth muscle progenitor cells (pSMCs) on the injured urethral sphincter in SUI, but the differentiation protocol required fluorescence-activated cell sorting (FACS) which is not practical for autologous clinical applications. In this study, we examined the efficacy and safety of hiPSC-derived pSMC populations sorted by FDA-approved magnetic-activated cell sorting (MACS) using cell-surface marker CD34 for restoring urethral sphincter function. Although the heterogeneity of MACS-sorted pSMCs was higher than that of FACS-sorted pSMCs, the percentage of undifferentiated cells dramatically decreased after directed differentiation in vitro. In vivo studies demonstrated long-term cell integration and no tumor formation of MACS-sorted pSMCs after transplantation. Furthermore, transplantation of MACS-sorted pSMCs into immunodeficient SUI rats was comparable to transplantation with FACS-sorted pSMCs for restoration of the extracellular matrix metabolism and function of the urethral sphincter. In summary, purification of hiPSC derivatives using MACS sorting for CD34 expression represent an efficient approach for production of clinical-scale pSMCs for autologous stem cell therapy for regeneration of smooth muscle tissues. Stem Cells Translational Medicine 2017;6:1158-1167.


Use of real-world data to assess the effectiveness of ustekinumab in treating IBD patients: a retrospective linked database study in northwest London.
Data on the optimum positioning of biologics in the treatment of inflammatory bowel disease (IBD) are limited. This was a longitudinal retrospective study of linked health-care data from northwest London, UK, for adults who started ustekinumab for IBD from 1 April 20161 April 2016 to 1 April 20211 April 2021. We compared outcomes by line of therapy (1 vs. 2 or 3+) and age group (18‒59 years or ≥ 60 years). In an analysis of CD patients, we calculated risks of IBD-related hospitalization, IBD-related abdominal surgery, ustekinumab persistence, and switching by line of therapy. Of 163 patients screened, 149 were eligible. Age had no effect on outcomes. Elective all-cause hospital admissions were significantly higher when ustekinumab was used as second-line or third-line therapy compared with first-line treatment (p = 0.0048 and p = 0.001, respectively). In CD patients the numbers of hospital admissions were also higher with second-line or third-line therapy (p = 0.040 and p = 0.018, respectively). Use of ustekinumab as third-line therapy significantly increased the risk of IBD-related hospitalization (hazard ratio 2.5, 95% CI 1.1‒5.6, p = 0.029), IBD-related abdominal surgery (9.45, 1.2‒75.7, p = 0.03), and switching (14.6, 1.6‒131.0, p = 0.02). Drug persistence risks did not differ. These findings support the use of ustekinumab as first-line therapy.


Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras.
The ras proto-oncogene is frequently mutated in human tumors and functions to chronically stimulate signal transduction cascades resulting in the synthesis or activation of specific transcription factors, including Ets, c-Myc, c-Jun, and nuclear factor kappa B (NF-kappaB). These Ras-responsive transcription factors are required for transformation, but the mechanisms by which these proteins facilitate oncogenesis have not been fully established. Oncogenic Ras was shown to initiate a p53-independent apoptotic response that was suppressed through the activation of NF-kappaB. These results provide an explanation for the requirement of NF-kappaB for Ras-mediated oncogenesis and provide evidence that Ras-transformed cells are susceptible to apoptosis even if they do not express the p53 tumor-suppressor gene product.


Synthesis, crystal structures, and optical/electronic properties of sphere-rod shape amphiphiles based on a [60]fullerene-oligofluorene conjugate.
A series of sphere-rod shape amphiphiles, in which a [60]fullerene (C60) sphere was connected to the center of an oligofluorene (OF) rod through a rigid linkage (OF-C60), were designed and synthesized. Alkyl chains of various lengths were attached onto the OFs on both sides of the C60 spheres. These compounds, denoted as alkyl-OF-C60, were fully characterized by (1)H NMR, (13)C NMR, and FTIR spectroscopy and by MALDI-TOF mass spectrometry. The morphologies and structures of their crystals were elucidated by wide-angle X-ray diffraction (WAXD) and by electron diffraction in transmission electron microscopy (TEM). Butyl-OF-C60 forms a monoclinic unit cell (a=1.86, b=3.96, c=2.24 nm; α=γ=90°, β=68°; space group P2), octyl-OF-C60 also forms a monoclinic unit cell (a=2.21, b=4.06, c=1.81 nm; α=γ=90°, β=75.5°; space group C2m), and dodecanyl-OF-C60 forms a triclinic structure (a=1.82, b=4.35, c=2.26 nm; α=93.1°, β=94.5°, γ=92.7°; space group P1). The inequivalent spheres and rods were found to pack into an alternating layered structure of C60 and OF in the crystals, thus resembling a "double-cable" structure. UV/Vis absorption spectroscopy revealed an electron perturbation between the two individual chromophores (C60 and OF) in their ground states. Fluorescence spectroscopy exhibited complete fluorescence quenching of their solutions in toluene, thus suggesting an effective energy transfer from OF to C60. Cyclic voltammetry indicated that the energy-level profiles of C60 and OF remained essentially unchanged. This work has broad implications in terms of understanding the self-assembly and molecular packing of conjugated materials in crystals and has potential applications in organic field-effect transistors and bulk heterojunction solar cells.


Usability and Acceptance of Wearable Biosensors in Forensic Psychiatry: Cross-sectional Questionnaire Study.
The use of wearable biosensor devices for monitoring and coaching in forensic psychiatric settings yields high expectations for improved self-regulation of emotions and behavior in clients and staff members. More so, if clients have mild intellectual disabilities (IQ 50-85), they might benefit from these biosensors as they are easy to use in everyday life, which ensures that clients can practice with the devices in multiple stress and arousal-inducing situations. However, research on (continuous) use and acceptance of biosensors in forensic psychiatry for clients with mild intellectual disabilities and their caretakers is scarce. Although wearable biosensors show promise for health care, recent research showed that the acceptance and continuous use of wearable devices in consumers is not as was anticipated, probably due to low expectations. The main goal of this study was to investigate the associations between and determinants of the expectation of usability, the actual experienced usability, and the intention for continuous use of biosensors. A total of 77 participants (31 forensic clients with mild intellectual disabilities and 46 forensic staff members) participated in a 1-week trial. Preceding the study, we selected 4 devices thought to benefit the participants in domains of self-regulation, physical health, or sleep. Qualitative and quantitative questionnaires were used that explored the determinants of usability, acceptance, and continuous use of biosensors. Questionnaires consisted of the System Usability Scale, the Technology Acceptance Model questionnaire, and the extended expectation confirmation model questionnaire. Only the experienced usability of the devices was associated with intended continuous use. Forensic clients scored higher on acceptance and intention for continuous use than staff members. Moderate associations were found between usability with acceptance and continuous use. Staff members showed stronger associations between usability and acceptance (r=.80, P<.001) and usability and continuous use (r=.79, P<.001) than clients, who showed more moderate correlations between usability and acceptance (r=.46, P=.01) and usability and continuous use (r=.52, P=.003). The qualitative questionnaires in general indicated that the devices were easy to use and gave clear information. Contrary to expectations, it was the actual perceived usability of wearing a biosensor that was associated with continuous use and to a much lesser extent the expectancy of usability. Clients scored higher on acceptance and intention for continuous use, but associations between usability and both acceptance and continuous use were markedly stronger in staff members. This study provides clear directions on how to further investigate these associations. For example, whether this is a true effect or due to a social desirability bias in the client group must be investigated. Clients with mild intellectual disabilities might benefit from the ease of use of these devices and their continuing monitoring and coaching apps. For these clients, it is especially important to develop easy-to-use biosensors with a minimum requirement on cognitive capacity to increase usability, acceptance, and continuous use.


Initial cloning and sequencing of hydHG, an operon homologous to ntrBC and regulating the labile hydrogenase activity in Escherichia coli K-12.
To isolate genes from Escherichia coli which regulate the labile hydrogenase activity, a plasmid library was used to transform hydL mutants lacking the labile hydrogenase. A single type of gene, designated hydG, was isolated. This gene also partially restored the hydrogenase activity in hydF mutants (which are defective in all hydrogenase isoenzymes), although the low hydrogenase 1 and 2 levels were not induced. Therefore, hydG apparently regulates, specifically, the labile hydrogenase activity. Restoration of this latter activity in hydF mutants was accompanied by a proportional increase of the H2 uptake activity, suggesting a functional relationship. H2:fumarate oxidoreductase activity was not restored in complemented hydL mutants. These latter strains may therefore lack, in addition to the labile hydrogenase, a second component (provisionally designated component R), possibly an electron carrier coupling H2 oxidation to the anerobic respiratory chain. Sequence analysis showed an open reading frame of 1,314 base pairs for hydG. It was preceded by a ribosome-binding site but apparently lacked a promoter. Minicell experiments revealed a single polypeptide of approximately 50 kilodaltons. Comparison of the predicted amino acid sequence with a protein sequence data base revealed strong homology to NtrC from Klebsiella pneumoniae, a DNA-binding transcriptional activator. The 411 base pairs upstream from pHG40 contained a second open reading frame overlapping hydG by four bases. The deduced amino acid sequence showed considerable homology with the C-terminal part of NtrB. This sequence was therefore assumed to be part of a second gene, encoding the NtrB-like component, and was designated hydH. The labile hydrogenase activity in E. coli is apparently regulated by a multicomponent system analogous to the NtrB-NtrC system. This conclusion is in agreement with the results of Birkmann et al. (A. Birkmann, R. G. Sawers, and A. Böck, Mol. Gen. Genet. 210:535-542, 1987), who demonstrated ntrA dependence for the labile hydrogenase activity.


