New approach to detect and classify stroke in skull CT images via analysis of brain tissue densities.
Cerebral vascular accident (CVA), also known as stroke, is an important health problem worldwide and it affects 16 million people worldwide every year. About 30% of those that have a stroke die and 40% remain with serious physical limitations. However, recovery in the damaged region is possible if treatment is performed immediately. In the case of a stroke, Computed Tomography (CT) is the most appropriate technique to confirm the occurrence and to investigate its extent and severity. Stroke is an emergency problem for which early identification and measures are difficult; however, computer-aided diagnoses (CAD) can play an important role in obtaining information imperceptible to the human eye. Thus, this work proposes a new method for extracting features based on radiological density patterns of the brain, called Analysis of Brain Tissue Density (ABTD). The proposed method is a specific approach applied to CT images to identify and classify the occurrence of stroke diseases. The evaluation of the results of the ABTD extractor proposed in this paper were compared with extractors already established in the literature, such as features from Gray-Level Co-Occurrence Matrix (GLCM), Local binary patterns (LBP), Central Moments (CM), Statistical Moments (SM), Hu's Moment (HM) and Zernike's Moments (ZM). Using a database of 420 CT images of the skull, each extractor was applied with the classifiers such as MLP, SVM, kNN, OPF and Bayesian to classify if a CT image represented a healthy brain or one with an ischemic or hemorrhagic stroke. ABTD had the shortest extraction time and the highest average accuracy (99.30%) when combined with OPF using the Euclidean distance. Also, the average accuracy values for all classifiers were higher than 95%. The relevance of the results demonstrated that the ABTD method is a useful algorithm to extract features that can potentially be integrated with CAD systems to assist in stroke diagnosis.


Stereotactic heavy-particle irradiation of intracranial arteriovenous malformations.
Stereotactic irradiation appears to be effective in causing partial or complete thrombosis of AVM that are not surgically resectable. Use of heavy particles generated in a cyclotron allows better spatial definition and dose distribution than do other methods, allowing larger AVM to be treated. From these preliminary results, it is evident that heavy-particle irradiation therapy, like proton beam therapy, does not offer protection from recurrent hemorrhage for at least 12 months, nor is it devoid of major complications; it does offer a noninvasive mode of therapy for AVM that are difficult to treat surgically, however.


Activation and inhibition of leukotriene A4 hydrolase aminopeptidase activity by diphenyl ether and derivatives.
The synthesis and biological evaluation of a series of diphenyl ether derivatives were described. The compounds can either activate or inhibit the aminopeptidase activity of leukotriene A(4) hydrolase, while at the same time do not influence the hydrolase activity. Further enzyme kinetics and molecular modeling investigation on these novel chemical activators revealed their possible activation mechanism. These compounds can be used as probes to regulate the aminopeptidase activity of leukotriene A(4) hydrolase.


Use of locking plates for fixation of the greater trochanter in patients with hip replacement.
Fixation of the greater trochanter with total hip replacement is challenging and associated with short- and long-term complications. Locking plate technology has been used for fixation of other bones and may be applied successfully in trochanteric fixation. The purpose of this retrospective study was to analyze the utility of the use of trochanteric locking plates in total hip arthroplasty (THA) patients. From 2004 to 2014, 32 procedures were performed to fix the greater trochanter in patients with trochanteric fracture, osteotomy, or nonunion in the setting of THA. The median age at the time of surgery was 69 years. This was a primary arthroplasty in 8 of the patients, conversion from prior hip surgery in 5, and a revision in 19. The greater trochanter was fixed with locking plate alone in 15 hips and with the addition of a single cerclage cable in 17 hips. Patients were followed clinically and radiographically until healing occurred. The median duration of radiographic follow-up was 41.6 months (range: 10-112 months). Osseous union occurred in 29 (90.6%) of 32 hips. The median Harris hip score was 94 (range 54-100, standard deviation = 10.4) at latest follow-up. Complications included broken hardware in 5 (15.6%) patients, of which 3 underwent subsequent hardware removal. Two additional patients elected hardware removal due to trochanteric pain. Locking plate technology is a successful method of fixation of the greater trochanter in patients with THA. Postoperative trochanteric pain and reoperation for hardware-related issues remain a challenge.


MiR-29b mimics promotes cell apoptosis of smooth muscle cells via targeting on MMP-2.
The phenotypic transformation and dysfunctions of vascular smooth muscle cells (SMCs) such as abnormality proliferation and apoptosis are key pathological basis of atherosclerosis. The recent study aimed to detect the role of miR-29b in phenotypic transformation of SMCs. In this study, we investigated the expression level of miR-29b and MMP-2 in acute coronary syndrome (ACS) patients, verified whether MMP-2 is the target gene of miR-29b by luciferase reporter gene system, and explored the role of miR-29b in the viability and apoptosis of SMCs. We found that the plasma level of miR-29b was significantly downregulated to 56% of controls (p < 0.01). The plasma level of MMP-2 in health controls was 34.9 ± 6.9 ng/mL, and that it significantly increased to 46.2 ± 13.2 ng/mL in ACS patients. MMP-2 is a target gene of miR-29b. The overexpression of miR-29b significantly downregulated the expression of MMP-2 mRNA and protein. miR-29b mimics inhibited the cell viability of SMCs, and cell apoptosis was significantly enhanced compared with the NC group, especially in the early stage. In the presence of MMP-2 inhibitor SB-3CT, the cell viability and apoptosis of SMC cells were significantly reduced and enhanced, respectively, while the miR-29b -inhibited cell viability and -induced cell apoptosis were not significantly changed. Taken together, miR-29b was downregulated in ACS patients. MiR-29 mimics inhibits cell viability and promotes cell apoptosis via directly targeting on MMP-2, which could be a potentially promising therapy target for cardiovascular diseases.


