Specific interests as a social boundary and bridge: A qualitative interview study with autistic individuals.
Growing evidence shows that specific interests can help autistic individuals cope with difficulties in social communication and interaction. However, it is unclear which specific characteristics of these interests make them suitable for this coping role. Therefore, this study explored how specific interests can help autistic individuals navigate social communication and interaction. We conducted semi-structured interviews with nine autistic individuals to inquire about their perspectives on the meanings and functions of their specific interest in their (social) life. We found that specific interests served two important social functions. First, the interests provided a way to disconnect from the challenging outside world, through a shift in the attentional focus of participants. Second, the interests served as a "social compass," providing structure and meaning to social situations and helping the participants feel more connected to others. Based on these findings, we propose a conceptual model suggesting that specific interests create the experience of a "protective boundary" between oneself and others, which helps autistic individuals feel safe during social interactions. Namely, engaging in specific interests not only creates a space where autistic individuals can retreat when they feel overwhelmed, but also provides a framework with delineations in time and space, as well as explicit rules for social interactions, which make them more predictable and regulated. The study suggests that incorporating specific interests into therapy can help improve social communication and interaction for autistic individuals while still prioritizing their personal well-being.


The effects of different modes of supervision on vigilance behaviour.
Experiment I was run to determine if a closed-circuit television and a one-way window mode of supervision were as effective as the direct physical presence of an experimenter in inducing enhanced levels of signal detection in a Mackworth-type vigilance task. A control condition of complete subject privacy was also examined. The results indicated that both the television and the window conditions had a positive effect on overall performance which was similar to that observed in the experimenter-presence condition; however, the performance decrement over the 90 min vigil was equivalent for the four modes. A second experiment involving the variable of camera position with an addition of a fourth 30 min. period yielded no significant differences between the camera positions, but overall performance in the television condition was again better than in the control condition. This study suggested that performance can be enhanced even without the physical presence of the experimenter.


Advances in the prevention of children's injuries: an examination of four common outdoor activities.
Injuries remain the leading cause of death for children. Experts in paediatrics and child health have a current interest in promoting children's healthy active living. This review highlights findings from recent literature regarding the prevention of injuries from four common outdoor activities: bicycling, snowboarding and skiing, walking and playground activity. There is sound evidence for the effectiveness of bicycle helmets, the promotion of bicycle helmets at a community level and through physician counselling, and legislation; for the effectiveness of helmets for skiing and snowboarding; for the effectiveness of implementing playground safety standards; and for the effectiveness of modifications to the pedestrian physical environment. The science of injury prevention has advanced considerably. The highest level of evidence, including systematic reviews, is now available regarding the effectiveness of protective measures, engineering approaches to the environment and legislation. Healthcare providers caring for children play a leading role in injury prevention through child and family counselling, advocacy and research.


The influence of dietary leucine above recommendations and fixed ratios to isoleucine and valine on muscle protein synthesis and degradation pathways in broilers.
This study investigated the hypothesis that dietary supplementation of leucine (Leu) above actual recommendations activates protein synthesis and inhibits protein degradation pathways on the molecular level and supports higher muscle growth in broilers. Day-old male Cobb-500 broilers (n = 180) were allotted to 3 groups and phase-fed 3 different corn-wheat-soybean meal-based basal diets during periods 1 to 10, 11 to 21, and 22 to 35 D. The control group (L0) received the basal diet which met the broiler's requirements of nutrients and amino acids for maintenance and growth. Groups L1 and L2 received basal diets supplemented with Leu to exceed recommendations by 35 and 60%, respectively, and isoleucine (Ile) and valine (Val) were supplemented to keep Leu: Ile and Leu: Val ratios fixed. Samples of liver and breast muscle and pancreas were collected on days 10, 21, and 35. The gene expression and abundance of total and phosphorylated proteins involved in the mammalian target of rapamycin pathway of protein synthesis, in the ubiquitin-proteasome pathway and autophagy-lysosomal pathway of protein degradation, in the general control nonderepressible 2/eukaryotic translation initiation factor 2A pathway involved in the inhibition of protein synthesis, and in the myostatin-Smad2/3 pathway involved in myogenesis were evaluated in the muscle, as well as expression of genes involved in the growth hormone axis. Growth performance, feed intake, the feed conversion ratio, and carcass weights did not differ between the 3 groups (P > 0.05). Plasma concentrations of Leu, Ile, and Val and of their keto acids, and the activity of the branched-chain α-keto acid dehydrogenase in the pancreas increased dose dependently with increasing dietary Leu concentrations. In the breast muscle, relative mRNA abundances of genes and phosphorylation of selected proteins involved in all investigated pathways were largely uninfluenced by dietary Leu supplementation (P > 0.05). In summary, these data indicate that excess dietary Leu concentrations do not influence protein synthesis or degradation pathways, and subsequently do not increase muscle growth in broilers at fixed ratios to Ile and Val.


Messenger RNA structure and gene regulation at the translational level in Escherichia coli: the case of threonine:tRNAThr ligase.
Previous work showed that the expression of the Escherichia coli threonine:tRNAThr ligase (EC 18.104.22.168)-encoding gene (thrS) is negatively autoregulated at the translational level and that a region called the operator that is located between 10 and 50 base pairs upstream of the translation initiation codon of the thrS gene is directly involved in that control. The conformation of an in vitro synthesized RNA fragment extending over the thrS regulatory region has been investigated using chemical and enzymatic probes. This study shows that the RNA folds into four well-defined secondary-structure domains, one of them displaying structural similarities to the anticodon arm of tRNAThr. The conformation of three constitutive mutants containing single base changes in the operator region leading to the loss of the regulatory control was also investigated. The replacement of a base in the anticodon-like loop does not induce any conformational change, suggesting that the residue concerned is directly involved in the regulatory process. However, single mutations in or close to the anticodon-like stem result in a partial or complete reorganization of the structure of the operator region. These rearrangements should affect the binding of the ligase to the operator, leading to loss of the regulatory process.


The effects of high-fat diet on exercise-induced changes in metabolic parameters in Zucker fa/fa rats.
The objectives of this study were to document the effects of moderate aerobic exercise on insulin secretion and other metabolic indices in fa/fa rats and to determine if a high-fat (HF) diet altered these effects. Six-week-old fa/fa and lean Zucker rats were either sedentary or exercised by daily swimming for 4 weeks. Half of the exercised and sedentary rats were fed a diet with 16% fat and 44% carbohydrate, while the control groups were fed a diet with 4.5% fat and 49% carbohydrate. At the end of 4 weeks, caloric intake, weight gain, plasma hormone and nutrient levels, and oral glucose tolerance were measured. The pancreatic islet beta-cell function was assessed by measuring glucose-stimulated insulin secretion, glucose phosphorylating activity, and free fatty acid (FFA) oxidation in cultured islets. In fa/fa rats fed the control diet, exercise reduced weight gain, caloric intake, and fasting plasma triglyceride (TG) concentrations without affecting fasting glucose and insulin concentrations. HF diet blocked the effects of exercise on weight gain and food intake and worsened insulin resistance of fa/fa rats. In vitro, neither exercise nor HF diet alone affected islet beta-cell function. However, in combination, exercise and high dietary fat reduced glucokinase sensitivity to glucose and increased islet cell response to mannoheptulose inhibitory actions. We conclude that beneficial effects of moderate exercise on metabolism are not mediated by effects on pancreatic beta cells. Diets elevated in fat decrease the beneficial effects of exercise on metabolic indices in vivo.


Enhanced contraction to 5-hydroxytryptamine is not due to "unmasking" of 5-hydroxytryptamine(1b) receptors in the mesenteric artery of the deoxycorticosterone acetate-salt rat.
5-Hydroxytryptamine(1B) (5-HT(1B)) receptors have been implicated in mediating arterial contraction to 5-HT. Additionally, the 5-HT(1B) receptor has been reported to be "unmasked" by depolarizing stimuli. We hypothesized that 5-HT(1B) receptors in arteries from hypertensive animals, arteries reported to have a depolarized resting membrane potential in smooth muscle cells, are unmasked and participate in the supersensitivity observed to 5-HT in hypertension. We used the isolated tissue bath apparatus and examined the response of superior mesenteric arteries from normotensive sham and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. The 5-HT(1B) agonists CP93129 and sumatriptan (10(-9) to 10(-5) mol/L) caused a maximal contraction (50+/-12% of phenylephrine [10(-5) mol/L] contraction) in arteries from DOCA-salt rats; no contraction was observed in arteries from normotensive rats. The 5-HT(1B) receptor antagonist GR55562 (100 nmol/L) inhibited both the 5-HT- (4-fold rightward shift) and CP93129-induced (11-fold rightward shift) contractions in mesenteric arteries from hypertensive DOCA-salt rats. In other experiments, arteries from normotensive rats were incubated with 15 mmol/L KCl, as a depolarizing stimulus, and then exposed to 5-HT and CP93129. In the presence of KCl, a small leftward shift to 5-HT was observed. However, the presence of a depolarizing stimulus was unable to produce changes in the 5-HT maximal response to resemble that of arteries from DOCA-salt rats, nor was contraction to CP93129 observed. These data support the conclusions that 5-HT(1B) receptors mediate contraction in mesenteric arteries from hypertensive rats and that this enhanced response to 5-HT is not due to membrane depolarization alone.


Greater glycogen utilization during 1- than 2-adrenergic receptor stimulation in the isolated perfused rat heart.
Differences in energy metabolism during beta(1)- and beta(2)-adrenergic receptor (AR) stimulation have been shown to translate to differences in the elicited functional responses. It has been suggested that differential access to glycogen during beta(1)- compared with beta(2)-AR stimulation may influence the peak functional response and modulation of the response during sustained adrenergic stimulation. Interleaved (13)C- and (31)P-NMR spectroscopy was used during beta(1)- and beta(2)-AR stimulation at matched peak workload (2.5 times baseline) in the isolated perfused rat heart to monitor glycogen levels, phosphorylation potential, and intracellular pH. Simultaneous measurements of left ventricular (LV) function [LV developed pressure (LVDP)], heart rate (HR), and rate-pressure product (RPP = LVDP x HR) were also performed. The heart was perfused under both substrate-free (SF) conditions and with exogenous glucose (G). The greater glycogenolysis was observed during beta(1)- than beta(2)-AR stimulation with G (54% vs. 38% reduction, P = 0.006) and SF (92% vs. 79% reduction, P = 0.04) perfusions. The greater beta(1)-AR-mediated glycogenolysis was correlated with greater ability to sustain the initial contractile response. However, with SF perfusion, the duration of this ability was limited: excessive early glycogen depletion caused an earlier decline in LVDP and phosphorylation potential during beta(1)- than beta(2)-AR stimulation. Therefore, endogenous glycogen stores are depleted earlier and to a greater extent, despite a slightly weaker overall inotropic response, during beta(1)- than beta(2)-AR stimulation. These findings are consistent with beta(1)-AR-specific PKA-dependent glycogen phosphorylase kinase signaling.