Mapping the Binding Site of an Aptamer on ATP Using MicroScale Thermophoresis.
Characterization of molecular interactions in terms of basic binding parameters such as binding affinity, stoichiometry, and thermodynamics is an essential step in basic and applied science. MicroScale Thermophoresis (MST) is a sensitive biophysical method to obtain this important information. Relying on a physical effect called thermophoresis, which describes the movement of molecules through temperature gradients, this technology allows for the fast and precise determination of binding parameters in solution and allows the free choice of buffer conditions (from buffer to lysates/sera). MST uses the fact that an unbound molecule displays a different thermophoretic movement than a molecule that is in complex with a binding partner. The thermophoretic movement is altered in the moment of molecular interaction due to changes in size, charge, and hydration shell. By comparing the movement profiles of different molecular ratios of the two binding partners, quantitative information such as binding affinity (pM to mM) can be determined. Even challenging interactions between molecules of small sizes, such as aptamers and small compounds, can be studied by MST. Using the well-studied model interaction between the DH25.42 DNA aptamer and ATP, this manuscript provides a protocol to characterize aptamer-small molecule interactions. This study demonstrates that MST is highly sensitive and permits the mapping of the binding site of the 7.9 kDa DNA aptamer to the adenine of ATP.


[Intraoperative ultrasound study in surgery].
Report on intraoperative sonography in 257 patients (89 with pancreatic and 67 with liver disease, 24 with vascular surgery and 24 with bile duct disease). Intraoperative sonography was helpful for the detection of tumors not evident by inspection and palpation. In vascular surgery it proved to be an excellent means for quality control. The main problems encountered concerned the evaluation of the bile ducts and of haemodynamically insignificant vessel wall lesions.


Maternal administration of dexamethasone stimulates choline-phosphate cytidylyltransferase in fetal type II cells.
Administration of dexamethasone to pregnant rats at 19 days gestation increased phosphatidylcholine synthesis (45%) from radioactive choline in type II cells. This enhanced synthesis of phosphatidylcholine was accompanied by an increased conversion of choline phosphate into CDP-choline. Similar results were obtained by incubating organotypic cultures of 19-day-fetal rat lung with cortisol. The increased conversion of choline phosphate into CDP-choline correlated with an enhanced choline-phosphate cytidylyltransferase activity (31% after dexamethasone treatment; 47% after cortisol exposure) in the cell homogenates. A similar increase (26% after dexamethasone treatment; 39% after cortisol exposure) was found in the microsomal-associated enzyme. No differences in cytosolic enzyme activity were observed. The specific activity of the microsomal enzyme was 3-4 times that of the cytosolic enzyme. Most of the enzyme activity was located in the microsomal fraction (58-65%). The treatments had no effect on the total amount of enzyme recovered from the cell homogenates. These results, taken collectively, are interpreted to indicate that the active form of cytidylyltransferase in type II cells is the membrane-bound enzyme and that cytidylyltransferase activation in type II cells from fetal rat lung after maternal glucocorticoid administration occurs by binding of inactive cytosolic enzyme to endoplasmic reticulum.


Serum Eosinophilic Cationic Protein (ECP) in Asthmatic Malaysian Children.
Eosinophilic inflammation in the airways is important in the pathogenesis of childhood asthma. Serum eosinophilic cationic protein (ECP), a marker of eosinophil activation was measured in 20 asthmatic children and 19 non-asthmatic controls. There was no difference in the socio-demography, passive smoke exposure, urinary cotinine levels and family history of asthma between the 2 groups. The median serum ECP in asthmatic children was 27.0 mcg/L (IQ1 8.8, IQ3 59.0); which was higher than in non-asthmatic controls [5.9 mcg/L (IQ1 3.0, IQ3 11.9), p=0.002]. An elevated serum ECP level can be helpful as supportive evidence in the diagnosis of bronchial asthma in Malaysia children.


The need for epididymovasostomy at vasectomy reversal plateaus in older vasectomies: a study of 1229 cases.
Vasectomy reversal involves either vasovasostomy (VV) or epididymovasostomy (EV), and rates of epididymal obstruction and EV increase with time after vasectomy. However, as older vasectomies may not require EV for successful reversal, we hypothesized that sperm production falls after vasectomy and can protect the system from epididymal blowout. Our objective was to define how the need for EV at reversal changes with time after vasectomy through a retrospective review of consecutive reversals performed by three surgeons over a 10-year period. Vasovasotomy was performed with Silber score 1-3 vasal fluid. EVs were performed with Silber score 4 (sperm fragments; creamy fluid) or 5 (sperm absence) fluid. Reversal procedure type was correlated with vasectomy and patient age. Post-operative patency rates, total spermatozoa and motile sperm counts in younger (<15 years) and older (>15 years) vasectomies were assessed. Simple descriptive statistics determined outcome relevance. Among 1229 patients, 406 had either unilateral (n = 252) or bilateral EV's (n = 154) constituting 33% (406/1229) of reversals. Mean patient age was 41.4±7 years (range 22-72). Median vasectomy interval was 10 years (range 1-38). Overall sperm patency rate after reversal was 84%. The rate of unilateral (EV/VV) or bilateral EV increased linearly in vasectomy intervals of 1-22 years at 3% per year, but plateaued at 72% in vasectomy intervals of 24-38 years. Sperm counts were maintained with increasing time after vasectomy, but motile sperm counts decreased significantly (p < 0.001). Pregnancy, secondary azoospermia, varicocoele and sperm granuloma were not assessed. In conclusion, and contrary to conventional thinking, the need for EV at reversal increases with time after vasectomy, but this relationship is not linear. EV rates plateau 22 years after vasectomy, suggesting that protective mechanisms ameliorate epididymal 'blowout'. Upon reversal, sperm output is maintained with time after vasectomy, but motile sperm counts decrease linearly, suggesting epididymal dysfunction influences semen quality after reversal.


Software-based fusion of PET and CT images for suspected recurrent lung cancer.
The purpose of this study was to compare the diagnostic performance of the manual fusion of positron emission tomography (PET) and computed tomography (CT) images with that of CT alone and that of side-by-side PET and CT (PET/CT) in patients with suspected recurrent lung cancer. Fifty-three patients who had previously had surgery for lung cancer underwent a whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET scan, followed by a diagnostic CT scan. The PET and CT images were fused on a workstation. CT alone, PET/CT, and fused images were evaluated separately using a five-point grading scale (0=definitely negative, 1=probably negative, 2=equivocal, 3=probably positive, and 4=definitely positive). Lesions of grade 3 or 4 were considered positive, and diagnostic accuracy and certainty were evaluated. Overall, 67 lesions in 33 patients were considered true positive pathologically or clinically. Of these 67 lesions, the evaluation of CT, PET/CT, and fused images detected 46, 55, and 66 lesions, respectively, with the number of grade 4 lesions detected being 38, 50, and 63, respectively. The diagnostic accuracy of CT, PET/CT, and fused images according to patients was 75%, 79%, and 87%, respectively. These results suggest that interpreting fused images increased diagnostic certainty for detecting recurrence and provided more accurate diagnoses.


Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis.
The antitumor effect and mechanisms activated by murine IL-12 and IL-18, cytokines that induce IFN-gamma production, were studied using engineered SCK murine mammary carcinoma cells. In syngeneic A/J mice, SCK cells expressing mIL-12 or mIL-18 were less tumorigenic and formed tumors more slowly than control cells. Neither SCK.12 nor SCK.18 cells protected significantly against tumorigenesis by distant SCK cells. However, inoculation of the two cell types together synergistically protected 70% of mice from concurrently injected distant SCK cells and 30% of mice from SCK cells established 3 d earlier. Antibody neutralization studies revealed that the antitumor effects of secreted mIL-12 and mIL-18 required IFN-gamma. Interestingly, half the survivors of SCK.12 and/or SCK.18 cells developed protective immunity suggesting that anti-SCK immunity is unlikely to be responsible for protection. Instead, angiogenesis inhibition, assayed by Matrigel implants, appeared to be a property of both SCK.12 and SCK.18 cells and the two cell types together produced significantly greater systemic inhibition of angiogenesis. This suggests that inhibition of tumor angiogenesis is an important part of the systemic antitumor effect produced by mIL-12 and mIL-18.


Executive function as a mechanism linking socioeconomic status to internalizing and externalizing psychopathology in children and adolescents.
The association between low socioeconomic status (SES) in childhood and increased risk for psychopathology is well established, but the mechanisms explaining this relationship are poorly understood. Here, we investigate the potential role of difficulties in executive functioning (EF) as a mechanism linking childhood and adolescent SES with externalizing and internalizing psychopathology. We examined whether difficulties with EF mediated the association between SES and externalizing and internalizing psychopathology in two cross-sectional samples of children and adolescents (Study 1: N = 94, ages 6-18, 51.1% male; Study 2: N = 259, ages 8-16, 54.1% male) from diverse SES backgrounds in the United States. EF was measured through behavioral tasks and parent-reported behavioral regulation (BR). In both samples, children and adolescents from lower SES families were more likely to experience both externalizing and internalizing psychopathology than youth from more advantaged backgrounds and exhibited greater EF difficulties - they had lower performance on a task measuring inhibitory control and lower parent-rated BR. Reduced inhibitory control and BR, in turn, were associated with higher externalizing and internalizing psychopathology. In Study 1, difficulties with BR mediated the association of low-SES with both externalizing and internalizing psychopathology. In Study 2, low inhibitory control mediated the association between low-SES and externalizing psychopathology. These findings largely persisted after adjusting for exposure to violence, a form of adversity that is common in children from low-SES backgrounds. These findings suggest that reduced EF may be an underlying mechanism through which low-SES confers risk for psychopathology in children and adolescents.


