Increased level of neuronal phosphoinositide 3-kinase gamma by the activation of mu-opioid receptor in the mouse periaqueductal gray matter: further evidence for the implication in morphine-induced antinociception.
It has been proposed that phosphoinositide 3-kinase (PI3K), one of the phosphatidylinositol kinases, can be regulated by G-protein-coupled receptor as well as nerve growth factor-associated receptors. The aim of the present study was to investigate whether in vivo treatment with morphine, a mu-opioid receptor (MOR) agonist, could directly regulate PI3Kgamma isoform in the mouse periaqueductal gray matter (PAG). Using the polyclonal antibody recognizing a p110gamma catalytic subunit of PI3Kgamma, PI3Kgamma-like immunoreactivity (IR) was mostly seen in the membrane of the cell labeled by anti-neuron-specific nuclear protein. A single s.c. injection of morphine caused a marked increase in the number of PI3Kgamma-IR expressing cells in the PAG. Double immunolabeling assay showed that MOR-IR was mostly overlapped with PI3Kgamma-IR on the cell surface in the PAG section. Additionally, phosphorylated-phospholipase Cgamma1 (PLCgamma1-IR) was highly detected in the membrane compartment of the increased PI3Kgamma-IR-positive cells of this region. Further pharmacological evidence for the critical role of PI3Kgamma in MOR-mediated antinociceptive response was provided by the warm-plate test. The dose-response lines for antinociceptive effects of morphine were significantly shifted to the right following i.c.v. treatment with PI3K inhibitors. These findings suggested that acute treatment with morphine may directly activate the PI3Kgamma/PLCgamma1 pathway in the PAG. This effect may, at least in part, result in the expression of morphine-induced pharmacological actions including antinociception in mice.


Dietary and blood selenium are inversely associated with the prevalence of stroke among Inuit in Canada.
Inuit in Canada have high selenium intake from the consumption of country food such as fish and marine mammals. The health consequence is not known. This study examines the association between blood selenium concentration and prevalence of stroke among Canadian Inuit. The International Polar Year Inuit Health Survey was conducted in 2007-2008. Among the 2077 adults participants (≥18years old) who completed a questionnaire and gave blood samples, 49 stroke cases were reported, 31 of which were from women. The crude prevalence of stroke was 2.4% in the participants. Participants with stroke had lower blood selenium (geometric mean: 260μg/L vs. 319μg/L) and dietary selenium (144μg/day vs. 190μg/day) compared to individuals without stroke. Participants with high blood/dietary selenium exposure (quartiles 3 and 4) had a lower prevalence of stroke compared to those with low selenium exposure (quartile 1). The adjusted odds ratio ranged from 0.09 to 0.25 among subgroups (e.g. age, sex, and blood mercury). An L-shaped relationship between prevalence of stroke with blood and dietary selenium was observed, based on the cubic restricted spline and segmented regression analyses. The estimated turning points of the L-shaped curve for blood selenium and dietary selenium were 450μg/L and 350μg/day, respectively. Below the turning points, it was estimated that each 50-μg/L increase in blood selenium was associated with a 38% reduction in the prevalence of stroke, and each 50-μg/day increase in dietary selenium was associated with a 30% reduction in the prevalence of stroke. In conclusion, blood and dietary selenium are reversely associated with the prevalence of stroke in Inuit, which follows an L-shaped relationship. Whether this relationship applies to other population needs further investigation.


Foreign Body in the Cervical Oesophagus: A Case Report.
Foreign bodies in the upper aerodigestive tract represent an uncommon cause of visits to emergency departments. In the majority of cases, foreign bodies do not go beyond the pharynx. They cause dyspnoea or pneumonia if they reach the tracheobronchial tree. If ingested, they will pass spontaneously through the gastrointestinal canal in the majority of cases. Nevertheless, especially in the case of sharp-pointed or large objects, the foreign bodies can stop in the oesophagus. In case of dysphagia, stinging sensation and/or odynophagia occurring after eating a meal, a foreign body in the upper aerodigestive tract should be suspected. If not clinically visible, imaging is required. A 72-year-old woman presented to the Emergency Department with pharyngodynia, odynophagia, stinging, dysphagia, and sialorrhea for 12 hours. Her symptoms started after eating a meal involving meat. The patient underwent a standard two-projection radiogram of the neck. The antero-posterior projection radiogram was unremarkable. The lateral projection radiogram showed 16 millimetres in maximum length radiopaque foreign body within the cervical oesophagus. The patient underwent transoral flexible oesophagoscopy under general anaesthesia, which resulted in successful removal of the foreign body (bony fragment). Her symptoms improved rapidly after the procedure, and the patient was discharged after 48 hours in good health. A foreign body in the cervical oesophagus may lead to visceral perforation. Once suspected, every effort should be made to identify and remove the foreign body to avoid potentially catastrophic consequences. In some cases, imaging could be necessary to detect the foreign body.


Knockdown of RON inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells.
Altered Recepteur d'Origine nantais (RON) expression transduces signals inducting invasive growth phenotype that includes cell proliferation, migration, matrix invasion, and protection of apoptosis in human cancer cells. The aims of the current study were to evaluate whether RON affects tumor cell behavior and cellular signaling pathways including activator protein-1 (AP-1) and Akt/forkhead box O (FoxO) in human colorectal cancer cells. To study the biological role of RON on tumor cell behavior and cellular signaling pathways in human colorectal cancer, we used small interfering RNA (siRNA) to knockdown RON gene expression in human colorectal cancer cell line, DKO-1. Knockdown of RON diminished migration, invasion, and proliferation of human colorectal cancer cells. Knockdown of RON decreased AP-1 transcriptional activity and expression of AP-1 target genes. Knockdown of RON activated cleaved caspase-3, -7, -9, and PARP, and down-regulated the expression of Mcl-1, survivin and XIAP, leading to induction of apoptosis. Knockdown of RON induced cell cycle arrest in the G2/M phase of cancer cells by an increase of p27 and a decrease of cyclin D3. Knockdown of RON inhibited the phosphorylation of Akt/FoxO signaling proteins such as Ser473 and Thr308 of Akt and FoxO1/3a. These results indicate that knockdown of RON inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells.


A six-year retrospective analysis of shoulder dystocia and delivery of the shoulders.
To investigate the diagnosis, incidence and management of shoulder dystocia. Retrospective review of all the deliveries between 1988 and 1993 which were coded on the computer data base as 'moderate difficulty with the shoulders' or 'shoulder dystocia'. A teaching hospital in the south of England. The study population consisted of 15,658 women who had cephalic vaginal deliveries of babies weighing > 2.5 kg. The sample consisted of the 257 women reported to have moderate difficulty with the shoulders or shoulder dystocia at delivery. There was a significant fall in the reported incidence of shoulder dystocia during the period under investigation. Eighty-six (1.1%) of the deliveries between 1988 and 1990 were reported to have been complicated by shoulder dystocia. In 1991 a second option was introduced to allow both shoulder dystocia or moderate difficulties with the shoulders to be coded after delivery. Following this change in categorisation, the incidence of shoulder dystocia was reduced to 30 (0.6%) reported cases in 1992-1993. Over the same period the reported incidence of moderate difficulty rose significantly from 29 (1.1%) in 1992 to 60 (2.4%) in 1993 (P < 0.001). Disparity was noted between the experience of practitioners and contemporary definitions of shoulder dystocia and this was highlighted by the number of reported cases of moderate difficulty. In this study practitioners used the term shoulder dystocia in a general sense to describe a range of difficulties encountered with the delivery of the shoulders and they identified many varied manifestations. In comparison, contemporary literature describes shoulder dystocia as a discrete entity. Shoulder dystocia is a complex clinical scenario and perceptions of the incidence may be influenced by alterations in the delivery technique and changes in the diagnosis and documentation. The application of traction may interfere with the normal mechanisms of labour and the spontaneous birth of the shoulders, whilst increasing the risk of trauma to the baby. It may be unnecessary to use such interventions routinely in the care of normal labouring women.


Early- and mid-term outcomes after transcatheter aortic valve implantation. Data from a single-center registry.
Transcatheter aortic valve implantation (TAVI) is a less invasive treatment option for elderly, high-risk patients with symptomatic severe aortic stenosis (AS) than aortic valve replacement. More importantly, TAVI improves survival and quality of life as compared to medical treatment in inoperable patients. To assess early- and mid-term clinical outcomes after TAVI. All consecutive high-risk patients with severe symptomatic AS undergoing TAVI from November 2008 to August 2014 were enrolled. The clinical and procedural characteristics, as well as clinical outcomes including mortality during 12-month follow-up, were assessed. A total of 101 consecutive patients underwent TAVI for native aortic valve stenosis (100%). Patients were elderly, with a median age of 81.0 (76.0-84.0) years, 60.4% were female and 83.2% presented with NYHA III/IV. Median baseline EuroSCORE I and STS scores were 14.0 (10.0-22.5)% and 12.0 (5.0-24.0)%, respectively. The main periprocedural and in-hospital complications were minor vascular complications, bleeding requiring blood transfusions, and the need for a permanent pacemaker. In-hospital, 30-day, 6-month and 12-month mortality rates were 6.9%, 10.9%, 15.8% and 17.8%, respectively. A mortality rate of < 20% after 12 months seems acceptable given the high-risk population enrolled.


Prevalence of R5 strains in multi-treated HIV subjects and impact of new regimens including maraviroc in a selected group of patients with CCR5-tropic HIV-1 infection.
Maraviroc currently represents an important antiretroviral drug for multi-experienced and viremic HIV patients. This study focused on two main points: (1) determining the prevalence of R5 and X4 HIV strains in antiretroviral-experienced patients using two main tests currently in use to determine viral tropism, and (2) the follow-up to 3 years of a limited number of patients who started a new antiretroviral protocol including maraviroc. A group of 56 HIV patients, previously multi-treated, were first analyzed by genotyping assay and Trofile™ to establish their eligibility for maraviroc treatment. In addition, 25 subjects selected to follow a new therapeutic protocol including a CCR5 antagonist were monitored by HIV RNA viral load and CD4+ cell count. The determination of viral tropism showed a large percentage of patients with an R5 profile (72% by genotyping assay and 74% by Trofile). The follow-up of most (21 out 25) patients who started the new antiretroviral protocol showed an undetectable viral load throughout the observation period, accompanied by a major improvement in CD4 cell count (cells/mm(3)) (baseline: median CD4 cell count 365, interquartile range (IQR) 204-511; 12 months: median value 501, IQR 349-677, p=0.042; 24 months: median value 503, IQR 386-678, p=0.026; 36 months: median value 601, IQR 517-717, p=0.001). Among the four non-responder subjects, two showed a lack of drug compliance and two switched from R5 to X4. Although our patient cohort was small, the results showed a high prevalence of R5 viral strains in multi-experienced patients. As well as showing the advantages of genotyping, which can be performed in plasma samples with low viral load replication, the follow-up of HIV patients selected for an alternative drug protocol, including a CCR5 antagonist, showed a persistent undetectable viral replication and a good recovery of CD4 cell count in most treated HIV patients.