Value of Myocardial Contrast Echocardiography in Detecting Coronary Microcirculatory Dysfunction in Ischemia With Non-obstructive Coronary Artery Disease.
The aim of this study was to evaluate the value of myocardial contrast echocardiography (MCE) in detecting coronary microcirculation function dysfunction in ischemia with non-obstructive coronary artery (INOCA) disease. Twenty-one patients with a clinical diagnosis of INOCA were admitted to the First Affiliated Hospital of Xinjiang Medical University because of chest pain. All participants underwent MCE and [18F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography myocardial metabolic imaging. With the results of FDG PET taken as the gold standard, all myocardial segments were divided into a normal control group and a coronary artery microcirculation dysfunction (CMCD) group. We used MCE to measure myocardial perfusion parameters, including the ascending slope (β), time to peak (TTP), A and A × β. The receiver operating characteristic (ROC) curves of β, TTP, A and A × β were calculated to evaluate the diagnostic value of MCE for CMCD. A total of 122 and 218 segments were investigated in the CMCD and control groups, respectively. On the basis of the statistical analysis of the MCE parameters of the two groups, the myocardial perfusion parameters β, A and A × β of all segments in the CMCD group decreased, and the TTP in the basal segment of the CMCD group was longer than that of the normal control group (all p values <0.05). On the basis of analysis of the ROC curve, β had the highest diagnostic efficiency in the middle segment. This study found that MCE is valuable in the diagnosis of non-obstructive coronary artery complicated by CMCD.


The Role of Stereotactic Biopsy in Brain Metastases.
Brain metastases (BrM) affect up to 20% of patients with cancer and represent an increasing portion of patients with surgical brain tumors owing to improving prognoses of cancer patients in general and in many cases even of those with brain metastases. With advances in molecular biology and targeted therapy, the indications for neurosurgical sampling and specifically stereotactic biopsy are likely to change in the future. In this review the authors address some of the scientific advances in BrM biology, the clinical rationale and range of techniques currently used to perform stereotactic biopsy, and how the advent of molecular interrogation may potentially alter the way patients with BrM are managed in the future.


Synaptic reorganization in the medial amygdaloid nucleus after lesion of the accessory olfactory bulb of adult rat. I. Quantitative and electron microscopic study of the recovery of synaptic density.
The time course of the appearance of degenerating synapses and the loss and reappearance of intact synapses was investigated in the medial amygdaloid nucleus (MAN) following lesions of the accessory olfactory bulb (AOB). Degenerating synapses were concentrated in the molecular layer of MAN. A quantitative electron microscopic analysis of the molecular layer was performed at 2, 4, 8, 16, 32 and 64 days after the placement of kainic acid injections within AOB. At each survival time, counts of synapses were made from photomicrographic montages. The degenerating synapses were observed at 2 days after lesion. Their density reached a peak at 2 or 4 days after the lesion and decreased thereafter. No degenerating synapses were found at 64 days following the lesion. Shrinkage of the thickness of molecular layer was observed following the AOB lesion. This was most pronounced at 4 or 8 days after the lesion at which time the thickness was 70-75% of the contralateral molecular layer. The shrinkage receded moderately (85% of contralateral layer at 64 days after lesion). The compensated synaptic density of intact synapses was reduced to less than half of the control density at 4 or 8 days after the lesion. Thereafter synaptic density increased gradually and reached more than 80% of control density at 64 days after lesion. The recovery in number of intact synapses following the lesion suggests the possibility of synaptic reorganization by remaining afferent fibers.


Cognitive reserve and long-term change in cognition in aging and preclinical Alzheimer's disease.
We examined if baseline levels of cognitive reserve (CR) and of Alzheimer's disease (AD) biomarkers modify the rate of change in cognition among individuals with normal cognition at baseline (n = 303, mean baseline age = 57 years, mean follow-up = 12 years); 66 participants subsequently developed mild cognitive impairment (MCI) or dementia due to AD. CR was indexed by years of education, reading, and vocabulary measures. AD biomarkers were measured with a composite score composed of measures of amyloid, phosphorylated tau, and neurodegeneration. Higher CR scores were associated with better cognitive performance but did not modify the rate of change in cognition among those who remained cognitively normal, nor among those who progressed to MCI before symptom onset, independent of baseline biomarker levels. However, higher CR scores were associated with faster cognitive decline after symptom onset of MCI. These results suggest that the mechanism by which CR mediates the relationship between pathology and cognitive function is by delaying the onset of symptoms rather than reducing the rate of cognitive decline.


Effect of Roux-en-Y gastric bypass-induced weight loss on the transcriptomic profiling of subcutaneous adipose tissue.
The changes in the transcriptomic profiling of subcutaneous adipose tissue (SAT) when weight loss stabilizes after a Roux-en-Y gastric bypass (RYGB) are still largely unknown. To investigate the changes produced in SAT gene expression of morbidly obese women when their weight loss stabilizes 2 years after RYGB. University hospital. SAT biopsies of the periumbilical area were taken before and 2 years after RYGB. Gene expression levels were assessed by microarray analysis and significant differences in gene expression were validated by real-time quantitative polymerase chain reaction. The findings were also confirmed in an independent population of morbidly obese women. Microarray analysis revealed that the overexpressed differentially expressed genes have a prominent role in the pathways involved in biosynthetic processes, especially lipid or carboxylic ones (stearoyl-Coenzyme A desaturase-1, fatty acid desaturase-1, fatty acid elongase-6, ATP citrate lyase, fatty acid synthase, lipin-1, monoacylglycerol O-acyltransferase, patatin-like phospholipase domain containing-3, phosphate cytidylyltransferase-2, cholesteryl ester transfer protein, transmembrane 7 superfamily member 2, pyruvate carboxylase, and glycogen synthase 2). Most of the underexpressed differentially expressed genes are related with immune system and inflammation processes (immune responses, response to stress, cell death, regulation of biological quality, immune effector process, the response to endogenous stimulus, and the response to other types of stimulus). An improvement of the SAT inflammatory and immune profile and an induction of genes involved in the regulation of lipid metabolism are shown when weight loss stabilizes 2 years after RYGB. Most of the genes shown are clearly linked to obesity and other metabolic disorders.