CSF cytology in a patient with vertigo and earache.
Large atypical cells in cerebrospinal fluid in a patient with earache and vertigo. In this Enigma Portal case, we described uncommon cerebrospinal fluid findings in a case of vertigo and earache in a 40-year-old man.


Protective and Predisposing Morphological Factors in Suprascapular Nerve Entrapment Syndrome: A Fundamental Review Based on Recent Observations.
Suprascapular nerve entrapment syndrome (SNES) is a neuropathy caused by compression of the nerve along its course. The most common compression sites include the suprascapular notch and the spinoglenoid notch. The aim of this article was to review the anatomical factors influencing the occurrence of SNES in the light of the newest reports. Potential predisposing morphological factors include a V-shaped, narrow, or "deep" suprascapular notch; a band-shaped, bifurcated, or completely ossified superior transverse scapular ligament (STSL); particular arrangements of the suprascapular nerve and vessels at the suprascapular notch. A very recent report indicates structures at the suprascapular notch region that may protect from SNES, such as the suprascapular notch veins (SNV). The role of the anterior coracoscapular ligament (ACSL) is still not clear. While some studies indicate that it may predispose for SNES, the newest study proposes a protective function. Knowledge of these variations is essential for arthroscopic and other surgical procedures of this area in order to avoid iatrogenic injury of the suprascapular nerve or unexpected bleeding from the suprascapular vessels running alongside the STSL.


Total syntheses and in vivo quantitation of novel neurofuran and dihomo-isofuran derived from docosahexaenoic acid and adrenic acid.
Neurofurans (NeuroFs) and dihomo-isofurans (dihomo-IsoFs) are produced in vivo by non-enzymatic free-radical pathways from docosahexaenoic and adrenic acids, respectively. As these metabolites are produced in minute amounts, their analyses in biological samples remain challenging. Syntheses of neurofuran and dihomo-isofurans described are based on a pivotal strategy, thanks to an enantiomerically enriched intermediate, which allowed, for the first time, access to both families: the alkenyl and enediol. Owing to this formation, quantitation of specific NeuroF and dihomo-IsoFs in biological samples was attainable.


REACTION NORMS OF MORPHOLOGICAL TRAITS IN DROSOPHILA: ADAPTIVE SHAPE CHANGES IN A STENOTHERM CIRCUMTROPICAL SPECIES?
Reaction norms of wing length, thorax length, and ovariole number were studied according to growth temperature in the circumtropical Drosophila ananassae, and compared to similar data from the cosmopolitan D. melanogaster. In the two species convex reaction norms were observed, but they were not parallel and sometimes exhibited intersections either at high (wing) or at low (thorax) temperature. On average, D. ananassae may be considered as a species with a bigger thorax but shorter wings than D. melanogaster. The shapes of reaction norms were analyzed and compared after quadratic polynomial adjustments. Significant differences were observed, in several cases between polynomial parameters, and in all cases between characteristic points that is, Maximum Value (MV) and Temperature of Maximum Value (TMV). The wing/thorax ratio may also be considered as a specific trait related to wing loading. Major differences were observed between the two species for the mean value and the shape of the response curves of this trait. The main observation of this work was however a shift of TMVs for wing and thorax length and ovariole number in D. ananassae toward higher temperatures. These variations in the reaction norms corresponded to a shift in the species thermal range, suggesting that temperature adaptation was accompanied by a modification of the shape of the response curves.


Tp44 molecules involved in antigen-independent T cell activation are expressed on human plasma cells.
We have analyzed cells of the B lineage for expression of the Tp44 antigen, a 44,000 homodimer detected by monoclonal antibody 9.3 on approximately 80% of mature human T lymphocytes. Previous evidence has suggested that Tp44 may function as a receptor for accessory signals in T cell activation. High level Tp44 expression was observed on plasmacytomas grown in cell culture and on plasma cells from bone marrow biopsies of multiple myeloma patients. This antigen is not present on resting B cells from either peripheral blood or lymphoid organs, or on any other B cell tumor. The growth kinetics and Ig production in plasmacytomas are not affected by the binding of antibody 9.3. Moreover, the Tp44 molecule is co-expressed with PCA-1, an antigen characteristic of plasma cells, on peripheral blood B cells stimulated in vitro to differentiate toward plasma cells. Tp44 may represent a later stage of B cell differentiation than PCA-1 because unlike the PCA-1 antigen, this molecule could not be detected on any EBV-transformed cell line or Burkitt's lymphoma lines. The m.w. of the Tp44 molecule expressed on plasma cells and on T cells is identical, as determined by immunoprecipitation of radioiodinated cell surface proteins with monoclonal antibody 9.3. This antigen might be useful in studying the mechanism of growth and differentiation of human B cells, the heterogeneity within plasma cell populations, and B cell interactions with other components of the immune system.


Investigation of germline variants in Bahraini women with breast cancer using next-generation sequencing based-multigene panel.
Germline variants in BRCA1 and BRCA2 (BRCA1/2) genes are the most common cause of hereditary breast cancer. However, a significant number of cases are not linked to these two genes and additional high-, moderate- and low-penetrance genes have been identified in breast cancer. The advent of next-generation sequencing (NGS) allowed simultaneous sequencing of multiple cancer-susceptibility genes and prompted research in this field. So far, cancer-predisposition genes other than BRCA1/2 have not been studied in the population of Bahrain. We performed a targeted NGS using a multi-panel covering 180 genes associated with cancer predisposition to investigate the spectrum and frequency of germline variants in 54 women with a positive personal and/or family history of breast cancer. Sequencing analysis revealed germline variants in 29 (53.7%) patients. Five pathogenic/likely pathogenic variants in four DNA repair pathway-related genes were identified in five unrelated patients (9.3%). Two BRCA1 variants, namely the missense variant c.287A>G (p.Asp96Gly) and the truncating variant c.1066C>T (p.Gln356Ter), were detected in two patients (3.7%). Three variants in non-BRCA1/2 genes were detected in three patients (1.85% each) with a strong family history of breast cancer. These included a monoallelic missense variant c.1187G>A (p.Gly396Asp) in MUTYH gene, and two truncating variants namely c.3343C>T (p.Arg1115Ter) in MLH3 gene and c.1826G>A (p.Trp609Ter) in PMS1 gene. Other variants of uncertain significance (VUS) were also detected, and some of them were found together with the deleterious variants. In this first application of NGS-based multigene testing in Bahraini women with breast cancer, we show that multigene testing can yield additional genomic information on low-penetrance genes, although the clinical significance of these genes has not been fully appreciated yet. Our findings also provide valuable epidemiological information for future studies and highlight the importance of genetic testing, and an NGS-based multigene analysis may be applied supplementary to traditional genetic counseling.


Repression of the expression of TET2 by ZEB1 contributes to invasion and growth in glioma cells.
Malignant gliomas are the most common and aggressive type of brain tumor. The suppressive role of ten-eleven translocation 2 (TET2) has been implicated in certain types of cancer, however, its role in gliomas remains to be elucidated. The present study aimed to determine the expression pattern and biological role of TET2 in glioma, using RT-qPCR and immunohistochemistry, and its results indicated that the expression of TET2 was frequently decreased in gliomas and that repression of the expression of TET2 correlated with the progression of glioma. The ectopic expression of TET2 inhibited the invasive potential of glioma cells, and inhibited glioma cell proliferation in vitro and growth in vivo. Additionally, the expression of Zinc finger E‑box‑binding homeobox 1 (ZEB1) was increased in gliomas and was positively correlated with progression, but inversely correlated with the expression of TET2. ZEB1 was also confirmed to physically bind to the TET2 promoter. ZEB1 knockdown resulted in an increase in the expression of TET2 and elevation of TET2 promoter activity in glioma cells. These findings indicated that the downregulation of TET2 by ZEB1 is a critical oncogenic event in gliomas.


[A patient education program after breast cancer surgery].
In France, one woman in eight is treated for breast cancer before the age of 75. The 2009-2013 cancer plan recommends providing support for women after cancer. A therapeutic education programme helps them reintegrate into their daily life.


Simple heart rate and QT parameters during stress exercise testing to assess presence and severity of stable coronary artery disease.
Aim: The relationship between QT prolongation and myocardial ischemia is well known, however not many studies have correlated corrected QT interval and heart rate recovery with the severity of coronary artery disease (CAD). Methods: This was a single-center, prospective, observational study which included 127 patients with CAD and 124 patients without CAD. Results: Corrected QT variability from peak to recovery correlated well with CAD with a p value of 0.03. Receiver operative characteristic analysis did not show any significant diagnostic accuracy with any heart rate or QT parameters for predicting the presence or severity of CAD. Conclusion: Coronary artery disease is predicted by reduced ability of the heart rate to rise from rest to peak exercise and reduced recovery of heart rate and corrected QT from peak exercise to recovery at 1 min.


