Elastographic Assessment of Xenograft Pancreatic Tumors.
High tissue pressures prevent chemotherapeutics from reaching the parenchyma of pancreatic ductal adenocarcinoma, which makes it difficult to treat this aggressive disease. Researchers currently use invasive probes to monitor the effectiveness of pressure-reducing therapies, but this practice introduces additional complications. Here, we hypothesize that Young's modulus is a good surrogate for tissue pressure because collagen density and hyaluoronic acid, the key features of the tumor microenvironment responsible for high tissue pressures, also affect modulus elastograms. To corroborate this hypothesis, we used model-based quasi-static elastography to assess how the Young's modulus of naturally occurring AsPc-1 pancreatic tumors varies with collagen density and hyaluoronic acid concentration. We observed that Young's moduli of orthotopically grown xenograft tumors were 6 kPa (p < 0.05) higher than that of their subcutaneously grown counterparts. We also observed a strong correlation between Young's modulus and regions within the tumors with high collagen (R2 ≈ 0.8) and hyaluoronic acid (R2 ≈ 0.6) densities. These preliminary results indicate that hyaluronic acid and collagen density, features of the pancreatic ductal adenocarcinoma tumor microenvironment responsible for high tissue pressure, influence Young's modulus.


Requirement of the glycosyl parts in platycodin D to stimulate pancreatic exocrine secretion.
The whole structure of platycodin D is found to be essential to stimulate the volumetric increase in the pancreatic exocrine secretion, while the prosapogenins prepared from platycodin D increased only protein output of pancreatic juice.


PTEN-negative endometrial cancer cells protect their genome through enhanced DDB2 expression associated with augmented nucleotide excision repair.
Endometrial cancer (EC) arises from uterine endometrium tissue and is the most prevalent cancer of the female reproductive tract in developed countries. It has been predicted that the global prevalence of EC will increase in part because of its positive association with economic growth and lifestyle. The majority of EC presented with endometrioid histology and mutations in the tumor suppressor gene PTEN, resulting in its loss of function. PTEN negatively regulates the PI3K/Akt/mTOR axis of cell proliferation and thus serves as a tumorigenesis gatekeeper. Through its chromatin functions, PTEN is also implicated in genome maintenance procedures. However, our comprehension of how DNA repair occurs in the absence of PTEN function in EC is inadequate. We utilized The Cancer Genome Atlas (TCGA) data analysis to establish a correlation between PTEN and DNA damage response genes in EC, followed by a series of cellular and biochemical assays to elucidate a molecular mechanism utilizing the AN3CA cell line model for EC. The TCGA analyses demonstrated an inverse correlation between the expression of the damage sensor protein of nucleotide excision repair (NER), DDB2, and PTEN in EC. The transcriptional activation of DDB2 is mediated by the recruitment of active RNA polymerase II to the DDB2 promoter in the PTEN-null EC cells, revealing a correlation between increased DDB2 expression and augmented NER activity in the absence of PTEN. Our study indicated a causal relationship between NER and EC that may be exploited in disease management.


Kinetics of lactose conversion to galacto-oligosaccharides by β-galactosidase immobilized on PVDF membrane.
Experimental studies were made for immobilization of enzymes on microporous polyvinylidene fluoride (PVDF) membrane in order to carry out enzymatic reaction of lactose into galacto-oligosaccharides using β-galactosidase. The present work, however, is the first part in the direction of enzymatic membrane reactor studies for carrying out reaction followed by membrane based separation to purify galacto-oligosaccharides out of reaction mixture. The middle of the three compartment cell, separated by two immobilized (enzyme) membranes, was utilized to feed lactose solution; whereas, adjacent compartments were filled with distilled water. The reacted mixture solution was analyzed for tri-, tetra- and penta-forms of GOS. The formation of product GOS strongly depended on varying amounts of initial lactose concentration (ILC). Total GOS formation increased from 7% to 28% for ILC from 50 to 200 g/L. However, tri-saccharide was the major (67%) in comparison to tetra (27%) and penta (6%) forms of GOS. Further, based on Michaelis-Menten kinetics, a six-step-eleven-parameter model was developed. The model incorporated enzyme inhibition and formation of glucose and galactose separately. Simulated results from developed model matched exceeding well with experimental results.


Peroxiredoxin 1 knockdown sensitizes cancer cells to reactive oxygen species-generating drugs - an alternative approach for chemotherapy.
Peroxiredoxins have multiple cellular functions as major antioxidants, signaling regulators and tumor suppressors. Peroxiredoxin 1 (PRX1) is the most abundant among the six isoforms of human peroxiredoxins, catalyzing the reduction of peroxides utilizing thioredoxin 1as an electron donor. PRX1 is frequently over-expressed in various cancer cells, which is thought to be associated with carcinogenesis, metastasis and resistance to radiotherapy or chemotherapy. We investigated how modulations of intracellular redox system, especially PRX1, affect cancer cell sensitivity to reactive oxygen species (ROS)-generating drugs. We observed that stable and transient Prx1 knockdown (Prx1-) significantly enhances HeLa cell sensitivity to β-lapachone (β-lap), a potential anticancer agent, and to other ROS-generating molecules. ROS accumulation played a crucial role in drug-enhanced Prx1- cell death. For β-lap, Prx1- cells sensitization is achieved through combined action of accumulation of ROS and enhancement of mitogen-activated protein kinase pathway activation. The effect of other ROS-inducing drugs on Prx1- cell survival will also be presented and discussed. Taken together, our data provide evidence that PRX1 could be an interesting anticancer target and modulation of intracellular redox states through PRX1 inhibition could be an alternative approach to enhance cancer cell sensitivity to ROS-generating drugs.


Knowledge, perceptions, and behavior regarding children's oral health among Syrian pediatricians: a cross-sectional study.
Oral health has a direct impact on health-related quality of life (HRQoL). Hence, general health and oral health cannot be separated. Pediatricians play a pivotal role in providing primary care for infants and are the first to interact with them since birth. Therefore, the aim of this study was to evaluate the knowledge, perceptions, and behavior of Syrian pediatricians regarding children's oral health. This was a cross-sectional study. The questionnaire consisted of six main sections and required answers regarding demographic characteristics, knowledge, behavior, perceptions, and training received in oral health. The association between categorical variables was tested with Pearson's chi-square tests and Fishers exact tests using SPSS ver. 23. The response rate was 43.12% (229/531). Most of the participants (64.02%) got a poor level of knowledge and no significant association was found between knowledge level and years of experience (p = 0.270). The majority of the participants (99.13%) perceived that diet, bacteria, and sugar exposure time are the etiological factors of dental caries. The overwhelming majority of the participants (98.25%) acknowledged the need for further oral health training during residency. Most pediatricians reported a poor level of knowledge. It is recommended to update the postgraduate and residency curriculum to equip pediatricians with adequate knowledge regarding children's oral health.


Influence of the proximal small intestine on the gastric hypersecretion in pylorus-ligated rats.
The mechanism of the gastric secretory inhibition caused by the simultaneous ligation of the upper and lower duodenum or the jejunum in pylorus-ligated rats was studied. The data obtained from the experiments on surgical manipulation of the small intestine indicated that the absorption of certain substances appeared to be important in maintaining gastric secretion of pylorus-ligated rats. The participation of biliary secretion was negligible, while the ligation procedure per se, which results in the accumulation of duodenal contents, might be partly involved in the mechanism of acid secretion. Pharmacological techniques suggested that the inhibition appeared to be independent of cholinergic nervous reflex and hormonal influence, which is assumed to be released by intestinal acidification.


Rotational state-changing collisions of C2H- and C2N- anions with He under interstellar and cold ion trap conditions: A computational comparison.
We present an extensive range of quantum calculations for the state-changing rotational dynamics involving two simple molecular anions that are expected to play some role in the evolutionary analysis of chemical networks in the interstellar environments, C2H- (X1Σ+) and C2N- (X3Σ-), but for which inelastic rates are only known for C2H-. The same systems are also of direct interest in modeling selective photo-detachment experiments in cold ion traps where the He atoms function as the chief buffer gas at the low trap temperatures. This study employs accurate, ab initio calculations of the interaction potential energy surfaces for these anions, treated as rigid rotors, and the He atom to obtain a wide range of state-changing quantum cross sections and rates at temperatures up to about 100 K. The results are analyzed and compared for the two systems to show differences and similarities between their rates of state-changing dynamics.


Randomised clinical trial: effects of MD-7246 on irritable bowel syndrome with diarrhoea.
MD-7246, a delayed-release formulation of linaclotide, is designed to target the ileocaecal junction and caecum with the aim of relieving abdominal pain independently of bowel function. To evaluate the efficacy, safety and dose-response of MD-7246 in patients with irritable bowel syndrome with diarrhoea (IBS-D). A randomised, double-blind, phase 2 clinical trial enrolled adult patients with IBS-D (Rome IV criteria). Patients were randomised to placebo or once-daily oral MD-7246 300, 600 or 1200 μg for 12 weeks. Abdominal and bowel symptoms were assessed daily. Key efficacy endpoints were change from baseline in abdominal pain and responder rates for a 30% reduction in abdominal pain in 6/12 weeks. Additional abdominal pain responder and exploratory bowel function endpoints were also assessed. Among the 388 randomised patients, there was no significant difference in mean change from baseline in abdominal pain between the MD-7246 300 μg, 600 μg and 1200 μg groups and placebo (-1.93, -1.58, -1.95 and - 2.01, respectively; p > 0.05 for each group vs placebo). The abdominal pain responder rates in the MD-7246 groups were similar to or lower than those in the placebo group. All doses of MD-7246 had a minimal effect on bowel function and were generally well tolerated. MD-7246 at the doses studied did not improve abdominal pain relative to placebo in an IBS-D patient population. Similarly, most additional efficacy endpoints showed no improvement with MD-7246 relative to placebo.