Estimation of oxygen consumption of lithobiid field populations from laboratory measurements.
The oxygen consumption of two lithobiid populations in an old beech stand in the Solling is estimated. Respiration of single individuals was determined at different temperatures in a Warburg respirometer. Respiration rate depends exponentially on temperature (Q10 about 3). Respiration per unit weight decreases considerably with increasing weight in Lithobius mutabilis, whereas in Lithobius curtipes these differences are much lower. With regard to the transferability of the laboratory values to field conditions, the error introduced by use of an arithmetic temperature mean instead of integration over the actual temperature cycle is estimated. Respiration values determined with arithmetic and biological (after Nielsen 1978) temperature means are compared. It is shown that under the temperature conditions in the Solling the use of an arithmetic instead of a biological daily temperature mean (based on hourly temperature readings), and the use of an arithmetic instead of a biological monthly temperature mean (based on arithmetic daily means) only give slight underestimates, about 0.8% and 1.2% respectively. The use of an arithmetic instead of a biological annual mean (based on arithmetic monthly means) gives an underestimate of 14%. The influence of other factors affecting the Warburg apparatus is discussed. It is concluded that the metabolism of L. mutabilis and L. curtipes measured in a Warburg respirometer should be multiplied by a factor of about 1.75 to give an estimate of respiration in the field. The population of L. mutabilis respires 5.5×1.75=9.63 kJm-2 year-1, the population of L. curtipes 2.2×1.75=3.85 kJ m-2 year-1. The results obtained are compared with a short-cut method proposed by Phillipson (1970), the "best estimate". Possible improvements of the method are discussed.


Sex mediated lipid metabolism in human aortic smooth muscle cells.
When human aortic smooth muscle cells in culture were treated with pharmacological doses of estrogen and testosterone for 48 hrs, the rate of cholesterol synthesis measured both by acetate incorporation and the 3, hydroxy 3-methylglutaryl Co enzyme A reductase (HMG-CoA) activity declined significantly as compared to control. However, the rate of cholesterol esterification increased by 132% and 45% in response to testosterone and estrogen respectively. Also, acetate incorporation into fatty acids and fatty acid synthetase enzyme activity increased by hormonal treatment but remained in the free form especially by estrogen. Testosterone treatment resulted in more esterification (p less than .025) of fatty acid than estrogen treatment. Incubation with hormones for 48 hrs resulted in enhanced uptake of 14C-labeled cholesterol along with increased accumulation of cellular cholesterol. Increased synthesis of phospholipid and triglyceride by estrogen may be responsible for excretion of cellular sterol and fat. These results indicate that sex-hormones have an important effect on the regulation of lipid metabolism in human aortic cells.


Serum laminin P1 in small cell lung cancer: a valuable indicator of distant metastasis?
Serum laminin P1 was studied in patients with small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), respiratory infections, pulmonary fibrosis, and in normal subjects. The level of serum laminin P1 was elevated (greater than 1.27 U ml-1) in 58.9% of SCLC and in 11.5% of NSCLC patients. Median value in SCLC was significantly higher than that in NSCLC (P less than 0.01), respiratory infection (P less than 0.01), and in normal subjects (P less than 0.01), but not statistically different from that in pulmonary fibrosis. The levels of serum laminin P1 in SCLC were related to therapeutic response. However, no certain correlation was established between the level of laminin P1 and the clinical stage of SCLC.


Spatial patterns in electoral wards with high lymphoma incidence in Yorkshire health region.
The possibilities of clustering between those electoral wards which display higher than expected incidences of cases of the lymphomas occurring between 1978 and 1982 are examined. Clusters are defined as being those wards with cases in excess (at a probability of less than 10%) which are geographically adjacent to each other. A separate analysis extends the definition of cluster to include high incidence wards that are adjacent or separated by one other ward. The results indicate that many high incidence lymphoma wards do occur close together and when computer simulations are used to compute expected results, many of the observed results are shown to be highly improbable both in the overall number of clustering wards and in the largest number of wards comprising a 'cluster'.


Trends in Medical Claims and Utilization of Limited Ultrasonography Among Emergency Physicians and Radiologists Within a Large Health Plan Provider.
The goal of this study was to evaluate trends in medical claim submissions for limited ultrasound studies performed (1) during emergency department (ED) encounters and (2) by ED providers compared to radiologists. We conducted a retrospective, descriptive study using medical claims data from Medica Health Plans from January 1, 2011 to December 31, 2015. Current procedural terminology codes were abstracted for limited ultrasound applications performed during an ED visit and further stratified by studies performed by ED providers compared with radiologists. We excluded claims for which we could not determine provider specialty. We identified 42,576 encounters with limited US claims, of which, 32,666 were submitted by ED providers (N = 9649) or radiologists (N = 23,017). Among ED providers, there was a significant linear increase in the annual number of claims for retroperitoneal (P < .001) and nonlinear increases for thoracic, soft tissue, cardiac, transvaginal genitourinary (GU) and transabdominal GU claims (all P < .001). Compared with radiologists, there was a linear increase in the annual proportion of claims submitted for retroperitoneal (P = .023), transabdominal GU (P = .003), and transvaginal GU (P < .001) studies by ED providers. There was a nonlinear decrease in the annual proportion of limited abdomen claims (P < .001) submitted by ED providers compared with radiologists. Using data from a large health plan provider, we show that medical claims for many limited ultrasound studies are increasing among ED providers. Compared with radiologists, ED providers are increasingly submitting claims for retroperitoneal, soft tissue, and transabdominal GU studies.


Experimental design by response surface methodology for efficient cefixime uptake from hospital effluents using anion exchange membrane.
The excessive use of antibiotics and their ultimate routes to the environment have prompted the drug resistance, which is becoming a major ecological issue. In this work, we have evaluated the performance of quaternary ammonium poly (2, 6-dimethyl-1,4-phenylene oxide) and polyvinyl alcohol (QPPO/PVA) based anion exchange membrane against cefixime (a third generation cephalosporin antibiotic) present in hospital effluents. The membrane's surface morphology was studied through scanning electron microscopy. The optimization of experimental parameters through Response Surface Methodology helped to evaluate the inter parameter dependence and predict maximum uptake capacity (qe). The speculated value of qe (6.72 mg g-1) obtained through central composite design was close to the experimental value of 7.01 mg g-1 with percent relative error of 4.31%. Further, the evaluation of experimental data using isotherms (Langmuir and Freundlich) and kinetic models (pseudo-first-order and second-order) proposed that the interactions between cefixime and the membrane were physisorptive in nature. The intra-day and inter-day assays exhibited lower %RSD values of 0.4% (n = 5) and 0.3% (n = 5). Furthermore, a percentage recovery of 98.2% (n = 9) and limit of detection 1 × 10-5 μg mL-1 was observed. The chromatogram of the treated water samples presented only negligible amount of cefixime indicating a great potential of QPPO/PVA membrane for the removal of cefixime from real water samples. The membrane could be regenerated for three consecutive cycles without any prominent loss in efficiency.