The prevalence of drug-resistant and virulent Staphylococcus spp. in a municipal wastewater treatment plant and their spread in the environment.
Drug-resistant and pathogenic Staphylococcus spp. strains can reach surface waters and air with wastewater evacuated to the environment. These strains increase the environmental pool of genetic determinants conferring antibiotic resistance and virulence, and constitute a health risk for the employees of wastewater treatment plants (WWTP) who come into daily contact with bioaerosols. The aim of this study was to identify the genetic determinants of drug resistance and virulence in Staphylococcus spp. strains isolated from untreated (UWW) and treated wastewater (TWW), an activated sludge (AS) bioreactor, river water collected upstream and downstream from the wastewater discharge point (URW and DRW), and WWTP employees. All isolates were analysed for the presence of the rpoB gene, and were subjected to clonal analysis by ERIC fingerprinting. As a result, 249 of the 455 analysed isolates were selected for PCR. The presence of the gene encoding nuclease activity in S. aureus (nuc), the methicillin resistance gene (mecA), vancomycin resistance gene (vanA), antiseptic resistance gene (qacA/B) and virulence genes (sasX, pvl, tst1, hla, sec) was determined. The prevalence of nuc, mecA, vanA and qacA/B genes in wastewater and river water was determined by quantitative PCR (qPCR). In the group of strains isolated from wastewater and water samples, 63% were identified as S. aureus, and 20% of the strains carried the vanA gene. The hla virulence gene was present in 80% of the isolates, and the pvl gene was detected in 27% of the isolates. In the group of strains isolated from the employees, 82% were identified as S. aureus, and the presence of vanA and mecA genes was confirmed in 14% and 16% of the isolates, respectively. The most prevalent virulence gene was hla (74%), whereas pvl was observed in 43% of the isolates. The quantitative analysis revealed the highest concentrations of the studied genes in UWW samples, at 2.56x104 gene copies/ml for nuc, 1.18x103 gene copies /ml for mecA, 8.28x105 gene copies /ml for vanA and 3.83x105 gene copies /ml for qacA/B. Some of analysed genes were identified in the isolates from both URW and DRW samples, as well as in genomic DNA of these samples. These results indicate that wastewater is not effectively treated in the analysed WWTP, which could contribute to the dissemination of antibiotic resistance genes (ARGs) and antibiotic-resistant bacteria (ARB) to the environment. An analysis of the genetic relatedness of selected isolates revealed clusters of strains originating from UWW samples, AS samples and the employees. These observations suggest that ARGs and ARB are transmitted by wastewater bioaerosols to the upper respiratory tract mucosa of the plant's employees, thus increasing their exposure to infectious factors.


[A randomized controlled study of chemotherapy: etoposide combined with oxaliplatin or cisplatin regimens in the treatment of extensive-stage small cell lung cancer in elderly patients].
Etoposide combined cisplatin (EP) is the most commonly-used first-line treatment combination chemotherapy regimen in the treatment of extensive-stage small cell lung cancer (SCLC), The side-effects of cisplatin, such as nausea and vomiting, influence patients' quality of life. This study aims to compare the efficacy and toxicities between etoposide plus oxaliplatin (EO) and etoposide plus cisplatin (EP) regimens as first-line chemotherapy for elderly patients with SCLC. Seventy-one old, extensive-stage SCLC patients, who had not received anti-tumor treatment, were randomly divided into two groups, namely, EO group (etoposide: 80 mg/m² d1-5+oxaliplatin; 130 mg/m² d1; repeated every 21 days) and EP group (etoposide: 80 mg/m² d1-5+cisplatin; 25 mg/m² d1-3; repeated every 21 days). Efficacy and toxicities were evaluated after 2 or more cycles. No statistical differences were observed between the EO and EP groups in the response rate (55.9% vs 54.3%, P=0.894), disease control rate (82.4% vs 77.1%, P=0.591), median progression free survival (5.5 months vs 4.7 months, P=0.638), and median survival time (10.5 months vs 9.1 months, P=0.862). In terms of toxicities, the incidence of nausea/vomiting in the EO group was significantly lower than that in the EP group (65.7% vs 97.2%, P=0.001), but the neurotoxicity of grade 1-2 in the EO group was more significant (74.3% vs 11.1%, P<0.001). The clinical efficiency of EO and EP regimens is similar to the first-line chemotherapy for extensive-stage SCLC in elderly patients. However, the tolerance of EO regimens is better than that in the EP regiments.


Eupatoriopicrin Inhibits Pro-inflammatory Functions of Neutrophils via Suppression of IL-8 and TNF-alpha Production and p38 and ERK 1/2 MAP Kinases.
During chronic inflammation, neutrophils acting locally as effector cells not only activate antibacterial defense but also promote the inflammatory response. Interleukin 8 (IL-8), the main cytokine produced by activated neutrophils, positively correlates with the severity of respiratory tract diseases. By screening European plants traditionally used for treating respiratory tract diseases, we found that extracts of aerial parts of Eupatorium cannabinum inhibit IL-8 release from neutrophils. Using bioassay-guided fractionation, we identified five sesquiterpene lactones, eupatoriopicrin (1), 5'-deoxyeupatoriopicrin (2), hiyodorilactone A (3), 3-hydroxy-5'- O-acetyleupatoriopicrin = hiyodorilactone D (4), and hiyodorilactone B (5), that efficiently (IC50 < 1 μM) inhibited IL-8 and TNF-α release in lipopolysaccharide (LPS)-stimulated human neutrophils. Moreover, all these sesquiterpene lactones suppressed the adhesion of human neutrophils to an endothelial monolayer by downregulating the expression of the β2 integrin CD11b/CD18 on the neutrophil surface. Furthermore, eupatoriopicrin efficiently suppressed LPS-induced phosphorylation of p38 MAPK and ERK and attenuated neutrophil infiltration in the thioglycolate-induced peritonitis model in mice. Altogether, these results demonstrate the potential of the sesquiterpene lactone eupatoriopicrin as a lead substance for targeting inflammation.


Neural Correlates of Risk Processing Among Adolescents: Influences of Parental Monitoring and Household Chaos.
Adolescent risky behavior is related to developmental changes in decision-making processes and their neural correlates. Yet, research investigating how the family environment relates to risk processing in the adolescent brain is limited. In this study, longitudinal data were collected from 167 adolescents (13-15 years, 53% male) who self-reported household chaos and their parent's monitoring practices, and completed a decision-making task during functional MRI at Time 1 and Time 2 (1 year apart). Parental knowledge was positively related to insular risk processing only among adolescents in low-chaos environments at both time points. Results highlight environmental correlates of insular risk processing in the developing brain.


Dual photo-functionalized amphiphile for photo-reversible liquid crystal alignments.
Without the conventional polymer-based liquid crystal (LC) alignment process, a newly synthesized dual photo-functionalized amphiphile (abbreviated as ADMA1 ) was successfully applied as a robust photo-reversible LC alignment layer by self-assembly and photo-polymerization. The LC alignment layer constructed by directly adding dual photo-functionalized amphiphiles into LC media significantly cuts the manufacturing cost as well as opens new doors for the fabrication of novel electro-optical devices.


Anti-P. gingivalis response correlates with atherosclerosis.
Significant associations between atherosclerosis and both Porphyromonas gingivalis, a major periodontopathogen, and the respiratory pathogen, Chlamydia pneumoniae, have been shown. Many individuals with evidence of atherosclerosis demonstrate seropositivity to these pathogens. The aim of the present study was to examine the atherogenic effect of repeated immunizations with either or both of these agents, and to determine if molecular mimicry of bacterial heat-shock protein (HSP), termed GroEL, and host (h) HSP60 was involved. Atherogenesis was examined in apolipoprotein-E-deficient (-/-) mice following intraperitoneal immunizations with P. gingivalis, C. pneumoniae, P. gingivalis, and C. pneumoniae or vehicle. Lesion area in the proximal aorta and levels of serum antibodies to P. gingivalis, C. pneumoniae, and GroEL were measured. The increased pathogen burden of P. gingivalis, but not of C. pneumoniae, enhanced atherosclerosis. hHSP60 was detected in lesions, and in P. gingivalis-immunized mice, lesion development was correlated with anti-GroEL antibody levels, supporting the involvement of molecular mimicry between GroEL and hHSP60.


A technique for hypophysectomy.
The procedure of hypophysectomy may offer some hope in metastatic carcinoma of the breast. Certainly further clinical trial is indicated. The anterior intracranial approach through the sphenoid sinus was used in eight cases. It offers a technically easier route by which to perform hypophysectomy. The immediate risk of operation does not appear to be too great. Caution must be urged against delaying this procedure until the patient is in a terminal condition.


The Effect of Chia Seeds on High-Density Lipoprotein (HDL) Cholesterol.
Chia seeds are touted as a healthy food capable of providing a beneficial effect on high-density lipoprotein (HDL) cholesterol. Similar claims have been made for oats in various forms, claiming that they improve cholesterol or are in some way "heart healthy." This study aims to demonstrate the effect of daily consumption of chia seeds, if any, on HDL cholesterol levels and compare this to the effects of oats on HDL levels. This pilot study is a randomized controlled trial performed at an academic primary care center. Participation was voluntary, and all participants provided written consent prior to enrollment. There were no exclusion criteria other than that participants must be adults and willing to come in to get their cholesterol profiles checked at the beginning and end of the study. The participants consumed their assigned breakfast in a standard serving size for a month with blood draws and weights recorded before and after the diet. The patients' cholesterol profiles were also compared with their weights. To standardize the delivery of chia seeds, the group consuming chia seeds mixed them with oatmeal. The three meal groups consisted of Cheerios (red group), oatmeal (white group), and oatmeal with chia seeds (blue group). Initially, there were a total of 11 subjects, three in the red group, four in the white group, and four in the blue group. Two subjects were lost to follow-up, one each from the red and white groups. Statistical analysis including one-way analysis was done with the means, Wilcoxon/Kruskal-Wallis, and one-way analysis tests. The results showed a similar weight gain pattern between the three groups, with an average of 2.8 lbs gained in the red group, 2.4 lbs gained in the white group, and 2.6 lbs gained in the blue group. The average HDL levels decreased by 1.00 mg/dL in the red group (standard deviation (SD) 2.82843), increased by 2.00 mg/dL in the white group (SD 8.88819), and increased by 5.75 mg/dL in the blue group (SD 8.01561). The HDL:total cholesterol ratios decreased by 0.00748 in the red group (SD 0.002660), an average of 0.04053 in the white group (SD 0.028138), and an average of 0.01614 in the blue group (SD 0.023808). The results suggest that both chia seeds and oatmeal may be good dietary sources to naturally increase HDL cholesterol, more substantially so with the diet including chia seeds, but may or may not improve total cholesterol:HDL ratios. The effect of weight gain is unclear, as all groups gained weight similarly. Hence, further study is warranted.


Impingement-related osteolysis in Motec total wrist arthroplasty: an explant analysis and review of the literature.
We present five cases of osteolysis in the Motec total wrist prosthesis, three around the radial implant, one around the metacarpal implant and one around both. Three of these were progressive and required revision, and biomechanical explant analyses of these revised prostheses were performed. Ex vivo testing of the contact points of the Motec implants was also performed at maximum extension. Here, impingement occurs between the metacarpal screw and the dorsal rim of the cup (non-articulating surfaces) with the short-necked prosthesis, leading to metacarpal screw damage, titanium debris formation and osteolysis. An analysis of three previously published cases suggests that this may have been the likely mode of failure in those cases. This complication is preventable by avoiding use of the short-neck prosthesis.Level of evidence: IV.