Parathyroid hormone and prostaglandin E2 stimulate both inositol phosphates and cyclic AMP accumulation in mouse osteoblast cultures.
Parathyroid hormone (PTH) and prostaglandin E2 (PGE2) are physiological agonists which stimulate bone cells to resorb bone, a process by which the mineralized extracellular bone matrix is dissolved. Bone resorption has a key role in the maintenance of plasma calcium levels. It has been established that both PTH and PGE2 activate adenylate cyclase in osteoblasts, but it is apparent that (1) the two agents have qualitatively different effects on osteoblasts, and (2) the generation of cyclic AMP cannot account for all the effects of PTH on bone cell metabolism. Others have demonstrated that PTH and PGE2 may also elevate intracellular calcium levels, but the mechanism by which this is achieved has not been fully defined. Here we have investigated the effects of PTH on neonatal mouse osteoblasts in culture and shown that physiological concentrations of the hormone (50 nM) caused a small increase (22%) in total inositol phosphates accumulation, with a larger increase (40%) in inositol trisphosphate. We found that this activation occurred at lower concentration than was necessary to activate adenylate cyclase. PGE2 was a more effective activator of inositol phosphates accumulation than PTH, causing up to 300% increase in the total inositol phosphates after 30 min. Both PTH and PGE2 stimulated cyclic AMP accumulation, but the activation of adenylate cyclase by forskolin did not enhance inositol phosphates production. We conclude that both PTH and PGE2 stimulate phosphoinositide turnover in mouse osteoblasts and suggest that this mechanism may contribute to their elevation of intracellular calcium in bone cells.


Detection of 17 β-Estradiol in Environmental Samples and for Health Care Using a Single-Use, Cost-Effective Biosensor Based on Differential Pulse Voltammetry (DPV).
Environmental estrogen pollution and estrogen effects on the female reproductive system are well recognized scientifically. Among the estrogens, 17 β-estradiol is a priority in environmental estrogen pollution, and it is also a major contributor to estrogen which regulates the female reproductive system. 17 β-estradiol is carcinogenic and has a tumor promotion effect relating to breast cancer, lung cancer and others. It also affects psychological well-being such as depression, fatigue and others. Thus, a simple method of detecting 17 β-estradiol will be important for both environmental estrogen pollution and health care. This study demonstrates a single-use, cost-effective 17 β-estradiol biosensor system which can be used for both environmental and health care applications. The bio-recognition mechanism is based on the influence of the redox couple, K₃Fe(CN)₆/K₄Fe(CN)₆ by the interaction between 17 β-estradiol antigen and its α-receptor (ER-α; α-estrogen antibody). The transduction mechanism is an electrochemical analytical technique, differential pulse voltammetry (DPV). The levels of 17 β-estradiol antigen studied were between 2.25 pg/mL and 2250 pg/mL; Phosphate buffered saline (PBS), tap water from the Cleveland regional water district, and simulated urine were used as the test media covering the potential application areas for 17 β-estradiol detection. An interference study by testosterone, which has a similar chemical structure and molecular weight as those of 17 β-estradiol, was carried out, and this 17 β-estradiol biosensor showed excellent specificity without any interference by similar chemicals.


[Gastric motility based on gastric impedance measurement data after truncal and combined vagotomies in duodenal ulcer].
The motor function of the stomach was investigated by the gastroimpedansometric method in 73 patients: 32 of them with ulcer of the duodenum before operation, 17--after truncal vagotomy and 13 after combined (anterior selective proximal and posterior truncal) vagotomy with Finney's pyloroplasty within the period from 4 to 10 years. Motor activity in the cardial and antral parts and the stomach body was evaluated using the computer medical complex "Gastrolog" by the indicator of local motility and contraction rate. The indicator of local motility was reliably higher in patients with ulcer of the duodenum than in healthy subjects. At later terms after truncal vagotomy a normokinetic type of motor activity was noted in all parts of the stomach, the level of motility of the antral part being reliably higher after combined vagotomy with saved anterior Latarget's nerve (p < 0.01).


Strain coupling of a nitrogen-vacancy center spin to a diamond mechanical oscillator.
We report on single electronic spins coupled to the motion of mechanical resonators by a novel mechanism based on crystal strain. Our device consists of single-crystal diamond cantilevers with embedded nitrogen-vacancy center spins. Using optically detected electron spin resonance, we determine the unknown spin-strain coupling constants and demonstrate that our system resides well within the resolved sideband regime. We realize coupling strengths exceeding 10 MHz under mechanical driving and show that our system has the potential to reach strong coupling. Our novel hybrid system forms a resource for future experiments on spin-based cantilever cooling and coherent spin-oscillator coupling.


Presentation and management of acute coronary syndromes among adult persons with haemophilia: results of an international, retrospective, 10-year survey.
Sparse data are available on presentation and management of acute coronary syndromes (ACS), including unstable angina and non-ST- and ST-elevation myocardial infarction, among persons with haemophilia (PWH). The aim of this study was to determine demographics, bleeding disorder characteristics, cardiovascular risk factors (CRFs), interventions, haemostatic protocol, revascularization outcomes and complications among PWH with ACS. Members of an international consortium comprising >2000 adult PWH retrospectively completed case report forms for episodes of ACS in a >10-year follow-up period (2003-2013). Twenty ACS episodes occurred among 19 patients [rate, 0.8% (95% CI 0.4, 1.2)]. Seven patients (37%) were aged <50 years; 10 (53%) had ≥3 CRFs. In 5/20 episodes (25%), the initial ACS management protocol was altered because of the bleeding disorder. None of the eight patients with severe haemophilia underwent coronary artery bypass grafting (CABG), compared with 54.5% of patients with non-severe disease (P = 0.02). Revascularization with percutaneous coronary intervention (PCI) or CABG was rated successful in 13/13 cases, with no excessive bleeding during initial management. During chronic exposure to antiplatelet agents, secondary haemophilia prophylaxis was more prevalent in patients with severe haemophilia compared with non-severe haemophilia (85.7% vs. 30%, P = 0.05). No ACS-related deaths occurred during initial management, but one patient with severe haemophilia A died of undetermined cause 36 months after the ACS event while on aspirin therapy. ACS occurs even among relatively younger PWH, typically in association with multiple CRFs. Revascularization with PCI/CABG is feasible, and antiplatelet agents plus secondary prophylaxis appears to be well tolerated in selected PWH with ACS.


Normal and surface-enhanced Raman spectroscopy of nitroazobenzene submonolayers and multilayers on carbon and silver surfaces.
Raman and ultraviolet-visible (UV-Vis) absorption spectra were obtained for nitroazobenzene (NAB) chemisorbed on smooth and rough silver, and they were compared to published spectra for NAB on sp(2) hybridized pyrolyzed photoresist film (PPF) surfaces. High signal-to-noise ratio Raman spectra were obtained for 4.5 nm thick NAB films on PPF and smooth Ag due to significant enhancement of the NAB scattering relative to that observed in solution. The UV-Vis spectra of chemisorbed NAB exhibited a significant shift toward longer wavelength, thus bringing the NAB absorption closer to the 514.5 nm laser wavelength. The red shift was larger for PPF than for smooth Ag, consistent with the approximately 5x stronger Raman signal obtained on PPF. Deposition of Ag onto quartz without a chromium adhesion layer produced a rough Ag surface that enhanced the Raman spectrum of chemisorbed NAB by a factor of approximately 1000, as expected for roughened Ag due to electromagnetic field enhancement. The strong Raman signal permitted observation of NAB at low coverage and revealed changes in the NAB spectrum as the film progressed from submonolayer to multilayer thicknesses. Finally, deposition of Ag onto PPF/NAB samples through a metal grid produced Ag squares on top of the NAB, which enhanced the Raman scattering of the NAB layer by a factor of approximately 100. Deposition of a final conducting film on the Ag squares should permit in situ observation of a wide range of molecules in operating molecular electronic junctions.


Multifocal electroretinograms in cases of central areolar choroidal dystrophy.
To study multifocal electroretinograms (mfERG) in patients with early-stage central alveolar choroidal dystrophy (CACD) with well-demarcated atrophic areas. Eight eyes of eight patients with CACD (ages, 47-67 years) and 20 normal control subjects were examined. The first- and second-order kernels (K1 and K2) were extracted from the responses elicited by 61 standard hexagonal elements of a visual response imaging system. The amplitudes and peak times of the focal responses at various retinal eccentricities were studied. The amplitudes of K1 were reduced in the visibly atrophic areas, and they were also decreased in areas with no visible atrophy. The peak time was slightly delayed in many loci, but the delay was not as long as that in congenital stationary night blindness or diabetic retinopathy. The amplitude of K2 was very small in the central and peripheral areas, but the K2/K1 ratio in both areas was not significantly reduced, compared with that in normal subjects. Although the atrophic area was ophthalmoscopically well demarcated in patients with CACD, the abnormality of retinal function extended beyond the borders of the ophthalmoscopic and angiographic lesions. The retinal dysfunction outside the atrophic areas suggests a centrifugal progression of the disease, and abnormal K2 and K1 with preserved K2/K1 ratio are consistent with a presynaptic mechanism for the retinal dysfunction in this disease.