Ranuncoside's attenuation of scopolamine-induced memory impairment in mice via Nrf2 and NF-ĸB signaling.
Scopolamine is a well-known pharmacological agent responsible for causing memory impairment in animals, as well as oxidative stress and neuroinflammation inducer which lead to the development of Alzheimer disease. Although a cure for Alzheimer's disease is unavailable. Ranuncoside, a metabolite obtained from a medicinal plant has demonstrated antioxidant and anti-inflammatory properties in vitro, making it a promising treatment with potential anti-Alzheimer disease properties. However, as ranuncoside has not been evaluated for its antioxidant and anti-neuroinflammatory properties in any in vivo model, our study aimed to evaluate its neurotherapeutic efficacy against scopolamine-induced memory impairment in adult male albino mice. Mice were randomly divided into four experimental groups. Mice of group I was injected with saline, group II was injected with scopolamine (1 mg/kg/day) for 3 weeks. After receiving a daily injection of scopolamine for 1 week, the mice of group III were injected with ranuncoside (10 mg/kg) every other day for 2 weeks along with scopolamine daily and group IV were injected with ranuncoside on 5th alternate days. Behavioral tests (i.e., Morris water maze and Y-maze) were performed to determine the memory-enhancing effect of ranuncoside against scopolamine's memory deleterious effect. Western blot analysis was also performed to further elucidate the anti-neuroinflammatory and antioxidant effects of ranuncoside against scopolamine-induced neuroinflammation and oxidative stress. Our results showed memory-enhancing, anti-neuroinflammatory effect, and antioxidant effects of ranuncoside against scopolamine by increasing the expression of the endogenous antioxidant system (i.e., Nrf2 and HO-1), followed by blocking neuroinflammatory markers such as NF-κB, COX-2, and TNF-α. The results also revealed that ranuncoside possesses hypoglycemic and hypolipidemic effects against scopolamine-induced hyperglycemia and hyperlipidemia in mice as well as scopolamine's hyperglycemic effect. In conclusion, our findings suggest that ranuncoside could be a potential agent for the management of Alzheimer's disease, hyperglycemia, and hyperlipidemia.


Limited immune reconstitution at intermediate stages of HIV-1 infection during one year of highly active antiretroviral therapy in antiretroviral-naive versus non-naive adults.
Although several reports have attributed the clinical benefits of highly active antiretroviral therapy (HAART) to a possible immune restoration, long-term data are still scarce and most derive from patients with either advanced or very early stages of HIV infection. In the present study, changes in lymphocyte subsets, activation markers, and adhesion molecules in CD4+ and CD8+ lymphocytes were carefully monitored over a 1-year period in 27 HIV-infected adults at an intermediate stage of HIV infection. Cytokine-producing patterns were also studied. In these patients the HIV viral load disappeared by month 4 of HAART. Only limited immunological changes were observed: an incomplete recovery of naive CD4+ T cells, a less activated state of CD8+ T cells, and a repopulation of IL-2- and IFN-gamma-producing CD4+ T cells. These changes were observed principally in patients with more advanced disease. Furthermore, HIV-infected subjects who had received HAART previously showed less marked immunological changes than antiretroviral-naive individuals. In conclusion, the sustained viral suppression during 1 year of HAART was accompanied by limited immunological recovery at intermediate stages of HIV infection. This finding indicates a need for longer HIV suppression in order to achieve effective recovery of the immune system.


Cerebral venous and sinus thrombosis.
Cerebral venous and sinus thrombosis (CVST) can present with a variety of clinical symptoms ranging from isolated headache to deep coma. Prognosis is better than previously thought and prospective studies have reported an independent survival of more than 80% of patients. Although it may be difficult to predict recovery in an individual patient, clinical presentation on hospital admission and the results of neuroimaging investigations are--apart from the underlying condition--the most important prognostic factors. Comatose patients with intracranial haemorrhage (ICH) on admission brain scan carry the highest risk of a fatal outcome. Available treatment data from controlled trials favour the use of anticoagulation (AC) as the first-line therapy of CVST because it may reduce the risk of a fatal outcome and severe disability and does not promote ICH. A few patients deteriorate despise adequate AC which may warrant the use of more aggressive treatment modalities such as local thrombolysis. The risk of recurrence is low (< 10%) and most relapses occur within the first 12 months. Analogous to patients with extracerebral venous thrombosis, oral AC is usually continued for 3 months after idiopathic CVST and for 6-12 months in patients with inherited or acquired thrombophilia but controlled data proving the benefit of long-term AC in patients with CVST are not available.


[Refinements in the labia minor reduction procedures].
The aim of this study is to appreciate the hypertrophy of labia minor, its psychological and functional effects and the different techniques of reduction available. From August 2004 to June 2007, 14 patients have been operated with a posterior wedge resection technique associated with a Z plasty. A questionnaire has been sent to each patient in order to make a retrospective study of the different reasons of consultation and their degree of satisfaction after surgery. Among the 12 patients who answered the questionnaire, main part of them was satisfied or very satisfied of the morphologic and functional results. All of them were satisfied to have decided on this surgery. We can notice an increase of the requests concerning the vulvar morphologic changing, either due to aesthetics preoccupations or functional disorders. Technically, the wedge resection brings the most satisfactory results. The addition of a Z plasty and the posterior location of the scar should prevent dyspareunia and per-partum tears. This preliminary clinical study focuses on the different techniques, enables a better knowledge of these women expectations and confirms our technique.