Identification of functional consequence of a novel selection signature in CYP11b1 gene for milk fat content in Bubalus bubalis.
Genomic selection for traits of economic importance is an emerging approach carrying tremendous potentials. Many of polygenic traits as milk fat, protein and yield have been characterize at genomic level and important selection signatures have been identified. Cytochrome P450 enzymes are potential loci for affecting many of dairy capabilities. Present study was conducted for genomic dissection of CYP11b1 gene in riverine buffaloes and seven genetic variations were identified. Out of these, one novel polymorphism (p.A313T) was found well associated with milk fat %age. AB genotyped buffaloes were found to have higher milk fat %age (8.9%) for this loci. p.A313T was further validated at larger data set by restriction digestion using CviAII enzyme. Functional consequences of this locus were also predicted by studying three dimensional structure of CYP11b1 protein. For this purpose, 3D protein model was predicted by homology modeling, secondary structural attributes were determined, signal peptide was predicted and a transmembrane helix was also identified. One of polymorphism (p.Y205L) was found in the vicinity of functionally significant F-G loop region, which is the part of protein gets attached to the inner mitochondrial membrane. But this variation could not be associated and needs further investigation. p.A30V, a popular selection marker in cattle, was found in buffaloes as well but could not be associated and might need further confirmation on larger data set. Results of this study illustrate the impending potential of this gene in determining dairy capabilities of buffaloes and might have a role in selection of superior dairy buffaloes.


Volumetric and histologic responses to radiotherapy or radiochemotherapy of metastatic cervical lymph nodes of oral squamous cell carcinoma.
The relationship between the volumetric and histologic responses of metastatic cervical nodes to radiotherapy or chemotherapy in the oral and maxillofacial region is unclear. In this study, we evaluated the correlation between the initial volume and regression rate of metastatic nodes with their histologic response to preoperative radiotherapy or radiochemotherapy. The volume of 54 metastatic nodes in 32 patients with squamous cell carcinoma in the oral and maxillofacial region was measured by ultrasonography before and after preoperative therapy, and the rate of the volume change was calculated. All surgically removed nodes were histologically classified as poor, good, or complete response according to their histologic features. There was no significant difference in initial volume among the 3 response groups. Good and complete response nodes showed a significant increase in regression rate compared with poor response nodes. All 11 nodes showing no regression were poor response nodes, and 7 with a regression rate of more than 90% were good or complete response nodes. The remaining 36 nodes (regression rate, 0% to 90%) represented all 3 types of histologic response. Of these, 7 of 9 complete response nodes were found in 5 patients who received combination chemotherapy consisting of 5-fluorouracil, leucovorin, and cisplatin. The initial nodal volume before therapy is not a good indicator for the response to radiotherapy and/or chemotherapy. A regression rate of more than 90% may be a useful predictor of the effectiveness of preoperative treatments, but it was difficult to define the cutoff values in regression rates for differentiating types of histologic response.


[Prophylaxis of cytomegalovirus infection in renal transplantation].
Cytomegalovirus (CMV) infection remains a major problem in renal transplant recipients. CMV produces not only febrile syndromes and/or visceral disease but also contributes to the development of acute rejection and chronic graft failure. Valganciclovir prophylaxis has represented a major advance in controlling this infection, but late CMV infection after prophylaxis can occur, especially when universal prophylaxis is used. The use of valganciclovir prophylaxis for 200 days is more effective than prophylaxis for 100 days but does not completely prevent this problem. Prophylaxis based on the detection of CMV viremia (early prophylaxis or preemptive therapy) may prevent the development of delayed CMV disease, but has the disadvantage of requiring more intensive monitoring of viremia and does not prevent the development of viremia and its potential consequences in the long term. This article reviews current recommendations for prophylaxis of CMV disease in renal transplantation.


Simulation and analysis of split gradient coil performance in MRI.
Split magnet systems for hybrid imaging, such as positron emission tomography-magnetic resonance imaging (PET-MRI) and Radiotherapy-MRI, require gradient coils designed with similar shapes as their corresponding main magnet. This introduces challenges in the gradient coil design of good performance and manufacturing. In this paper the effect of the gap size in shielded transverse split gradient coils and split cryostat "warm" bore over the coil efficiency, shielding efficiency, wire spacing, cryostat ohmic power loss and mechanical vibration have been simulated and studied. A "free-surface" gradient coil design method was used to design the split, actively-shielded transverse gradient coils with an axial gap. A network method was used to calculate the eddy currents induced in the split cryostat "warm" bore. The shielding efficiency and the minimum wire spacing were found to decrease when the size of the central gap is increased. The ohmic power loss and the amplitude of the radial vibrations in the split cryostat "warm" bore increases when the gap size in the gradient coil and "warm" bore is increased. It is hoped that these investigations will be useful for the development of new hybrid imaging modalities involving MRI.


Longitudinal effects of smoking cessation on carotid artery atherosclerosis in contemporary smokers: The Wisconsin Smokers Health Study.
We quantified the effects of smoking and smoking cessation on carotid artery atherosclerosis and wall thickness in two unique cohorts of smokers making a quit attempt. Our primary analysis included 726 smokers making a quit attempt in a randomized clinical trial with long-term follow-up. Our secondary analysis included 889 smokers making a quit attempt in a subsequent trial. Participants underwent carotid artery ultrasonography at baseline and up to 3 subsequent visits. Primary outcomes were changes in carotid plaque score and intima media-thickness (IMT). We calculated a smoking burden score (SBS) that reflected the number of visits in which participants reported smoking after the quit attempt. Multivariable regression examined relations between SBS and carotid artery outcomes with adjustments for cardiovascular disease risk factors. In the primary analysis, participants were mean (standard deviation) 46.1 (10.3) years old (57.9% female) and smoked 21.1 (8.9) cigarettes per day (CPD). After a median of 7 years, lower SBS predicted less increase in carotid plaque score (Chi-squared = 13.0, p = 0.012). SBS independently predicted change in carotid plaque score (p = 0.007; SBS 0 vs 4) as did baseline CPD (p = 0.024) and age (p<0.0001). SBS did not affect carotid IMT change. In the secondary analysis, increasing SBS was associated with increased likelihood of new plaques over 3 years among participants that smoked ≥15 CPD, (Chi-squared = 6.51, p = 0.011). Smoking cessation is associated with less progression of carotid plaque, but not IMT. Salutary associations of smoking cessation with carotid plaque progression are related to degree of abstinence.


PGJ2 inhibition of LPS-induced inflammatory mediator expression from rat alveolar macrophages.
Studies suggested that 15-deoxy-delta-(12,14)-prostaglandin J2 (PGJ2) may exert anti-inflammatory effects, including in the lung. Thus, in vitro studies were conducted to (1) investigate whether PGJ2 inhibited the production of inflammatory mediators from lipopolysaccharide (LPS)-exposed primary rat alveolar macrophages (AM), and (2) investigate possible mechanisms underlying PGJ2-mediated inhibition of inflammatory mediator production. These studies determined that PGJ2 inhibited LPS-induced nitric oxide (NO) production in a concentration- and time-dependent manner. PGJ2-mediated inhibition of NO, as well as of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2), was also determined to be dependent on the time of addition of PGJ2 relative to LPS, and suggested the PGJ2 inhibitory mechanism is an early event. PGJ2 was shown not to interfere with binding or internalization of LPS by AM, indicating this was not responsible for PGJ2 inhibitory effects. Another possible mechanism underlying PGJ2-mediated inhibition was via peroxisome proliferator-activated receptor-gamma (PPAR-gamma). However, biochemical studies suggested that PGJ2-mediated inhibition was not occurring through PPAR-gamma dependent mechanism, and molecular studies further established that both LPS and PGJ2 decrease PPAR-gamma mRNA expression. A third possible mechanism underlying PGJ2-mediated inhibition was by alteration of nuclear factor (NF)-kappaB. Molecular studies confirmed that LPS stimulated NF-kappaB mRNA expression, and PGJ2 reduced this stimulation, which is consistent with PGJ2 effect on LPS-induced production of NO, TNF-alpha and MIP-2. Thus, data in this study established that PGJ2 inhibited LPS-induced inflammatory mediator production in rat AM, and this inhibition is mediated, at least in part, by reducing the expression of NF-kappaB mRNA.


Medicago truncatula shows distinct patterns of mycorrhiza-related gene expression after inoculation with three different arbuscular mycorrhizal fungi.
Different arbuscular mycorrhizal fungi (AMF) alter growth and nutrition of a given plant differently. Plant gene expression patterns in response to fungal colonization show a certain overlap when colonized by fungi of the Glomeraceae. However, little is known of plant responses to fungi of different fungal taxa, e.g. the Gigasporaceae. We therefore compared the impact of colonization by three taxonomically different AMF species (Glomus intraradices, Glomus mosseae and Scutellospora castanea) on Medicago truncatula at the physiological and transcriptional level using quantitative-PCR. Each AMF developed a species-typical colonization pattern, with a colonization degree of 60% for G. intraradices and 30% for G. mosseae. Both species developed appressoria, intraradical hyphae, arbuscules and vesicles. S. castanea showed a colonization degree of 10% and developed appressoria, intraradical hyphae, arbuscules and arbusculate coils. All AMF enhanced the plant biomass accumulation and nutritional status although not in correlation with the colonization degree. The expression of 10 mycorrhiza-specific or mycorrhiza-associated plant genes could be separated into two clusters. The first cluster, containing arbuscule-induced genes, was highly induced in interactions with G. intraradices and G. mosseae but also slightly induced by S. castanea. The second cluster of genes contained genes that were induced primarily by S. castanea. In conclusion, genes that respond to colonization by fungi of the genus Glomus also respond to Scutellospora. However, there is also a group of genes that is significantly induced only by Scutellospora and not by Glomus species in this study. Our data indicate that genes may be differentially regulated in response to the different AM fungi.


Size and shape influence of luminescent orthovanadate nanoparticles on their accumulation in nuclear compartments of rat hepatocytes.
In this paper the process of nonfunctionalized negatively charged orthovanadate nanoparticle accumulation and redistribution in cells dependent on their shape and size was investigated. Aqueous colloidal solutions of nReVO4:Eu(3+) (Re=Gd, Y, La) luminescent nanocrystals of different sizes and shapes have been synthesized. The average sizes of spherical particles were 2, 20, and 300 nm, of spindle-like particles - 22×6.3 nm, and of rod-like particles - 57×4.4 nm. Luminescence of nReVO4:Eu(3+) nanocrystals was effectively excited by UV and visible irradiation. By means of luminescence microscopy and luminescence microspectroscopy, it has been revealed that spherical nanocrystals with an average diameter of 2 nm tend to accumulate mainly in the rat hepatocyte nuclei in situ and also in the isolated nuclei of these cells. An additional experiment has shown that nanoparticles reveal tropism to nuclear structural components. The penetration into nuclei does not require any modifications of the surface of nanoparticle and is governed by the shape and size of nanoparticle and also is determined by the cellular type.