Ventilatory muscle strength in cystic fibrosis patients: a literature review.
The ventilatory mechanic changes that occur in cystic fibrosis (CF) patients may lead to alterations in the respiratory muscle strength levels. However, the findings regarding the strength profile in these patients are still contradictory. To evaluate, trough a literature review, the respiratory muscle strength behavior in CF patients. We have performed a search in Medline/Pubmed, Scielo, IBECS and LILACS databases selecting observational cross-sectional, prospective or retrospective studies, as well as randomized clinical trials, published between 1981 and 2011, using the following terms: cystic fibrosis, respiratory muscle strength, inspiratory maximal pressure and muscle training. The majority of the studies 71.24% have shown normal or above normal respiratory muscle strength, whilst 28.57% demonstrated reduced or near-normal values. Most of these findings were attributed to an increased work of breathing as a result of airway obstruction and chronic persistent cough. Taken together, the analyses of selected studies have showed conflicting findings regarding respiratory muscle strength behavior in these patients. However, most of the studies seem to indicate that CF patients presented maximum respiratory pressures normal or above predicted values.


Effect of Simulation on Learner Stress as Measured by Cortisol: An Integrative Review.
Simulated learning has become a mainstay in nursing education. Current literature focuses primarily on the development and implementation of simulation, although little is known about the stress that students experience. This integrative review examines studies evaluating learner stress in simulated settings as measured by cortisol. Findings suggest that cortisol is a valid measure of stress in simulation. Evidence is inconclusive on whether elevated stress during simulation promotes performance.


Heparin in patients with venous thromboembolism and contraindications to oral anticoagulant therapy.
After an initial course of heparin therapy, patients with venous thromboembolism require continuing anticoagulant therapy for several months after hospital discharge to prevent recurrences. For most patients oral anticoagulants are the treatment of choice. However, patients receiving therapy need to participate in frequent and careful laboratory monitoring, and a patient's inability or unwillingness to cooperate in such procedures should contraindicate the use of oral anticoagulants. Oral anticoagulants may also be contraindicated in patients with serious coexisting conditions. Finally, several authors consider the oral anticoagulants should not be administered to elderly people, and when administered to pregnant women, they may be associated with embryopathy. Several trials have demonstrated that subcutaneous heparin may be an acceptable alternative to coumarin. However, the high doses required for continuing prophylaxis have raised concerns about the risks of development of osteoporosis and bone fractures. The recently developed low-molecular-weight heparins constitute a good alternative.


Association of the Arabidopsis CTR1 Raf-like kinase with the ETR1 and ERS ethylene receptors.
In Arabidopsis thaliana, signal transduction of the hormone ethylene involves at least two receptors, ETR1 and ERS, both of which are members of the two-component histidine protein kinase family that is prevalent in prokaryotes. The pathway also contains a negative regulator of ethylene responses, CTR1, which closely resembles members of the Raf protein kinase family. CTR1 is thought to act at or downstream of ETR1 and ERS based on double mutant analysis; however, the signaling mechanisms leading from ethylene perception to the regulation of CTR1 are unknown. By using the yeast two-hybrid assay, we detected a specific interaction between the CTR1 amino-terminal domain and the predicted histidine kinase domain of ETR1 and ERS. We subsequently verified these interactions by using an in vitro protein association assay(s). In addition, we determined that the amino-terminal domain of CTR1 can associate with the predicted receiver domain of ETR1 in vitro. Based on deletion analysis, the portion of CTR1 that interacts with ETR1 roughly aligns with the regulatory region of Raf kinases. These physical associations support the genetic evidence that CTR1 acts in the pathway of ETR1 and ERS and suggest that these interactions could be involved in the regulation of CTR1 activity.


Characterization and application of aptamers for Taq DNA polymerase selected using an evolution-mimicking algorithm.
Using an evolution-mimicking algorithm (EMA), we have recently identified DNA aptamers that inhibit Taq DNA polymerase. In the present study, we have attempted to improve further the inhibitory activities of aptamers, as well as to characterize those aptamers with the most potent inhibitory activities. To characterize the most potent aptamer and demonstrate its applicability, the abilities to inhibit Tth DNA polymerase and to modulate specific amplification in PCR were investigated. This aptamer inhibited both Tth DNA polymerase and Taq DNA polymerase and improved the specificity of detection of a low-copy-number target gene in PCR using these DNA polymerases.


High-grade glioma with anterior skull base erosion and intranasal extension: case report.
The authors describe the case of a large WHO Grade III anaplastic oligoastrocytoma extending through the anterior skull base and into the right nasal cavity and sinuses. Glial neoplasms are typically confined to the intracranial compartment within the brain parenchyma and rarely extend into the nasal cavity without prior surgical or radiation therapy. This 42-year-old woman presented with progressive headaches and sinus congestion. MR imaging findings revealed a large intracranial lesion with intranasal extension. Endoscopic nasal biopsy revealed pathology consistent with an infiltrating glioma. The patient subsequently underwent a combined transcranial/endonasal endoscopic approach for resection of this lesion. Pathological diagnosis revealed a WHO Grade III oligoastrocytoma. This report reviews the mechanisms of extradural glioma extension. To the authors' knowledge, it is the second report of a high-grade glioma exhibiting nasal extension without prior surgical or radiation treatment.


Locally Identified Priorities for Continuous Quality Improvement (CQI) During Early Implementation of an Evidence-Based Early Childhood Home Visiting Program.
The 2010 Affordable Care Act provided for evidence-based home visiting and an accompanying continuous quality improvement (CQI) process in all states and territories. This is an organizational-level study of one state's qualitative approach to CQI during early implementation, when data system infrastructure and local agency capacity were still developing. We examined the CQI topics created by local agencies and operationalized through a qualitative, strength-based CQI process. During the first 18 months, state and local site teams (n = 21) participated in 150 CQI teleconferences. We used qualitative content analysis of teleconference notes to identify issues important to sites and that could be addressed through a qualitative CQI process. Seven categories of CQI topics emerged: participant enrollment and retention; administrative infrastructure and capacity; programmatic resources and practices; community advisory boards; home visitor skill development; systems integration and strategic partnerships; and hiring home visiting staff. Sites added local nuances to frame and address CQI topics. When local sites identify their own CQI topics in early implementation, they addressed program need at multiple levels of influence. A few sites addressed individually focused topics traditional to CQI. Most often, sites engaged with institution- or community-focused topics atypical for CQI but nonetheless essential to launching a program: building skills and capacity for administrative and program implementation, and engaging with the local system of services. Oversight agencies should be prepared to address program, organization, partner or system level issues through CQI to foster program establishment. A site-centered, strength-based approach can support programs even when quantitative data are limited.


Systemic inflammatory response syndrome (SIRS) and a left bundle branch block (LBBB) due to nitrofurantoin.
We present a case of a 74-year-old woman, who was on nitrofurantoin treatment for urinary tract infection (UTI), with fever and chills 7 hours after taking nitrofurantoin. She was hospitalised and evaluated for worsening UTI and sepsis. Initially, it appeared to be secondary to post-UTI sepsis because of possible resistant infection or conditions like pulmonary embolism or acute hepatitis. The patient also developed systemic inflammatory response syndrome, left bundle branch block (LBBB), thrombocytopaenia and transaminitis. Considering the side effects of nitrofurantoin, it was stopped. The patient showed improvement and recovered completely with symptomatic and supportive treatment. During follow-up visits with her primary care physician, thrombocytopaenia, transaminitisandLBBB were found to have been resolved.


Eye growth changes in myopic children in Singapore.
To assess the longitudinal changes in biometric parameters and associated factors in young myopic children aged 7--9 years followed prospectively in Singapore. Children aged 7--9 years from three Singapore schools were invited to participate in the SCORM (Singapore Cohort study Of the Risk factors for Myopia) study. Yearly eye examinations involving biometry measures were performed in the schools. Only myopic children (n=543) with 3 year follow up data were included in this analysis. The 3 year increases in axial length, anterior chamber depth, lens thickness, vitreous chamber depth, and corneal curvature were 0.89 mm, -0.02 mm, -0.01 mm, 0.92 mm, and 0.01 mm, respectively. Children who were younger, female, and who had a parental history of myopia were more likely to have greater increases in axial length. After adjustment for school, age, sex, race, parental myopia and reading in books per week, the age (p<0.001), sex (p=0.012), and parental myopia (p=0.027) remained significantly associated with the 3 year change in axial length. Reading in books per week, however, was not associated with axial length change. Children with faster rates of progression of myopia had greater increases in axial length (Pearson correlation coefficient (r)=-0.69) and vitreous chamber depth (r=-0.83). The 3 year change in axial length of Singapore children aged 7--9 years at baseline was high and greater in younger children, females, and children with a parental history of myopia. Myopia progression was driven largely by vitreous chamber depth increase.


Caraway and caper: potential anti-hyperglycaemic plants in diabetic rats.
The hypoglycaemic effect of aqueous extracts of Carum carvi (CC) and Capparis spinosa L. (CS) fruit were investigated in normal and streptozotocin (STZ) diabetic rats. After a single dose or 14 daily doses, oral administration of the aqueous CC and CS extracts (20 mg/kg) produced a significant decrease on blood glucose levels in STZ diabetic rats (P < 0.001); the blood glucose levels were nearly normalised 2 weeks after daily repeated oral administration of both aqueous CC and CS extracts (20 mg/kg) (P < 0.001). No highly significant changes on blood glucose levels were noticed in normal rats after both acute and chronic treatments with CS and CC. In addition, no changes were observed in basal plasma insulin concentrations after treatment with these plants in either normal or STZ diabetic rats indicating that the underlying mechanism of this pharmacological activity seems to be independent of insulin secretion. We conclude that aqueous extracts of CC and CS exhibit a potent anti-hyperglycaemic activity in STZ rats without affecting basal plasma insulin concentrations.


Ezrin, maspin, peroxiredoxin 2, and heat shock protein 27: potential targets of a streptococcal-induced autoimmune response in psoriasis.
Psoriasis is an HLA-Cw6-associated T cell-mediated autoimmune disease of the skin that is often triggered by streptococcal angina. To identify keratinocyte proteins, which may become psoriatic autoantigens as the result of an immune response against streptococci, rabbits were immunized with heat-killed Streptococcus pyogenes. Streptococcal immunization induced Ab formation against various human keratinocyte proteins. Sera from psoriasis patients reacted against several of these proteins as well. Common serologic reactivities of rabbits and patients included the proteins ezrin, maspin, peroxiredoxin 2 (PRDX2), heat shock protein (hsp)27, and keratin 6. When used for stimulation of blood lymphocytes, ezrin, maspin, PRDX2, and hsp27 induced increased T cell activation in psoriasis patients, which was particularly evident for HLA-Cw6(+) individuals. Ag-specific T cell lines generated with these proteins consisted predominantly of CD8(+) T cells and used TCR beta-chain rearrangements, which were highly homologous to those expanded within the corresponding skin lesion. Several immunodominant epitopes on the different proteins could be defined according to sequence alignments with the whole genome of S. pyogenes. Our data indicate that maspin, ezrin, PRDX2, hsp27, and potentially keratin 6 could act as autoantigens of a streptococcal-induced autoimmune response and represent targets of the exaggerated T cell response in psoriasis. Additionally, ezrin and hsp27 might constitute antigenic links between psoriasis and inflammatory bowel disease, uveitis, or arteriosclerosis, which are clinically associated.