Autistic traits distribution in different psychiatric conditions: A cluster analysis on the basis of the Adult Autism Subthreshold Spectrum (AdAS Spectrum) questionnaire.
Increasing interest is being paid on full-threshold and sub-threshold autism spectrum conditions among adults. Sub-threshold autistic traits (AT) seem to be distributed in a continuum from the clinical to the general population, being particularly higher among subjects with other psychiatric disorders. The aim of the present study was to evaluate the distribution of AT in a sample of subjects with different psychiatric conditions by means of a cluster analysis on the basis of the score reported to the AdAS Spectrum instrument. A total of 738 subjects recruited by seven Italian Universities were divided in 5 groups depending on the clinical diagnosis: Autism spectrum disorder (ASD), subthreshold ASD symptoms (partial ASD), Bipolar disorder (BD), Feeding and eating disorders (FED), and controls (CTLs). All subjects were assessed with the AdAS Spectrum. The cluster analysis identified 3 clusters: the high, medium and low autism clusters. The Restricted interests and rumination domain reported the highest influence in forming the clusters. The high, medium and low autism clusters were respectively more represented in the ASD, partial ASD and CTL groups. The clusters were represented intermediately in the FED and BD groups, confirming the presence of intermediate levels of AT in these clinical populations.


Fast Spherical Mapping of Cortical Surface Meshes Using Deep Unsupervised Learning.
Spherical mapping of cortical surface meshes provides a more convenient and accurate space for cortical surface registration and analysis and thus has been widely adopted in neuroimaging field. Conventional approaches typically first inflate and project the original cortical surface mesh onto a sphere to generate an initial spherical mesh which contains large distortions. Then they iteratively reshape the spherical mesh to minimize the metric (distance), area or angle distortions. However, these methods suffer from two major issues: 1) the iterative optimization process is computationally expensive, making them not suitable for large-scale data processing; 2) when metric distortion cannot be further minimized, either area or angle distortion is minimized at the expense of the other, which is not flexible to generate application-specific meshes based on both of them. To address these issues, for the first time, we propose a deep learning-based algorithm to learn the mapping between the original cortical surface and spherical surface meshes. Specifically, we take advantage of the Spherical U-Net model to learn the spherical diffeomorphic deformation field for minimizing the distortions between the icosahedron-reparameterized original surface and spherical surface meshes. The end-to-end unsupervised learning scheme is very flexible to incorporate various optimization objectives. We further integrate it into a coarse-to-fine multi-resolution framework for better correcting fine-scaled distortions. We have validated our method on 800+ cortical surfaces, demonstrating reduced distortions than FreeSurfer (the most popularly used tool), while speeding up the process from 20 min to 5 s.


Significance of a new isovolumetric technique for the study of the myometrial dynamics in vitro.
Above usual values for active tension are measured in 10 uterine horns of rat under electric stimulation through an original isovolumetric technique. At the maximum length increase attained were 1.79 +/- 0.2 kg/cm2, with passive tension from 9--10% total tension. These values are within the range for other smooth and striated muscles. The isometric techniques efficacy to record total uterine tension, as well as the application of isometric activity to the analyse of uterine dynamics are discussed.


Effects of BMI on the risk and frequency of AIS 3+ injuries in motor-vehicle crashes.
Determine the effects of BMI on the risk of serious-to-fatal injury (Abbreviated Injury Scale ≥ 3 or AIS 3+) to different body regions for adults in frontal, nearside, farside, and rollover crashes. Multivariate logistic regression analysis was applied to a probability sample of adult occupants involved in crashes generated by combining the National Automotive Sampling System (NASS-CDS) with a pseudoweighted version of the Crash Injury Research and Engineering Network database. Logistic regression models were applied to weighted data to estimate the change in the number of occupants with AIS 3+ injuries if no occupants were obese. Increasing BMI increased risk of lower-extremity injury in frontal crashes, decreased risk of lower-extremity injury in nearside impacts, increased risk of upper-extremity injury in frontal and nearside crashes, and increased risk of spine injury in frontal crashes. Several of these findings were affected by interactions with gender and vehicle type. If no occupants in frontal crashes were obese, 7% fewer occupants would sustain AIS 3+ upper-extremity injuries, 8% fewer occupants would sustain AIS 3+ lower-extremity injuries, and 28% fewer occupants would sustain AIS 3+ spine injuries. Results of this study have implications on the design and evaluation of vehicle safety systems.


Hemodialysis in patients older than 65 years with end-stage renal failure--comparison of outcome in patients with and without diabetes.
During recent years, the number of patients with end-stage renal disease (ESRD) has been rising worldwide. Especially older patients and those with diabetes contribute to this rise. The aim of the present study was to evaluate whether patients older than 65 years with type 2 diabetes, who started first dialysis, have a higher prevalence of vascular diseases and co-morbidities, show a higher incidence of vascular complications and/or have a higher mortality rate than elderly non-diabetic patients with ESRD. In this study, 82 consecutive patients with ESRD, who had either type 2 diabetes or did not have diabetes and who had started chronic hemodialysis (HD) in our dialysis center during the years 1994 to 2002, were included. Patients were included when they were older than 65 years. Patients were divided into two groups: those with diabetes (DM) (n = 47) and those without diabetes (nDM) (n = 35). For both groups the number of co-morbidities as well as the prevalence of vascular diseases and vascular risk-factors at the start of HD was evaluated. In addition, the incidence of vascular complications was registered over a 3-year observation period. In both groups serum(S)-creatinine, blood urea nitrogen (BUN), creatinine clearance, hemoglobin, fasting blood glucose, HbA1c (in diabetic patients), cholesterol, triglycerides and phosphorus were evaluated. At the start of HD the creatinine clearance was significantly higher in diabetic subjects (nDM 7.1 +/- 2.1 vs DM 9.5 +/- 4.4 ml/min/1.73 m2; p < 0.005). For S-creatinine the difference was not statistically significant (nDM 8.7 +/- 3.3 mg/dl vs DM 7.4 +/- 2.4; p = 0.07). Fasting blood glucose was significantly higher in diabetic patients (p < 0.001). BUN, hemoglobin, phosphorus and lipids were not significantly different in both groups. There was no statistically significant difference in systolic or diastolic blood pressure, but a higher amount of antihypertensive drugs were necessary in the DM group for blood pressure control (p < 0.01). In both groups there was a high prevalence of vascular diseases at the start of HD. In the diabetic patients the prevalence of peripheral vascular disease was significantly higher. Furthermore, in the first and second year significantly more vascular complications were observed in the DM group (p < 0.01). Survival was low in both groups. The 3-year survival was 20.0% in non-diabetic and 17.0% in diabetic patients (NS). Patients older than 65 years with ESRD have a low survival with and without type 2 diabetes. The mortality rate was only slightly higher in the diabetic group and was not statistically significant. The prevalence of vascular diseases and co-morbidities is high in both groups; however, the incidence of cardiovascular complications was significantly higher in our diabetic patients.