Physical environmental and occupational factors inducing work-related neck and shoulder pains among self-employed tailors of informal sectors in Ethiopia, 2019: results from a community based cross-sectional study.
Musculoskeletal disorders (MSD) caused by occupational-related factors continue to place huge burdens on global workforces. Significant numbers of workers report potential adverse health outcomes related to the condition, such as physical injury, disability, and decline in quality of life. Occupational-related MSD also poses additional burdens to healthcare services and diminishes productivity at work. The condition usually worsens in informal sectors where the work environments are often poorly designed. This paper explored occupational and physical environmental factors that induce work-related neck and/or shoulder pains among self-employed tailors in Gondar city, Northwest Ethiopia. We conducted across-sectional survey from April to May 2019 on 422 tailors selected with systematic random sampling technique. Nordic Musculoskeletal questionnaire was used to measure pains in neck and/or shoulder, and the questionnaire was pretested and administered by interviewers. Work-related factors such as working posture, rest break, training in safety and health, and the availability of adjustable chairs at workplaces were assessed. The significance of associations was set at a < 0.05 p-value and adjusted odds ratios (AOR) with a confidence interval (CI) of 95% were used to determine strength of associations. A total of 419 tailors participated with a response rate of 99.3%. The mean age and mean years of experience were 29.23 (SD ± 7.03) and 1.48 (SD ± 0.50) years, respectively. The study found that the prevalence of pain in either neck or shoulder or both sites in the last 12 months was 66.6% (N = 279) [95% CI (62.1, 71.1)]. Pains in shoulder and neck were observed in 72.1% (N = 302)[95% CI (67.8, 76.4)] and 68.3% (N = 286) [95% CI (64.0, 72.6)] of the interviewees, respectively. The majority, 78.1% (n = 218) of those with pains indicated they were prevented from doing normal daily activities. Work experience (AOR = 1.81), rest break (AOR = 2.13), awkward working posture (AOR = 2.60), prolonged sitting (AOR = 2.00) and inadequate light (AOR = 5.02) were significantly associated factors of neck and/ or shoulder pains. Work-related neck and/or shoulder pain induced by physical factors of the work environment among self-employed tailors is pervasive in Ethiopia. Efforts to curb the condition, therefore, need to impalement diverse approaches addressing the physical environment and occupational factors. We also promote the integration of schemes for the effective use of rest breaks into health and safety programs in the workplace.


Nocardiosis Associated with Primary Immunodeficiencies (Nocar-DIP): an International Retrospective Study and Literature Review.
Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID). This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed. Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0-56) years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2-257) days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency. Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.


Biomimetic Microfluidic System for Fast and Specific Detection of Circulating Tumor Cells.
Improving the specific capture efficiency of CTCs, and meanwhile preventing the nonspecific adsorption of surrounding background cells, is the main focus of CTCs detection. Herein, a novel biomimetic microfluidic system was developed by combining the unique benefits of biomimetic nanoparticles and microfluidic techniques. The magnetic nanoclusters were camouflaged with leukocyte membrane fragments and decorated with aptamer SYL3C specific for EpCAM positive tumor cells and then loaded into the microfluidic chip with the help of magnets. By use of this system, more than 90% of the rare tumor cells in blood could be captured and detected within 20 min with almost no leukocyte background, indicating a great practical application potential for CTCs detection.


Chlorine-mediated electrodeposition of hierarchical and hydrophobic copper electrocatalysts for efficient CO2 electroreduction to ethylene.
Hierarchical Cu dendrites fabricated via Cl-mediated electrodeposition afford high C2H4 efficiency (58% faradaic efficiency at -0.9 V vs. RHE) for CO2 electroreduction thanks to not only the optimal hydrophobicity/aerophilicity, but also the dominant distribution of active (100) and (110) facets.


Some effects of basic multicellular unit-based remodelling on photon absorptiometry of trabecular bone.
This article offers algorithms and an algebra for estimating effects of bone turnover, remodelling space, undermineralized bone and trabecular surface-to-volume ratio effects on trabecular bone mass estimation by photon absorptiometry. From published histomorphometric data and other evidence the algorithms suggest the amount of mineral in a given bone sample can suggest to absorptiometry an amount of bone that differs from the truth by over 40% in the extreme, and more commonly by 5-15%. They suggest that by reducing a bone's global mineral content high bone turnover causes underestimation of true bone mass. They suggest that by letting mineral return to the remodelling space and undermineralized bone, reduced bone turnover causes apparent gains in bone mass. The commonly suggested 5-15% magnitude of such errors exceeds those assumed in the past. The algorithms suggest that after a challenge to remodelling those bone mineral changes can take from 6 months to over 3 years to reach steady states. Those features could explain why many osteoporosis treatments judged effective from initial absorptiometric evidence failed when used for long periods in patients. Finally the algorithms suggest that a real increase in ideal bone volume can even appear to absorptiometry as no gain or an initial loss, which has already happened in two human experiments.


Red blood cell alloimmunization and other transfusion-related complications in patients with transfusion-dependent thalassemia: A multi-center study in Thailand.
Thalassemia is a common genetic disease in Southeast Asia. Red blood cell (RBC) transfusion is an essential treatment for severe forms of thalassemia. We performed a study to demonstrate RBC alloimmunization and other transfusion-related complications in patients with transfusion-dependent thalassemia (TDT). A multi-center web-based registry of TDT was conducted in eight medical centers across Thailand. Thalassemia information, transfusion therapy, and transfusion-related complications were collected. Factors associated with each complication were demonstrated using the logistic regression analysis. Of 1000 patients recruited for the study, 449 were males (44.9%). The mean age was 23.9 ± 15.4 years. The majority of patients, 738 (73.8%) had hemoglobin E/beta-thalassemia. In the study, 421 transfusion-related complications were reported from 357 patients (35.7%). Alloimmunization was the most common complication which was found in 156 patients (15.6%) with 284 positive antibody tests. The most frequent antibodies against RBC were anti-E (80/284, 28.2%) followed by anti-Mia (45/284, 15.8%) and anti-c (32/284, 11.3%). Age ≥3 years at initial blood transfusion, splenomegaly, higher frequencies, and volumes of transfusion were significant factors associated with alloimmunization. None of the patients had to terminate blood transfusion due to multiple alloantibodies. Other commonly seen complications were allergic reactions (130, 13.0%), autoimmune hemolytic anemia (70, 7.0%) and febrile non-hemolytic transfusion reaction (54, 5.4%). Transfusion-related complications, especially alloimmunization, were common among Thai patients with TDT. Extended RBC antigen-matching for the Rh system and Mia should be implemented to prevent the development of alloantibodies in multi-transfused patients.


Syntabulin regulates neuronal excitation/inhibition balance and epileptic seizures by transporting syntaxin 1B.
Epilepsy is a widespread neurological disorder affecting more than 65 million people, but the mechanisms of epilepsy remains unknown. Abnormal synaptic transmission has a crucial role in the occurrence and development of epilepsy. Here, we found that syntabulin, a neuronal transporter, was mainly localized in neurons, and its expression was increased in epileptic tissues. Knockdown of syntabulin increased susceptibility and severity of epilepsy, whereas overexpression of syntabulin had the opposite effect. Mechanistically, in the epileptic brain tissue, syntabulin mainly translocated syntaxin 1B (STX1B) rather than syntaxin 1A (STX1A) to the presynaptic membrane, which resulted in increased presynaptic transmitter release. Further studies showed that syntabulin had a more significant effect on presynaptic functionality of GABAergic activity over that of excitatory synapses and resulted in an excitation/inhibition (E/I) imbalance, thereby regulating the epileptic phenotype. In addition, we found that the increased expression of syntabulin in epileptic brain tissue was mainly regulated by transcription factor TFAP2A. In summary, syntabulin plays a protective role in epilepsy by maintaining a proper E/I balance in the hippocampus.


Measurements of angular distance and momentum ratio distributions in three-jet and Z + two-jet final states in pp collisions.
Collinear (small-angle) and large-angle, as well as soft and hard radiations are investigated in three-jet and Z + two-jet events collected in proton-proton collisions at the LHC. The normalized production cross sections are measured as a function of the ratio of transverse momenta of two jets and their angular separation. The measurements in the three-jet and Z + two-jet events are based on data collected at a center-of-mass energy of 8 TeV , corresponding to an integrated luminosity of 19.8 fb - 1 . The Z + two-jet events are reconstructed in the dimuon decay channel of the Z boson. The three-jet measurement is extended to include s = 13 TeV data corresponding to an integrated luminosity of 2.3 fb - 1 . The results are compared to predictions from event generators that include parton showers, multiple parton interactions, and hadronization. The collinear and soft regions are in general well described by parton showers, whereas the regions of large angular separation are often best described by calculations using higher-order matrix elements.


m5UPred: A Web Server for the Prediction of RNA 5-Methyluridine Sites from Sequences.
As one of the widely occurring RNA modifications, 5-methyluridine (m5U) has recently been shown to play critical roles in various biological functions and disease pathogenesis, such as under stress response and during breast cancer development. Precise identification of m5U sites on RNA is vital for the understanding of the regulatory mechanisms of RNA life. We present here m5UPred, the first web server for in silico identification of m5U sites from the primary sequences of RNA. Built upon the support vector machine (SVM) algorithm and the biochemical encoding scheme, m5UPred achieved reasonable prediction performance with the area under the receiver operating characteristic curve (AUC) greater than 0.954 by 5-fold cross-validation and independent testing datasets. To critically test and validate the performance of our newly proposed predictor, the experimentally validated m5U sites were further separated by high-throughput sequencing techniques (miCLIP-Seq and FICC-Seq) and cell types (HEK293 and HAP1). When tested on cross-technique and cross-cell-type validation using independent datasets, m5UPred achieved an average AUC of 0.922 and 0.926 under mature mRNA mode, respectively, showing reasonable accuracy and reliability. The m5UPred web server is freely accessible now and it should make a useful tool for the researchers who are interested in m5U RNA modification.