Aggressive therapy for cancer of the pancreas. Does it help?
Aggressive therapy clearly plays a role in the management of pancreatic cancer, be it localized to that organ, limited to the upper abdomen, or metastatic. A significant percentage of patients with resectable disease can be salvaged by radical resection of the cancer and aggressive adjuvant therapies. Five-year survival rates exceeding 30% have been reported from Japan. A supportive-care-only treatment philosophy ensures that almost all patients will die of cancer and that new treatment regimens will not be evaluated, creating a self-fulfilling prophecy. Such a policy is no longer tenable.


Circulating Syndecan-1 Levels Are Associated with Chronological Coagulofibrinolytic Responses and the Development of Disseminated Intravascular Coagulation (DIC) after Trauma: A Retrospective Observational Study.
The purpose of this study was to evaluate the association between endotheliopathy represented by high levels of circulating syndecan-1 (SDC-1) and coagulofibrinolytic responses due to trauma, which can lead to disseminated intravascular coagulation (DIC). We retrospectively evaluated 48 eligible trauma patients immediately admitted to our hospital and assessed SDC-1 and coagulofibrinolytic parameters for 7 days after admission. We compared the longitudinal changes of coagulofibrinolytic parameters and SDC-1 levels between two groups (high and low SDC-1) according to median SDC-1 value on admission. The median circulating SDC-1 level was 99.6 (61.1-214.3) ng/mL on admission, and levels remained high until 7 days after admission. Coagulofibrinolytic responses assessed by biomarkers immediately after trauma were correlated with SDC-1 elevation (thrombin-antithrombin complex, TAT: r = 0.352, p = 0.001; antithrombin, AT: r = -0.301, p < 0.001; plasmin-α2-plasmin inhibitor complex, PIC: r = 0.503, p = 0.035; tissue plasminogen activator, tPA: r = 0.630, p < 0.001). Sustained SDC-1 elevation was associated with intense and prolonged coagulation activation, impairment of anticoagulation, and fibrinolytic activation followed by inhibition of fibrinolysis, which are the primary responses associated with development of DIC in the acute phase of trauma. Elevation of circulating SDC-1 level was also associated with consumption coagulopathy and the need for transfusion, which revealed a significant association between high SDC-1 levels and the development of DIC after trauma (area under the curve, AUC = 0.845, cut-off value = 130.38 ng/mL, p = 0.001). High circulating levels of syndecan-1 were associated with intense and prolonged coagulation activation, impairment of anticoagulation, fibrinolytic activation, and consumption coagulopathy after trauma. Endotheliopathy represented by SDC-1 elevation was associated with trauma induced coagulopathy, which can lead to the development of DIC.


Lactational exposure to low levels of the six indicator non-dioxin-like polychlorinated biphenyls induces DNA damage and repression of neuronal activity, in juvenile male mice.
Previously, we evaluated the effects of lactational exposure to a representative mixture of the six indicator non-dioxin-like polychlorinated biphenyls (∑6 NDL-PCBs) at low levels on the neurobiological changes and developmental/behavioral performances in mice. In this study, we analyzed the global gene expression profile in cerebellar neurons isolated from male mice presenting the most significant induction of anxiety-like behavior in our previous study (10 ng/kg ∑6 NDL-PCBs). Our results revealed changes in the expression of 16658 genes in the neurons of the exposed mice. Among these, 693 upregulated [fold change (FC)>2; p<0.05] and 665 downregulated (FC<2; p<0.05) genes were statistically linked to gene ontology terms (GO). Overexpressed genes belonged to GO terms involved with the cell cycle, DNA replication, cell cycle checkpoint, response to DNA damage stimulus, regulation of RNA biosynthetic processes, and microtubule cytoskeleton organization. Downregulated genes belonged to terms involved with the transmission of nerve impulses, projection neurons, synapse hands, cell junctions, and regulation of RNA biosynthetic processes. Using qPCR, we quantified gene expression related to DNA damage and validated the transcriptomic study, as a significant overexpression of Atm-Atr Bard1, Brca2, Fancd2, Figf, Mycn, p53 and Rad51 was observed between groups (p<0.001). Finally, using immunoblots we determined the expression level of six selected proteins. We found that changes in the protein expression of Atm Brca1, p53, Kcnma1, Npy4r and Scn1a was significant between exposed and control groups (p<0.05), indicating that the expression pattern of these proteins agreed with the expression pattern of their genes by qPCR, further validating our transcriptomic findings. In conclusion, our study showed that early life exposure of male mice to a low level of ∑6 NDL-PCBs induced p53-dependent responses to cellular stress and a decrease in the expression of proteins involved in the generation, conduction, and transmission of electrical signals in neurons.


The Botanical Drug Substance Crofelemer as a Model System for Comparative Characterization of Complex Mixture Drugs.
Crofelemer is a botanical polymeric proanthocyanidin that inhibits chloride channel activity and is used clinically for treating HIV-associated secretory diarrhea. Crofelemer lots may exhibit significant physicochemical variation due to the natural source of the raw material. A variety of physical, chemical, and biological assays were used to identify potential critical quality attributes (CQAs) of crofelemer, which may be useful in characterizing differently sourced and processed drug products. Crofelemer drug substance was extracted from tablets of one commercial drug product lot, fractionated, and subjected to accelerated thermal degradation studies to produce derivative lots with variations in chemical and physical composition potentially representative of manufacturing and raw material variation. Liquid chromatography, UV absorbance spectroscopy, mass spectrometry, and nuclear magnetic resonance analysis revealed substantial changes in the composition of derivative lots. A chloride channel inhibition cell-based bioassay suggested that substantial changes in crofelemer composition did not necessarily result in major changes to bioactivity. In 2 companion papers, machine learning and data mining approaches were applied to the analytical and biological data sets presented herein, along with chemical stability data sets derived from forced degradation studies, to develop an integrated mathematical model that can identify CQAs which are most relevant in distinguishing between different populations of crofelemer.


Ecotoxicological effects of per- and polyfluoroalkyl substances (PFAS) and of a new PFAS adsorbing organoclay to immobilize PFAS in soils on earthworms and plants.
A novel adsorptive organoclay (Intraplex A®) was developed for the in situ immobilization of per- and polyfluoroalkyl substances (PFAS) in the vadose zone. We provide the first evaluation of the effects of Intraplex A® on earthworms and plants in a PFAS-contaminated soil. Ecotoxicological tests were carried out on control soil with and without Intraplex A® (C + I and C, respectively) and PFAS-contaminated soil with and without Intraplex A® (PFAS + I and PFAS, respectively). We investigated the acute ecotoxicological effects of PFAS and Intraplex A® on the growth, reproduction and survival of earthworms (Eisenia fetida) and on plant growth (oat - Avena sativa and turnip - Brassica rapa L. silvestris). Earthworm lethality was 7.6 lower in PFAS + I than in PFAS soil. Earthworms avoided 100% C + I and PFAS + I soils, and reduced earthworms' reproduction was observed in both these soils. For both plant species, the PFAS + I soil yielded less fresh and dry shoot biomass than the PFAS soil, while root growth remained unaffected (all tests: p < 0.05). Soils with Intraplex A® had some negative effects on plants and earthworms, which must be balanced with its benefits as an in situ PFAS adsorbent.


Responses of systemic vascular smooth muscle to hypoxia.
The rapidity and extent of hypoxic relaxation of vascular smooth muscle (VSM) from different systemic vessels is relevant to the study of mechanisms of vasodilation in different vascular beds. Variations between sites may also assist understanding of the link between oxygen tension and mechanical activity, which has been shown not to be a simple deprivation of aerobic processes. Strips of rat portal vein (RPV), rabbit ear artery (REA) and rabbit common carotid artery (RCC) were studied under isotonic conditions, contracted by 10(-6) noradrenaline (NA). Reduction of Po2 to less than 3KPa during NA constraction led to relaxation which was rapid and 90% complete in RPV, rapid and 60% in REA: the relaxation began when tissue Po2 was decreasing and was not lower than 5.5 K Pa. RCC responded slowly and only some strips relaxed. The rapidity and magnitude of relaxation for each type of vessel was comparable to that produced by removal of external calcium. Also for any one type of VSM the response to NA was abolished or diminished to a similar extent by preliminary exposure to hypoxia, or by preliminary removal of calcium. Preliminary hypoxia diminished 50 mmol.1(-1) K+ contractions as much as it diminished NA contractions. Preliminary 1-2 hour exposure to hyperoxia diminished the subsequent relaxant effect of hypoxia. Inhibition of glycolysis (iodoacetic acid) had no effect on normoxic NA contraction or on hypoxic relaxation, but prevented or diminished the subsequent recovery on reoxygenation. Low oxygen tension appears to act in VSM as though it interferes with net influx or utilisation of external calcium.


Acoustic rhinometry: an explanation of some common artefacts associated with nasal decongestion.
The nasal cavities of 51 healthy volunteers were examined using acoustic rhinometry before and after nasal decongestant. Several specific dimensions were studied, which included the minimum cross-sectional area, and three volumes corresponding to the anterior, middle and posterior regions of the nasal airway. An average acoustic rhinometry trace was constructed for the whole group of subjects, before and after decongestion, from data extracted from the raw data files written to the computer hard disk for each subject. A 27.5% (P < 0.0001) increase in the minimum cross-sectional area was observed, with no shift in its position. The greatest increase in nasal dimensions was seen in the anterior and middle parts of the nose, however, significant changes were also seen in the posterior nasal cavity and post nasal space. There are a number of possible sources of artefact. First, confusion of the first and second minima may produce apparent movement of the minimum cross-sectional area following nasal decongestion. Second, a postulated change in the acoustic path length may lead to apparent changes in volume in certain regions of the nose. Third, a variable and uncontrollable degree of sound energy loss will occur into the opposite nasal cavity beyond the posterior border of the septum. An apparent increase in the dimensions of this region will be seen as the opposite cavity decongests. We feel that all users of the acoustic rhinometer need to be aware of these potential sources of artefact, and attention needs to be focused on an agreed definition of the components of the acoustic rhinometry trace.