Use of an exposure-response model to aid early drug development of an oral sphingosine 1-phosphate receptor modulator.
Pharmacokinetic (PK) and exposure-response modeling of a selective sphingosine 1-phosphate receptor-1 modulator (CS-0777) was conducted in an iterative process to guide early clinical development decisions. A model based on preclinical data from monkeys was extrapolated to humans to support a single ascending dose (SAD) study. The model was updated after each cohort, providing guidance on both maximal inhibition and time to recovery for lymphocyte counts. A 2-compartment PK model with first-order absorption and elimination was found to describe the monkey and human datasets. The relationship between lymphocyte counts and active metabolite (M-1) concentrations was modeled via an indirect response model, whereby M-1 inhibited the reentry of lymphocytes to the circulation. The indirect-response model based on SAD data had an Imax of approximately 85% and an IC50 of 0.24 ng/mL. Additionally, based on SAD data, similar models were developed for lymphocyte subsets, including CD4 cells. Subsequently, simulations were utilized to design a multiple ascending dose study with adaptive dosing regimens that would meet targeted pharmacodynamic (PD) response thresholds (eg, minimum 40% reduction in lymphocytes) while maintaining CD4 counts above a reasonable safety threshold. In conclusion, model-based development and use of adaptive designs for dose optimization can reduce the time and number of subjects needed in early clinical development.


Development of electrochemical method for the determination of olaquindox using multi-walled carbon nanotubes modified glassy carbon electrode.
A simple and highly sensitive method for the electrochemical determination of olaquindox (OLA) was developed, which was carried out on the multi-walled carbon nanotubes (MWCNT) modified glassy carbon electrode (MWCNT/GCE) using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The results showed that MWCNT remarkably enhanced the reduction of OLA, which improved the cathodic peak current of OLA significantly. Under the optimum condition, the linear range for the calibration curve was 0.3-18.0 μg mL(-1) with a detection limit of 0.26 μg mL(-1). The MWCNT/GCE showed a well reproducibility and the relative standard deviation (R.S.D.) was 3.5% (n=9). And a great anti-interference ability of the MWCNT/GCE was also observed. Finally, the MWCNT/GCE was satisfactorily employed to analyze some synthetic and real water samples.


Proton translocation induced by ATPase activity in chloroplasts.
Proton uptake by chloroplasts was induced by light-triggered ATPase activity. A quotient of two was obtained when the initial rate of proton uptake was divided by the rate of P(i) released from ATP. Gramicidin accelerated the rate of ATPase activity and reduced the H(+)/P(i) ratio to 1.4. The results were found to be consistent with the chemiosmotic theory.


The autosomal dominant form of "pure" familial spastic paraplegia: clinical findings and linkage analysis of a large pedigree.
We studied 33 affected members in a family with autosomal dominant "pure" familial spastic paraplegia (FSP). Symptoms began in the fourth or fifth decade, expression varied, and progression was slow. We excluded close linkage to the HLA locus (distal end of short arm of chromosome 6); C8 alpha-gamma locus (proximal end of short arm of chromosome 1); PGM1 (middle region of short arm of chromosome 1); and P blood group (location unknown). Although there was no statistically significant linkage between FSP and any of the other markers, lod scores were positive with loci for GC (vitamin D binding globulin) located on chromosome 4 (4q11-q13) and Rh located on chromosome 1 (1p34-p36).


Chronometrical analysis of event-related potentials and reaction time in patients with multiple lacunar infarcts.
We measured the visual event-related potentials (ERPs) and reaction time (RT) in 31 patients with multiple lacunar infarcts and 18 age-equivalent normal subjects. The N2 and RT latencies of the patients were significantly longer than those of normal subjects, although P2 and P3 latencies did not differ between the two groups. However, the time from N2 to RT did not differ between the two groups. These observations suggest that the impairment of cognitive information processing in these patients arises from an uncertainty in classifying the perceived event, while motor organization time is relatively well preserved. In addition, the N2 latency may be more sensitive in detecting cognitive impairment in such patients.


Specificity of a monoclonal antibody for the NH2-terminal region of fibrin.
A monoclonal antibody (MAb/T2G1s) was prepared by fusion using spleen cells from mice immunized with the NH2-terminal CNBr fragment of human fibrin II, the so-called (T)N-DSK [(A alpha 17-51, B beta 15-118, gamma 1-78)2]. In competition experiments, this antibody reacted with (T)N-DSK as well as peptide B beta 15-42 which can be obtained from (T)N-DSK by digestion with plasmin. Little or no reaction was observed with intact fibrinogen, the NH2-terminal CNBr fragments from fibrinogen (N-DSK) or fibrin I [(B)N-DSK], respectively, as well as peptide B beta 1-42. These results suggest that MAb/T2G1s is directed to an epitope on the B beta chain in fibrin II but not in fibrinogen or fibrin I. As such, MAb/T2G1s differs completely from another antibody (MAb/1-8C6)--also specific for the NH2-terminal region of the B beta chain--which was recently described [Kudryk et al. (1983) Molec. Immun. 20, 1191-1200].