MtrA modulates Mycobacterium tuberculosis cell division in host microenvironments to mediate intrinsic resistance and drug tolerance.
The success of Mycobacterium tuberculosis (Mtb) is largely attributed to its ability to physiologically adapt and withstand diverse localized stresses within host microenvironments. Here, we present a data-driven model (EGRIN 2.0) that captures the dynamic interplay of environmental cues and genome-encoded regulatory programs in Mtb. Analysis of EGRIN 2.0 shows how modulation of the MtrAB two-component signaling system tunes Mtb growth in response to related host microenvironmental cues. Disruption of MtrAB by tunable CRISPR interference confirms that the signaling system regulates multiple peptidoglycan hydrolases, among other targets, that are important for cell division. Further, MtrA decreases the effectiveness of antibiotics by mechanisms of both intrinsic resistance and drug tolerance. Together, the model-enabled dissection of complex MtrA regulation highlights its importance as a drug target and illustrates how EGRIN 2.0 facilitates discovery and mechanistic characterization of Mtb adaptation to specific host microenvironments within the host.


Can glycoprofiling be helpful in detecting prostate cancer?
Glycans are chains of carbohydrates attached to proteins (glycoproteins and proteoglycans) or lipids (glycolipids). Glycosylation is a posttranslational modification and glycans have a wide range of functions in a human body including involvement in oncological diseases. Change in a glycan structure cannot only indicate presence of a pathological process, but more importantly in some cases also its stage. Thus, a glycan analysis has a potential to be an effective and reliable tool in cancer diagnostics. Lectins are proteins responsible for natural biorecognition of glycans, even carbohydrate moieties still attached to proteins or whole cells can be recognized by lectins, what makes them an ideal candidate for designing label-free biosensors for glycan analysis. In this review we would like to summarize evidence that glycoprofiling of biomarkers by lectin-based biosensors can be really helpful in detecting prostate cancer.


Process Improvements Positively Impact the Use of Intravesical Mitomycin C after Transurethral Resection of Nonmuscle Invasive Bladder Cancer in a Large, Urban Urology Practice.
We assessed the rate of intravesical mitomycin C therapy in patients with nonmuscle invasive bladder cancer who underwent transurethral resection of the bladder, as well as the impact of procedural changes governing its use. A retrospective review of our bladder cancer database identified patients who underwent transurethral resection of the bladder with mitomycin C therapy during January 2008 to July 2014. Since our mitomycin C protocols were revised during 2013, patients were stratified based on date of service. Patient demographics and data describing mitomycin C use were tabulated. During January 2008 to May 2013, 276 of 737 (37.5%) ideal patients received mitomycin C (not accounting for patients in whom mitomycin C was contraindicated). Conversely 461 of 737 patients (62.5%) did not receive mitomycin C. Shortages of mitomycin C were responsible for nonuse in 18.4% of cases while no specified reason for nonuse was given in 59%. When cases in which mitomycin C use was contraindicated were taken into account, mitomycin C was used in 51.6% overall. After the implementation of new mitomycin C operating procedures, mitomycin C use increased significantly to 76.0% (p <0.001) (accounting for appropriate nonuse). During this period mitomycin C shortages were not responsible for any case in which mitomycin C was not used. During 2008 to 2013 mitomycin C was not used in a significant proportion of patients who underwent transurethral resection of the bladder. The implementation of a revised protocol governing mitomycin C use significantly and positively impacted mitomycin C use. Importantly, pharmacy shortages no longer contribute to the nonuse of mitomycin C in patients with bladder cancer. These data highlight the impact of continual improvement initiatives on standard clinical practice.


Carbonation of steel slag at low CO2 concentrations: Novel biochar cold-bonded steel slag artificial aggregates.
Carbonation technology resolves the volume expansion of steel slag by combining CO2 with f-CaO, but the previous stringent carbonation conditions (99%vol) significantly limit the application prospect of steel slag. To achieve the carbonation of steel slag at lower CO2 concentrations, a novel cold-bonded artificial aggregates (CASSAs) based on steel slag and biochar is produced in this paper. The carbon capture capacities of CASSAs with different biochar contents (5 wt%, 10 wt%, and 15 wt%) are investigated in a low-CO2 concentration environment (10.79 % vol) and natural environment using the porosity and CO2 adsorption capacity of biochar. The changes in the performance of CASSAs before and after carbonation are investigated at different curing ages (7 d and 28 d). The results reveal that biochar increases the pores of the CASSAs. At 7 d, B15 achieves complete carbonation at low concentrations and can uptake 6.5 wt% of CO2. CO2 adsorption capacity by biochar in the natural environment facilitates the diffusion of CO2 in CASSAs. Regarding mechanical properties, the addition of biochar makes B15 at 7 d half as strong as B0, but B15 exhibits long-term strength development. B15 at 7 d has a strength of 8.49 MPa after carbonation, which is almost the same as B0. In addition, B15 achieves a net CO2 emission of -39.9 kg/ton. This study combines biochar with CASSAs to provide a potential method to carbonate steel slag at low CO2 concentrations. A new methodology was also used to quantitatively assess the ability of biochar CASSAs to solidify CO2 under low concentration conditions and natural environments from a macroscopic perspective. Biochar CASSAs have great potential to realize resource utilization and carbon capture from steel slag.


Long non-coding RNA ANRIL promotes carcinogenesis via sponging miR-199a in triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is a complex breast cancer subtype characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2). Long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) has been verified as oncogenic molecular in series of tumors, however, the role of ANRIL in TNBC carcinogenesis is still unclear. The purpose of present study is to investigate the expression and in-depth regulation of ANRIL on TNBC tumorigenesis. Expression level of ANRIL was up-regulated in TNBC tumor tissue and cell lines compared to noncancerous tissue and non-TNBC cells. Besides, the up-regulated ANRIL expression was closely correlated to poor prognosis. In vitro, loss-of-function experiments showed that ANRIL knockdown interfered by interference oligonucleotide could markedly suppress TNBC cells proliferation and enhance apoptosis. In vivo, ANRIL knockdown inhibited the tumor growth. Bioinformatics analysis and luciferase reporter assay revealed that miR-199a targeted ANRIL at 3'-UTR. Rescue experiments showed that miR-199a inhibitor could reverse the tumor-suppressing role of ANRIL knockdown on TNBC proliferation and apoptosis. Overall, present study demonstrated that ANRIL overexpression modulated TNBC tumorigenesis through acting as molecular 'sponge' for miR-199a, providing a novel insight and therapeutic target for TNBC.


The use of pharmacoeconomic evidence to support formulary decision making in Saudi Arabia: Methodological recommendations.
In pharmacoeconomics the costs and consequences of alternative medications are compared. Many countries have begun to use pharmacoeconomic evidence to support decisions on licensing, pricing, reimbursement, or addition to the formulary. In Saudi Arabia, it is not mandatory to submit cost effectiveness evidence to support licensing or addition to the formulary decisions however, data will be considered if submitted. Previous evidence suggests that the use of pharmacoeconomic evidence by Saudi Pharmacy and Therapeutic (P&T) committee members in formulary decisions making process is limited mainly because of lack of expertise and lack of resources. This paper intended to provide Saudi P&T decision makers with a clear set of best practice methodological recommendations to help in increasing the utilisation of pharmacoeconomic evidence in the formulary decisions making process.


Adaptation of TSH filter paper method for regionalized screening for congenital hypothyroidism.
A sensitive, specific, rapid radioimmunoassay is described for the determination of thyrotropin (TSH) in eluates from two 3 mm discs punched from dried blood filter-paper specimens. This method is sufficiently sensitive to easily discriminate between normal infants and infants with primary hypothyroidism. The use of two 3 mm discs enables screening laboratories to easily incorporate this methodology into the currently available, fully automated systems to screen for several metabolic disorders. Since mental retardation occurs in untreated infants with primary hypothyroidism, our TSH method as the primary screening test alone, or in association with a thyroxine (T4) screening test, should detect all infants with primary hypothyroidism with a very acceptable low false-positive recall rate.


Resveratrol derived butyrylcholinesterase inhibitors.
Novel polyhydroxylated (E)-stilbenes were synthesized by Mizoroki-Heck reactions and tested for their ability to inhibit the enzymes acetyl- and butyrylcholinesterase. Several of them are good inhibitors of butyrylcholinesterase; one of them carrying an extra fluorine substituent is a 94-fold stronger inhibitor of butyrylcholinesterase than of acetylcholinesterase.


Seroprevalence of Helicobacter pylori infection in Siberia.
Despite many population-based epidemiological studies of Helicobacter pylori prevalence in different parts of the world, Russia still represents a 'blank spot' in this map. The aims of the present study were to evaluate the seroprevalence of H. pylori infection among the population of Siberia and to assess whether there is an association between abdominal symptoms and H. pylori positivity in our population. Six hundred and forty-nine adults from five regions of Siberia and the Far East, and 79 children and adolescents from Novosibirsk participated in the study. Antibodies against H. pylori (IgG) were detected in serum using ELISA. The total percentage of infected adults varied from 70% to 92% depending on the region, and was somewhat lower in three populations living to the north of the 60th latitude compared with those under the 60th latitude. A lack of association was found between the presence of H. pylori and the gender, age and abdominal symptoms. Almost maximum prevalence of H. pylori infection occurred by 30 years of age with only a minor increase in older age groups. Half the children were infected with H. pylori by the age of 15. Helicobacter pylori infection is widespread among the Siberian populations with some trend in its prevalence to decrease northward. In Siberia age-specific prevalence rates of H. pylori infection are similar to those usual for developing countries.


Optimal Imaging Strategies for Rectal Cancer Staging and Ongoing Management.
Imaging determines the optimal treatment for rectal cancer patients. High-resolution magnetic resonance imaging (MRI) overcomes many of the known limitations of previous methods. When performed in accordance with the recommended standards, MRI enables accurate staging of both early and advanced rectal cancer, accurate response assessment, the delineation of recurrent disease and planning surgical treatment in a safe and effective manner. Tumour-related high-risk features with known adverse outcomes can be preoperatively identified and treated with neoadjuvant chemoradiotherapy. Further, MRI post-treatment tumour response assessment using TRG grading system also predicts the likely survival outcomes and in the future will be used to modify treatment further by stratification into good and poor responders. There is a paucity of literature with validated outcome data concerning use of diffusion-weighted imaging and positron emission tomography (PET)/computed tomography (CT), and in the absence of any validated methods and outcome data, their use in the initial assessment and restaging after treatment is limited to research protocols. Combination MRI and CT is essential for distant spread assessment and recurrent disease, and currently PET-CT is sometimes used in the workup of patients with recurrent and metastatic disease.