Quantification of Myofascial Taut Bands.
To assess the correlation of clinician-identified myofascial taut bands with their presence and characteristics on magnetic resonance elastography (MRE) imaging. Cross-sectional study. A magnetic resonance imaging (MRI) research laboratory. A convenience sample of adults (N=65; 45 women, 20 men) identified by skilled musculoskeletal physicians as having upper trapezius myofascial pain-associated taut bands. Subjects had their taut bands outlined and were positioned within a 1.5T MRI machine. Shear waves were induced with a pneumatic transducer located over the belly of the involved muscle. Wave propagation was visualized with MRE images across a vibration cycle. Imaging data were assessed independently by 2 skilled MRE interpreters. The primary outcome measure was the determination of the intra- and interrater reliabilities of MRE taut band identification and their correlation with clinician identification of band presence. Secondary outcomes consisted of the elucidation of the physical characteristics of taut bands and their surrounding muscle tissue. MRE intra- and interrater reliability was excellent, with kappa coefficients and 95% confidence intervals (CIs) of .86 (.68-1.00) and .93 (.79-1.00), respectively. Stiffness in MRE-identified taut bands was elevated at a mean ± SD of 11.5±2.4 kPa and fell to 5.8±0.9 kPa in surrounding muscle tissue (P<.001); muscular tone in trapezius muscles without a taut band was relatively uniform at 6.6±2.1 kPa. Agreement between the physicians and the MRE raters, however, was relatively poor (63.1%; 95% CI, 50.2%-74.7%). Our findings suggest that while clinicians may overestimate, and current MRE techniques may underestimate, the presence of taut bands, these bands do exist, can be assessed quantitatively, and do represent localized areas of increased muscle stiffness.


The influence of amylose content on the modification of starches by glycogen branching enzymes.
Glycogen branching enzymes (GBEs) have been used to generate new branches in starches for producing slowly digestible starches. The aim of this study was to expand the knowledge about the mode of action of these enzymes by identifying structural aspects of starchy substrates affecting the products generated by different GBEs. The structures obtained from incubating five GBEs (three from glycoside hydrolase family (GH) 13 and two from GH57) on five different substrates exhibited minor but statistically significant correlations between the amount of longer chains (degree of polymerization (DP) 9-24) of the product and both the amylose content and the degree of branching of the substrate (Pearson correlation coefficient of ≤-0.773 and ≥0.786, respectively). GH57 GBEs mainly generated large products with long branches (100-700 kDa and DP 11-16) whereas GH13 GBEs produced smaller products with shorter branches (6-150 kDa and DP 3-10).


Correction of the posterior palatal seal by using a visible light-cured resin: a clinical report.
This article presents a technique for correcting an inadequate posterior palatal seal using a visible light-cured resin. The procedure is accomplished conveniently at chairside instead of depriving the patient of the denture for a laboratory correction.


Expression interference of a number of Heterodera avenae conserved genes perturbs nematode parasitic success in Triticum aestivum.
The cereal cyst nematode, Heterodera avenae is distributed worldwide and causes substantial damage in bread wheat, Triticum aestivum. This nematode is extremely difficult to manage because of its prolonged persistence as unhatched eggs encased in cysts. Due to its sustainable and target-specific nature, RNA interference (RNAi)-based strategy has gained unprecedented importance for pest control. To date, RNAi strategy has not been exploited to manage H. avenae in wheat. In the present study, 40 H. avenae target genes with different molecular function were rationally selected for in vitro soaking analysis in order to assess their susceptibility to RNAi. In contrast to target-specific downregulation of 18 genes, 7 genes were upregulated and 15 genes showed unaltered expression (although combinatorial soaking showed some of these genes are RNAi susceptible), suggesting that a few of the target genes were refractory or recalcitrant to RNAi. However, RNAi of 37 of these genes negatively altered nematode behavior in terms of reduced penetration, development and reproduction in wheat. Subsequently, wheat plants were transformed with seven H. avenae target genes (that showed greatest abrogation of nematode parasitic success) for host-induced gene silencing (HIGS) analysis. Transformed plants were molecularly characterized by PCR, RT-qPCR and Southern hybridization. Production of target gene-specific double- and single-stranded RNA (dsRNA/siRNA) was detected in transformed plants. Transgenic expression of galectin, cathepsin L, vap1, serpin, flp12, RanBPM and chitinase genes conferred 33.24-72.4 % reduction in H. avenae multiplication in T1 events with single copy ones exhibiting greatest reduction. A similar degree of resistance observed in T2 plants indicated the consistent HIGS effect in the subsequent generations. Intriguingly, cysts isolated from RNAi plants were of smaller size with translucent cuticle compared to normal size, dark brown control cysts, suggesting H. avenae developmental retardation due to HIGS. Our study reinforces the potential of HIGS to manage nematode problems in crop plant.


BH3 mimetics efficiently induce apoptosis in mouse basophils and mast cells.
Basophil granulocytes and mast cells are recognized for their roles in immunity and are central effectors of diverse immunological disorders. Despite their similarities, there is emerging evidence for non-redundant roles of the circulating yet scarce basophils and tissue-resident mast cells, respectively. Because of their importance in allergic pathogenesis, specific induction of apoptosis in basophils and mast cells may represent an interesting novel treatment strategy. The pro-inflammatory cytokine interleukin-3 serves as a key factor for basophil and mouse mast cell survival. Interleukin-3 increases the expression of anti-apoptotic BCL-2 family members, such as BCL-2, BCL-XL or MCL-1; however, little is known how strongly these individual proteins contribute to basophil survival. Here, we were applying small molecule inhibitors called BH3 mimetics, some of which show remarkable success in cancer treatments, to neutralize the function of anti-apoptotic BCL-2 family members. We observed that expression levels of anti-apoptotic BCL-2 proteins do not necessarily correlate with their respective importance for basophil survival. Whereas naive in vitro-differentiated mouse basophils efficiently died upon BCL-2 or BCL-XL inhibition, interleukin-3 priming rendered the cells highly resistant toward apoptosis, and this could only be overcome upon combined targeting of BCL-2 and BCL-XL. Of note, human basophils differed from mouse basophils as they depended on BCL-2 and MCL-1, but not on BCL-XL, for their survival at steady state. On the other hand, and in contrast to mouse basophils, MCL-1 proved critical in mediating survival of interleukin-3 stimulated mouse mast cells, whereas BCL-XL seemed dispensable. Taken together, our results indicate that by choosing the right combination of BH3 mimetic compounds, basophils and mast cells can be efficiently killed, even after stimulation with potent pro-survival cytokines such as interleukin-3. Because of the tolerable side effects of BH3 mimetics, targeting basophils or mast cells for apoptosis opens interesting possibilities for novel treatment approaches.


Influence of group resilience on job satisfaction among Korean nurses: A cross-sectional study.
This study examined whether the individual and organisational factors of ecological systems theory are associated with job satisfaction among nurses in South Korea. Nursing shortages and high turnover rates are a global issue in healthcare settings, and job satisfaction is significantly associated with the turnover intention of nurses. Therefore, efforts to promote job satisfaction are needed to decrease the high turnover rates among nurses and promote care quality and patient safety. A cross-sectional study was performed. This paper adhered to the STROBE guidelines. A sample of 438 nurses working in five secondary or tertiary hospitals was surveyed. The study instruments included work-life balance, resilience, insomnia and job satisfaction. Using multilevel analysis, both individual and organisational factors were associated significantly with job satisfaction, and variance at the group level accounted for 19.98% of the total variance of job satisfaction. Among the individual factors, marital status and work-life balance were significantly associated with job satisfaction. At the organisational level, the group mean resilience score was significantly associated with job satisfaction (p < .05). The psychosocial characteristics of individual nurses and their affiliated groups (nursing units) were significant in explaining the job satisfaction of nurses. Both individual-focused and group-focused interventions are needed to improve job satisfaction and decrease the turnover intention.


Unequal branch point filtering action in different types of dorsal root ganglion neurons of frogs.
The influence of the intraganglionic branch point on impulse conduction in single neurons of frog dorsal root ganglia (DRG) has been determined by measuring the least interval at which it will conduct two action potentials into the dorsal root. At 21-23 degrees C, branch points of myelinated fibers had long least conduction intervals and low safety factors for orthodromic impulse conduction compared to nodes of Ranvier in peripheral nerve. DRG neurons with broad somatic spikes with a shoulder on the falling phase and slowly conducting myelinated or non-myelinated axons had the longest least conduction intervals (lowest safety factors). DRG neurons with brief somatic spikes with little or no shoulder on the falling phase had short least conduction intervals (higher safety factor) regardless of their conduction velocity. The results indicate that certain DRG neurons have found a way to minimize branch point filtering action.


Working memory training and perceptual discrimination training impact overlapping and distinct neurocognitive processes: Evidence from event-related potentials and transfer of training gains.
There is emerging evidence that working memory (WM) can potentially be enhanced via targeted training protocols. However, the differential effects of targeted training of WM vs. training of general attentional processes on distinct neurocognitive mechanisms is not well understood. In the present study, we compared adaptive n-back WM training to an adaptive visual search training task that targeted perceptual discrimination, in the absence of demands on WM. The search task was closely matched to the n-back task on difficulty and participant engagement. The training duration for both protocols was 20 sessions over approximately 4 weeks. Before and after training, young adult participants were tested on a battery of cognitive tasks to examine transfer of training gains to untrained tests of WM, processing speed, cognitive control, and fluid intelligence. Event-related brain potential (ERP) measures obtained during a Letter 3-Back task and a Search task were examined to determine the neural processes that were affected by each training protocol. Both groups improved on measures of cognitive control and fluid intelligence at post- compared to pretest. However, n-back training resulted in more pronounced transfer effects to tasks involving WM compared to search training. With respect to ERPs, both groups exhibited enhancement of P3 amplitude following training, but distinct changes in neural responses were also observed for the two training protocols. The search training group exhibited earlier ERP latencies at post- compared to pretest on the Search task, indicating generalized improvement in processing speed. The n-back group exhibited a pronounced enhancement and earlier latency of the N2 ERP component on the Letter 3-back task, following training. Given the theoretical underpinnings of the N2, this finding was interpreted as an enhancement of conflict monitoring and sequential mismatch identification. The findings provide evidence that n-back training enhances distinct neural processes underlying executive aspects of WM.