Induction of prostaglandin E2 synthesis and microsomal prostaglandin E synthase-1 expression in murine microglia by glioma-derived soluble factors. Laboratory investigation.
Microglia are one of the members of monocyte/macrophage lineage in the central nervous system (CNS) and exist as ramified microglia in a normal resting state, but they are activated by various stimuli, such as tumors. Activated microglia induce immune responses in the CNS, but the precise functions of microglia in glioma microenvironments are not clear. It has been reported that glioma cells produce prostaglandin (PG)E2, which promotes the growth of tumor cells and possesses immunosuppressive activity. The authors previously reported that PGE2 production by peritoneal macrophages was enhanced by glioma-derived soluble factors, which induce an immunosuppressive state. In this study, they investigated PGE2 production by microglia treated with glioma cells and assessed the role of microglia in glioma microenvironments in the mouse. Microglia and peritoneal macrophages were cultured in vitro with or without lipopolysaccharide, and tumor necrosis factor (TNF) and PGE2 in the culture supernatant were measured using L929 bioassay and enzyme immunoassay. The expression of mRNA was measured using reverse transcriptase polymerase chain reaction, and the protein expression was assayed with Western blotting. In some experiments glioma cells and conditioned glioma medium were added to the microglia cultures. Glioma cells studied in this report did not produce a significant amount of PGE2. However, the coculture of microglia with glioma cells or conditioned glioma medium led to the production of a large amount of PGE2. The enhancement of PGE2 production by microglia was more significant than that by peritoneal macrophages. The expression of cyclooxygenase (COX)-2 and particularly the expression of microsomal PGE synthase (mPGES)-1 (a terminal enzyme of the arachidonate cascade) in microglia were enhanced by conditioned glioma medium. The enhancement of mPGES-1 expression in microglia was more significant than that in peritoneal macrophages. The production of TNF was suppressed when culturing microglia with conditioned glioma medium, but this suppression was abrogated by the addition of a COX inhibitor (NS-398) and a PGE2 receptor (EP4) antagonist. Furthermore, TNF production was not suppressed in microglia from mPGES-1-deficient mice. These results indicate that PGE2 production by microglia is enhanced by conditioned glioma medium, which induces an immunosuppressive state in the CNS. Therefore, the manipulation of microglia, from the standpoint of PGE2, provides investigators with an important strategy to induce an effective antiglioma immune response.


Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew).
Marijuana has been reported to interfere with nausea and vomiting in chemotherapy patients. The principal cannabinoids found in marijuana include the psychoactive compound Delta-9-tetrahydrocannabinol (THC) and the non-psychoactive compound cannabidiol (CBD). The experiments reported here evaluated the potential of THC and CBD to interfere with vomiting in the Suncus murinus (house musk shrew) produced by lithium chloride (LiCl), which is the most commonly employed unconditioned stimulus for taste avoidance. To evaluate the potential of the principal components of marijuana, THC and CBD, to suppress Li-induced vomiting in the house musk shrew. Shrews were injected with vehicle or one of two cannabinoids [Delta-9-THC (1-20 mg/kg), or CBD (2.5-40 mg/kg)] 10 min prior to an injection of LiCl (390 mg/kg of 0.15 M) and were then observed for 45 min. The frequency of vomiting episodes and the latency to the first episode were measured. The role of the CB1 receptor in these effects was also evaluated by pretreatment with SR-141716. Delta-9-THC produced a dose-dependent suppression of Li-induced vomiting, with higher doses producing greater suppression than lower doses. CBD produced a biphasic effect with lower doses producing suppression and higher doses producing enhancement of Li-induced vomiting. The suppression of Li-induced vomiting by THC, but not by CBD, was reversed by SR-141716. These results indicate that two major cannabinoid compounds found in marijuana, THC and CBD, are effective treatments for Li-induced vomiting; however, only THC acts by the CB1 receptor. The effects of THC and CBD on vomiting were dose dependent; with THC the effect was linear, but with CBD the effect was biphasic.


[Effectiveness of combined treatment of lumbar spondylolisthesis with MED, Quadrant, and Sextant-R systems].
To analyze the effectiveness of combined treatment of lumbar spondylolisthesis with MED, Quadrant, and Sextant-R systems. Between August 2006 and June 2011, 35 patients with lumbar spondylolisthesis were treated, including 11 cases of isthmic spondylolisthesis and 24 cases of degenerative spondylolisthesis. There were 25 males and 10 females, with a mean age of 55 years (range, 33-71 years). The mean disease duration was 37 months (range, 8-75 months). Spondylolisthesis occurred at L4,5 level in 21 patients and at Ls, S1 level in 14 patients. According to Meyerding classification, 35 cases were rated as dergee I. The minimally invasive surgeries were performed by paraspinal muscle approach; Quadrant system was used for decompression and fusion at severe side, MED system for windowing of lamina at mild side, and Sextant-R system for fixation and reduction. Visual analogue scale (VAS) score was used to evaluate pain, Oswestry disability index (ODI) to evaluate clinical outcomes, spondylolishesis ratio and intervertebral height to evaluate spondylolisthesis reduction. RESYKTS: Lumbar continuous thin layer CT at postoperation showed that no pedicle screw invaded spinal canal and intervertebral fusion device was at good position. Incisions healed by first intention. All patients were followed up 18-38 months (mean, 26 months). All patients got bone fusion and had no internal fixation failure by radiologic examination at 1 year after operation. Low back pain was relieved, lumbar function improved obviously, and satisfactory reduction of spondylolisthesis was obtained. At 2 weeks and 1 year after operation, the VAS score, ODI score, spondylolisthesis ratio, and intervertebral height were significantly improved when compared with preoperative ones (P < 0.05). VAS score and ODI score showed significant differences (P < 0.05) between at 2 weeks and 1 year after operation. Spondylolisthesis ratio and intervertebral height showed no significant difference (P > 0.05) between at 2 weeks and at 1 year after operation. Minimally invasive surgical management for lumbar spondylolisthesis via MED, Quadrant, and Sextant-R systems is a safe and effective surgical technique. However, its indications should be well considered.


Evaluation of Microdissection Testicular Sperm Extraction Results in Patients with Non-Obstructive Azoospermia: Independent Predictive Factors and Best Cutoff Values for Sperm Retrieval.
Testicular sperm extraction (TESE) for intracytoplasmic sperm injection (ICSI) was first introduced for the treatment of non-obstructive azoospermia. This study was conducted to detect predictive factors affecting the success of microTESE. We retrospectively evaluated the results of 191 cases who underwent microTESE. For each patient, the testicular volume, endocrine profile [follicle stimulating hormone (FSH), luteinizing hormone (LH), free testosterone (FT), total testosterone (TT)], serum inhibin B level, karyotype analysis, and Y chromosome microdeletions were recorded, and all data were analyzed to detect any predictors. The receiver operating characteristic curve, two-sample t-test and regression analysis were used for the statistical analysis. The mean age of the patients was 34.4 ± 5.6 years. Sperm retrieval was successful in 104 (54.5%) patients, and there was no sperm in 87 (45.5%). Seven factors including, testicular size, Johnson score, Y chromosome microdeletion, and serum FSH, LH, FT and TT levels were different between the successful and unsuccessful groups. Six patients had Klinefelter syndrome, and ten patients (5.2%) had a Y chromosome microdeletion (5 AZF-c, 1 AZF-b, 2 AZF-bc, 1 AZF-abc, and 1 AZF-ac). The Johnson score, TT level, family history and Y chromosome microdeletions were determined to be independent predictive factors for sperm found. According to the testicular histology, the sperm-found ratios were 36%, 48.6%, and 95.5% in the sertoli cell only syndrome, maturation arrest, and hypospermatogenesis groups, respectively. According to our results, the Johnson score, TT level, family history-related infertility, and Y chromosome microdeletions were determined to be independent predictive factors for sperm found.


Defining and Clarifying the Terms Canine Possessive Aggression and Resource Guarding: A Study of Expert Opinion.
The terms possessive aggression and resource guarding are often used interchangeably to describe behavior patterns used by a dog to control primary access to a perceived valuable item. The use of inconsistent terminology may impact the effectiveness of communication between dog owners and clinicians, affect treatment and management success for the behavior, and inhibit research progress. The aim of this study was to explore the opinions of canine behavior experts on the meaning of and preference for the terms possessive aggression and resource guarding, as well as to develop and propose an operational ethological definition for the preferential term identified. Eighty-five individuals met the inclusion criteria and were invited to participate in a two-stage online survey. Results from the two-stage survey found that the majority of participants preferred the term resource guarding. Detailed exploration of meaning and definitions required in-depth discussion beyond traditional survey methods, therefore, respondents from the second stage of the survey were invited to participate in an online discussion board. Following content analysis of the data from the discussion board, we conclude that the majority of participants preferred the term resource guarding. Considering 100% consensus was not reached regarding terminology among experts in the field, future authors and clinicians should provide clear definitions where terms are applied to ensure effective communication between all parties and to ensure consistency in canine behavior research. Based on expert contributions, we define resource guarding as "the use of avoidance, threatening, or aggressive behaviors by a dog to retain control of food or non-food items in the presence of a person or other animal."


Causes and outcomes of emergency presentation of rectal cancer.
Emergency presentation of rectal cancer carries a relatively poor prognosis, but the roles and interactions of causative factors remain unclear. We describe an innovative statistical approach which distinguishes between direct and indirect effects of a number of contextual, patient and tumour factors on emergency presentation and outcome of rectal cancer. All patients diagnosed with rectal cancer in Ireland 2004-2008 were included. Registry information, linked to hospital discharge data, provided data on patient demographics, comorbidity and health insurance; population density and deprivation of area of residence; tumour type, site, grade and stage; treatment type and optimality; and emergency presentation and hospital caseload. Data were modelled using a structural equation model with a discrete-time survival outcome, allowing us to estimate direct and mediated effects of the above factors on hazard, and their inter-relationships. Two thousand seven hundred and fifty patients were included in the analysis. Around 12% had emergency presentations, which increased hazard by 80%. Affluence, private patient status and being married reduced hazard indirectly by reducing emergency presentation. Older patients had more emergency presentations, while married patients, private patients or those living in less deprived areas had fewer than expected. Patients presenting as an emergency were less likely to receive optimal treatment or to have this in a high caseload hospital. Apart from stage, emergency admission was the strongest determinant of poor survival. The factors contributing to emergency admission in this study are similar to those associated with diagnostic delay. The socio-economic gradient found suggests that patient education and earlier access to endoscopic investigation for public patients could reduce emergency presentation.