No Child Left in the Morgue: Standing in as Hope's Family.
This personal reflection expresses a chaplaincy department's feelings as they became the surrogate family for a child whose body was abandoned by its mother in the hospital morgue.


[Relationship between medical treatment compliance and the degree of control in patients with high blood pressure, non-insulin dependent diabetes mellitus and dyslipidemia].
To study the relationship between therapeutic compliance and the control of arterial hypertension, non insulin dependent diabetes mellitus and hyperlipidemia. Prospective study performed on 174 hypertensive patients, 107 with diabetes and 107 with hyperlipidemia evaluating compliance by counting of tablets in two home visits. 34% hypertensive patients, 20% diabetics and 37% hyperlipidemics that took medication as instructed or more than they should were badly controlled. The control grade of high blood pressure, non insulin dependent diabetes mellitus and hyperlipidemia not only depends on improving compliance but also in adapting pharmacologic prescriptions.


Genomic analyses of microbial virulence.
Genomic sequencing of bacterial pathogens is providing an increasing wealth of new data. It is, however, still unclear how this information can be used to develop new experimental approaches. Here, we describe recent efforts to complement existing bacterial genetics with genomic methods for the study of pathogenesis.


Mitomycin C trabeculectomy in eyes with cicatricial conjunctiva.
To demonstrate favorable outcome of mitomycin C-augmented trabeculectomy in eyes with broad cicatricial conjunctiva created by previous surgeries. Forty-six eyes (40 patients) with extensive conjunctival scarring that had undergone mitomycin C trabeculectomy were reviewed retrospectively. After a mean follow-up +/- SD of 13.7 +/- 7.8 months (range, 6 to 36 months), intraocular pressure was well controlled, below or equal to 16 mm Hg and 21 mm Hg, respectively, in 33 (72%) and 44 (96%) of the 46 eyes. In all eyes, a functional filtering bleb was present during the follow-up periods. Mitomycin C trabeculectomy after dissection of conjunctival scar tissue may be useful for treating refractory glaucoma.


Aspirative cytology with fine-needle in the abdomen, retroperitoneum and pelvic cavity: a seven year experience of the Portuguese Institute of Oncology, Center of Porto.
A review was made of 236 fine-needle aspiration cytologies (FNAC), guided by ultrasound, computerized tomography or fluoroscopy, performed in the abdomen, retroperitoneum and pelvic cavity. Seventy-three FNAC were from the liver, 41 from the kidneys, 30 from the pelvic cavity, 26 from the retroperitoneum, 24 from the peritoneal cavity, 13 from the pancreas, 11 from the adrenal glands, nine from the abdominal wall, seven from the spleen and two from the digestive tract. The total accuracy rate was 90%, ranging from 77% in the abdominal wall lesions to 100% in the splenic lesions. Indications for FNAC and results are discussed as well as the accuracy rate obtained with different guiding modalities. We conclude considering FNAC a safe, unexpensive and reliable method to confirm the diagnosis of malignant lesions in the abdomen, retroperitoneum and pelvic cavity.


Symptomatic cyst of the choroid plexus of the lateral ventricle.
A case of symptomatic cyst of the choroid plexus of a lateral ventricle in a child is reported. The characteristics of the case are compared with those of the other three cases in the literature.


Performance of an algorithm for diagnosing acute cholecystitis using clinical and sonographic parameters.
Identify an algorithm using clinical and ultrasound (US) parameters with high diagnostic performance for acute cholecystitis. Consecutive emergency department (ED) patients from 4/1/2019 to 12/31/2019 were retrospectively reviewed to record non-US parameters and make US observations. Outcomes were categorized as either: (1) acute cholecystitis; or (2) negative acute cholecystitis. Pivot tables identified parameter combinations either not found with acute cholecystitis or with predictive value for acute cholecystitis to establish the algorithm. US Division radiologists finalized an US report prior to ED disposition without use of the algorithm. Radiologist impression and algorithm prediction for acute cholecystitis were categorized as either (1) acute cholecystitis; (2) negative acute cholecystitis; or (3) inconclusive. Three hundred and sixty-six studies on 357 patients (mean age, 51 yrs ± 20 yrs; 215 women) met the inclusion criteria. 10.9% (40/366) of US studies had acute cholecystitis, 12.6% (46/366) had pathologically identified chronic cholecystitis without acute cholecystitis, and 76.5% (280/366) were negative acute cholecystitis. Algorithm compared to radiologist diagnostic performance was as follows: (1) sensitivity: 90.0% vs. 55.0%, p < 0.001; (2) augmented sensitivity (defined as when inconclusive categorization is considered consistent with acute cholecystitis): 100% vs. 85.0%, p < 0.001; (3) specificity: 93.6% vs. 94.8%, p = 0.50; (4) diagnostic rate (opposite of inconclusive rate): 96.4% vs. 93.2%, p = 0.04; (5) adverse outcome rate: 0.0% vs. 1.6%, p undefined. For acute cholecystitis, an algorithm using non-binary ultrasound and clinical assessments had higher sensitivity, higher diagnostic rate, and fewer adverse outcomes, than subspecialty radiologist impressions.


Effect of middle cerebral artery occlusion on mRNA expression for the sodium-coupled vitamin C transporter SVCT2 in rat brain.
The sodium-vitamin C co-transporter SVCT2 is primarily responsible for the accumulation of the important antioxidant ascorbate into brain cells. In vitro studies have demonstrated strong expression of this transporter in cultured astrocytes, whereas in situ hybridization analysis has so far detected SVCT2 only in neurons. In the present study, we examined the response of SVCT2 mRNA expression in the brain to focal ischemia induced for 2 h by unilateral middle cerebral artery occlusion. The mRNA expression patterns of SVCT2 and the glutamate-activated immediate early gene Arc were investigated at 2 and 22 h after ischemia. SVCT2 and Arc mRNA expression was lost in the ischemic core at both time points. In areas outside the core, Arc was strongly up-regulated, primarily at 2 h, whereas SVCT2 showed an increase at 2 and 22 h. SVCT2 expression was increased in neurons as well as in astrocytes, providing the first evidence for SVCT2 expression in astrocytes in situ. These findings underscore the importance of ascorbate as a neuroprotective agent and may have implications for therapeutic strategies. In addition, the increase of SVCT2 in astrocytes after ischemia suggests that cultured astrocytes are exposed to chronic oxidative stress.


Regional and systemic chemotherapy for primary hepatobiliary cancers and for colorectal cancer metastatic to the liver.
Hepatic arterial infusional (HAI) chemotherapy is based on the premise that primary and metastatic tumors derive their blood supply from the hepatic artery, whereas normal liver derives its blood supply from the portal vein. This approach has been extensively studied in liver-only colorectal metastasis patients, with 10 published prospective randomized clinical trials comparing fluoropyrimidine-based HAI therapy with systemic chemotherapy. Most of these studies showed a statistically significant superior response rate and improved disease-free survival with HAI chemotherapy compared with systemic fluoropyrimidine-based chemotherapy alone. More advanced chemotherapeutic regimens including biologically targeted agents have clearly impacted survival in metastatic colorectal cancer patients and are currently under investigation with HAI-based trials. In contrast, hepatobiliary tumors remain difficult to treat with overall poor response and survival with systemic chemotherapy. Few clinical trials have attempted to address the role of HAI-based therapy for these regional tumors, although encouraging response rates up to 60% have been reported. Therefore, the regional approach for hepatobiliary tumors deserves further investigation as well as randomized trials for adequate comparison to new systemic chemotherapies.


Association between Recurrence or Exacerbation at Time of Disaster and Allergic Symptoms Several Years Later in Schoolchildren with Asthma or Atopic Dermatitis: The ToMMo Child Health Study.
Asthma and atopic dermatitis are common among schoolchildren. The Great East Japan Earthquake of 2011 caused serious damage to buildings and infrastructure as well as the total or partial collapse of many hospitals and medical clinics. The aim of this study was to examine the association between recurrence or exacerbation (recurrence/exacerbation) of asthma or atopic dermatitis at the time of disaster and allergic symptoms several years later in schoolchildren. A cross-sectional survey was conducted via a parent-administered questionnaire between 2013 and 2015 in Miyagi Prefecture, northeast Japan. We analyzed the data of 2,399 schoolchildren with a diagnosis of asthma and 2,107 with a diagnosis of atopic dermatitis. Among those who had experienced recurrence/exacerbation of their symptoms soon after the disaster, the prevalence of later wheezing and eczema was 71.2% (N = 195) and 81.9% (N = 379), respectively. Recurrence/exacerbation of allergic symptoms just after the disaster was positively associated with wheezing (odds ratio, OR 6.54, 95% confidence interval, 95% CI 4.94-8.67) and eczema (OR 8.12, 95% CI 6.25-10.55) several years later. Disasters might have long-term effects on the allergy symptoms of children. It is necessary to prepare for prevention of recurrence/exacerbation, to treat allergic symptoms, and to support children to continue their allergy treatments and daily care when a disaster strikes.


Amino acid sequences of phospholipases A2 from the venom of an Australian elapid snake (king brown snake, Pseudechis australis).
Two basic phospholipases A2 (Pa-11 and Pa-13) have been isolated from the venom of an Australian elapid snake, Pseudechis australis (king brown snake). The reduced and S-carboxymethylated phospholipases A2 were digested with trypsin and the resulting peptides were purified by a combination of chromatography on a DEAE-cellulose DE-52 column and gel filtration procedures. Eleven main peptides from Pa-11 and 9 peptides from Pa-13 could account for the amino acid compositions of the respective enzyme molecules. The alignment of the tryptic peptides and unelucidated regions of the amino acid sequences of tryptic peptides were established by the analysis of the peptides obtained by chymotryptic and/or Staphylococcal protease digestions. Each phospholipase A2 consisted of a single chain of 118 amino acid residues, including 14 half-cystine residues. Although Pa-11 is enzymatically 30-times as active as Pa-13 and highly toxic as compared to Pa-13, they are highly homologous in their amino acid sequences. They are also homologous to the enzymes from mammalian pancreas and the other snake venom phospholipases A2, especially to those from snakes belonging to the subfamilies Acanthophiinae and Laticaudinae.