Influence of bending pre-load on the tensile response of the lumbar spine.
Previous full body cadaver testing has shown that both obliquely oriented seats in survivable aircraft crashes and far-side oblique crashes in vehicles present distinctive occupant kinematics that are not yet well understood. Knowledge surrounding how these loading scenarios affect the lumbar spine is particularly lacking as there exists minimal research concerning oblique loading. The current study was created to evaluate a novel experimental method through comparison with existing literature, and to examine the impact of a static bending pre-load (posture) on the load-displacement response for the whole lumbar spine loaded in non-destructive axial distraction. T12-S1 lumbar spines were tested in tension to 4 mm of displacement while positioned in one of three pre-load postures. These postures were: the spine's natural, unloaded curvature (neutral), flexed forward (flexed), and combined flexion and lateral bending (oblique). Deviations from a neutral spine position were shown to significantly increase peak loads and tensile stiffness. The presence of a flexion pre-load caused statistically significant increases in tensile stiffness, tensile force, and bending moments. The addition of a lateral bending pre-load to an already flexed spine did not significantly alter the tensile response. However, the flexion moment response was significantly affected by the additional postural pre-load. This work indicates that the initial conditions of distraction loading significantly affect lumbar spine load response. Therefore, future testing that seeks to emulate crash dynamics of obliquely seated occupants must account for multi-axis loading.


Impact of expression of EMP enzymes on glucose metabolism in Zymomonas mobilis.
Zymomonas mobilis is the only known microorganism that utilizes the Entner-Doudoroff (ED) pathway anaerobically. In this work, we investigated whether the overexpression of a phosphofructokinase (PFK), the only missing Embden-Meyerhof-Parnas (EMP) pathway enzyme, could establish the pathway in this organism. Introduction of a pyrophosphate-dependent PFK, along with co-expression of homologous fructose-1,6-bisphosphate aldolase and triosephosphate isomerase, did not result in an EMP flux to any appreciable level. However, the metabolism of glucose was impacted significantly. Eight percent of glucose was metabolized to form a new metabolite, dihydroxyacetone. Reducing flux through the ED pathway by as much as 40 % through antisense of a key enzyme, ED aldolase, did not result in a fully functional EMP pathway, suggesting that the ED pathway, especially the lower arm, downstream from glyceraldehyde-3-phosphate, is very rigid, possibly due to redox balance.


Compressive force-induced LincRNA-p21 inhibits mineralization of cementoblasts by impeding autophagy.
The mineralization capability of cementoblasts is the foundation for repairing orthodontic treatment-induced root resorption. It is essential to investigate the regulatory mechanism of mineralization in cementoblasts under mechanical compression to improve orthodontic therapy. Autophagy has a protective role in maintaining cell homeostasis under environmental stress and was reported to be involved in the mineralization process. Long noncoding RNAs are important regulators of biological processes, but their functions in compressed cementoblasts during orthodontic tooth movement remain unclear. In this study, we showed that compressive force downregulated the expression of mineralization-related markers. LincRNA-p21 was strongly enhanced by compressive force. Overexpression of lincRNA-p21 downregulated the expression of mineralization-related markers, while knockdown of lincRNA-p21 reversed the compressive force-induced decrease in mineralization. Furthermore, we found that autophagy was impeded in compressed cementoblasts. Then, overexpression of lincRNA-p21 decreased autophagic activity, while knockdown of lincRNA-p21 reversed the autophagic process decreased by mechanical compression. However, the autophagy inhibitor 3-methyladenine abolished the lincRNA-p21 knockdown-promoted mineralization, and the autophagy activator rapamycin rescued the mineralization inhibited by lincRNA-p21 overexpression. Mechanistically, the direct binding between lincRNA-p21 and FoxO3 blocked the expression of autophagy-related genes. In a mouse orthodontic tooth movement model, knockdown of lincRNA-p21 rescued the impeded autophagic process in cementoblasts, enhanced cementogenesis, and alleviated orthodontic force-induced root resorption. Overall, compressive force-induced lincRNA-p21 inhibits the mineralization capability of cementoblasts by impeding the autophagic process.


Efficacy of Perioperative Infusion of N(2)-L-alanyl-L-glutamine in Glycemic Control for Patients With Uncontrolled Diabetes Mellitus Presented for Urgent Coronary Artery Bypass Surgery: A Randomized Controlled Trial.
To evaluate the efficacy of preoperative glutamine infusion in reducing insulin requirements in patients with uncontrolled type 2 diabetes, defined as glycated hemoglobin (HbA1c) >7%, undergoing urgent coronary artery bypass graft (CABG) surgery. A randomized controlled trial. At Ain Shams University Hospital, Cardiothoracic Academy. Ninety-three patients (of both sexes) with uncontrolled diabetes presenting for urgent CABG were categorized into 2 groups. The dipeptiven group (n = 46) was given an infusion of dipeptiven 1.5 mL/kg body weight dissolved in normal saline (200 mL) over 3 hours before surgery. The control group (n = 47) received a normal saline infusion (200 mL). The dipeptiven group demonstrated statistically significant lower intraoperative (173.74 ± 19.97 mg/dL v 198.22 ±14.64 mg/dL) and postoperative (162.36 ±13.11 mg/dL v 176.13 ±14.86 mg/dL) mean blood glucose levels. In addition, dipeptiven infusion was found to reduce mean total insulin requirements intraoperatively by 3.64 ± 0.56 units/h and postoperatively by 37.109 ± 4.30 units/24 h in comparison to placebo (50.98 ± 16.55 units/24 h and 5.10 ± 2.28 units/h, respectively). A preoperative infusion of dipeptiven can contribute to ameliorating stress hyperglycemia in uncontrolled diabetic patients undergoing urgent CABG.


Effect of phenobarbital on serum and biliary parameters in a patient with Crigler-Najjar syndrome, type II and acquired cholestasis.
The effect of phenobarbital treatment on bilirubin metabolism and bile secretion was studied in a patient with Crigler-Najjar syndrome, type II and acquired cholestasis. Following cholecystectomy and choledochostomy, a balloon inflatable T tube was inserted to facilitate bile collection. Hepatic UDP-glucuronyltransferase in surgically obtained liver tissue was 25% of normal activity and bilirubin monoconjugates accounted for greater than 80% of the pigments in bile. Phenobarbital therapy decreased the concentration of fasting serum bile acids by 33% and partially reestablished their enterohepatic cycling postprandially. The total fasting serum bilirubin concentration (greater than 90% unconjugated) increased 21% during phenobarbital treatment and was unaffected by caloric intake. Bile flow was increased 2.7 times after phenobarbital treatment. The biliary concentration of total bilirubin was increased 2.4 times, primarily due to monoconjugated bilirubin, which accounted for 91% of the biliary pigments. Bile acid, phospholipid, cholesterol, and calcium concentrations in bile were significantly increased after phenobarbital. The data indicate that even in the presence of cholestasis an underlying deficiency in bilirubin conjugation may be confirmed by biliary pigment analysis.


Financial Hardship and Quality of Life Among Patients With Advanced Cancer Receiving Outpatient Palliative Care: A Pilot Study.
Patients with advanced cancer are increasingly experiencing financial hardship (FH) and associated negative health outcomes. The aims of this study were to describe FH and explore its relationship to quality of life (QOL) in patients with advanced cancer receiving outpatient palliative care (PC). Validated questionnaires assessed FH, QOL dimensions, symptom burden, and sociodemographic and clinical characteristics. Descriptive statistics characterized the sample and described FH. Pearson correlation and linear regression assessed relationships between FH and QOL. The average participant (n = 78) age was 56.6 (SD, 12.2) years. Most were female (56.4%), White (50%) or Black (46.2%), and had a range of education, partner statuses, and cancer diagnoses. Median time since cancer diagnosis was 35.5 months (interquartile range, 9-57.3 months). Highest mean symptom burden scores were for pain (2.5 [SD, 1.0]) and fatigue (2.0 [SD, 1.1]), on a 0- to 3-point scale (higher score representing worse symptom burden). The median COST (COmphrehensive Score for financial Toxicity) score was 15.0 (interquartile range, 9.0-23.0). Most (70%) had some (n = 43) or extreme (n = 9) difficulty paying for basic needs. Greater than 28% (n = 21) incurred cancer-related debt. Multivariate models indicated that FH negatively affected role limitations due to physical health ( P = .008), pain ( P = .003), and emotional well-being ( P = .017) QOL dimensions. Financial hardship, QOL, and symptom burden scores demonstrate need for continued support for and research among patients with advanced cancer. Data support links between FH and important QOL dimensions. Larger, longitudinal studies are needed to understand how FH affects QOL in patients with advanced cancer. Proactive financial assessment and interventions are needed to support patients with advanced cancer experiencing the cumulative effects of cancer and its treatment.


Accelerated exhaustive search procedure for filter design by merit function minimization.
A scheme that permits a considerable reduction of the computation time needed by exhaustive search procedures for merit function minimization in optical filter design is presented.


Mechanism of stereo- and regioselectivity in the Paternò-Büchi reaction of furan derivatives with aromatic carbonyl compounds: importance of the conformational distribution in the intermediary triplet 1,4-diradicals.
Temperature and substituent effects on the stereo- and regioselectivity have been investigated in the photochemical [2 + 2] cycloaddition reaction, the so-called Paternò-Büchi (PB) reaction, of unsymmetrically substituted furans 2a,b (2-methyl- and 3-methylfuran) with aromatic carbonyl compounds 1a,b (benzaldehyde and benzophenone). The regio-random but stereoselective (exo/endo > 97/3) formation of lower substituted oxetane 3a and higher substituted oxetane 4a is found in the reaction with benzaldehyde (1a). The exclusive stereoselectivity is not dependent on the position of methyl substituent on the furan ring and the reaction temperature. The double-bond selection (3a versus 4a) is slightly dependent on the reaction temperature (3a/4a = 55/45 to 40/60). The Eyring plots of the regioselectivity are linear. Contrastively, in the reaction with benzophenone (1b), the double-bond selection (3b versus 4b) largely depends on the reaction temperature. The Eyring plots are not linear, but the inflection points are observed. The transient absorption spectroscopic analyses (picosecond time scale) clarify the intervention of triplet 2-oxabutane-1,4-diyls in the photochemical processes. Computational studies reveal the equilibrium structures of the triplet diradicals, energy barriers between the conformers, and the equilibrium constants. A rational mechanism is herein proposed by the support of both experimental and computational investigations to account for not only the exclusive formation of the exo-configured oxetanes 3a and 4a but also the nonlinear Eyring plots observed in the reaction with 1b.