IgG Fc receptor polymorphisms and association with autoimmune disease.
The aim of this study was to investigate whether a genetic polymorphism of Fc gammaRIII exists in mice, which could explain the different susceptibility to pathogenic IgG anti-collagen type II (CII) antibodies in mice carrying the collagen-induced arthritis (CIA)-susceptible H-2q haplotype. The gene for Fc gammaRIII was sequenced in 11 common mouse strains, and the results revealed three different haplotypes of mouse Fc gammaRIII: Fc gammaRIII:V, Fc gammaRIII:H and Fc gammaRIII:T. To study the consequences of this polymorphism, we generated mice carrying the Fc gammaRIII:H haplotype from the CIA-susceptible, H-2q-positive DBA/1 mouse or the Fc gammaRIII:V haplotype from the CIA-resistant, H-2q-positive SWR mouse. After CII immunization or transfer of IgG anti-CII antibodies, Fc gammaRIII:H-expressing mice, but not Fc gammaRIII:V-expressing mice, developed progressively severe arthritis. We also investigated if C5, in addition to Fc gammaRIII polymorphism, could affect the susceptibility to the pathogenic IgG anti-CII antibodies in H-2q-positive mice. Here we show that SWR mice, naturally deficient in C5, can develop CIA when supplemented with C5 and that anti-C5 antibody treatment of Fc gammaRIII:H-expressing mice inhibits arthritis development. These data demonstrate for the first time a genetic polymorphism of Fc gammaRIII in mice that may, together with C5, regulate induction of autoimmune disease.


Effect of aspirin on ionic movement and acid hydrolase activity of explants of canine antral and duodenal mucosae.
Lucite chambers, applied to antral and proximal duodenal mucosae with blood supply intact, were used to compare ionic flux and the total, labilized activity of several acid hydrolases including cathepsin D, alpha and beta-galactosidase, beta-N-acetyglucosaminidase, arylsulfatase, and acid phosphatase. Insorption of H+ ion by the antrum is increased by the application of aspirin-acid-salt solution, which also stimulates acid hydrolase activity; acute erosions develop very rapidly. On the other hand, H+ ion is much more rapidly removed from chambers applied to the duodenal mucosa, isolated by the chamber from bile and pancreatic secretions. The same aspirin-acid-salt solution reduces net H+ ion loss from the duodenal chamber, depresses levels of the acid hydrolases, and no ulcers develop.


The Development of the Overstitch System and Its Potentials.
Endoscopic suturing device for flexible endoscopy was conceptualized by Apollo Group in collaboration with Olympus Optical Ltd. The first modification of suturing device for flexible endoscopy (Eagle Claw) was manufactured by Olympus engineers and extensively used by members of Apollo Group in numerous bench-top experiments on isolated pig stomachs and in live porcine model. The suturing system for flexible endoscopy in humans (Overstitch) was cleared for general clinical use in the United States in 2008. The latest model is compatible with more than 20 single-channel flexible endoscopes with diameters ranging from 8.8 mm to 9.8 mm made by major endoscope manufacturers.


Chronotype and diurnal patterns of positive affect and affective neural circuitry in primary insomnia.
While insomnia is a well-established risk factor for the initial onset, recurrence or relapse of affective disorders, the specific characteristics of insomnia that confer risk remain unclear. Patients with insomnia with an evening chronotype may be one particularly high-risk group, perhaps due to alterations in positive affect and its related affective circuitry. We explored this possibility by comparing diurnal patterns of positive affect and the activity of positive affect-related brain regions in morning- and evening-types with insomnia. We assessed diurnal variation in brain activity via the relative regional cerebral metabolic rate of glucose uptake by using [(18) F]fluorodeoxyglucose-positron emission tomography during morning and evening wakefulness. We focused on regions in the medial prefrontal cortex and striatum, which have been consistently linked with positive affect and reward processing. As predicted, chronotypes differed in their daily patterns in both self-reported positive affect and associated brain regions. Evening-types displayed diurnal patterns of positive affect characterized by phase delay and smaller amplitude compared with those of morning-types with insomnia. In parallel, evening-types showed a reduced degree of diurnal variation in the metabolism of both the medial prefrontal cortex and the striatum, as well as lower overall metabolism in these regions across both morning and evening wakefulness. Taken together, these preliminary findings suggest that alterations in the diurnal activity of positive affect-related neural structures may underlie differences in the phase and amplitude of self-reported positive affect between morning and evening chronotypes, and may constitute one mechanism for increased risk of mood disorders among evening-type insomniacs.


Protein kinase D3 is a pivotal activator of pathological cardiac hypertrophy by selectively increasing the expression of hypertrophic transcription factors.
Fetal cardiac gene reactivation is a hallmark of pathological cardiac hypertrophy (PCH) driven by cardiac transcription factors (TFs) such as nuclear factor of activated T-cells (NFATs). Nuclear import of dephosphorylated NFATs catalyzed by calcineurin (CaN) is a well-established hypertrophic mechanism. Here we report that NFATc4 expression is also up-regulated by newly expressed protein kinase D3 (PKD3) to induce PCH. In both in vitro and in vivo cardiac hypertrophic models, the normally undetectable PKD3 was profoundly up-regulated by isoproterenol followed by overt expression of cardiac TFs including NFATc4, NK family of transcription factor 2.5 (Nkx2.5), GATA4 and myocyte enhancer factor 2 (MEF2). Using gene silencing approaches, we demonstrate PKD3 is required for increasing the expression of NFATc4, Nkx2.5, and GATA4 while PKD1 is required for the increase in MEF2D expression. Upstream induction of PKD3 is driven by nuclear entry of CaN-activated NFATc1 and c3 but not c4. Therefore, PKD3 is a pivotal mediator of the CaN-NFATc1/c3-PKD3-NFATc4 hypertrophic signaling cascade and a potential new drug target for the PCH.


Change in taste preference related to aging of taste cells in rat.
Following the suppression of renewal of rat taste cells by vinblastine sulphate, the preference for sucrose decreased markedly while the aversion to quinine did not change. The results suggest that the sensitivity of taste cells to sucrose decreases with their aging, but the sensitivity to quinine increases.