Somatic 9p24.1 alterations in HPV- head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity.
Somatic copy number alterations (SCNAs), generally (1) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors (2); however, genomic regions mediating these effects are unclear and probably tissue specific. Previously, 9p21.3 loss was found to be an early genetic driver of human papillomavirus-negative (HPV-) head and neck squamous cancer (HNSC), associated with an immune-cold tumor microenvironment (TME) signal, and recent evidence suggested that this TME-cold phenotype was greatly enhanced with 9p21 deletion size, notably encompassing band 9p24.1 (3). Here, we report multi-omic, -threshold and continuous-variable dissection of 9p21 and 9p24 loci (including depth and degree of somatic alteration of each band at each locus, and each gene at each band) and TME of four HPV- HNSC cohorts. Preferential 9p24 deletion, CD8 T-cell immune-cold associations were observed, driven by 9p24.1 loss, and in turn by an essential telomeric regulatory gene element, JAK2-CD274. Surprisingly, same genetic region gains were immune hot. Related 9p21-TME analyses were less evident. Inherent 9p-band-level influences on anti-PD1 ICT survival rates, coincident with TME patterns, were also observed. At a 9p24.1 whole-transcriptome expression threshold of 60th percentile, ICT survival rate exceeded that of lower expression percentiles and of chemotherapy; below this transcript threshold, ICT survival was inferior to chemotherapy, the latter unaffected by 9p24.1 expression level (P-values < 0.01, including in a PD-L1 immunohistochemistry-positive patient subgroup). Whole-exome analyses of 10 solid-tumor types suggest that these 9p-related ICT findings could be relevant to squamous cancers, in which 9p24.1 gain/immune-hot associations exist.


Preoperative Remnant Liver Function Evaluation Using a Routine Clinical Dynamic Gd-EOB-DTPA-Enhanced MRI Protocol in Patients with Hepatocellular Carcinoma.
To investigate the clinical feasibility of preoperative routine clinical dynamic Gd-EOB-DTPA-enhanced MRI alone to predict post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). 116 patients with HCC who underwent liver resection in Southwest Hospital from 2014 through 2017 were selected in this retrospective cohort study. The remnant function (RF) of the liver RFUR and RFRE15 were calculated by the sum of the uptake rate (UR) or relative enhancement at 15 min (RE15) from dynamic Gd-EOB-DTPA-enhanced MR images in the remnant liver regions, and standardized by standard liver volume (SLV) to generate sRFUR (standardized RFUR) and sRFRE15 (standardized RFRE15). Student's t test or Mann-Whitney U test, logistic regression, and ROC analyses were used to test the associations of preoperative RFUR, sRFUR, RFRE15, sRFRE15, the remnant liver volume (RLV)/SLV, ICG retention rate at 15 min (ICG R15) and sRFICG-K [ICG clearance rate (ICG-K) × RLV/SLV] with PHLF. 28 patients were found to have PHLF, who showed lower RFUR, sRFUR, RFRE15, sRFRE15, RLV/SLV, sRFICG-K, and higher ICG R15 than patients without PHLF (p < 0.001 for all). After adjusting for clinical parameters, RFUR (p = 0.001), sRFUR (p = 0.001), RFRE15 (p = 0.002), or sRFRE15 (p = 0.003) was found to be independently significant indicator in multivariable logistic regression, respectively. RFUR (0.882) and sRFUR (0.882) had larger AUCs than RLV/SLV (0.731, p = 0.008; p = 0.005), ICG R15 (0.765, p = 0.039; p = 0.044) and sRFICG-K (0.767, p = 0.031; p = 0.023). RFRE15 (0.845) and sRFRE15 (0.839) had larger AUCs than RLV/SLV (0.731, p = 0.027; p = 0.025). The remnant liver function parameters preoperatively estimated from a routine clinical dynamic Gd-EOB-DTPA-enhanced MRI protocol can predict PHLF in patients with HCC, and may be better predictors than conventional methods.


Mirabegron versus vibegron in previously untreated female patients with overactive bladder: A randomized, single-clinic, open-label trial.
This study aimed to assess the efficacy and safety of mirabegron compared with vibegron (both 50 mg once daily) in Japanese female patients with symptoms of overactive bladder (OAB). This prospective, 12-week, two-arm, parallel-group, open-label randomized trial (UMIN000038288) was conducted at a single clinic from December 2019 to September 2022. The primary efficacy outcome measure was the change in mean total overactive bladder symptom scores (OABSSs) from baseline to end of treatment (EOT) (Week 12). The secondary efficacy outcome measures were changes in mean International Prostate Symptom Score from baseline to EOT, the ratio of patients who achieved a minimal clinically important change (MCIC) of total OABSS, and individual domains of the King's Health Questionnaire. Safety assessments, such as adverse events (AEs), postvoid residual volume, and patient-reported incidences, were recorded at every visit. There was no statistically significant adjusted mean difference between mirabegron and vibegron in terms of the primary outcome of the mean change from baseline to EOT in the total OABSS. The difference in the percentage of patients in the mirabegron and vibegron groups achieving an MCIC on the total OABSS was not statistically significant but appeared to be clinically important. The incidence of treatment-related AEs was significantly higher for the vibegron group (38.5%) than the mirabegron group (19.1%) (p = .047). These results showed that both drugs were effective in female OAB patients, with no significant differences in terms of efficacy. However, the safety of vibegron requires further investigation.


Bedřich Roth: pioneer in sleep medicine.
Bedřich Roth was a Czech neurologist who dedicated his professional life to the study of sleep medicine. Shortly after WW2 he initiated a research program with an exclusive focus on narcolepsy and the hypersomnias. At the young age of 38 years, he published his first book. It was in Czech but had extensive English and Russian summaries. In 1967 he spent a study period in Marseille with Professor Henri Gastaut, who was very impressed by this bright and hardworking young neurologist. Dr. Roth, with his colleague Sona Nevšímalová, was the first to publish on the high frequency of depression in patients with narcolepsy and hypersomnia. He was the first person to define Idiopathic Hypersomnia and, along with Allan Rechtschaffen, to document the high frequency of sleep drunkenness in such patients. His many contributions, and his 65th birthday, were celebrated in 1984. Dr. Roth developed Hodgkin's lymphoma and passed away in November 1989. A conference celebrating his life and career took place in Prague in 2009. In 2015 the annual worldwide Idiopathic Hypersomnia Awareness Week organized by Michelle Chadwick celebrated the 35th anniversary of his 1980 book "Narcolepsy and Hypersomnia". Dr. Roth was the first physician to dedicate his entire career to sleep medicine and his publications predated by more than two decades those of all other authors. Bedřich Roth should therefore be considered to be the true father of sleep medicine. He was known widely for his integrity, humility, honesty, and his perseverance to achieve his goals.


Origin of the twist of cellulosic materials.
Molecular Mechanics, Hartree-Fock, and semi-empirical geometry optimizations were carried out on cellulose oligomers and crystallites with and without water solvation. The intramolecular bonding is visualized with the Delocalized Molecular Orbitals (DLMOs). Internal coordinates were relaxed and the structures were gradient optimized for cellulose oligomers composed of 4, 10, 12, 14, 19, and 65 glucose units. The cellulose conformation of minimum energy deviates from the flat ribbon conformation giving rise to half-twist repeating units of about 3-4nm and 60nm along the chain axis. An optimized cellulose chain which is ten glucose units long is 9.57kcal/mol more stable than the flat ribbon model. The DLMOs show the twisted model retains the same hydrogen bonding scheme as the flat model while minimizing steric interactions between H1 and H4'. In cellulose crystallites the twist, which can be left- or right-handed, calls into question the assumption of twofold symmetry in the current flat unit cell. Additionally the hydrogen bonded sheets reorient themselves, suggesting the crystallites are in fact crystalloids. The overall length of the crystal twist is dependent on the cross-section of the crystal. Powder X-ray diffraction patterns of the optimized crystallites were simulated.


[Management of the avulsion of the flexor pollicis longus and flexor indicis profundus tendons by tendon transfer. Case report].
Tendon injuries are common in hand wounds and their functional consequences are not negligible. In emergency, tendon repairs techniques are well codified to restore function. These tendon repairs can be made in one session, in two sessions, or even use tendon transfers. Tendon transfers are not usual in the emergency but more common in the treatment of sequelae or failure of primary repair. We report one case of transfer to restore thumb flexion in emergency.


Temporary cement tectoplasty: a technique to improve prefabricated hip spacer stability in two-stage surgery for infected hip arthroplasty.
This technical note describes an intraoperatively custom-made, antibiotic-loaded bone cement roof, used in conjunction with a prefabricated hip spacer to improve component stability, as part of the first stage of a two-stage procedure for an infected hip implant. This technique was successfully used in seven cases who presented with extensive superior and/or posterio-superior acetabular defect, which created a risk of spacer dislocation. With this technique we were able to avoid any further dislocation in these seven cases. We believe that the technique may reduce postoperative spacer dislocation in cases with extensive acetabular defects, while improving clinical outcomes.


The continuous impact of cognitive flexibility on the development of emotion understanding in children aged 4 and 5 years: A longitudinal study.
The current study investigated the impact of cognitive flexibility on the development of emotion understanding using a longitudinal tracking study. A total of 98 children aged 4 and 5 years were tested for cognitive flexibility, emotion understanding, and verbal ability across three time points within a year. The cross-lagged analyses indicated that early cognitive flexibility played a predictive role in the development of emotion understanding. More precisely, cognitive flexibility at Time 1 predicted emotion understanding at Time 2 and Time 3, and cognitive flexibility at Time 2 predicted emotion understanding at Time 3. Furthermore, mediation analysis showed that verbal ability mediated the impact of cognitive flexibility on emotion understanding. Early cognitive flexibility contributed to later emotion understanding by improving children's verbal ability. These findings suggest that there is a verbal ability-mediated pathway from cognitive flexibility to emotion understanding that provides a new perspective for the development mechanism of children's emotion understanding.