[Role of p38MAPK signaling pathway in rats with phantom limb pain].
To investigate the role of p38MAPK signal pathway in spinal cord and dorsal root ganglion (DRG) in rats with phantom limb pain and the effects of specific inhibitors. Methods: Healthy adult male SD rats (n=48) were cut off one side of the sciatic under anesthesia to establish a model of phantom limb pain. In addition, the healthy rats were taken as a sham group (group S, n=24). The animals were scored by observing the action of chewing (0=no chewing, 13=the worst chewing) after the operation and were sacrificed on the following day after the operation. The successful model of phantom limb pain were randomly divided into 2 groups: a phantom limb pain group (group P, n=24) and a phantom limb pain plus inhibitor group (group P+I, n=24). SB203580 was given to the rat at 0.8 mg/kg on every Monday until the rats were sacrificed, the rest of the rats received an equal amount of saline. Eight rats from each group were randomly taken for the determination of levels of P-p38MAPK in spinal cord and DRG before administration and on the 4th, 6th, 8th weekend following the administration, respectively. Results: In the sham group, no animal developed chewing. Meanwhile, rats in successful model of phantom limb pain group began chewing from the 2nd day after operation with scores at eight to eleven. The chewing scores in the P+I group were reduced after the treatment. Compared with group S, P-p38MAPK levels were elevated in groups of P and P+I (P<0.05 or P<0.01). Compared with group P, P-p38MAPK level was decreased in the group P+I (P<0.05 or P<0.01). Conclusion: P38MAPK signal pathway involves in the development of phantom limb pain.


Multiple-junction quantum cascade photodetectors for thermophotovoltaic energy conversion.
The use of intersubband transitions in quantum cascade structures for thermophotovoltaic energy conversion is investigated numerically. The intrinsic cascading scheme, spectral agility, and design flexibility of these structures make them ideally suited to the development of high efficiency multiple-junction thermophotovoltaic detectors. A specific implementation of this device concept is designed, based on bound-to-continuum intersubband transitions in large-conduction-band-offset In(0.7)Ga(0.3)As/AlAs(0.8)Sb(0.2) quantum wells. The device electrical characteristics in the presence of thermal radiation from a blackbody source at 1300 K are calculated, from which a maximum extracted power density of 1.4 W/cm(2) is determined. This value compares favorably with the present state-of-the-art in interband thermophotovoltaic energy conversion, indicating that quantum cascade photodetectors may provide a promising approach to improve energy extraction from thermal sources.


Transcatheter Aortic Valve Replacement in Low-Population Density Areas: Assessing Healthcare Access for Older Adults With Severe Aortic Stenosis.
Restricting transcatheter aortic valve replacement (TAVR) to centers based on volume thresholds alone can potentially create unintended disparities in healthcare access. We aimed to compare the influence of population density in state of Florida in regard to access to TAVR, TAVR utilization rates, and in-hospital mortality. From 2011 to 2016, we used data from the Agency for Health Care Administration to calculate travel time and distance for each TAVR patient by comparing their home address to their TAVR facility ZIP code. Travel time and distance, TAVR rates, and mortality were compared across categories of low to high population density (population per square miles of land). Of the 6531 patients included, the mean (SD) age was 82 (9) years, 43% were female and 91% were White. Patients residing in the lowest category (<50/square miles) were younger, more likely to be men, and less likely to be a racial minority. Those residing in the lowest category density faced a longer unadjusted driving distances and times to their TAVR center (mean extra distance [miles]=43.5 [95% CI, 35.6-51.4]; P<0.001; mean extra time (minutes)=45.6 [95% CI, 38.3-52.9], P<0.001). This association persisted regardless of the methods used to determine population density. Excluding uninhabitable land, there was a 7-fold difference in TAVR utilization rates in the lowest versus highest population density regions (7 versus 45 per 100 000, P-for-pairwise-comparisons <0.001) and increase in TAVR in-hospital mortality (adjusted OR, 6.13 [95% CI, 1.97-19.1]; P<0.001). Older patients living in rural counties in Florida face (1) significantly longer travel distances and times for TAVR, (2) lower TAVR utilization rates, and (3) higher adjusted TAVR mortality. These findings suggest that there are trade-offs between access to TAVR, its rate of utilization, and procedural mortality, all of which are important considerations when defining institutional and operator requirements for TAVR across the country.


Charcot-Marie-Tooth disease Type 2E/1F mutant neurofilament proteins assemble into neurofilaments.
Charcot-Marie-Tooth disease Type 2E/1F (CMT2E/1F) is a peripheral neuropathy caused by mutations in neurofilament protein L (NFL), which is one of five neurofilament subunit proteins that co-assemble to form neurofilaments in vivo. Prior studies on cultured cells have shown that CMT2E/1F mutations disrupt neurofilament assembly and lead to protein aggregation, suggesting a possible disease mechanism. However, electron microscopy of axons in peripheral nerve biopsies from patients has revealed accumulations of neurofilament polymers of normal appearance and no evidence of protein aggregates. To reconcile these observations, we reexamined the assembly of seven CMT2E/1F NFL mutants in cultured cells. None of the mutants assembled into homopolymers in SW13vim- cells, but P8R, P22S, L268/269P, and P440/441L mutant NFL assembled into heteropolymers in the presence of neurofilament protein M (NFM) alone, and N98S, Q332/333P, and E396/397K mutant NFL assembled in the presence of NFM and peripherin. P8R, P22S, N98S, L268/269P, E396/397K, and P440/441L mutant NFL co-assembled into neurofilaments with endogenous NFL, NFM, and α-internexin in cultured neurons, although the N98S and E396/397K mutants showed reduced filament incorporation, and the Q332/333P mutant showed limited incorporation. We conclude that all the mutants are capable of assembling into neurofilaments, but for some of the mutants this was dependent on the identity of the other neurofilament proteins available for co-assembly, and most likely also their relative expression level. Thus, caution should be exercised when drawing conclusions about the assembly capacity of CMT2E/1F mutants based on transient transfections in cultured cells.


An integrative review of the factors influencing new graduate nurse engagement in interprofessional collaboration.
To analyse critically the barriers and facilitators to new graduate nurse engagement in interprofessional collaboration. The acculturation of new graduate nurses must be considered in strategies that address the global nursing shortage. Interprofessional collaboration may support the transition and retention of new graduate nurses. Whittemore and Knafl's revised framework for integrative reviews guided the analysis. A comprehensive multi-step search (published 2000-2012) of the North American interprofessional collaboration and new graduate literature indexed in the CINAHL, Proquest, Pubmed, PsychINFO and Cochrane databases was performed. A sample of 26 research and non-research reports met the inclusion criteria. All 26 articles were included in the review. A systematic and iterative approach was used to extract and reduce the data to draw conclusions. The analysis revealed several barriers and facilitators to new graduate engagement in interprofessional collaboration. These factors exist at the individual, team and organizational levels and are largely consistent with conceptual and empirical analyses of interprofessional collaboration conducted in other populations. However, knowledge and critical thinking emerged as factors not identified in previous analyses. Despite a weak-to-moderate literature sample, this review suggests implications for team and organizational development, education and research that may support new graduate nurse engagement in IPC.


Antisignature oligonucleotides and their analogs as inhibitors of mollicutes-cofactors of HIV.
Inhibition of mollicutes by synthetic oligonucleotides and their analogs complementary to specific "signature" regions of 16S rRNA and corresponding sequences of ribosomal operon DNA was studied. It was shown that antisignature oligonucleotides inhibited transcription in vitro for above 79% interacting specifically with ribosomal operon and non-specific with DNA-dependent RNA-polymerase. The inhibition efficiency depended on oligonucleotide sequence and type of modification. Translation in vitro was suppressed most efficiently (up to 60%) by oligonucleotides complementary to 3'-end region of 16S rRNA, also depending on their modification. Translation in vivo was inhibited most efficiently (up to 73%) by thiophosphate analogs of oligonucleotides complementary to sequences 499-507 and 523-532 of 16S rRNA responsible for binding of ribosomal "core" protein S4 starting the assembly of 30S ribosome subunit. With the simultaneous use of the last two oligonucleotides, the growth of mollicutes in SM IMV-72 medium rich in exogenous sources of nucleosides was suppressed for over 90%. It is supposed that under conditions where mollicutes have no free access to starting materials for their own synthesis of nucleic acid these nucleotides could suppress microorganisms completely. Antisignature oligonucleotides are considered as superspecific agents not leading to the development of resistance of mollicutes and believed to be the main future remedy against diseased caused by microorganisms lacking the system of nucleoside synthesis.


Exploring the Effects of an Acute Dose of Antipsychotic Medication on Motivation-mediated BOLD Activity Using fMRI and a Perceptual Decision-making Task.
The left inferior frontal gyrus and the bilateral ventral striatum are thought to be involved in motivation-mediated decision-making. Antipsychotics may influence this relationship, and atypical antipsychotics improve secondary negative symptoms in schizophrenia, such as loss of motivation, although the acute effects of pharmacological medication on motivation are not fully understood. In this single-blinded, randomized controlled trial, 49 healthy volunteers were randomized into three groups to receive a single dose of haloperidol, aripiprazole or placebo. Between 4.0 and 5.6 h later, participant's brain blood-oxygen-level dependent (BOLD) activity was recorded using functional magnetic resonance imaging (fMRI) while completing a perceptual decision-making fMRI task consisting of one neutral and one motivated condition. Response bias, reflecting the participant's willingness to say that the target stimulus is present, was calculated using signal detection theory. Concurrent with widespread changes in BOLD signal in the motivated vs. neutral condition, a less conservative, mathematically optimal response bias was observed in the motivated condition across the whole sample. Within-group differences in BOLD signal in the left inferior frontal gyrus and bilateral ventral striatum were observed between conditions in the aripiprazole and haloperidol groups, but not in the placebo group. No robust between-group differences in brain activity in the left inferior frontal gyrus or the bilateral ventral striatum were found. Overall, we found no robust evidence for an effect of either aripiprazole or haloperidol on motivationally mediated behavior. An interesting pattern of correlations possibly related to pharmacologically induced alterations in the dopamine system was observed, although findings remain inconclusive and must be replicated in larger samples.