Chronic diseases, inflammation, and spices: how are they linked?
Extensive research within the last several decades has revealed that the major risk factors for most chronic diseases are infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and diet. It is now well established that these factors induce chronic diseases through induction of inflammation. However, inflammation could be either acute or chronic. Acute inflammation persists for a short duration and is the host defense against infections and allergens, whereas the chronic inflammation persists for a long time and leads to many chronic diseases including cancer, cardiovascular diseases, neurodegenerative diseases, respiratory diseases, etc. Numerous lines of evidence suggest that the aforementioned risk factors induced cancer through chronic inflammation. First, transcription factors NF-κB and STAT3 that regulate expression of inflammatory gene products, have been found to be constitutively active in most cancers; second, chronic inflammation such as pancreatitis, prostatitis, hepatitis etc. leads to cancers; third, activation of NF-κB and STAT3 leads to cancer cell proliferation, survival, invasion, angiogenesis and metastasis; fourth, activation of NF-κB and STAT3 leads to resistance to chemotherapy and radiation, and hypoxia and acidic conditions activate these transcription factors. Therefore, targeting these pathways may provide opportunities for both prevention and treatment of cancer and other chronic diseases. We will discuss in this review the potential of various dietary agents such as spices and its components in the suppression of inflammatory pathways and their roles in the prevention and therapy of cancer and other chronic diseases. In fact, epidemiological studies do indicate that cancer incidence in countries such as India where spices are consumed daily is much lower (94/100,000) than those where spices are not consumed such as United States (318/100,000), suggesting the potential role of spices in cancer prevention.


Unrestricted generation of pure two-qubit states and entanglement diagnosis by single-qubit tomography.
We present an experimental proof-of-principle for the generation and detection of pure two-qubit states that have been encoded in degrees of freedom that are common to both classical-light beams and single photons. Our protocol requires performing polarization tomography on a single qubit from a qubit pair. The degree of entanglement in the qubit pair is measured by concurrence, which can be directly extracted from intensity measurements-or photon counting-entering single-qubit polarization tomography.


Cytochrome P450s in human immune cells regulate IL-22 and c-Kit via an AHR feedback loop.
The mechanisms how environmental compounds influence the human immune system are unknown. The environmentally sensitive transcription factor aryl hydrocarbon receptor (AHR) has immune-modulating functions and responds to small molecules. Cytochrome P4501 enzymes (CYP1) act downstream of the AHR and metabolize small molecules. However, it is currently unknown whether CYP1 activity is relevant for immune modulation. We studied the interdependence of CYP1 and AHR in human primary immune cells using pharmacological methods. CYP1 inhibition increased the expression levels of the stem cell factor receptor (c-Kit) and interleukin (IL)-22 but decreased IL-17. Single cell analyses showed that CYP1 inhibition especially promoted CD4+ helper T (Th) cells that co-express c-Kit and IL-22 simultaneously. The addition of an AHR antagonist reversed all these effects. In addition to T cells, we screened other human immune cells for CYP and found cell-specific fingerprints, suggesting that similar mechanisms are present in multiple immune cells. We describe a feedback loop yet unknown in human immune cells where CYP1 inhibition resulted in an altered AHR-dependent immune response. This mechanism relates CYP1-dependent metabolism of environmental small molecules to human immunity.


Differential effects of leukotrienes C4, D4, and E4 in the pulmonary and systemic vasculature of sheep.
We investigated the comparative direct and cyclooxygenase-mediated effects of the constituents of slow-reacting substance of anaphylaxis (SRS-A), i.e., leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) on pulmonary and systemic haemodynamics of sheep. In 20 conscious sheep, measurements of pulmonary vascular resistance (Rpv) and systemic vascular resistance (Rsv) were obtained before and after a rapid intravenous injection of LTC4 (0.1 micrograms X kg-1), LTD4 (0.1 micrograms X kg-1) and LTE4 (1 microgram X kg-1). The same protocol was carried out after pretreatment with the leukotriene antagonist FPL-57231 or the cyclooxygenase inhibitor indomethacin. LTD4 increased mean Rpv to 421% of baseline (p less than 0.001) and had a biphasic effect on mean Rsv, which, following an initial decrease of 18% (p less than 0.05), increased to 143% of baseline (p less than 0.05). LTC4 and LTE4 had no significant effects on Rpv, while they increased mean Rsv to 144% and 143% of baseline, respectively (p less than 0.05). This effect was not preceded by a decrease in Rsv. FPL-57231 completely blocked the effects of LTC4, LTD4 and LTE4 on Rsv, and of LTD4 on Rpv. Indomethacin had no effect on LTC4, LTD4 and LTE4-induced increases in mean Rsv, while it prevented the LTD4-induced initial decrease in mean Rsv. Indomethacin also prevented the LTD4-induced increase in Rpv. A dose-response curve (0.05, 0.1, 0.5 and 1 microgram X kg-1) demonstrated that in raising Rsv, LTE4 was approximately 10 times less potent than LTC4 and LTD4.(ABSTRACT TRUNCATED AT 250 WORDS)


Findings, phenotypes, and outcomes in Freeman-Sheldon and Sheldon-Hall syndromes and distal arthrogryposis types 1 and 3: protocol for systematic review and patient-level data meta-analysis.
Freeman-Sheldon and Sheldon-Hall syndromes (FSS and SHS) and distal arthrogryposis types 1 and 3 (DA1 and DA3) are rare, often confused, congenital syndromes. Few studies exist. With reported diagnosis unreliable, it would be scientifically inappropriate to consider articles describing FSS, SHS, DA1, or DA3, unless diagnoses were independently verified, rendering conventional systematic review and meta-analysis methodology inappropriate and necessitating patient-level data analysis (PROSPERO: CRD42015024740). As part of a clinical practise guideline development process, we evaluate (1) diagnostic accuracy from 1938-2017, using the Stevenson criteria; (2) the most common physical findings, possible frequency clusters, and complications of physical findings amongst patients with FSS; and (3) treatment types and outcomes. All papers reporting diagnosis of FSS, SHS, DA1, and DA3 are included in searching PubMed and Google Scholar from December 2014 to July 2015 and again before final analyses. Patients with FSS are divided into four phenotype-defined sub-types; all patients are grouped by published diagnosis and medical speciality. Significance of physical findings and historical data is evaluated by chi-square. Associations of physical findings and history with diagnosis and treatment outcome are evaluated by Pearson correlation and linear regression analysis. Two-tailed alpha level of 0.05 is used throughout. The need for detailed patient-level data extraction may limit the types of articles included and questions able to be answered. For treatment and psychosocial health outcomes, we anticipate enhanced difficulties, which may limit significance, power, and results' usability. We hope to outline knowledge gaps and prioritise areas for clinical investigation. CRD42015024740 Universal Trial Number: U1111-1172-4670.


Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease.
Graft coronary artery disease (GCAD) is the leading cause of death after the first year of heart transplantation. The reduced bioavailability of endothelium-derived nitric oxide (NO) may play a role in endothelial vasodilator dysfunction and the structural changes that are characteristic of GCAD. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor. We hypothesized that lowering ADMA concentrations by dimethylarginine dimethylaminohydrolase (DDAH) overexpression in the recipient might suppress GCAD and long-term immune responses in murine cardiac allografts. In one series, donor hearts of C-H-2(bm12)KhEg (H-2(bm12)) wild-type (WT) mice were heterotopically transplanted into C57BL/6 (H-2b) transgenic mice overexpressing human DDAH-I or WT littermates and procured after 4 hours of reperfusion (WT and DDAH-I recipients, n=6 each). In a second series, donor hearts were transplanted into DDAH-I-transgenic or WT mice and procured 30 days after transplantation (n=7 each). In DDAH-I recipients, plasma ADMA concentrations were lower, in association with reduced myocardial generation of superoxide anion (WT versus DDAH-I, 465.7+/-79.8 versus 173.4+/-32.3 micromol.L(-1).mg(-1).h(-1); P=0.02), inflammatory cytokines, adhesion molecules, and chemokines. GCAD was markedly reduced in cardiac allografts of DDAH-I-transgenic recipients as assessed by luminal narrowing (WT versus DDAH, 79+/-2% versus 33+/-7%; P<0.01), intima-media ratio (WT versus DDAH, 1.1+/-0.1 versus 0.5+/-0.1; P<0.01), and the percentage of diseased vessels (WT versus DDAH, 100+/-0% versus 62+/-10%; P<0.01). Overexpression of DDAH-I attenuated oxidative stress, inflammatory cytokines, and GCAD in murine cardiac allografts. The effect of DDAH overexpression may be mediated by its reduction of plasma and tissue ADMA concentrations.


Spectroscopy in Complex Environments from QM-MM Simulations.
The applications of multiscale quantum-classical (QM-MM) approaches have shown an extraordinary expansion and diversification in the last couple of decades. A great proportion of these efforts have been devoted to interpreting and reproducing spectroscopic experiments in a variety of complex environments such as solutions, interfaces, and biological systems. Today, QM-MM-based computational spectroscopy methods constitute accomplished tools with refined predictive power. The present review summarizes the advances that have been made in QM-MM approaches to UV-visible, Raman, IR, NMR, electron paramagnetic resonance, and Mössbauer spectroscopies, providing in every case an introductory discussion of the corresponding methodological background. A representative number of applications are presented to illustrate the historical evolution and the state of the art of this field, highlighting the advantages and limitations of the available methodologies. Finally, we present our view of the perspectives and open challenges in the field.


Comparison of teat dips with differing iodine concentrations in prevention of mastitis infection.
Six commercial dairy herds were used to test the relative efficacy of three concentrations of iodine as a teat dip over 12 mo. Concentrations were .1, .25, and 1% iodine with free iodine contents of 3.5, 4.0, and 1.0 ppm. Two concentrations were compared in each herd. The greatest number of new infections (71) occurred in approximately 120 cows whose teats were dipped with the 1% iodine dip, and the fewest (52) occurred in a similar number of cow quarters dipped in .1% iodine; however, differences were not significant. Clinical mastitis was highest in the 1% group. If all clinical mastitis were the result of infection, even if bacteria were not isolated from the pretreatment sample or from samples collected at the start of the study and those quarters were added to the totals, then reduction of new infection with the .1% product would be significant.