Differential association of polymorphisms in the TNFalpha region with psoriatic arthritis but not psoriasis.
To investigate the potential association of tumour necrosis factor alpha (TNFalpha) microsatellite and promoter alleles with psoriatic arthritis (PsA). DNA from 89 white patients with PsA, 65 patients with psoriasis, and 99 healthy white controls was investigated for two TNFalpha promoter (-238 and -308) and three microsatellite polymorphisms (TNFa, c, and d). Patients had previously been studied by serology for HLA class I antigens and by sequence-specific polymerase chain reaction for DRB1* alleles. In addition, TNFalpha production of Ficoll separated peripheral blood mononuclear cells (PBMC) into culture supernatants after stimulation with lipopolysaccharide, alphaCD3 antibodies, phytohaemagglutinin, and streptococcal superantigen C was determined. A significant, HLA class I independent increase of the TNFa6c1d3 haplotype was found in the group with PsA but not among patients with psoriasis (32% v. 8%, pc<0.008; relative risk (RR)=5.3). In addition, patients with PsA showed a marked decrease of the TNF308A promoter allele (6% v. 18%; pc<0.008; RR=3.5) compared with healthy controls, which was independent of the increased frequency of the -238A polymorphism in this group. PBMC from patients with PsA secreted significantly less TNFalpha than cells from patients without arthritis. In particular, the TNFa6 microsatellite was associated with decreased TNFalpha production. These data indicate that allelic variations at the TNFalpha locus influence susceptibility to PsA. Decreased production of TNFalpha is at least in part genetically determined and might be related to the development of arthritis. However, the association of the TNF308G allele with the disease also points to other disease related haplotypes with still unknown susceptibility genes.


PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration.
Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.


Seaweed Essential Oils as a New Source of Bioactive Compounds for Cyanobacteria Growth Control: Innovative Ecological Biocontrol Approach.
The application of natural compounds extracted from seaweeds is a promising eco-friendly alternative solution for harmful algae control in aquatic ecosystems. In the present study, the anti-cyanobacterial activity of three Moroccan marine macroalgae essential oils (EOs) was tested and evaluated on unicellular Microcystis aeruginosa cyanobacterium. Additionally, the possible anti-cyanobacterial response mechanisms were investigated by analyzing the antioxidant enzyme activities of M. aeruginosa cells. The results of EOs GC-MS analyses revealed a complex chemical composition, allowing the identification of 91 constituents. Palmitic acid, palmitoleic acid, and eicosapentaenoic acid were the most predominant compounds in Cystoseira tamariscifolia, Sargassum muticum, and Ulva lactuca EOs, respectively. The highest anti-cyanobacterial activity was recorded for Cystoseira tamariscifolia EO (ZI = 46.33 mm, MIC = 7.81 μg mL-1, and MBC = 15.62 μg mL-1). The growth, chlorophyll-a and protein content of the tested cyanobacteria were significantly reduced by C. tamariscifolia EO at both used concentrations (inhibition rate >67% during the 6 days test period in liquid media). Furthermore, oxidative stress caused by C. tamariscifolia EO on cyanobacterium cells showed an increase of the activities of superoxide dismutase (SOD) and catalase (CAT), and malondialdehyde (MDA) concentration was significantly elevated after 2 days of exposure. Overall, these experimental findings can open a promising new natural pathway based on the use of seaweed essential oils to the fight against potent toxic harmful cyanobacterial blooms (HCBs).


A conditional time-varying multivariate latent growth curve model for the relationships between academics' servant leadership behavior, affective commitment, and job performance during the Covid-19 pandemic.
In our study, we investigated the change patterns in academics' servant leadership behavior and affective commitment during and after the first Covid-19 lockdown (April 2020-August 2020) in Malaysia. Furthermore, we evaluated the influence of academics' servant leadership behavior on job performance through affective commitment. We applied additional analyses to determine the degree to which the two former constructs are influenced by age and academic rank. To do so, we leveraged multivariate latent growth curve (LGC) modeling in analyzing the longitudinal data collected from 220 academics at three time points over a course of four months during the Covid-19 pandemic. Our results showed that, while servant leadership and affective commitment were stable over time, servant leadership was a driver of affective commitment and job performance. We also observed that affective commitment significantly mediated the relationship between academics' servant leadership behavior and job performance. Moreover, we found interindividual differences in servant leadership and affective commitment in terms of age and academic rank at the beginning of the Covid-19 lockdown. Our multi-disciplinary research is among the limited number of studies applying a rigorous, longitudinal approach to examine behaviors (i.e., servant leadership and job performance) and attitudes (i.e., affective commitment) during the Covid-19 pandemic in higher education research.


Fluorescence studies on the Ca2+ and Zn2+ binding properties of the alpha-subunit of bovine brain S-100a protein.
The single cysteine on the alpha-subunit of bovine brain S-100a protein has been modified with the thiol specific probe, Acrylodan. When the labelled apoprotein was excited at 380 nm the fluorescence emission maximum was centered at 484 +/- 2 nm, suggesting that the probe is in a fairly hydrophobic environment. Addition of Ca2+ to the protein caused the emission maximum to undergo a red shift to 504 +/- 2 nm, implying that the fluorophore is now more exposed to the solvent. Zn2+, when added to the protein, induced only a small perturbation and the emission maximum shifted to 481 +/- 2 nm. Ca2+ was able to perturb the fluorophore in the presence of Zn2+. 2-p-Toluidinylnaphthalene-6-sulfonate (TNS)-labelled alpha-subunit when excited at 345 nm exhibited very little fluorescence in the absence of Ca2+. Addition of Ca2+ resulted in an increase in TNS fluorescence accompanied by a blue shift of the emission maximum to 445 +/- 1 nm indicating that the probe in the presence of Ca2+ moves to a hydrophobic domain. The fact that Ca2+ and Zn2+ can perturb the labelled sulfhydryl group in the presence of each other clearly demonstrates that the binding sites for the two metal ions must be different on the alpha-subunit as well as on the S-100a protein.


Rate effect on mechanical properties of hydraulic concrete flexural-tensile specimens under low loading rates using acoustic emission technique.
Acoustic emission (AE) waveform is generated by dislocation, microcracking and other irreversible changes in a concrete material. Based on the AE technique (AET), this paper focuses on strain rate effect on physical mechanisms of hydraulic concrete specimens during the entire fracture process of three point bending (TPB) flexural tests at quasi-static levels. More emphasis is placed on the influence of strain rate on AE hit rate and AE source location around peak stress. Under low strain rates, namely 0.77×10(-7)s(-1), 1×10(-7)s(-1) to 1×10(-6)s(-1) respectively, the results show that the tensile strength increases as the strain rate increases while the peak AE hit rate decreases. Meanwhile, the specimen under a relatively higher strain rate shows a relatively wider intrinsic process zone in a more diffuser manner, lots of distributed microcracks relatively decrease stress intensity, thus delay both microcracking localization and macrocrack propagation. These phenomena can be attributed to Stéfan effect. In addition, further tests, namely the combination of AE monitoring and strain measuring systems was designed to understand the correlation between AE event activity and microfracture (i.e., microcracking and microcracking localization). The relative variation trend of cumulative AE events accords well with that of the load-deformation curve.


Assessing stimulus equivalence with a precursor to the relational evaluation procedure.
Previous research has demonstrated that, after being trained on multiple match-to-sample (MTS) tasks (A-B, B-C), most human adults respond in accordance with symmetry (B-A, C-B) and equivalence (C-A) when measured with MTS tests and with a precursor to the Relational Evaluation Procedure (pREP). The latter procedure involves conditional go/no-go discrimination tasks, requiring subjects to press a bar during a 5s interval after the successive presentation of two same-class stimuli, and not to press after the presentation of two different-class stimuli (e.g. Ci -->Ai -->press, Ci -->Aj -->no press). The present study was an effort to replicate these findings. The study consisted of five experiments. Very few subjects evidenced pREP symmetry and equivalence unless they had (a) already demonstrated symmetry and equivalence in a MTS test before, or (b) received pREP pretraining with unrelated stimulus pairs and symmetry was tested before equivalence. Failures to show symmetry were always associated with pressing at or close to 50% of these trials. Failures to show equivalence were associated with pressing or not pressing on (almost) all trials. Current findings are similar to those obtained in equivalence studies involving MTS probes permitting the subjects not to respond to the designated comparisons.


The hierarchical organization of semantic memory: executive function in the processing of superordinate concepts.
Research on the processing of objects at different hierarchical levels has suggested that understanding superordinate concepts (e.g. fruit), relative to basic level concepts (e.g. apple), requires greater semantic control demands. Yet, it is unclear which factors underlie this difference in executive processing. We built on previous research showing that superordinate concepts have less shared features among their members and therefore may involve higher semantic control requirements. To test this hypothesis, we developed an fMRI study in which we orthogonally manipulated feature sharedness (more shared vs. less shared) and concept level (superordinate vs. basic) in a sentence verification task. Sentences involving less shared features, relative to more shared features, significantly engaged the L lateral PFC. Importantly, sentences that included superordinate concepts, relative to those with basic level concepts, also revealed a stronger response in L lateral PFC, along with posterior temporal gyrus activation. There was also a significant interaction between feature sharedness and concept level in several PFC regions and L posterior temporal areas. The results suggest that relative to basic level concepts, processing superordinate concepts requires extra semantic control in L lateral PFC to coordinate information that is less shared by other members of the category level. These findings demonstrate that feature sharedness impacts the neural basis of semantic knowledge, and is a critical dimension in the processing of superordinate concepts.


Negative inotropic effects of angiotensin II, endothelin-1 and phenylephrine in indo-1 loaded adult mouse ventricular myocytes.
Angiotensin II (Ang II). endothelin-1 (ET-1) and phenylephrine are receptor agonists that share the signal transduction acting through acceleration of phosphoinositide hydrolysis in the heart. Because the regulation of myocardial contractility induced by these receptor agonists shows a wide range of species-dependent variation among experimental animals, we carried out experiments to elucidate the mechanism of contractile regulation induced by these agents in mice which are employed currently more as transgenic models. Effects of Ang II, ET-1 and phenylephrine on cell shortening and Ca2+ transients were investigated in single ventricular myocytes loaded with indo-1/AM. Ang II (10(-8), 10(-7) M), ET-1 (10(-10), 10(-9) M) and phenylephrine (10(-6), 10(-5) M in the presence of the beta-adrenoceptor antagonist timolol) decreased the cell shortening [Ang II: 58.4+/-9.03 (n = 8), 50.3+/-11.90% (n = 6); ET-1: 48.4+/-8.27, 31.2+/-6.45% (n = 5); phenylephrine: 45.7+/-11.60, 28.7+/-5.89% (n = 5)]. By contrast, the amplitude of Ca2+ transients was not significantly influenced by these agonists. The selective protein kinase C inhibitor chelerythrine at 10(-6) M significantly inhibited the decrease in cell shortening induced by these receptor agonists. These results indicate that Ang II, ET-1 and phenylephrine elicit a negative inotropic effect with insignificant alteration of Ca2+ transients, which may be mainly mediated by activation of protein kinase C in mouse ventricular cardiomyocytes.