Functional significance of delay-period activity of primate prefrontal neurons in relation to spatial working memory and reward/omission-of-reward expectancy.
The lateral prefrontal cortex (LPFC) is important in cognitive control. During the delay period of a working memory (WM) task, primate LPFC neurons show sustained activity that is related to retaining task-relevant cognitive information in WM. However, it has not yet been determined whether LPFC delay neurons are concerned exclusively with the cognitive control of WM task performance. Recent studies have indicated that LPFC neurons also show reward and/or omission-of-reward expectancy-related delay activity, while the functional relationship between WM-related and reward/omission-of-reward expectancy-related delay activity remains unclear. To clarify the functional significance of LPFC delay-period activity for WM task performance, and particularly the functional relationship between these two types of activity, we examined individual delay neurons in the primate LPFC during spatial WM (delayed response) and non-WM (reward-no-reward delayed reaction) tasks. We found significant interactions between these two types of delay activity. The majority of the reward expectancy-related neurons and the minority of the omission-of-reward expectancy-related neurons were involved in spatial WM processes. Spatial WM-related neurons were more likely to be involved in reward expectancy than in omission-of-reward expectancy. In addition, LPFC delay neurons observed during the delayed response task were not concerned exclusively with the cognitive control of task performance; some were related to reward/omission-of-reward expectancy but not to WM, and many showed more memory-related activity for preferred rewards than for less-desirable rewards. Since employing a more preferred reward induced better task performance in the monkeys, as well as enhanced WM-related neuronal activity in the LPFC, the principal function of the LPFC appears to be the integration of cognitive and motivational operations in guiding the organism to obtain a reward more effectively.


Prosthetic Pulmonary Valve Stenosis: A Different Way to Solve the Problem.
To avoid a third major cardiovascular surgery in an 84-year-old man, a Melody Transcatheter Pulmonary Valve was implanted in a functionally stenotic bioprosthesis in the pulmonary position. The intervention was free of complications with good results.


Anal pressure measurements in the study of hemorrhoid etiology and their relation to treatment.
The etiology of hemorrhoids has been explained in the past based on anatomic principles, but this study examines the relationship of resting anal pressures to hemorrhoid etiology in 38 patients with hemorrhoids and 29 controls with no perianal symptoms. Three months after treatment by elastic band ligation, anal pressures were again measured in the hemorrhoid group. Anal pressures were significantly higher in the hemorrhoid group before treatment (102 +/- 26.33 mmHg) as compared with the controls (76.75 +/- 19.56 mmHg) (P less than .001). Three months following elastic band ligation there was a small drop in anal pressure (100 +/- 26.84 mmHg) but it remained significantly higher than the control group. There was also a significant correlation between symptoms and level of anal pressures. The results indicate that persons with hemorrhoids have higher anal pressures than controls. Elastic band ligation relieves the symptoms but should not affect the anal sphincter pressure. The fact that the anal pressures remained high after treatment could imply that higher pressures are an etiologic component in the formation of hemorrhoids.


The effect of a steep high-frequency hearing loss on growth-of-masking functions in simultaneous masking for f(m)<f(s).
In normal-hearing subjects, the slope of the growth-of-masking (GOM) function obtained in simultaneous masking when the masker frequency (f(m)) is much less than the signal frequency (f(s)) often changes from a value near 2.0 to a value near 1.0 at high levels. The purpose of the present study was to evaluate whether this change in slope reflects a basal shift in the peak of the signal's basilar-membrane vibration pattern. To discourage the use of basally shifted peak excitation, GOM functions were obtained in seven subjects with a precipitously sloping high-frequency hearing loss. The signal was located at the normal-hearing edge of the loss, and the masker was located 3 equivalent rectangular bandwidths below f(s). In addition, GOM functions for an f(s) of 2000 Hz were obtained in four subjects with normal hearing, either "in quiet" or in the presence of a restrictor tone with a frequency of 2400 or 2600 Hz and a level of 90 dB SPL. Overall, the results generally are not consistent with the change in slope at high levels being due to a basal shift in the peak of the signal's basilar-membrane vibration pattern. Instead, the results are consistent with a decrease in compression at high input levels at the place corresponding to f(s).


Metal oxide nanoparticles resonate to ammonium removal through influencing Mg2+ absorption by Pseudomonas putida Y-9.
Most metal oxide nanoparticles (NPs) can impact ammonium removal, but the underlying mechanism remains unclear. In this study, high doses of NiO, CuO, ZnO and TiO2 (>1 mg/L) inhibited the ammonium removal performance of Pseudomonas putida Y-9. Interestingly, low levels of CuO NPs (0.1, 0.5 mg/L) and NiO NPs (0.1 mg/L) enhanced ammonium removal efficiency. Moreover, a decrease in Mg2+ levels was significantly positively correlated with ammonium removal efficiency, while negatively correlated with the Ti2+, Zn2+, and Cu2+ release of NPs. Further research on effect of NPs and their corresponding cations on ammonium removal revealed that four NPs affected Mg2+ absorption in Y-9 via different routes, thus impacting NH4+ removal efficiency, i.e., the effect of NiO NPs was caused by itself, TiO2 NPs' impact was solely due to the release Ti4+, while the influence of CuO NPs and ZnO NPs was based on both the particles and released ions.


Anesthetic mishaps and the cost of monitoring: a proposed standard for monitoring equipment.
Review of insurance data indicates that approximately 1.5 claims are paid per 10,000 anesthetic procedures, a conservative estimate of the incidence of preventable serious injury associated with anesthesia. Insurance data permit estimation of the premium cost for the anesthesiologist and hospital, per operating room per year, of $69,429.00. We propose the use of an enhanced monitoring standard requiring a pulse oximeter, capnograph, spirometer, halometer, automatic sphygmomanometer, breathing circuit oxygen analyzer, stethoscope, electrocardiographic monitor, and temperature monitor. We suggest that this premium cost, together with the estimate that 50% of incidents would be avoided, predicts a resultant saving of over $27,000/operating room/year, a savings equal to the entire cost of the enhanced monitoring system in approximately 8 months, or a yearly savings of over five times the annualized expense of the monitoring system. Thus, in addition to the moral imperative to monitor a patient during anesthesia to avoid injury and death, there is an economic incentive to monitor effectively.


Pharmacokinetic interaction in beagle dogs of antiplatelet drugs: acetylsalicylic acid, dipyridamole and calcium dobesilate.
In clinical practice, the co-administration of antiplatelet drugs, such as acetylsalicylic acid (ASA) and dipyridamole (DP) and calcium dobesilate, is often recommended in order to obtain secondary prophylaxis against certain ischaemic diseases. Therefore the possible pharmacokinetic interactions between these three drugs were studied after a single-dose in beagle dogs. The plasma concentrations of ASA, DP and CaDb were measured by HPLC. It was found that the DP and CaDb kinetics were unaffected by concurrent intake of ASA, DP or CaDb. However, concurrent DP or CaDb improved the bioavailability of ASA, particularly the increased Cmax and (AUC).


Targeting the endocannabinoid system: to enhance or reduce?
As our understanding of the endocannabinoids improves, so does the awareness of their complexity. During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals. These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases. When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment.


Protection by ascorbic acid from denaturation and release of cytochrome c, alteration of mitochondrial membrane potential and activation of multiple caspases induced by H(2)O(2), in human leukemia cells.
We investigated peroxide and superoxide accumulation, cytochrome c nature and release from mitochondria, as well as caspase activation during exposure of HL-60 cells to H(2)O(2) and the protective effect of ascorbic acid. Exposure of the cells to 100 microM H(2)O(2) resulted in intracellular accumulation of peroxides, denaturation of cytochrome c that was identified in the mitochondria and cytosol, release of native cytochrome c to the cytosol and fall in mitochondrial membrane potential (DeltaPsi(m)). Loading of cells with ascorbic acid before exposure to H(2)O(2) resulted in a dose-dependent protective effect against: intracellular accumulation of peroxides, DeltaPsi(m) alteration, cytochrome c denaturation and release. The accumulation of peroxides induced processings and activations of procaspase-8, -9 and -3. Double staining with antiserum which recognizes the p18 subunit of cleaved caspase-3 and with Hoechst had shown that a high percentage of cells exposed to 100 microM H(2)O(2) stained positively with the antibody and showed features of apoptosis. Ascorbic acid loading prevented caspase activation induced by H(2)O(2). We conclude that ascorbic acid protects against activation of apoptotic cascades in HL-60 cells exposed to H(2)O(2) and against apoptosis.


The myoglobin of the Cape fox (Vulpes chama).
Tryptic, peptic and chymotryptic peptides from the myoglobin of the Cape fox (Vulpes chama) have been aligned with the sequence of the myoglobin of the domestic dog. No amino acid difference was found. Seven carnivore myoglobins now known are compared amongst themselves and it is noted that though the differences between them are found in many different parts of the myoglobin molecule, there seems to be a higher incidence along the loop formed by helix G, the interhelical region GH and the helix H.


Hyperbranched Poly(amido amine) Entrapped Tetraphenylethene as a Fluorescence Probe for Sequential Quadruple-Target Detection and Its Potential as a Chemical Logic Gate.
Fluorescence sensors exhibit great potential as molecular logic gates to perform computation on a nanometer scale. For achieving the more complex artificial intelligence activities, developing complex logic gates using multitarget sensing systems with multi-input characteristics is highly desirable. Herein, a water-soluble quadruple-target fluorescence sensor that embeds a small amount (4.1 wt %) of tetraphenylethene (TPE) units into hyperbranched poly(amido amine) (TPE-HPA) has been designed. The nonfluorescent TPE-HPA could experience the fluorescence "off-on-off-on-off" by sequential addition of sodium hexametaphosphate (SHMP), Fe3+, ascorbic acid (AA), and H2O2. The as-prepared quadruple-target sensor showed good sensitivity and selectivity to SHMP, Fe3+, AA, and H2O2, and the limit of detection values were 29 nM, 20 nM, 0.66 μM, and 0.78 μM, respectively. On the basis of the multitarget sensing nature of TPE-HPA, chemical or electrochemical-induced logic gates were constructed, including YES, NOT, OR, NOR, NAND, INHIBIT, IMP, and higher logic systems.