Production and identification repetition priming in amnestic mild cognitive impairment.
The experiment reported here examined implicit memory function, as measured through repetition priming, in amnestic mild cognitive impairment (MCI) to examine whether impairments exist in this aspect of memory function. Young adults, healthy older controls, Alzheimer's disease patients, and MCI participants were asked to perform two types of implicit memory tests (word stem completion and threshold identification repetition priming tasks), as well as a recognition test for studied items. As expected, young adults performed better than the other participants on the recognition test and the word stem completion task; there was equivalent priming across groups on the word identification task. While both the older control and MCI participants showed lower levels of priming on the word stem completion task relative to the young adults, the magnitude of priming was equivalent for these two groups, and reliably greater than that of the dementia participants. These results suggest that not all aspects of memory function are impaired in MCI relative to healthy aging.


Extended fluorochromism of anthracene trimers with a meta-substituted triphenylamine or triphenylphosphine core.
Combining meta-triphenylamine or triphenylphosphine with three anthracene fluorophores gives rise to fluorescent non-planar triskelions 1 and 2. The emissive properties of 1 are highly solvatochromic, yielding blue to pale green and even pale yellow fluorescence, whereas the blue emission of 2 is solvent-insensitive. Anthracene trimers 1 and 2 are both emissive in the solid state, displaying yellow and pale green fluorescence, respectively, with moderate quantum yields.


Low-Symmetry Mixed Fluorinated Subphthalocyanines as Fluorescence Imaging Probes in MDA-MB-231 Breast Tumor Cells.
Boron subphthalocyanines (SPcs) are aromatic macrocycles that possess a combination of physical and optical properties that make them excellent candidates for application as fluorescent imaging probes. These molecules have intense electronic absorption and emission, and structural versatility that allows for specific tuning of physical properties. Herein, we report the synthesis of a series of low-symmetry fluorinated SPcs and compare them to analogous compounds with varying numbers of peripheral fluorine atoms and varied aromaticity. Across the series, with increasing addition of fluorine atoms to the periphery of the ring, a downfield chemical shift in 19F NMR and a bathochromic shift of electronic absorption were observed. Expanding the size of the aromatic ring by replacing peripheral benzo- groups with naphtho- groups prompted a far more drastic bathochromic shift to absorption and emission. Fluorescence quantum yields (Φf) proved to be sufficiently high to observe intracellular fluorescence from MDA-MB-231 breast tumor cells in vitro by epifluorescence microscopy; fluorination proved vital for this purpose to improve solubility. This report lays the groundwork for the future development of these promising SPcs for their ultimate application as near-infrared (NIR) fluorescent imaging probes in biological systems.


Inhibition of vasoactive intestinal polypeptide (VIP) induces resistance to dextran sodium sulfate (DSS)-induced colitis in mice.
VIP is highly expressed in the colon and regulates motility, vasodilatation, and sphincter relaxation. However, its role in the development and progress of colitis is still controversial. Our aim was to determine the participation of VIP on dextran sodium sulfate (DSS)-induced colonic mucosal inflammation using VIP(-/-) and WT mice treated with VIP antagonists. Colitis was induced in 32 adult VIP(-/-) and 14 age-matched WT litter-mates by giving 2.5 % DSS in the drinking water. DSS-treated WT mice were injected daily with VIP antagonists, VIPHyb (n = 22), PG 97-269 (n = 9), or vehicle (n = 31). After euthanasia, colons were examined; colonic cytokines mRNA were quantified. VIP(-/-) mice were remarkably resistant to DSS-induced colitis compared to WT. Similarly, DSS-treated WT mice injected with VIPHyb (1 μM) or PG 97-269 (1 nM) had significantly reduced clinical signs of colitis. Furthermore, colonic expression of IL-1ϐ, TNF-α, and IL-6 was significantly lower in VIP(-/-) and VIPHyb or PG 97-269 compared to vehicle-treated WT. Genetic deletion of VIP or pharmacological inhibition of VIP receptors resulted in resistance to colitis. These data demonstrate a pro-inflammatory role for VIP in murine colitis and suggest that VIP antagonists may be an effective clinical treatment for human inflammatory bowel diseases.


Apoptosis of peripheral blood lymphocytes T in nephrotic children.
The purpose of the study was to assess the intensity of lymphocyte T apoptosis in nephrotic children's peripheral blood before, during and after the treatment with prednisone. The percentages of apoptotic lymphocyte T were determined by flow cytometry using annexin V. The study comprised 26 nephrotic children aged 3-14 years. The controls were 15 healthy children. In acute phase of the nephrotic syndrome before institution of the therapy the mean percentage of apoptotic lymphocytes T was 2.61%. It was significantly higher than that in controls (1.08%). During treatment with prednisone a statistically significant increase in the mean percentage of apoptotic lymphocytes T was observed. After four-week therapy with prednisone and after completion of the treatment the percentages of apoptotic lymphocytes T were 7.96% and 9.51%, respectively. They were significantly higher than those in patients before treatment and in healthy children.


Impaired hypothalamus-pituitary-adrenal axis in men with spinal cord injuries.
Twenty-five men with spinal cord injuries were studied for evaluation of the hypothalamus-pituitary-adrenal axis, using corticotropin-releasing hormone and insulin-induced hypoglycemia. Twenty-five age-matched healthy male volunteers served as controls. Three spinal cord-injured subjects had hyperprolactinemia, three had elevated basal follicle-stimulating hormone levels, one had an elevated basal luteinizing hormone level, and four had hypotestosteronemia. The mean plasma adrenocorticotropin response to corticotropin-releasing hormone of spinal cord-injured subjects was smaller than that of the healthy controls but did not reach a statistical significance. The cortisol response to corticotropin-releasing hormone of the spinal cord-injured subjects was significantly lower than that of healthy controls. However, the difference disappeared if a correction was made for baseline values. Six spinal cord-injured subjects did not have a cortisol response to insulin-induced hypoglycemia, and they had either a minimal or no adrenocorticotropin response. Another 11 spinal cord-injured subjects had a maximal cortisol response to insulin-induced hypoglycemia below the lowest limit of normal, i.e., 0.5 micromol/l. Among these spinal cord-injured subjects, three had a less than 50% increase of plasma adrenocorticotropin after insulin-induced hypoglycemia. These findings are consistent with the notion that spinal cord-injured subjects have an altered central neurotransmitter tone and substantiate the hypothesis that an afferent neural pathway exists between the adrenal and hypothalamus and may modulate stress-induced secretion of adrenocorticotropin. Long-term abnormal adrenocorticotropin secretion may cause mild adrenocortical atrophy and, thereby, a reduced cortisol response.


Technical Advancements in Abdominal Diffusion-weighted Imaging.
Since its first observation in the 18th century, the diffusion phenomenon has been actively studied by many researchers. Diffusion-weighted imaging (DWI) is a technique to probe the diffusion of water molecules and create a MR image with contrast based on the local diffusion properties. The DWI pixel intensity is modulated by the hindrance the diffusing water molecules experience. This hindrance is caused by structures in the tissue and reflects the state of the tissue. This characteristic makes DWI a unique and effective tool to gain more insight into the tissue's pathophysiological condition. In the past decades, DWI has made dramatic technical progress, leading to greater acceptance in clinical practice. In the abdominal region, however, acquiring DWI with good quality is challenging because of several reasons, such as large imaging volume, respiratory and other types of motion, and difficulty in achieving homogeneous fat suppression. In this review, we discuss technical advancements from the past decades that help mitigate these problems common in abdominal imaging. We describe the use of scan acceleration techniques such as parallel imaging and compressed sensing to reduce image distortion in echo planar imaging. Then we compare techniques developed to mitigate issues due to respiratory motion, such as free-breathing, respiratory-triggering, and navigator-based approaches. Commonly used fat suppression techniques are also introduced, and their effectiveness is discussed. Additionally, the influence of the abovementioned techniques on image quality is demonstrated. Finally, we discuss the current and future clinical applications of abdominal DWI, such as whole-body DWI, simultaneous multiple-slice excitation, intravoxel incoherent motion, and the use of artificial intelligence. Abdominal DWI has the potential to develop further in the future, thanks to scan acceleration and image quality improvement driven by technological advancements. The accumulation of clinical proof will further drive clinical acceptance.


Radioprotective effects of dextran sulphate in mice.
Influence of a single i.p. injection of dextran sulphate on radiosensitivity of mice was investigated. The administration of dextran sulphate 24, 48 and 72 hours prior to irradiation increased formation of endogenous colonies of the hemopoietic tissue on the surface of the spleen. DRF calculated from an equieffective exposure for 5 colonies was 1.96 when dextran sulphate was administered 24 hours before irradiation, and 2.25 when dextran sulphate was administered 72 hours before irradiation. The radioprotective effects of dextran sulphate were manifested also in the survival of animals exposed to lethal doses of short-termed as well as long-termed gamma radiation.


Glucocorticoids and Aggression: A Tripartite Interaction.
The effects of glucocorticoids on aggression can be conceptualized based on its mechanisms of action. These hormones can affect cell function non-genomically within minutes, primarily by affecting the cell membrane. Overall, such effects are activating and promote both metabolic preparations for the fight and aggressive behavior per se. Chronic increases in glucocorticoids activate genomic mechanisms and are depressing overall, including the inhibition of aggressive behavior. Finally, excessive stressors trigger epigenetic phenomena that have a large impact on brain programming and may also induce the reprogramming of neural functions. These induce qualitative changes in aggression that are deemed abnormal in animals, and psychopathological and criminal in humans. This review aims at deciphering the roles of glucocorticoids in aggression control by taking in view the three mechanisms of action often categorized as acute, chronic, and toxic stress based on the duration and the consequences of the stress response. It is argued that the tripartite way of influencing aggression can be recognized in all three animal, psychopathological, and criminal aggression and constitute a framework of mechanisms by which aggressive behavior adapts to short-term and log-term changes in the environment.