Assessment of Post-Operative Pseudophakic Glaucoma by Ultrasound Biomicroscopy.
Pseudophakic glaucoma is a secondary glaucoma in which intra-ocular pressure is elevated following cataract removal. The current study aimed to evaluate the role of ultrasound biomicroscopy (UBM) in assessing post-operative pseudophakic glaucoma. This is a case series, prospective, observational and analytical study. It included 29 eyes of 29 patients with post-operative pseudophakic glaucoma. The patients were evaluated by medical history, detailed ophthalmologic examination and UBM. UBM examination has unmasked different causes of pseudophakic glaucoma. The detected causes were classified into 3 main groups, including intraocular lens (IOL)-related causes, lens remnants and intra-ocular inflammation. Haptic-related causes were present in 9 eyes, while 6 eyes had decentered or tilted IOLs. Soemmering's ring was the main cause in 3 eyes while in one eye the cause was lens particle in the anterior chamber (AC). Silicone oil in AC with seclusio pupillae was the main cause in one eye. Peripheral anterior synechiae were detected in 8 eyes while, posterior synechiae were evident in 7 eyes. Uveitis induced by anterior chamber IOL (ACIOL) was found in 3 eyes and one eye had peripheral anterior synechiae due to neovascular glaucoma. UBM is a helpful diagnostic tool to evaluate causes of pseudophakic glaucoma through adequate visualization of different angle structures.


PTPRQ as a potential biomarker for idiopathic normal pressure hydrocephalus.
Idiopathic normal pressure hydrocephalus (iNPH) is caused by the accumulation of cerebrospinal fluid (CSF) and is characterized by gait disturbance, urinary incontinence, and dementia. iNPH dementia is treatable by shunt operation; however, since the cognitive symptoms of iNPH are often similar to those of other dementias, including Alzheimer's disease (AD), accurate diagnosis of iNPH is difficult. To overcome this problem, the identification of novel diagnostic markers to distinguish iNPH and AD is warranted. Using comparative proteomic analysis of CSF from patients with iNPH and AD, protein tyrosine phosphatase receptor type Q (PTPRQ) was identified as a candidate biomarker protein for discriminating iNPH from AD. ELISA analysis indicated that the PTPRQ concentration in the CSF was significantly higher in patients with iNPH compared with those with AD. In addition, the PTPRQ concentration in the CSF of non‑responders to shunt operation (SNRs) tended to be relatively lower compared with that in the responders. PTPRQ may be a useful biomarker for discriminating between patients with iNPH and AD, and may be a potential companion biomarker to identify SNRs among patients with iNPH. Additional large‑scale analysis may aid in understanding the novel aspects of iNPH.


Evolving attitudes toward robotic surgery among Canadian urology residents.
Robotic-assisted laparoscopic surgery (RAS) has not been adopted as rapidly or widely in Canada as in the U.S. In 2011, Canadian urology residents felt that RAS represented an expanding field that could potentially negatively impact their training. We re-evaluate trainee exposure and attitudes to RAS in Canadian residency training five years later. All Canadian urology residents were asked to participate in an online survey designed to assess current resident exposure to and perception of RAS. The response rate was 39% (61/157). Seventy-seven percent of residents reported being involved in at least one RAS procedure (52% in 2011), and the majority had exposure to <10 cases. For those in hospitals with access to RAS, 96% desired more console time, while only 50% of those without access wanted more console experience. Of all residents, 50% felt that RAS will become the gold standard in certain urological surgeries (34% in 2011), but only 28% felt that RAS would play an increasingly important role in urology (59% in 2011). Despite an increase in exposure to RAS in residency programs over the past five years, console experience remains limited. Although these residents desire more access to RAS, many voice uncertainty of the role of RAS in Canada. We cannot conclude whether RAS is perceived by residents to be beneficial or detrimental to their training nationwide. Moving forward in the robotic era, it will be important to either modify residency curricula to address RAS experience or to limit RAS to fellowship training.


Chronic mesenteric vascular syndrome. Results of reconstructive surgery.
Since 1961, 14 patients at the University Hospital of Leiden, the Netherlands, have undergone reconstructive surgery for treatment of chronic mesenteric vascular syndrome. Of the 42 mesenteric arteries, 31 were severely obstructed (mean, 2.2 stenotic arteries per patient). A total of 23 mesenteric arteries were repaired. Long-term follow-up data were available for all 13 surviving patients (mean follow-up, 11.8 years). Symptoms were relieved immediately after surgery, and relief was maintained during follow-up. Digital subtraction angiography at long-term follow-up evaluation was performed in eight patients (13 reconstructions) with these results: 11 (85%) of the 13 reconstructions were patent and severe stenoses were found in eight (33%) of the 24 mesenteric arteries (mean, 1.0 stenotic artery per patient). We conclude that reconstructive surgery for patients with chronic mesenteric vascular syndrome promptly relieves symptoms, provides excellent patency, and has long-lasting beneficial results.


Modulation of lipid-synthesizing enzymes by insulin in differentiated ob17 adipose-like cells.
ob17 cells convert into adipose-like cells when maintained in the presence of physiological concentrations of insulin and tri-iodothyronine. After this conversion, insulin removal from differentiated ob17 cells gives within 24-48 h a large decrease in fatty acid synthetase, glycerol 3-phosphate dehydrogenase and acid:CoA ligase activities, as well as in the rate of fatty acid synthesis determined by [14C]acetate incorporation into lipids. All parameters are restored by insulin addition to initial values within 24-48 h. Dose-response curves of insulin on the restoration of glycerol 3-phosphate dehydrogenase activity and of fatty acid synthesis give half-maximally effective concentrations close to 1 nM, in agreement with the affinity for insulin of the insulin receptors previously characterized in these cells. Immunotitration experiments indicate that the changes in the specific activity of fatty acid synthetase are due to parallel changes in the cellular enzyme content. Therefore the ob17 cell line should be a useful model to study the long-term effects of insulin on the modulation of lipid synthesis in adipose cells.


Use of the designation "shedder" in mucosal detection of herpes simplex virus DNA involving repeated sampling.
We evaluated two methods to describe detection of herpes simplex virus (HSV) from the genital mucosa. We assessed genital swabs from HSV-2 seropositive people participating in longitudinal studies of HSV DNA detection at the University of Washington Virology Research Clinic. We determined the length of observation period necessary to ensure some HSV detection for most individuals. We compared two measures to assess differences in shedding according to HIV status, the shedding rate ratio, defined as the proportion of total samples with detectable HSV in HIV-1 seropositive versus HIV-1 seronegative participant, and the ratio of "shedders", defined as the proportion of people with any shedding over the interval in HIV-1 seropositive versus HIV-1 seronegative people. While only 17% (51/308) of HSV-2 seropositive people shed on their first day on study, 77% (238/308) had some genital shedding over 30 days (any HSV DNA detected on genital swabs). Shedding rate ratios (SRR) for HIV-seropositive versus HIV-seronegative people varied from SRR = 1.42 using 10 samples to SRR = 1.35 using 50 samples. The ratio of "shedders" (RS) approached 1 as the observation period increased (RS = 1.13 using 10 samples to RS = 1.01 using 50 samples). In a hypothetical case, the ratio of "shedders" was shown to exceed 1 when shedding rates were equal. Most HSV-2 seropositive people shed HSV from the genital mucosa. Dichotomisation of people into "shedders" and "non-shedders" or "high" and "low" shedders yields inferences that depend upon sampling interval length. Overall shedding rates provide consistent measures regardless of the number of swabs collected.


[Buccal epithelium reactivity in children].
The purpose of this study was the analysis of the buccal smears from 200 healthy children and children with chronic tonsillitis and chicken pox. The smears were stained using Pappenheim's method. The peculiarity of buccal mucosa cytograms of children of different ages was the significant increase in mature forms of the cells (presence of differentiation stage 5 and 6 cells) in adolescents. They also had a lower area of epitheliocytes at all the stages of differentiation and of their nuclei. In chronic tonsillitis and chicken pox, the complex of cytological changes was detected, that included the increase of the leukocyte number, changes in the proportions of epitheliocytes in cell population, augmentation of inflammation-destruction and destruction indexes.


Wandering Spleen: An Overview.
An ectopic (or "wandering") spleen results from abnormal ligamentous laxity failing to fixate the spleen in its normal location in the left upper quadrant. Ligamentous laxity can be acquired due to conditions, such as splenomegaly or pregnancy, but is often congenital. Because of this laxity, there is an elongated vascular pedicle, which is prone to torsion and resultant splenic infarction. These patients generally present with abdominal pain and other nonspecific symptoms making the diagnosis very difficult to make clinically. As such, the radiologist plays a crucial role in the diagnosis and care of these patients, as often the diagnosis is only considered after imaging.


Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies.
The principal therapy in patients with myocardial infarction to limit infarct size is myocardial reperfusion by mechanical or pharmacological intervention. Reperfusion has been proposed to cause myocardial injury beyond that caused by the preceding ischaemia, termed "reperfusion injury" (RI). While the precise mechanism of RI is still incompletely understood, a large number of clinical studies have been performed over the past decade targeting some of the postulated mechanisms of RI. These clinical studies were based on experimental data demonstrating significant myocardial salvage. Nevertheless, clinical benefits were absent or very limited. The purpose of this review is to provide an overview of the various strategies that inhibit RI and to discuss potential mechanisms that may contribute to the discrepancy between the promising pre-clinical data and the rather disappointing results obtained from prospective clinical trials. There are numerous differences between the experimental models and clinical studies, including the fact that experimental studies typically use abrupt occlusion and reperfusion protocols in animals with previously healthy myocardium that apparently do not predict the therapeutic efficacy of novel cardioprotective agents in a clinical setting with pre-existing progressive coronary disease, intermittent coronary occlusion, and relatively late reperfusion. However, discrepancies also exist between experimental studies. Future experimental studies of reperfusion injury should use models that mimic the clinical situation more closely. Furthermore, future large clinical trials should only be performed in cases where the drug under investigation proved to reduce RI in a series of well-designed (possibly multicenter) experimental studies and in clinical trials with predefined subgroups.


Adaptive fitting of potential energy surfaces of small to medium-sized molecules in sum-of-product form: Application to vibrational spectroscopy.
A semi-automatic sampling and fitting procedure for generating sum-of-product (Born-Oppenheimer) potential energy surfaces based on a high-dimensional model representation is presented. The adaptive sampling procedure and subsequent fitting rely on energies only and can be used for re-fitting existing analytic potential energy surfaces in the sum-of-product form or for direct fits from ab initio computations. The method is tested by fitting ground electronic state potential energy surfaces for small to medium sized semi-rigid molecules, i.e., HFCO, HONO, and HCOOH, based on ab initio computations at the coupled-cluster single double and perturbative triples-F12/cc-pVTZ-F12 or MP2/aug-cc-pVTZ levels of theory. Vibrational eigenstates are computed using block improved relaxation in the Heidelberg multi-configurational time dependent Hartree package and compared to available experimental and theoretical data. The new potential energy surfaces are compared to the best ones currently available for these molecules in terms of accuracy, including resulting vibrational states, required number of sampling points, and number of fitting parameters. The present procedure leads to compact expansions and scales well with the number of dimensions for simple potentials such as single or double wells.


In vitro and in vivo multidrug resistance reversal activity by a Betti-base derivative of tylosin.
The multidrug resistance (MDR) proteins are present in a majority of human tumours. Their activity is important to understand the chemotherapeutic failure. A search for MDR-reversing compounds was conducted among various Betti-base derivatives of tylosin. Here, we evaluate the in vitro and in vivo P-glycoprotein (P-gp)-modulating activity of the most promising compound N-tylosil-1-alpha-amino-(3-bromophenyl)-methyl-2-naphthol (TBN) using human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines. In vitro experiments showed that TBN dramatically increased the P-gp-mediated cellular uptake of the fluorescent substrate rhodamine 123. Similarly, TBN was found to act as a very potent enhancer of the cytotoxicity of doxorubicin on the resistant cell line. We also provide in vivo evidence using DBA/2 mice in support for an increased tumoural accumulation of doxorubicin, without affecting its tissue distribution, resulting in an enhanced antitumoural effect. Our results suggest that TBN is a potent modulator of the P-gp membrane pump and that the compound could be of clinical relevance to improve the efficacy of chemotherapy in MDR cancers.


Regulation of ENaC and CFTR expression with K+ channel modulators and effect on fluid absorption across alveolar epithelial cells.
In a recent study (Leroy C, Dagenais A, Berthiaume Y, and Brochiero E. Am J Physiol Lung Cell Mol Physiol 286: L1027-L1037, 2004), we identified an ATP-sensitive K(+) (K(ATP)) channel in alveolar epithelial cells, formed by inwardly rectifying K(+) channel Kir6.1/sulfonylurea receptor (SUR)2B subunits. We found that short applications of K(ATP), voltage-dependent K(+) channel KvLQT1, and calcium-activated K(+) (K(Ca)) channel modulators modified Na(+) and Cl(-) currents in alveolar monolayers. In addition, it was shown previously that a K(ATP) opener increased alveolar liquid clearance in human lungs by a mechanism possibly related to epithelial sodium channels (ENaC). We therefore hypothesized that prolonged treatment with K(+) channel modulators could induce a sustained regulation of ENaC activity and/or expression. Alveolar monolayers were treated for 24 h with inhibitors of K(ATP), KvLQT1, and K(Ca) channels identified by PCR. Glibenclamide and clofilium (K(ATP) and KvLQT1 inhibitors) strongly reduced basal transepithelial current, amiloride-sensitive Na(+) current, and forskolin-activated Cl(-) currents, whereas pinacidil, a K(ATP) activator, increased them. Interestingly, K(+) inhibitors or membrane depolarization (induced by valinomycin in high-K(+) medium) decreased alpha-, beta-, and gamma-ENaC and CFTR mRNA. alpha-ENaC and CFTR proteins also declined after glibenclamide or clofilium treatment. Conversely, pinacidil augmented ENaC and CFTR mRNAs and proteins. Since alveolar fluid transport was found to be driven, at least in part, by Na(+) transport through ENaC, we tested the impact of K(+) channel modulators on fluid absorption across alveolar monolayers. We found that glibenclamide and clofilium reduced fluid absorption to a level similar to that seen in the presence of amiloride, whereas pinacidil slightly enhanced it. Long-term regulation of ENaC and CFTR expression by K(+) channel activity could benefit patients with pulmonary diseases affecting ion transport and fluid clearance.


Adaptive Adolescent Flexibility: Neurodevelopment of Decision-making and Learning in a Risky Context.
Research on adolescence has largely focused on the particular biological and neural changes that place teens at risk for negative outcomes linked to increases in sensation-seeking and risky behavior. However, there is a growing interest in the adaptive function of adolescence, with work highlighting the dual nature of adolescence as a period of potential risk and opportunity. We examined how behavioral and neural sensitivity to risk and reward varies as a function of age using the Balloon Analog Risk Task. Seventy-seven children and adolescents (ages 8-17 years) completed the Balloon Analog Risk Task during an fMRI session. Results indicate that adolescents show greater learning throughout the task. Furthermore, older participants showed increased neural responses to reward in the OFC and ventral striatum, increased activation to risk in the mid-cingulate cortex, as well as increased functional OFC-medial PFC coupling in both risk and reward contexts. Age-related changes in regional activity and interregional connectivity explain the link between age and increases in flexible learning. These results support the idea that adolescents' sensitivity to risk and reward supports adaptive learning and behavioral approaches for reward acquisition.


Within and across country variations in treatment of patients with heart failure and diabetes.
To compare within-country variation of health care utilization and spending of patients with chronic heart failure (CHF) and diabetes across countries. Patient-level linked data sources compiled by the International Collaborative on Costs, Outcomes, and Needs in Care across nine countries: Australia, Canada, England, France, Germany, New Zealand, Spain, Switzerland, and the United States. Patients were identified in routine hospital data with a primary diagnosis of CHF and a secondary diagnosis of diabetes in 2015/2016. We calculated the care consumption of patients after a hospital admission over a year across the care pathway-ranging from primary care to home health nursing care. To compare the distribution of care consumption in each country, we use Gini coefficients, Lorenz curves, and female-male ratios for eight utilization and spending measures. In all countries, rehabilitation and home nursing care were highly concentrated in the top decile of patients, while the number of drug prescriptions were more uniformly distributed. On average, the Gini coefficient for drug consumption is about 0.30 (95% confidence interval (CI): 0.27-0.36), while it is, 0.50 (0.45-0.56) for primary care visits, and more than 0.75 (0.81-0.92) for rehabilitation use and nurse visits at home (0.78; 0.62-0.9). Variations in spending were more pronounced than in utilization. Compared to men, women spend more days at initial hospital admission (+5%, 1.01-1.06), have a higher number of prescriptions (+7%, 1.05-1.09), and substantially more rehabilitation and home care (+20% to 35%, 0.79-1.6, 0.99-1.64), but have fewer visits to specialists (-10%; 0.84-0.97). Distribution of health care consumption in different settings varies within countries, but there are also some common treatment patterns across all countries. Clinicians and policy makers need to look into these differences in care utilization by sex and care setting to determine whether they are justified or indicate suboptimal care.


In vivo confocal microscopy and anterior segment optical coherence tomography follow-up of cysteamine treatment in corneal cystinosis.
A 36-year-old female presented initially with photophobia and visual deterioration. After examination and laboratory tests, patient was diagnosed with cystinosis. Cysteamine drops 4 × 1 drops/day was given as treatment for 1 year. During follow-up, in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) was performed. Photophobia was relieved and IVCM obtained the decrease in size and density of corneal crystals 1 year after. Depth of corneal crystals did not change but crystal density score reduced with cysteamine treatment.


Intraocular lens power calculation for emmetropia: a clinical study.
A series of 50 eyes received an intraocular lens (IOL) of power calculated for emmetropia from data of axial length, corneal curvature, and postoperative anterior chamber depth by R. D. Binkhorst's formulae. The postoperative refraction results were compared with those of 100 control eyes which received +19 D standard power IOLs without calculation. The calculated group had postoperative refractions which were closer to emmetropia, and the difference was os statistical significance, with 92% within the +/- 1D range and 98% within the +/- 2 D range from emmetropia. The calculated predictions of postoperative refraction were of a useful level of accuracy. Consideration of the sources of error indicates that there is no justification for the use of IOLs in power steps of less than 1 D. The calculation of IOL power allows the surgeon to control the postoperative refraction and avoid unwanted ametropia.


Repositioning therapeutic cancer vaccines in the dawning era of potent immune interventions.
Based on lessons learned with various immune interventions, this review aims to provide a constructive framework for repositioning therapeutic cancer vaccination. Intensive research throughout the past decade has identified key hurdles interfering with the efficacy of cancer vaccines. The vaccination concept still holds promise if positioned appropriately in minimal residual disease and select early disease stage cancer indications. However, in advanced cancer, it must be integrated with complementary immune interventions to ensure reconstruction of a functional immune repertoire and simultaneous blockade of immune inhibiting mechanisms. Vaccination could render complex and integrative immune interventions simpler, safer and more effective. The near future will witness an explosion of activities in the cancer immunotherapy arena, witnessing a rational repositioning of vaccines rather than their extinction.