A Longitudinal Study of the Relations Between Theory of Mind, Executive Function, and Lying in Children.
This study used longitudinal cross-lagged modeling to examine the contribution of theory of mind (ToM), executive function (EF) to children's lying development and of children's lying to ToM and EF development. Ninety-seven Chinese children (initial M age = 46 months, 47 boys) were tested three times approximately 4 months apart. Results showed that the diverse desire understanding and knowledge access understanding components of ToM, as well as the inhibitory control component of EF predicted the development of children's lying, while the diverse belief understanding and false belief understanding components of ToM, and the working memory component of EF did not predict development of children's lying. Meanwhile, children's lying predicted development of children's belief-emotion understanding components of ToM, but not any other ToM components, or EF components. These findings provide longitudinal evidence for the relation between ToM, EF, and children's lying during the preschool years.


Infectious diseases and the immunizations of today and tomorrow.
For decades, health care providers have administered immunizations for common childhood infections. These have been given at predicted times according to an agreed-upon schedule. However, in the past decade, common immunizations have been changed, the number of immunizations has increased, and the schedule for administration of vaccines officially changes every January. In addition, as science continues to grow, new vaccines are being developed faster than ever before.


MicroRNA biogenesis and function in plants.
A microRNA (miRNA) is a 21-24 nucleotide RNA product of a non-protein-coding gene. Plants, like animals, have a large number of miRNA-encoding genes in their genomes. The biogenesis of miRNAs in Arabidopsis is similar to that in animals in that miRNAs are processed from primary precursors by at least two steps mediated by RNAse III-like enzymes and that the miRNAs are incorporated into a protein complex named RISC. However, the biogenesis of plant miRNAs consists of an additional step, i.e., the miRNAs are methylated on the ribose of the last nucleotide by the miRNA methyltransferase HEN1. The high degree of sequence complementarity between plant miRNAs and their target mRNAs has facilitated the bioinformatic prediction of miRNA targets, many of which have been subsequently validated. Plant miRNAs have been predicted or confirmed to regulate a variety of processes, such as development, metabolism, and stress responses. A large category of miRNA targets consists of genes encoding transcription factors that play important roles in patterning the plant form.


Early Treatment with Human Albumin Solution in Continuous Renal Replacement Patients.
To study the impact of early human albumin solution (HAS) in continuous renal replacement therapy (RRT) patients. Analysis of Randomized Evaluation of Normal versus Augmented Level (RENAL) RRT trial data. Of 1,464 patients, 500 (34%) received early albumin. These patients had higher illness severity scores, greater use of mechanical ventilation, and 90-day mortality (51 vs. 41%; p < 0.001). However, early albumin carried similar RRT dependence risk among survivors at day 90 (4.9 vs. 5.8%; p = 0.62). On Cox proportional hazards regression, with standardized inverse probability of treatment weighting, early albumin was not associated with increased mortality (hazard ratio [HR]: 1.23, 95% CI: 0.97-1.55; p = 0.09) or recovery to RRT independence (HR: 0.92, 95% CI: 0.78-1.10; p = 0.38). Early albumin was administered to one-third of RENAL trial patients and in those with greater illness severity. Early albumin was not independently associated with mortality risk or rate of recovery to RRT independence.


Navafenterol (AZD8871) in patients with COPD: a randomized, double-blind, phase I study evaluating safety and pharmacodynamics of single doses of this novel, inhaled, long-acting, dual-pharmacology bronchodilator.
Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β2-agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). The pharmacodynamics, safety and tolerability of single doses of navafenterol were investigated in patients with moderate to severe COPD. This was a randomized, five-way complete cross-over study. Patients received single doses of navafenterol 400 μg, navafenterol 1800 μg and placebo (all double-blind) and indacaterol 150 μg and tiotropium 18 μg (both open-label active comparators). The primary pharmacodynamic endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 2. Safety and tolerability were monitored throughout. Thirty-eight patients were randomized and 28 (73.7%) completed the study. Navafenterol 400 μg and 1800 μg demonstrated statistically significant improvements vs placebo in change from baseline in trough FEV1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P < .0001). The changes were significantly greater with navafenterol 1800 μg vs the active comparators (least squares mean treatment difference: 0.065-0.069 L, both P < .05). The frequency of treatment-emergent adverse events was similar for placebo and the active comparators (range 34.4-37.5%), slightly higher for navafenterol 400 μg (52.9%), and lowest for navafenterol 1800 μg (22.6%). Both doses of navafenterol demonstrated sustained bronchodilation over 24 h. Navafenterol was well tolerated and no safety concerns were raised. ClinicalTrials.gov ; No.: NCT02573155 ; URL: www.clinicaltrials.gov . Registered 9th October, 2015.


Entomology: Asian honeybees parasitize the future dead.
The queen of a honeybee colony has a reproductive monopoly because her workers' ovaries are normally inactive and any eggs that they do lay are eaten by their fellow workers. But if a colony becomes queenless, the workers start to lay eggs, stop policing and rear a last batch of males before the colony finally dies out. Here we show that workers of the Asian dwarf red honeybee Apis florea from other colonies exploit this interval as an opportunity to move in and lay their own eggs while no policing is in force. Such parasitism of queenless colonies does not occur in the western honeybee A. mellifera and may be facilitated by the accessibility of A. florea nests, which are built out in the open.


Bipolar Effects in Photovoltage of Metamorphic InAs/InGaAs/GaAs Quantum Dot Heterostructures: Characterization and Design Solutions for Light-Sensitive Devices.
The bipolar effect of GaAs substrate and nearby layers on photovoltage of vertical metamorphic InAs/InGaAs in comparison with pseudomorphic (conventional) InAs/GaAs quantum dot (QD) structures were studied. Both metamorphic and pseudomorphic structures were grown by molecular beam epitaxy, using bottom contacts at either the grown n +-buffers or the GaAs substrate. The features related to QDs, wetting layers, and buffers have been identified in the photoelectric spectra of both the buffer-contacted structures, whereas the spectra of substrate-contacted samples showed the additional onset attributed to EL2 defect centers. The substrate-contacted samples demonstrated bipolar photovoltage; this was suggested to take place as a result of the competition between components related to QDs and their cladding layers with the substrate-related defects and deepest grown layer. No direct substrate effects were found in the spectra of the buffer-contacted structures. However, a notable negative influence of the n +-GaAs buffer layer on the photovoltage and photoconductivity signal was observed in the InAs/InGaAs structure. Analyzing the obtained results and the performed calculations, we have been able to provide insights on the design of metamorphic QD structures, which can be useful for the development of novel efficient photonic devices.


Stent implantation through rendezvous technique of PTBD and ERCP: the treatment of obstructive jaundice.
To study the technical method and clinical value of stent implantation through the rendezvous technique of percutaneous transhepatic biliary drainage (PTBD) and endoscopic retrograde cholangiopancreatography (ERCP) in patients with obstructive jaundice. Thirty-six patients with obstructive jaundice underwent the rendezvous technique of PTBD and ERCP after initially unsuccessful ERCP. The procedure of 36 cases were all successful. Sixteen cases underwent PTBD drainage from the bile duct through the right lobe approach and in 20 cases the left lobe approach was used. The one-stage procedure involved in the rendezvous technique of PTBD and ERCP was successful in 23 cases, while the other 13 cases underwent PTBD first and then rendezvous ERCP the next time. The serum total bilirubin 4 days later had decreased by 44.75%, and direct bilirubin had decreased by 45.61%. The main complication was infection of the bile duct. Stent implantation using the rendezvous technique of PTBD and ERCP is a new and feasible method to treat obstructive jaundice after initially unsuccessful ERCP. This may be of considerable value in clinical practice.


Tuning the electronic band structure of PCBM by electron irradiation.
Tuning the electronic band structures such as band-edge position and bandgap of organic semiconductors is crucial to maximize the performance of organic photovoltaic devices. We present a simple yet effective electron irradiation approach to tune the band structure of [6, 6]-phenyl-C61-butyric acid methyl ester (PCBM) that is the most widely used organic acceptor material. We have found that the lowest unoccupied molecular orbital (LUMO) level of PCBM up-shifts toward the vacuum energy level, while the highest occupied molecular orbital (HOMO) level down-shifts when PCBM is electron-irradiated. The shift of the HOMO and the LUMO levels increases as the irradiated electron fluence increases. Accordingly, the band-edge position and the bandgap of PCBM can be controlled by adjusting the electron fluence. Characterization of electron-irradiated PCBM reveals that the variation of the band structure is attributed to the molecular structural change of PCBM by electron irradiation.


Mazindol and amphetamine as inhibitors of the uptake and releasers of 3H-dopamine by rat striatal synaptosomes.
The effects of mazindol, amphetamine and fenfluramine on uptake and release of 3H-DA by synaptosomes were studied in different systems. In in vitro incubations of 3H-DA with synaptosomes isolated from the caudate nucleus of the rat, mazindol inhibited the uptake of the radioactivity more potently than did amphetamine. When the synaptosomes were isolated from the caudate nuclei of rats treated in vivo with either mazindol or amphetamine, the uptake of 3H-DA during in vitro incuation was lower with synaptosomes of amphetamine-treated rats than with those of mazindol-treated rats. When synaptosomes of untreated rats were prelabelled with 3H-DA and incubated in the presence of amphetamine or of mazindol, amphetamine caused a greater release of radioactivity than did mazindol. Fenfluramine was without activity in all these systems. In spite of the quantitative differences, both amphetamine and mazindol appear to have similar effects on uptake and release of dopamine, and this may account for their analogous pharmacological profile.


Clinical application of harmonic power Doppler imaging in the assessment of myocardial perfusion by contrast echocardiography.
Myocardial contrast echocardiography has moved from the research laboratory to clinical echocardiography. As with any emerging technology, background information and understanding the process of image acquisition will help to integrate the technology into everyday practice. Harmonic power Doppler imaging (HPDI) is a high-power, triggered imaging modality used to assess myocardial perfusion. Contrast agents used in echocardiography provide microvascular tracers that enable HPDI to accurately visualize myocardial blood flow. This article aims to provide direction in the clinical performance of myocardial contrast echocardiography by providing background in the theory and physics of HPDI and a guide to the technical acquisition of images and recognition of artifacts that arise during HPDI.