Inhibiting amyloid beta (1-42) peptide-induced mitochondrial dysfunction prevents the degradation of synaptic proteins in the entorhinal cortex.
Increasing evidence suggests that mitochondrial dysfunction and aberrant release of mitochondrial reactive oxygen species (ROS) play crucial roles in early synaptic perturbations and neuropathology that drive memory deficits in Alzheimer's disease (AD). We recently showed that solubilized human amyloid beta peptide 1-42 (hAβ1-42) causes rapid alterations at glutamatergic synapses in the entorhinal cortex (EC) through the activation of both GluN2A- and GluN2B-containing NMDA receptors. However, whether disruption of mitochondrial dynamics and increased ROS contributes to mechanisms mediating hAβ1-42-induced synaptic perturbations in the EC is unknown. Here we assessed the impact of hAβ1-42 on mitochondrial respiratory functions, and the expression of key mitochondrial and synaptic proteins in the EC. Measurements of mitochondrial respiratory function in wild-type EC slices exposed to 1 μM hAβ1-42 revealed marked reductions in tissue oxygen consumption and energy production efficiency relative to control. hAβ1-42 also markedly reduced the immunoexpression of both mitochondrial superoxide dismutase (SOD2) and mitochondrial-cytochrome c protein but had no significant impact on cytosolic-cytochrome c expression, voltage-dependent anion channel protein (a marker for mitochondrial density/integrity), and the immunoexpression of protein markers for all five mitochondrial complexes. The rapid impairments in mitochondrial functions induced by hAβ1-42 were accompanied by reductions in the presynaptic marker synaptophysin, postsynaptic density protein (PSD95), and the vesicular acetylcholine transporter, with no significant changes in the degradative enzyme acetylcholinesterase. We then assessed whether reducing hAβ1-42-induced increases in ROS could prevent dysregulation of entorhinal synaptic proteins, and found that synaptic impairments induced by hAβ1-42 were prevented by the mitochondria-targeted antioxidant drug mitoquinone mesylate, and by the SOD and catalase mimetic EUK134. These findings indicate that hAβ1-2 can rapidly disrupt mitochondrial functions and increase ROS in the entorhinal, and that this may contribute to synaptic dysfunctions that may promote early AD-related neuropathology.


Interstitial cystitis in persistent posthysterectomy chronic pelvic pain.
Hysterectomies may be performed unnecessarily in women with chronic pelvic pain if the diagnosis of interstitial cystitis is not considered. The objectives of this study were to investigate the prevalence of interstitial cystitis in patients with posthysterectomy chronic pelvic pain and to evaluate the efficacy of various therapies for interstitial cystitis. A study was performed of 111 patients with chronic pelvic pain whose pain persisted after hysterectomy. Patients were screened with the Pelvic Pain and Urgency/Frequency symptom scale, and underwent Potassium Sensitivity Testing. Patients were treated with dietary changes alone or in combination with cystoscopic hydrodistention or oral pentosan polysulfate, or both of these, for 3 to 6 months. Of the 111 patients enrolled, 79% (n=88) were diagnosed with bladder dysfunction consistent with interstitial cystitis. For patients treated with dietary modification alone (n=33), the mean score on the Pelvic Pain and Urgency/Frequency questionnaire improved 15.4%, from 13.18 at baseline to 11.15 at follow-up. For patients treated with pentosan polysulfate or cystoscopic hydrodistention, or both, plus diet changes (n=78), Pelvic Pain and Urgency/Frequency scores improved 34.2%, from 15.01 to 9.87. In this study, nonsurgical treatment for interstitial cystitis resulted in a marked improvement in symptoms that had not improved with surgery. Without determining the origin of bladder pain, gynecologists should not proceed to hysterectomy in patients with chronic pelvic pain.


Contributions by the Brain Renin-Angiotensin System to Memory, Cognition, and Alzheimer's Disease.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive neuron losses in memory-associated brain structures that rob patients of their dignity and quality of life. Five drugs have been approved by the FDA to treat AD but none modify or significantly slow disease progression. New therapies are needed to delay the course of this disease with the ultimate goal of preventing neuron losses and preserving memory functioning. In this review we describe the renin-angiotensin II (AngII) system (RAS) with specific regard to its deleterious contributions to hypertension, facilitation of neuroinflammation and oxidative stress, reduced cerebral blood flow, tissue remodeling, and disruption of memory consolidation and retrieval. There is evidence that components of the RAS, AngIV and Ang(1-7), are positioned to counter such damaging influences and these systems are detailed with the goal of drawing attention to their importance as drug development targets. Ang(1-7) binds at the Mas receptor, while AngIV binds at the AT4 receptor subtype, and these receptor numbers are significantly decreased in AD patients, accompanied by declines in brain aminopeptidases A and N, enzymes essential for the synthesis of AngIV. Potent analogs may be useful to counter these changes and facilitate neuronal functioning and reduce apoptosis in memory associated brain structures of AD patients.


Diagnostics hardening for harsh environment in Laser Megajoule (invited).
The diagnostic designs for the Laser Megajoule (LMJ) will require components to operate in environments far more severe than those encountered in present facilities. This harsh environment will be induced by fluxes of neutrons, gamma rays, energetic ions, electromagnetic radiations, and, in some cases, debris and shrapnel, at levels several orders of magnitude higher than those experienced today on existing facilities. The lessons learned about the vulnerabilities of present diagnostic parts fielded mainly on OMEGA for many years, have been very useful guide for the design of future LMJ diagnostics. The present and future LMJ diagnostic designs including this vulnerability approach and their main mitigation techniques will be presented together with the main characteristics of the LMJ facility that provide for diagnostic protection.


Comparison of Prophylactic Norepinephrine and Phenylephrine Infusions During Spinal Anaesthesia for Primary Caesarean Delivery in Twin Pregnancies: A Randomized Double-Blinded Clinical Study.
Norepinephrine has been associated with improved heart rate (HR) and cardiac output (CO) compared to phenylephrine as a treatment for post-spinal hypotension during caesarean delivery (CD) in singleton pregnancies. Our current study compared the effects of norepinephrine and phenylephrine in maintaining maternal hemodynamics after spinal anaesthesia in twin pregnancies during elective CD. This was a double-blinded, randomized, controlled study. From December 2017 to December 2018, 62 women with healthy twin term pregnancies undergoing elective CD under spinal anaesthesia were studied. Following spinal induction, either norepinephrine (6 μg/mL) or phenylepinephrine (75 μg/mL) was infused at 60 mL/h to maintain systolic blood pressure (SBP) near baseline until delivery. HR, SBP, systemic vascular resistance (SVR), and CO were collected using anaesthesia monitors and continuous-pulse waveform analysis. The primary outcome was maternal CO. Other parameters of maternal hemodynamics, umbilical cord blood gases, and adverse events were also compared. Hemodynamic variables (CO, SBP, HR, and SVR) between spinal anaesthesia induction to skin incision were similar between the two groups (P = 0.889, 0.057, 0.977, and 0.416, respectively). The incidence of bradycardia was significantly higher in the phenylephrine group (69%) than in the norepinephrine group (24.2%, P<0.001). Maternal nausea and vomiting, hypotension, reactive hypertension, and neonatal outcomes did not differ between the groups. When administered as a prophylactic fixed-rate infusion, phenylephrine and norepinephrine are both capable of maintaining maternal blood pressure following spinal anaesthesia in twin pregnancies. There were no differences in the maternal hemodynamics or foetal outcomes between women receiving norepinephrine and phenylephrine. Presented at the 51st Society for Obstetric Anesthesia and Perinatology Annual Meeting, Phoenix, Arizona, May 1-5, 2019. No. ChiCTR-IOR-17013358.


An update on the importance of plasma protein binding in drug discovery and development.
Introduction: Plasma protein binding (PPB) remains a controversial topic in drug discovery and development. Fraction unbound (fu) is a critical parameter that needs to be measured accurately, because it has significant impacts on the predictions of drug-drug interactions (DDI), estimations of therapeutic indices (TI), and developments of PK/PD relationships. However, it is generally not advisable to change PPB through structural modifications, because PPB on its own has little relevance for in vivo efficacy.Areas covered: PPB fundamentals are discussed including the three main classes of drug binding proteins (i.e., albumin, alpha1-acid glycoprotein, and lipoproteins) and their physicochemical properties, in vivo half-life, and synthesis rate. State-of-the-art methodologies for PPB are highlighted. Applications of PPB in drug discovery and development are presented.Expert opinion: PPB is an old topic in pharmacokinetics, but there are still many misconceptions. Improving the accuracy of PPB for highly bound compounds is an ongoing effort in the field with high priority. As the field continues to generate high quality data, the regulatory agencies will increase their confidence in our ability to accurately measure PPB of highly bound compounds, and experimental fu values below 0.01 will more likely be used for DDI predictions in the future.


The inverse problem for the Gross-Pitaevskii equation.
Two different methods are proposed for the generation of wide classes of exact solutions to the stationary Gross-Pitaevskii equation (GPE). The first method, suggested by the work of Kondrat'ev and Miller [Izv. Vyssh. Uchebn. Zaved., Radiofiz IX, 910 (1966)], applies to one-dimensional (1D) GPE. It is based on the similarity between the GPE and the integrable Gardner equation, all solutions of the latter equation (both stationary and nonstationary ones) generating exact solutions to the GPE. The second method is based on the "inverse problem" for the GPE, i.e., construction of a potential function which provides a desirable solution to the equation. Systematic results are presented for one- and two-dimensional cases. Both methods are illustrated by a variety of localized solutions, including solitary vortices, for both attractive and repulsive nonlinearity in the GPE. The stability of the 1D solutions is tested by direct simulations of the time-dependent GPE.


Radiological informed consent in cardiovascular imaging: towards the medico-legal perfect storm?
Use of radiation for medical examinations and tests is the largest manmade source of radiation exposure. No one can doubt the immense clinical and scientific benefits of imaging to the modern practice of medicine. Every radiological and nuclear medicine examination confers a definite (albeit low) long-term risk of cancer, but patients undergoing such examinations often receive no or inaccurate information about radiological dose exposure and corresponding risk directly related to the radiological dose received. Too detailed information on radiological dose and risk may result in undue anxiety, but information "economical with the truth" may violate basic patients' rights well embedded in ethics (Oviedo convention 1997) and law (97/43 Euratom Directive 1997). Informed consent is a procedure needed to establish a respectful and ethical relation between doctors and patients. Nevertheless, in an "ideal" consent process, the principle of patient autonomy in current radiological practice might be reinforced by making it mandatory to obtain explicit and transparent informed consent form for radiological examination with high exposure (>or= 500 chest x-rays). The form may spell-out the type of examination, the exposure in effective dose (mSv), derived from reference values in guidelines or - better - from actual values from their department. The dose equivalent might be also expressed in number of chest radiographs and the risk of cancer as number of extra cases in the exposed population, derived from most recent and authorative guidelines (e.g., BEIR VII Committee, release 2006). Common sense, deontological code, patients'rights, medical imaging guidelines, Euratom law, all coherently and concordantly encourage and recommend a justified, optimized, responsible and informed use of testing with ionizing radiation. Although the idea of informed consent for radiation dose does not seem to be on the immediate radar screen at least in the US, the current practice clashes against these guidelines and laws.