Biomarkers as a treatment guide in rheumatoid arthritis.
It is anticipated that biomarkers support rheumatologists to judge a group of patients that can improve the diagnosis and prognosis, and further facilitate appropriate and precise treatment with targeted therapy. In particular, biomarkers for predicting and monitoring response to biological disease modifying anti-rheumatic drugs (DMARDs) are demanding. Given the mechanism action of biological DMARDs is much more simple than the conventional synthetic DMARDs, a variety of approaches to find such biomarkers has been taken recent years. In this article, I will summarize the background for biomarker research and introduce recent topics in the research and the possible clinical applications of biomarkers to guide treatment in rheumatoid arthritis (RA).


Professional breastfeeding support for first-time mothers: a multicentre cluster randomised controlled trial.
To evaluate the effect of two postnatal professional support interventions on the duration of any and exclusive breastfeeding. Multicentre, three-arm, cluster randomised controlled trial. A cohort of 722 primiparous breastfeeding mothers with uncomplicated, full-term pregnancies. The three study interventions were: (1) standard postnatal maternity care; (2) standard care plus three in-hospital professional breastfeeding support sessions, of 30-45 minutes in duration; or (2) standard care plus weekly post-discharge breastfeeding telephone support, of 20-30 minutes in duration, for 4 weeks. The interventions were delivered by four trained research nurses, who were either highly experienced registered midwives or certified lactation consultants. Prevalence of any and exclusive breastfeeding at 1, 2, and 3 months postpartum. Rates of any and exclusive breastfeeding were higher among participants in the two intervention groups at all follow-up points, when compared with those who received standard care. Participants receiving telephone support were significantly more likely to continue any breastfeeding at 1 month (76.2 versus 67.3%; odds ratio, OR 1.63, 95% confidence interval, 95% CI 1.10-2.41) and at 2 months (58.6 versus 48.9%; OR 1.48, 95% CI 1.04-2.10), and to be exclusively breastfeeding at 1 month (28.4 versus 16.9%; OR 1.89, 95% CI 1.24-2.90). Participants in the in-hospital support group were also more likely to be breastfeeding at all time points, but the effect was not statistically significant. Professional breastfeeding telephone support provided early in the postnatal period, and continued for the first month postpartum, improves breastfeeding duration among first-time mothers. It is also possible that it was the continuing nature of the support that increased the effectiveness of the intervention, rather than the delivery of the support by telephone specifically.


Increasing awareness of food-choking and nutrition in children through education of caregivers: the CHOP community intervention trial study protocol.
Choking is one of the leading causes of death among unintentional injuries in young children. Food choking represents a considerable public health burden, which might be reduced through increased effective preventative education programs. We present a protocol for a community intervention trial termed CHOP (CHOking Prevention project) that aimed to teach Italian families how to prevent food choking injuries and increase knowledge relating to nutrition. Italian educational facilities were enrolled. Stratified randomization blocked by geographical area was performed. Each stratum was randomized to one of three different intervention strategies or to a control group. Educational intervention was delivered in the schools by experts and certified trainers as per the following three intervention strategies: directly to families (Strategy A); to teaching staff only, who subsequently delivered the same educational intervention to families (Strategy B); to health service staff only, who then delivered the educational intervention to teaching staff, who subsequently delivered the intervention to families (Strategy C). Participants completed a questionnaire about their knowledge on the topics presented during the educational interventions (pre-, post-, and follow-up of intervention). Information from the questionnaires was synthetized into 6 indicators in order to measure how effective each intervention strategy was. The issue of food choking injuries in children is relevant to public health. The protocol we present provides an opportunity to progress towards overcoming such challenges through a working model that can be implemented also in other countries. ClinicalTrials.gov NCT03218618. The study was registered on 14 July 2017.


Transepithelial transport characteristics of the antihypertensive peptide, Lys-Val-Leu-Pro-Val-Pro, in human intestinal Caco-2 cell monolayers.
An antihypertensive peptide, Lys-Val-Leu-Pro-Val-Pro (KVLPVP), can reduce blood pressure in hypertensive rats after being orally administered. In this study, the transepithelial transport of intact KVLPVP was examined by Caco-2 monolayers. The results were as follows: (i) The flux was not saturable for apical (AP) to basolateral (BL) or BL-AP transport when the concentration of KVLPVP was 1-8 mM. (ii) Sodium deoxycholate loosened the tight junction in the Caco-2 cells and significantly improved the transport process. (iii) Phenylarsine oxide, a transcytotic process inhibitor, had little effect on the transport process. (iv) The influx and eflux of KVLPVP remained unchanged in the presence of the ATP inhibitor sodium azide. (v) This transport was not inhibited by the peptide transporter substrates Gly-Pro or arphanine A. All these data indicate that paracellular transport diffusion was the major flux mechanism for the intact KVLPVP.


Anisotropic growth is achieved through the additive mechanical effect of material anisotropy and elastic asymmetry.
Fast directional growth is a necessity for the young seedling; after germination, it needs to quickly penetrate the soil to begin its autotrophic life. In most dicot plants, this rapid escape is due to the anisotropic elongation of the hypocotyl, the columnar organ between the root and the shoot meristems. Anisotropic growth is common in plant organs and is canonically attributed to cell wall anisotropy produced by oriented cellulose fibers. Recently, a mechanism based on asymmetric pectin-based cell wall elasticity has been proposed. Here we present a harmonizing model for anisotropic growth control in the dark-grown Arabidopsis thaliana hypocotyl: basic anisotropic information is provided by cellulose orientation) and additive anisotropic information is provided by pectin-based elastic asymmetry in the epidermis. We quantitatively show that hypocotyl elongation is anisotropic starting at germination. We present experimental evidence for pectin biochemical differences and wall mechanics providing important growth regulation in the hypocotyl. Lastly, our in silico modelling experiments indicate an additive collaboration between pectin biochemistry and cellulose orientation in promoting anisotropic growth.


ARTP statement on cardiopulmonary exercise testing 2021.
Cardiopulmonary exercise testing (CPET) has become an invaluable tool in healthcare, improving the diagnosis of disease and the quality, efficacy, assessment and safety of treatment across a range of pathologies. CPET's superior ability to measure the global exercise response of the respiratory, cardiovascular and skeletal muscle systems simultaneously in a time and cost-efficient manner has led to the application of CPET in a range of settings from diagnosis of disease to preoperative assessment. The Association for Respiratory Technology and Physiology Statement on Cardiopulmonary Exercise Testing 2021 provides the practitioner and scientist with an outstanding resource to support and enhance practice, from equipment to testing to leadership, helping them deliver a quality assured service for the benefit of all patient groups.


Self-assembling soft structures for intracellular NO release and promotion of neurite outgrowth.
Nitric oxide (NO), an endogenously produced free radical species, is an extremely important signalling molecule in several biochemical processes related to neurotransmission, neuronal communication, and vasodilation, to name a few. Other than relying on endogenous synthesis, intracellular NO delivery presents an interesting challenge to fully exploit the therapeutic potential of this gaseous molecule. We have applied a self-assembling peptide conjugate strategy to devise a construct carrying a NO-release arm, which can be activated under standard redox conditions. Consequently, a tryptophan-based peptide carrier was designed, which self-assembled in the solution phase to afford soft nanospherical structures, and released NO in Neuro2a cell line, resulting in neurite outgrowth.


Assessing the surgical and obstetrics-gynecology workload of medical officers: findings from 10 district hospitals in Ghana.
Surgical and obstetrics-gynecology (Ob-Gyn) workload of medical officers (MOs) is substantial and may inform policies for training investment and surveillance to strengthen surgical care at district hospitals in Ghana. Observational study. Academic research. Using standardized criteria, 12 trained on-site observers assessed the surgical and Ob-Gyn workload of MOs at 10 district hospitals in each of 10 administrative regions in Ghana, West Africa. The number of patients seen by MOs and the time spent managing each patient were recorded. According to each patient's diagnosis, the encounters were categorized as medical/nonsurgical, Ob-Gyn, or surgical. The proportions of patients having Ob-Gyn and surgical conditions and the time expended providing care to Ob-Gyn and surgical patients. Of the observed patient encounters, 1600 (64.5%) were classified as medical or nonsurgical, 514 (20.7%) as Ob-Gyn, and 368 (14.8%) as surgical (9.0% nontrauma and 5.8% trauma). The most common diagnosis among Ob-Gyn patients was obstetric complication requiring cesarean section. The most common diagnosis among surgical patients was inguinal hernia. Medical officers devoted 24.8% of their time to managing Ob-Gyn patients and 18.9% to managing surgical patients (which included 5.4% for the management of traumatic injuries). Surgical and Ob-Gyn patients represent a substantial proportion of the workload among MOs at district hospitals in Ghana. Strategies to increase surgical capacity at these facilities must include equipping MOs with the appropriate training and resources to address the significant surgical and Ob-Gyn workload they face.


[Strategy and perspectives for the control of cutaneous leishmaniasis in the state of São Paulo].
The multiplicity of factors involved in the transmission of American cutaneous leishmaniasis (ACL) make it difficult to formulate an efficient strategy for the control of the disease. On the basis of the number of notified cases per location, the State of São Paulo determines the application of DDT in houses in those areas where two or more human cases have occurred. This procedure, however, impairs part of the program because 40% of the counties report only one human case each. These and other factors are analyzed in the light of the increase in the incidence of the disease in the State, its advance in the extra-forest environment and the delay in the decision-making process about the efficacy of the program. It is recommended that the control strategy be reviewed.