Oxysterols induce mitochondrial impairment and hepatocellular toxicity in non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disorder affecting up to 25% of the general population. Several intracellular events leading to NAFLD and progression to non-alcoholic steatohepatitis (NASH) have been identified, including lipid accumulation, mitochondrial dysfunction and oxidative stress. Emerging evidence links both hepatic free fatty acids (FFAs) and cholesterol (FC) accumulation in NAFLD development; in particular oxysterols, the oxidative products of cholesterol, may contribute to liver injury. We performed a targeted lipidomic analysis of oxysterols in the liver of male Wistar rats fed a high-fat (HF), high-cholesterol (HC) or high-fat/high-cholesterol (HF/HC) diet. Both HF and HC diets caused liver steatosis, but the HF/HC diet resulted in steatohepatitis with associated mitochondrial dysfunction. Above all, the oxysterol cholestane-3beta,5alpha,6beta-triol (triol) was particularly increased in the liver of rats fed diets rich in cholesterol. To verify the molecular mechanism involved in mitochondrial dysfunction and hepatocellular toxicity, Huh7 and primary rat hepatocytes were exposed to palmitic acid (PA) and/or oleic acid (OA), with or without triol. This compound induced apoptosis in cells co-exposed to both PA and OA, and this was associated with impaired mitochondrial respiration as well as down-regulation of PGC1-alpha, mTFA and NRF1.In conclusion, our data show that hepatic free fatty acid or oxysterols accumulation per se induce low hepatocellular toxicity. On the contrary, hepatic accumulation of both fatty acids and toxic oxysterols such as triol are determinant in the impairment of mitochondrial function and biogenesis, contributing to liver pathology in NAFLD.


Augmenting Immunogenic Cell Death and Alleviating Myeloid-Derived Suppressor Cells by Sono-Activatable Semiconducting Polymer Nanopartners for Immunotherapy.
Inducing immunogenic cell death (ICD) by sonodynamic therapy (SDT) is promising for cancer immunotherapy, which however is inefficient due to oxygen depletion that compromises SDT effect and mediates recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs). The fabrication of sono-activatable semiconducting polymer nanopartners (SPNTi ) to simultaneously augment ICD and alleviate MDSCs for immunotherapy is reported. A sonodynamic semiconducting polymer, hydrophobic hypoxia-responsive tirapazamine (TPZ)-conjugate, and MDSC-targeting drug (ibrutinib) are encapsulated inside such SPNTi with surface shell of a singlet oxygen (1 O2 )-cleavable amphiphilic polymer. TPZ and ibrutinib serve as drug partners to enlarge immunotherapeutic effect. Upon sono-activation, SPNTi generate 1 O2 to break 1 O2 -cleavable polymers for in situ liberations of TPZ-conjugate and ibrutinib in tumor sites, and oxygen is consumed to create severe hypoxic tumor microenvironment, in which, TPZ-conjugate is activated for augmenting ICD action, while ibrutinib alleviates MDSCs for promoting antitumor immunological effect. In a bilateral tumor mouse model, SPNTi -mediated sono-activatable immunotherapy results in growth restraints of primary and distant tumors and noteworthy precaution of tumor metastases. This study thus provides a sono-activatable immunotherapeutic strategy with high precision and safety for cancer via overcoming post-treatment hypoxia and targeting MDSCs.


Gabapentin-lactam (8-aza-spiro[5,4]decan-9-on; GBP-L) inhibits oxygen glucose deprivation-induced [3H]glutmate release and is a neuroprotective agent in amodel of acute retinal ischemia.
The modulation of the enhanced release of [3H]glutamate following ischemia-like conditions was studied in rat hippocampal slices using a superfusion system. Ischemia was simulated by a glucose-free medium equilibrated with 95% N2 and 5% CO2. In this model the potential neuroprotective effects of several substances on [3H]glutamate release induced by ischemia-like conditions were investigated. Gabapentin-lactam (8-aza-spiro-5,4-decan-9-on; GBP-L) was synthesised and patented in our laboratory. GBP-L (100 microM) reduced the oxygen glucose deprivation-induced [3H]glutamate release by 42.5%, CI95=[33.4%, 51.5%]. The KATP channel antagonist glibenclamide (1 microM) blocked this effect completely. The high antagonist potency was reflected by an apparent pA2-value of glibenclamide of 8.3, CI95=[6.8, 9.4]. Minoxidil sulfate (10 microM), a KATP channel opener, mimicked the effect of GBP-L (inhibition by 22.8%, CI95=[13.2%, 32.5%]). Similarly to its lactam, also gabapentin (100 microM) reduced the oxygen glucose deprivation-induced [3H]glutamate release by 30.6%, CI95=[15.5%, 45.7%], whereas the "antiglutamatergic" drug riluzole was ineffective. GBP-L and gabapentin were also tested in an in vivo model of acute retinal ischemia in rats. The intraocular pressure was elevated for 1 h above the systolic blood pressure. In the control group, 17.5%, CI95=[13%, 22%], of retinal ganglion cells had survived after 2 weeks. GBP-L doubled the number of surviving ganglion cells up to 35%, CI95=[27%, 43%], while gabapentin had no effect. This difference between gabapentin and its lactam may be due to different pharmacokinetic properties: In contrast to the gamma-amino acid gabapentin, GBP-L is uncharged and therefore might diffuse more easily through biological membranes, e.g. the plasma membrane, to get access to an intracellular locus of action. Thus, the neuroprotective properties in vivo and the diminished oxygen glucose deprivation-induced [3H]glutamate efflux in vitro of the presumed KATP channel agonist GBP-L suggest that this substance might be therapeutically applied in pathological situations induced by a rise in extracellular glutamate and/or neuronal cell death.


Breast implant surface texture impacts host tissue response.
Surface texture of a breast implant influences tissue response and ultimately device performance. Characterizing differences among available surface textures is important for predicting and optimizing performance. Scanning electron microscopy (SEM) and X-ray computed tomography (CT)-imaging were used to characterize the topography and surface area of 12 unique breast implant surface textures from seven different manufacturers. Samples of these surface textures were implanted in rats, and tissue response was analyzed histologically. In separate experiments, the force required to separate host tissue from the implant surface texture was used as a measure of tissue adherence. SEM imaging of the top and cross section of the implant shells showed that the textures differed qualitatively in evenness of the surface, presence of pores, size and openness of the pores, and the depth of texturing. X-ray CT imaging reflected these differences, with the texture surface area of the anterior of the shells ranging from 85 to 551 mm2, which was 8-602% greater than that of a flat surface. General similarities based on the physical structure of the surfaces were noted among groups of textures. In the rat models, with increasing surface texture complexity, there was increased capsule disorganization, tissue ingrowth, and tissue adherence. Surface area and topography of breast implant textures are important factors contributing to tissue ingrowth and adherence. Based on surface area characteristics and measurements, it is possible to group the textures into four classifications: smooth/nanotexture (80-100 mm2), microtexture (100-200 mm2), macrotexture (200-300 mm2), and macrotexture-plus (> 300 mm2).


Does neighbours' grass matter? Testing spatial dependent heterogeneity in technical efficiency of Italian hospitals.
Testing for spatial dependent heterogeneity in hospital technical efficiency is crucial for separating spatial issues from the effects of regional institutional factors. We apply the Spatial Stochastic Frontier Analysis for studying the presence of spatial dependence by using novel data on Italian hospitals. This approach provides both a robust estimation of hospital technical efficiency and a careful assessment of spatial and regional issues. We find empirical support for the idea that regional and institutional factors are more important than neighbouring effects when looking at heterogeneity in hospital technical efficiency across Italy. The relevance of the regional organization of the Italian hospital system can justify our results. We also discuss the limitations of our analysis and provide sensitivity checks.


Primary structure and tissue distribution of guinea pig gastrin-releasing peptide.
The primary structure of gastrin-releasing peptide from the guinea pig stomach has been determined by automated Edman degradation and shown to be identical to porcine gastrin-releasing peptide. Extracts of guinea pig brain and small intestine contained both gastrin-releasing peptide and its COOH-terminal decapeptide (neuromedin C) but the stomach extracts contained only gastrin-releasing peptide. Within the small intestine, highest concentrations of gastrin-releasing peptide-like immunoreactivity were found in extracts of the circular and longitudinal smooth muscle layers.


Synthesis of the calcium transport ATPase of sarcoplasmic reticulum and other muscle proteins during development of muscles cells in vivo and in vitro.
The effect of medium Ca2+ concentration upon the concentration and the rate of synthesis of muscle proteins was investigated in chicken pectoralis muscle cultures. There is an easily identifiable class of muscle protein which includes the Ca2+-ATPase of sarcoplasmic reticulum, myosin, troponin C, ATP : creatine phosphotransferase, muscle specific actin, tropomysin 1 and 2, and muscle hemagglutinin, which show a large increase in concentration during normal development. The increased synthesis of these proteins was inhibited, without inhibition of cell proliferation, in culture media of relatively low Ca2+ concentration, 0.05--0.3 mM, where fusion was prevented. Similar medium Ca2+ concentration was required for the expression of all these proteins, suggesting their coordinate regulation. The proteins are denoted as 'calcium-modulated proteins'. The increased Ca2+ transport activity of sarcoplasmic reticulum in cultured chicken pectoralis muscle cells during development at 1.8 mM medium calcium concentration represents de novo synthesis of the Ca2+ transport ATPase, as shown by immunoprecipitation, active site labeling and direct identification of the Ca2+ transport ATPase on two-dimensional gel electropherograms of whole muscle homogenates. The concentration and the turnover rate of the majority of the muscle proteins is not affected significantly by medium Ca2+ concentration between 0.06 and 1.8 mM. It is proposed that increase in cytoplasmic free Ca2+ concentration during fusion plays a central role in the regulation of the synthesis of calcium-modulated proteins.


Selection of a fully human single domain antibody specific to Helicobacter pylori urease.
Helicobacter pylori bacteria are involved in gastroduodenal disorders, including gastric adenocarcinoma. Since the current therapies encounter with some significant shortcomings, much attention has been paid to the development of new alternative diagnostic and treatment modalities such as immunomedicines to target H. pylori. Having used phage display technology, we isolated fully humane small antibody (Ab) fragment (VL) against the Flap region of urease enzyme of H. pylori to suppress its enzymatic activity. Solution biopanning (SPB) and screening process against a customized biotinylated peptide corresponding to the enzyme Flap region resulted in the selection of VL single domain Abs confirmed by the enzyme-linked immunosorbent assay (ELISA), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and Western blotting. The selected Ab fragments showed a high affinity with a KD value of 97.8 × 10-9 and specificity to the enzyme with high inhibitory impact. For the first time, a VL single domain Ab was isolated by SPB process against a critical segment of H. pylori urease using a diverse semi-synthetic library. Based on our findings, the selected VL Ab fragments can be used for the diagnosis, imaging, targeting, and/or immunotherapy of H. pylori. Further, Flap region shows great potential for vaccine therapy.