Dioxadispiroketal Compounds and a Potential Acyclic Precursor from Amomum aculeatum.
Four new compounds having an unusual 1,7-dioxadispiro[126.96.36.199]-12-ene-11-one tricyclic ring system (1-4), their potential precursor, 5R-hydroxy-1-(4-hydroxyl-phenyl)-eicosan-3-one (5), and two known compounds, aculeatins A (6) and B (7), have been isolated from Amomum aculeatum. All compounds were characterized by spectroscopic methods and the configurations were established by 2D NOE correlations. Compounds 1-4, 6 and 7 showed cytotoxic activity against several human cancer cell lines.


Pharmacokinetic studies of methionine in rats using deuterium-labeled methionine quantitative assessment of remethylation.
The pharmacokinetics of methionine has been studied in rats by means of stable isotope methodology. After the i.v. bolus injection of [2H7]methionine (5 mg/kg body wt.), the plasma concentrations of [2H7]methionine, demethylated [2H4]homocysteine and remethylated [2H4]methionine were determined simultaneously with endogenous methionine and homocysteine by gas chromatography-mass spectrometry. The half-life for [2H7]methionine were 35.0 +/- 6.9 min. The appearance of the metabolites, [2H4]homocysteine and [2H4]methionine, in the plasma was very rapid. The fraction of [2H7]methionine that remethylated to [2H4]methionine through [2H4]homocysteine were 0.185 +/- 0.028. The administered [2H7]methionine did not influence the plasma levels of endogenous methionine and homocysteine. The present stable isotope methodology has made it possible to evaluate the pharmacokinetics of methionine, including the estimation of remethylation.


Palladium-catalyzed synthesis of indene derivatives via propargylic carbonates with in situ generated organozinc compounds.
The palladium-catalyzed carboannulation and arylation reaction of propargylic carbonates with in situ generated organozinc compounds produced an important new class of indene derivatives. The reaction proceeded under mild conditions, and indene products were isolated in good to excellent yields.


Systemic activity of closantel for control of lone star ticks, Amblyomma americanum (L.), on cattle.
Cattle were treated once at 5 mg/kg orally or subcutaneously or daily at 0.1-5 mg/kg orally or 0.1-1 mg/kg subcutaneously with closantel, N-[5-chloro-4-[(4-chlorophenyl)cyanomethyl]-2-methylphenyl]-2-hydroxy-3, 5-diiodobenzamide, and numbers and weights of engorged females, weights of egg masses and hatch of eggs of lone star ticks, Amblyomma americanum, were recorded. Effectiveness of treatments on reproduction was determined by comparing total estimated larvae (EL) (EL = wt. egg mass X est. % hatch X 20000) of ticks from treated cattle with that of ticks from untreated cattle. With certain treatments, we also determined the effect of manure of treated cattle on survival of larvae of the horn fly, Haematobia irritans, or effect on survival and of fecundity of adult horn flies or stable flies, Stomoxys calcitrans, fed on blood from treated animals. The single oral treatment afforded essentially complete control of total EL only of ticks placed on the animal on the day of treatment, while the single subcutaneous treatment afforded greater than 92% control of total EL of ticks placed on animal on treatment day and for 6 weeks posttreatment. Daily treatments of 0.5 mg/kg or greater orally and 0.1 mg/kg or greater subcutaneously afforded essentially complete control of total EL of ticks throughout the treatment period (3-12 weeks) and for 1-7 weeks after treatment was discontinued. An estimated concentration of greater than 9 micrograms/ml of blood was calculated by probit analysis to be necessary to provide greater than 90% control of total EL of lone star ticks; that same concentration also provided greater than 90% control of hatch of eggs laid by treated females. A higher concentration (40 micrograms/ml) was necessary to prevent engorging of the females. No treatments tested were effective against larvae of the horn fly or adult horn flies or stable flies.


Phylogenetic analysis of plant multi-domain SEC14-like phosphatidylinositol transfer proteins and structure-function properties of PATELLIN2.
SEC14L-PITPs guide membrane recognition and signaling. An increasingly complex modular structure of SEC14L-PITPs evolved in land plants compared to green algae. SEC14/CRAL-TRIO and GOLD domains govern membrane binding specificity. SEC14-like phosphatidylinositol transfer proteins (SEC14L-PITPs) provide cues for membrane identity by exchanging lipophilic substrates, ultimately governing membrane signaling. Flowering plant SEC14L-PITPs often have modular structure and are associated with cell division, development, and stress responses. Yet, structure-function relationships for biochemical-cellular interactions of SEC14L-PITPs are rather enigmatic. Here, we evaluate the phylogenetic relationships of the SEC14L-PITP superfamily in the green lineage. Compared to green algae, land plants have an extended set of SEC14L-PITPs with increasingly complex modular structure. SEC14-GOLD PITPs, present in land plants but not Chara, diverged to three functional subgroups, represented by the six PATELLIN (PATL) proteins in Arabidopsis. Based on the example of Arabidopsis PATL2, we dissect the functional domains for in vitro binding to phosphoinositides and liposomes and for plant cell membrane association. While the SEC14 domain and its CRAL-TRIO-N-terminal extension serve general membrane attachment of the protein, the C-terminal GOLD domain directs it to the plasma membrane by recognizing specific phosphoinositides. We discuss that the different domains of SEC14L-PITPs integrate developmental and environmental signals to control SEC14L-PITP-mediated membrane identity, important to initiate dynamic membrane events.


Metabolomics Profiling Predicts Ventricular Arrhythmia in Patients with an Implantable Cardioverter Defibrillator.
Implantable cardioverter defibrillators (ICDs) reduce sudden cardiac death (SCD) when patients experience life-threatening ventricular arrhythmias (LTVA). However, current strategies determining ICD patient selection and risk stratification are inefficient. We used metabolomics to assess whether dysregulated metabolites are associated with LTVA and identify potential biomarkers. Baseline plasma samples were collected from 72 patients receiving ICDs. Over a median follow-up of 524.0 days (range 239.0-705.5), LTVA occurred in 23 (31.9%) patients (22 effective ICD treatments and 1 SCD). After confounding risk factors adjustment for age, smoking, secondary prevention, and creatine kinase MB, 23 metabolites were significantly associated with LTVA. Pathway analysis revealed LTVA associations with disrupted metabolism of glycine, serine, threonine, and branched chain amino acids. Pathway enrichment analysis identified a panel of 6 metabolites that potentially predicted LTVA, with an area under the receiver operating characteristic curve of 0.8. Future studies are necessary on biological mechanisms and potential clinical use.


Triterpenoids from Drypetes chevalieri Beille (euphorbiaceae).
The CH2Cl2/CH3OH (1/1) extract of the dried stem of Drypetes chevalieri Beille afforded two new triterpenoïds named drypechevalin A (11-oxo-beta-amyrin-3beta-ylcaffeate) and drypechevalin B (3,7-dioxo-D:A-friedooleanan-24-al) along with five known compounds: lupeol, lupeone, erythrodiol, putranjivadione, friedelin. Their structures were established on the basis of spectroscopic analysis and chemical evidence.


Interrelationships among prostaglandins, vasopressin and cAMP in renal papillary collecting tubule cells in culture.
To determine the influence of prostaglandins on cAMP metabolism in renal papillary collecting tubule (RPCT) cells, intracellular cAMP levels were measured after incubating cells with prostaglandins (PGs) alone or in combination with arginine vasopressin (AVP). PGE1, PGE2 and PGI2, but not PGD2 or PGF2 alpha, increased intracellular cAMP concentrations. At maximal concentrations (10(-5) M) the effects of PGE2 plus PGI2 (or PGE1), but not of PGI2 plus PGE1, were additive suggesting that at least two different PG receptors may be present in RPCT cell populations. Bradykinin treatment of RPCT cells caused an accumulation of intracellular cAMP which was blocked by aspirin and was quantitatively similar to that observed with 10(-5) M PGE2. PGs, when tested at concentrations (e.g. 10(-9) M) which had no independent effect on intracellular cAMP levels, did not inhibit the AVP-induced accumulation of intracellular cAMP in RPCT cells. These results indicate that PGs do not block AVP-induced accumulation of intracellular cAMP in RPCT cells at concentrations of PGs which have been shown to inhibit the hydroosmotic effect of AVP on perfused collecting tubule segments. However, at higher concentrations of PGs (e.g. 10(-5) M), the effects of AVP plus PGE1, PGE2, PGI2 or bradykinin on intracellular cAMP levels were not additive. Thus, under certain conditions, there is an interaction between PGs and AVP at the level of cAMP metabolism in RPCT cells.


Risk groups in children under six months of age using self-organizing maps.
Fetal and infant growth tends to follow irregular patterns and, particularly in developing countries, these patterns are greatly influenced by unfavorable living conditions and interactions with complications during pregnancy. The aim of this study was to identify groups of children with different risk profiles for growth development. The study sample comprised 496 girls and 508 boys under six months of age from 27 pediatric primary health care units in the city of Rio de Janeiro, Brazil. Data were obtained through interviews with the mothers and by reviewing each child's health card. An unsupervised learning, know as a self-organizing map (SOM) and a K-means algorithm were used for cluster analysis to identify groups of children. Four groups of infants were identified. The first (139) consisted of infants born exclusively by cesarean delivery, and their mothers were exclusively multiparous; the highest prevalences of prematurity and low birthweight, a high prevalence of exclusive breastfeeding and a low proportion of hospitalization were observed for this group. The second (247 infants) and the third (298 infants) groups had the best and worst perinatal and infant health indicators, respectively. The infants of the fourth group (318) were born heavier, had a low prevalence of exclusive breastfeeding, and had a higher rate of hospitalization. Using a SOM, it was possible to identify children with common features, although no differences between groups were found with respect to the adequacy of postnatal weight. Pregnant women and children with characteristics similar to those of group 3 require early intervention and more attention in public policy.