Tick-borne diseases in Texas: a 10-year retrospective examination of cases.
The occurrence of Rocky Mountain spotted fever, human monocytotropic ehrlichiosis, tularemia, tick-borne relapsing fever, and a southern erythema migrans-like illness (Lyme/Lyme-like disease) is determined by the geographic distribution and seasonal activity of the particular vector tick(s). The flulike signs and symptoms early in the course of spotted fever rickettsiosis, ehrlichiosis, tularemia, and relapsing fever are nonspecific and do not readily suggest a particular diagnosis. Laboratory diagnosis, particularly during the acute stage of illness, often is elusive. Empiric treatment with doxycycline can be lifesaving for Rocky Mountain spotted fever and ehrlichiosis. This article provides insight into the significance of each of these tick-transmitted diseases in Texas.


Severe complications after intrathecal methotrexate (MTX) for treatment of primary central nervous system lymphoma (PCNSL).
Primary central nervous system lymphoma (PCNSL) is a rare and highly malignant tumor with increasing incidence. Survival has improved with the use of nonsurgical treatment modalities, of which methotrexate (MTX)-based intrathecal chemotherapy has been an important option. Here, we describe devastating complications in three patients with diffuse large B-cell lymphomas. After intrathecal MTX therapy two patients died secondary to fulminant brain edema. A third patient developed severe dementia, gait disturbance and urinary incontinence due to leukencephalopathy. Since bulky disease was present in all three patients, CSF flow may have been impaired. This might have exposed adjacent tissue to prolonged toxic drug concentrations. Regarding the severe complications seen in these patients, it is useful to consider high-dose intravenous MTX treatment only in periventricular PCNSL.


The antiviral protein human lactoferrin is distributed in the body to cytomegalovirus (CMV) infection-prone cells and tissues.
Lactoferrin has anti-Cytomegalovirus (CMV) and -HIV properties in vitro. However, the pharmacokinetic behavior of the 80-kD protein has not been well defined. We, therefore, assessed the plasma decay and body distribution of lactoferrin after intravenous administration to freely moving rats. Furthermore, the systemic availability of lactoferrin after intraperitoneal dosing was determined. After intravenous injection, human lactoferrin (hLF) was rapidly cleared from the plasma, but higher doses resulted in prolonged plasma levels. Immunohistochemical analysis revealed a pronounced distribution of hLF to endothelial cells in the liver whereas diffuse staining in hepatocytes indicated the presence of considerable amounts in this large cell population. This endothelial association, which also was found in other organ/tissues, including blood vessels. was confirmed by in vitro cell-binding studies. In addition, leukocytes in plasma that were infiltrated in various organs showed binding of hLF. A small fraction of hLF was transported into the lymphatic system. Western blot analysis revealed that hLF, present in the various organs. mainly consisted of an 80-kD protein. After intraperitoneal administration, small amounts of 80-kD hLF distributed to the general circulation. The bioavailability was 0.6% but increased to 3.6% after multiple administrations. The affinity of hLF for endothelial cells and leukocytes, and its penetration into the lymphatic system, indicates that this protein reaches target cells and body compartments that are crucial for CMV and HIV replication. The ability to reach the blood compartment after intraperitoneal dosing offers opportunities for parenteral administration of the protein in future studies on its antiviral effects in vivo.


Nucleolar stress regulation of endometrial receptivity in mouse models and human cell lines.
Embryo implantation is essential to the successful establishment of pregnancy. A previous study has demonstrated that actinomycin D (ActD) could initiate the activation of mouse delayed implantation. However, the mechanism underlying this activation remains to be elucidated. A low dose of ActD is an inducer of nucleolar stress. This study was to examine whether nucleolar stress is involved in embryo implantation. We showed that nucleolar stress occurred when delayed implantation was activated by ActD in mice. ActD treatment also stimulated the Lif-STAT3 pathway. During early pregnancy, nucleolar stress was detected in the luminal epithelial cells during the receptive phase. Blastocyst-derived lactate could induce nucleolar stress in cultured luminal epithelial cells. The inhibition of nucleophosmin1 (NPM1), which was a marker of nucleolar stress, compromised uterine receptivity and decreased the implantation rates in pregnant mice. To translate these mouse data into humans, we examined nucleolar stress in human endometrium. Our data demonstrated that ActD-induced nucleolar stress had positive effects on the embryo attachment by upregulating IL32 expression in non-receptive epithelial cells rather than receptive epithelial cells. Our data should be the first to demonstrate that nucleolar stress is present during early pregnancy and is able to induce embryo implantation in both mice and humans.


Comparing shallow, deep, and transfer learning in predicting joint moments in running.
Joint moments are commonly calculated in biomechanics research and provide an indirect measure of muscular behaviors and joint loads. However, joint moments cannot be easily quantified clinically or in the field, primarily due to challenges measuring ground reaction forces outside the laboratory. The present study aimed to compare the accuracy of three different machine learning (ML) techniques - functional regression [ MLfregress ], a deep neural network (DNN) built from scratch [ MLDNN ], and transfer learning [ MLTL ], in predicting joint moments during running. Data for this study came from an open-source dataset and two studies on running with and without external loads. Three-dimensional (3D) joint moments of the hip, knee, and ankle, were derived using inverse dynamics. 3D joint angle, velocity, and acceleration of the three joints served as predictors for each of the three ML techniques. Prediction performance was generally the best using MLDNN, and the worse using MLfregress. Absolute predictive performance was the best for sagittal plane moments, which ranged from a RMSE of 0.16 Nm/kg at the ankle using MLDNN, to a RMSE of 0.49Nm/kg at the knee using MLfregress. MLDNN resulted in the greatest improvement in relative prediction performance (relRMSE) by 20% compared to MLfregress for the ankle adduction-abduction moment. DNN with or without transfer learning was superior in predicting joint moments using kinematic inputs compared to functional regression. Synergizing ML with kinematic inputs has the potential to solve the constraints of obtaining high fidelity biomechanics data normally only possible during laboratory studies.


Evaluation of titanium dioxide coating on surface roughness of nickel-titanium archwires and its influence on Streptococcus mutans adhesion and enamel mineralization: A prospective clinical study.
This research aimed to evaluate the effect of titanium dioxide (TiO2) coating on surface roughness (Ra) of nickel-titanium (NiTi) archwires and its influence on Streptococcus mutans (S mutans) adhesion and enamel mineralization at the end of 1 month in orthodontic patients and to evaluate the integrity of the TiO2 coating. Twelve patients undergoing orthodontic treatment with preadjusted edgewise appliance formed the sample for this prospective clinical study. Uncoated NiTi archwires and TiO2 nanoparticle coated NiTi archwires in as-received condition and after 1 month of intraoral use were subjected to Ra analysis using surface profilometry, and surface topography using scanning electron microscopy. S mutans adhesion was evaluated on the retrieved archwires using real-time polymerase chain reaction (PCR). Enamel mineral content in the arches related to the uncoated and coated archwires was evaluated using DIAGNOdent. After 1 month of intraoral use, both coated and uncoated archwires exhibited a rougher surface with coated archwires demonstrating greater quantum of increase (control, P = 0.002; experimental, P = 0.002). S mutans adhesion was more in uncoated archwires (P = 0.0005). The TiO2 nanoparticle coating on the NiTi archwires showed delamination, deterioration and was lost by 60% at the end of 1 month. Laser fluorescence values did not show any significant difference (control, P = 0.182; experimental, P = 0.105). TiO2 nanoparticle coating on NiTi archwires causes an initial reduction in roughness; however, at the end of 1 month, the benefit was lost. S mutans adhesion was lesser on the coated wires, which could be attributed to reduced initial Ra and antibacterial property of TiO2. Orthodontic archwire appears to have a limited role in enamel demineralization.


Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-κB pathway.
Accumulating evidence suggests that adipose tissue is the main source of pro-inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration of SVS for 1month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-α, IL6, IL10, IL1β, KC, MIP-1α, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-κB) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-κB pathway.


NCS 613, a PDE4 inhibitor, by increasing cAMP level suppresses systemic inflammation and immune complexes deposition in kidney of MRL/lpr lupus- prone mice.
Nephritis remains the most common severe manifestation of systemic lupus erythematosus in which auto-antibodies mediate chronic inflammation and kidney damage. cAMP-phosphodiesterases regulate sodium excretion and inflammation in various tissues. How cAMP elevation can reduce systemic inflammation and suppress kidney inflammation and damage remains elusive. PDE4 signaling and cAMP metabolism were investigated along immune complex depositions in target tissues and kidney damage (histology). SLE disease progression is associated with changes in kidney PDE4 activity and expression. Moreover, lupus prone mice exhibit low kidney cAMP level which is associated to induction and relocation of nuclear and cytoskeleton PDE4 isoforms. Auto-antibodies-induced kidney damage was attested by mesangial proliferation and cellular infiltration. Interestingly, we reported that NCS 613 treatment decreases systemic auto-antibody secretion and their corresponding immune complex deposition in target tissues. Furthermore, NCS 613 is able to increase cAMP levels in the kidney; hence this compound rescues kidney PDE4 alterations in treated mice. NCS 613 overcomes disease progression in lupus prone mice by improving wellbeing and decreasing inflammation in treated mice. The PDE4 inhibitor, NCS 613, is a new anti-inflammatory compound that is believed to be a leading drug candidate for the treatment of inflammatory diseases such as lupus nephritis.


The prevalence of amblyopia in Iran: A systematic review.
The aim of this study was to determine the prevalence of amblyopia in the population of Iran. This article is a systematic review. A comprehensive search was conducted in PubMed, Scopus, Science Direct, Ovid, Web of Science, SID, Magiran, with appropriate terms. Information related to the sample size and the prevalence of amblyopia was extracted and summarized in tables. Analysis was performed using STATA software. From 551 articles that were originally extracted from the databases, 31 articles met the criteria for entering the review. These studies were conducted in different regions of Iran. The prevalence of amblyopia in different regions varied between 0.19 and 3.69%. Study results were heterogeneous (I2 = 99.7%), and therefore, a meta-analysis was not done. The prevalence of amblyopia in Iran is very different. In addition to conducting national screenings, it is necessary to report the incidence of amblyopia and its related factors in different parts of the country.


Blood pressure reduction in the morning yields beneficial effects on progression of chronic renal insufficiency with regression of left ventricular hypertrophy.
Self-monitoring values of blood pressure may better reflect the average long-term blood pressure value than sporadic measurements in the physician's office and be more useful for blood pressure control. In the present study, we compared the results of self-monitoring of blood pressure values, especially in the morning, with office blood pressure, and related these to progression of chronic renal insufficiency and left ventricular hypertrophy (LVH). Thirty-four patients were selected from 316 subjects with chronic renal insufficiency (average serum creatinine 1.72 +/- 0.15 mg/dl, mean age 52.6 +/- 3.5 yrs) in accordance with the following criteria (1) office blood pressure was less than 140/90 mmHg, (2) blood pressure was controlled with amlodipine (5-20 mg/day) combined with benazepril (2.5 mg/day), (3) morning blood pressure was greater than 150/90 mmHg at 6-9 AM and (4) LVH had been determined by echocardiography (posterior wall thickness; PWT > or = 12 mm). The patients were assigned to 2 groups at random and were given: (1) guanabenz (GB; 2-8 mg at I I PM, n = 17) or (2) placebo (n = 17). Two years later, the average blood pressure of both groups as measured in the office was not significantly different: however, BP in the morning was significantly reduced from 158 +/- 6 to 134 +/- 4 mmHg in GB treated group (P< 0.001). In 14 of 17 patients in GB treated group, LVH resolved and there was only mild progression of nephropathy (serum creatinine: 1.69 +/- 0.18 to 1.81 +/- 0.19 mg/dl). In 12 of 14 patients in placebo group, whose morning blood pressure remained at greater than 150/90 mmHg, LVH was retained and there was moderate progression of nephropathy (serum creatinine: 1.73 +/- 0.14 to 2.62 +/- 0.50mg/dl). From these results, it is suggested that antihypertensive treatment with combination therapy based on self-monitoring BP is cardio-renoprotective in patients with chronic renal insufficiency and LVH.


Bis-S-acyl-2-thioethyl (SATE)-bearing monophosphate prodrug of beta-L-FD4C as potent anti-HBV agent.
The S-acyl-2-thioethyl (SATE)-bearing 5'-monophosphate prodrug of beta-L-FD4C (8) was synthesized and evaluated for its activity against HBV in the 2.2.15 cell line. This pronucleotide (8) exhibited an excellent inhibitory effect against HBV with an EC50 value that is more than eight fold lower than that of the parent nucleoside (4) under some assay conditions. It is also important to note that pronucleotide (8) was capable of inhibiting HBV replication by 90%; whereas its parent, beta-L-FD4C (4), could only inhibit virus replication no greater than 70% in the same assay. When evaluated in the standard cytotoxicity assay in CEM cell line, pronucleotide (8) exhibited an IC50 value of 52 microM, which was four times less toxic than parent beta-L-FD4C (4) (IC50 = 13 microM).


Application of surface plasmon resonance spectroscopy for adsorption studies of different types of components on poly(dimethylsiloxane).
Surface plasmon resonance (SPR) spectroscopy is utilized to study in real-time and, by label-free means, the reversible and quasi-irreversible adsorption of small ionic or neutral molecules, pharmaceuticals, and proteins on poly(dimethylsiloxane) (PDMS) surfaces. The SPR sensor is covered with 0.2% (w/v) PDMS in octane. During the timescale of a typical lab-on-a-chip analysis or an electrophoretic separation, it was found that small neutral components containing a hydrophobic part do not adsorb or absorb onto PDMS, while larger, water-soluble polymer-like materials like proteins generally irreversibly adsorb to PDMS. The technique can be used to monitor the kinetics of adsorption and desorption of the molecules. For the non-specific adsorption of teicoplanin to PDMS, a Langmuir-like adsorption isotherm was obtained (K(d)=32±2 μmol L(-1)).


The Application of Graph Theoretical Analysis to Complex Networks in Medical Malpractice in China: Qualitative Study.
Studies have shown that hospitals or physicians with multiple malpractice claims are more likely to be involved in new claims. This finding indicates that medical malpractice may be clustered by institutions. We aimed to identify the underlying mechanisms of medical malpractice that, in the long term, may contribute to developing interventions to reduce future claims and patient harm. This study extracted the semantic network in 6610 medical litigation records (unstructured data) obtained from a public judicial database in China. They represented the most serious cases of malpractice in the country. The medical malpractice network of China was presented as a knowledge graph based on the complex network theory; it uses the International Classification of Patient Safety from the World Health Organization as a reference. We found that the medical malpractice network of China was a scale-free network-the occurrence of medical malpractice in litigation cases was not random, but traceable. The results of the hub nodes revealed that orthopedics, obstetrics and gynecology, and the emergency department were the 3 most frequent specialties that incurred malpractice; inadequate informed consent work constituted the most errors. Nontechnical errors (eg, inadequate informed consent) showed a higher centrality than technical errors. Hospitals and medical boards could apply our approach to detect hub nodes that are likely to benefit from interventions; doing so could effectively control medical risks.


Switching pattern and dose adjustment of antidepressants before and during pregnancy.
The purpose of the study is to examine the switching pattern and dose adjustment of antidepressants (ADs) prescribed to women from six months before to six months during pregnancy in the Netherlands. The recorded dispenses or refills were collected from the University of Groningen IADB.nl pregnancy subset for all singleton pregnancies in which the mother received ≥ 1 prescription of an AD dispensed before pregnancy and was present in the database at least six months after conception. The rates of continuation, discontinuation, and switching between 2001 and 2020 were assessed for the ADs studied. The mean number of Defined Daily Doses (DDDs) of the most frequently continued ADs used was calculated both before and during pregnancy, and a paired t-test was used to test for significant changes. The continuation rates for AD users, especially for SSRI and SNRI continued users, increased over time from 27% and 19% (2001-2005) to 65% and 65% (2016-2020). The switching rate between ADs remained consistently low from the start of the study (2001-2005) at 2.0% to the end of the study (2016-2020) at 2.3%. Most women who switched between antidepressants during pregnancy received a different SSRI monotherapy (85%), followed by an SNRI (6%), a TCA (4%), and an "other AD" (4%). In most cases observed, the dose adjustment for the mean DDDs during pregnancy compared to the mean DDDs before pregnancy only changed little (less than 10%). Continued use of SSRIs among singleton pregnancies doubled over the study period. The low rate of AD switching and little changes in the DDD adjustment for most AD continuers indicate that pregnant women prefer to continue their prepregnancy medication rather than switch it. Most observed findings cohere with the Dutch national guidelines for antidepressant use during pregnancy.


Transmission of haemotropic mycoplasma in the absence of arthropod vectors within a closed population of dogs on ectoparasiticides.
Dog-infecting haemotropic mycoplasmas (haemoplasmas), such as Mycoplasma haemocanis and Candidatus Mycoplasma haematoparvum are common blood-borne pathogens of canines that can potentially inflict a substantial burden of disease, particularly in immunosuppressed individuals. Nonetheless, the transmission of these pathogens remains debated as more evidence emerges that they may not be transmitted by vectors, but instead use alternative methods such as aggressive interactions and vertical transmission. Here, we treated forty dogs with two different topically-acting ectoparasiticide products able to prevent vector-borne pathogen infections during an 8-month community trial in Cambodia. A total absence of ectoparasites were observed at all time points, and no new infections caused by pathogens confirmed as being vectorially-transmitted were detected, i.e., Babesia vogeli, Ehrlichia canis, Anaplasma platys, and Hepatozoon canis. Conversely, the number of haemoplasma infections in dogs on both ectoparasiticides rose significantly, with an incidence of 26 infections per 100 dogs at risk per year, providing strong evidence of non-vectorial transmission. Over the study period, dog aggression and fighting were frequently observed, highlighting a different potential mode of transmission. This study presents the first robust evidence that canine haemoplasmas may be transmitted without arthropod vectors drawing attention to the need for new methods to prevent their transmission.


Vitamin D and the promoter methylation of its metabolic pathway genes in association with the risk and prognosis of tuberculosis.
A variety of abnormalities in vitamin D metabolism have been reported in patients with active tuberculosis. However, intervention trials have produced inconsistent results. We hypothesized that genetic and epigenetic changes in the key genes of the vitamin D metabolic pathway may partly explain the differences between studies. We performed a case-control study followed by a prospective cohort study. We recruited 122 patients with pulmonary tuberculosis and 118 healthy controls. The serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were measured. The methylation of the promoter regions of key genes in the vitamin D metabolic pathway (CYP24A1, CYP27A1, CYP27B1, CYP2R1, and VDR) was detected using the Illumina MiSeq platform. The specific methylation profiles were examined as epigenetic biomarkers. The sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to estimate the predictive value of the biomarkers. The baseline serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations in the cases were significantly lower than those in the controls (51.60 ± 27.25 nmol/L vs. 117.50 ± 75.50 nmol/L, Z = - 8.515, P < 0.001; 82.63 ± 51.43 pmol/L vs. 94.02 ± 49.26 pmol/L, Z = - 2.165, P = 0.03). We sequenced 310 CpG sites in five candidate genes. After Bonferroni correction, there were 55 differentially methylated CpG sites between cases and controls; 41.5% were in the CYP27B1 gene, 31.7% were in the CYP24A1 gene, 14.7% were in the VDR gene, and 12.3% were in the CYP27A1 gene. When we designated the CpG sites that remained significant after the Bonferroni correction as the biomarkers, the area under the curve (AUC) for the cumulative methylation was 0.810 (95% CI 0.754-0.866). There was an interaction between CYP27A1 methylation level and 1,25-dihydroxyvitamin D concentration associated with the risk of TB (ORinteraction = 4.11, 95% CI 1.26-13.36, P = 0.019). The serum 1,25-dihydroxyvitamin D concentration at the end of the intensive treatment stage was related to a patient's prognosis (P = 0.008). There were 23 CpG sites that were individually related to the treatment outcomes, but the relationships were not significant after the Bonferroni correction. Both serum vitamin D concentrations and the methylation levels of key genes in the vitamin D metabolic pathway are related to the risk and prognosis of tuberculosis.


Integrating multi-omics data for crop improvement.
Our agricultural systems are now in urgent need to secure food for a growing world population. To meet this challenge, we need a better characterization of plant genetic and phenotypic diversity. The combination of genomics, transcriptomics and metabolomics enables a deeper understanding of the mechanisms underlying the complex architecture of many phenotypic traits of agricultural relevance. We review the recent advances in plant genomics to see how these can be integrated with broad molecular profiling approaches to improve our understanding of plant phenotypic variation and inform crop breeding strategies.