San-Wu-Huang-Qin decoction attenuates tumorigenesis and mucosal barrier impairment in the AOM/DSS model by targeting gut microbiome.
A classic herbal formula San-Wu-Huang-Qin (SWHQ) decoction has been widely used in clinical practices to prevent and treat colorectal cancer (CRC) for years, but its anti-tumorigenic properties and the underlying mechanisms remain undetermined. The present study used a CRC mouse model to clarify whether and how SWHQ suppresses tumorigenesis. Different doses of SWHQ were gavaged to the AOM/DSS model mice to examine its anti-tumor efficacy in comparison with the positive control drug Aspirin. The underlying microbiota-driven anti-tumor action of SWHQ was proven with bacterial manipulations by fecal microbial transplantation (FMT) in vivo and anaerobic culturing in vitro. SWHQ decoction dose-dependently reduced colonic tumor numbers/loads of AOM/DSS models and suppressed their disease activity index scores. SWHQ also recovered epithelial MUC2 secretion and colonic tight junction protein (ZO-1 and claudin1) expression in the mouse model. Such inhibitory impact on tumorigenesis and mucosal barrier impairment was found to be associated with modulation of gut dysbiosis, particularly for suppressing lipopolysaccharide (LPS) producers. The FMT experiment confirmed the substantial contribution of SWHQ-reshaped microbiota to anti-tumor function and mucosal barrier protection. Moreover, LPS-activated TLR4/NF-κB signaling and its downstream pro-inflammatory factors were significantly suppressed in the colon of SWHQ-treated models and SWHQ-reshaped microbiota recipients. We demonstrated that the SWHQ effectively inhibited tumorigenesis and protect mucosal barrier in CRC at least partially by targeting gut microbiota. This study provides scientific basis for the clinical usage of SWHQ in CRC intervention and prevention.


Bone mass and metabolism in Whipple's disease: the role of hypogonadism.
Whipple's disease, like other malabsorption syndromes, ought to predispose to osteopenia. We therefore evaluated bone mass and mineral metabolism in a cohort of patients with this condition. Twelve male patients with Whipple's disease and 36 male age-matched healthy subjects took part in the study. None of the patients complained of diarrhea at the time of the study. Bone mineral density at the lumbar and femoral level and serum levels of indices of bone and mineral metabolism and of gonadal function were measured. Bone mineral density at the total femur and femoral neck were significantly lower in patients with Whipple's disease than in healthy volunteers, whereas no significant difference was found at the lumbar level. In patients with Whipple's disease serum levels of type-I collagen teleopeptide (ICTP) and sex-hormone-binding globulin were significantly higher, whereas serum levels of testosterone and luteinizing hormone were significantly lower than in healthy volunteers. Moreover, testosterone correlated significantly (P < 0.05) with lumbar bone mineral density (r(s) = 0.64) and serum ICTP levels (r(s) = -0.63). In patients with previously treated Whipple's disease and without any current symptoms of malabsorption, bone loss is generally moderate and linked to the presence of hypogonadism.


Thiazide diuretics and the risk of hip fracture after stroke: a population-based propensity-matched cohort study using Taiwan's National Health Insurance Research Database.
This study aimed to investigate the association between thiazide use and the risk of hip fracture after stroke. A population-based, propensity-matched cohort study was conducted on the basis of Taiwan's National Health Insurance Research Database. Patients with newly diagnosed ischaemic stroke between 2000 and 2011 were included. After propensity score matching, 7470 patients were included, of whom 3735 received thiazides and 3735 did not. HRs for developing hip fractures within 2 years after stroke were calculated using Cox proportional hazards regression model with adjustments for sociodemographic and coexisting medical conditions. Overall, patients using thiazides after stroke had a lower risk of hip fracture than those not using thiazides (8.5 vs 13.9 per 1000 person-years, adjusted HR=0.64, 95% CI 0.46 to 0.89, p=0.007). Further sensitivity analysis based on the duration of thiazide use revealed that the risk of hip fracture tended to decrease as the duration of exposure of thiazides increased. However, the effect was significant only in patients with long-term use of thiazides (using thiazides for >365 days within 2 years after stroke), with a 59% reduction in the risk of hip fracture when compared with patients not using thiazide (adjusted HR=0.41, 95% CI 0.22 to 0.79, p=0.008). The long-term use of thiazides is associated with a decreased risk of hip fracture after stroke.


Differential analgesic effects of morphine and gabapentin on behavioural measures of pain and disability in a model of osteoarthritis pain in rats.
Osteoarthritis (OA) is associated with chronic debilitating joint pain. Pain is the result of an emotional and sensory experience and preclinical models of OA can thus be useful to better understand the underlying mechanisms of the disease and test new therapeutic options. We induced unilateral knee OA in Sprague-Dawley rats using monosodium iodoacetate (MIA), a glycolysis inhibitor and assessed the effects of acute and chronic morphine and gabapentin using a battery of quantitative behavioural outcome measures of pain and disability. Animals received a single intra-articular injection of 2mg MIA in 25 microl saline, causing inflammation and progressive cartilage degradation. Mechanical and thermal sensitivity as well as ambulatory-evoked pain were then monitored using von Frey hairs, acetone and a rotarod. Once maximum nociceptive responses were reached, chronic bi-daily morphine (3mg/kg s.c.) or gabapentin (30 mg/kg s.c.) were administered for 5 days. We observed a marked biphasic mechanical hypersensitivity that increased and reached a plateau from day 14 (317.6% of control response, p<0.01, with von Frey 6g). Moreover we found a marked cooling hypersensitivity, and validated a novel ambulatory-evoked pain score. These measures were significantly reduced after both acute (13.3% of sham response, p<0.01, von Frey 6g) and chronic (38.3%, p<0.05) morphine whilst only chronic gabapentin (37.0%, p<0.05) had an effect. We show the reliability of the model in terms of mechanical hypersensitivity and demonstrate cooling hypersensitivity and ambulatory-evoked pain. In terms of translational research, the effects of morphine and gabapentin validate the model and suggest trials of these therapeutic approaches in OA patients.


Solitary actinic porokeratosis.
An 83-year-old man experienced abrupt onset of a solitary lesion of porokeratosis on his bald, actinically damaged scalp. The features in this case are unusual and represent another point in the broad spectrum of lesions characterized by the cornoid lamella of porokeratosis.


Comparison of internal energy distributions generated by supercritical fluid chromatography versus liquid chromatography hyphenated with electrospray high resolution mass spectrometry.
The internal energy distributions of thermometer ions dissolved in supercritical and liquid solvents and produced in the gas phase by electrospray (ESI) were measured and compared by the survival yield method. The influence of different chromatographic conditions such as the nature of solvents, the composition of the mobile phase, the pressure of the back pressure regulator was studied for supercritical fluid chromatography (SFC) whereas the influence of the composition and of the flow rate of the mobile phase was investigated for liquid chromatography (LC). The MS instrumental parameters were studied in parallel for SFC and LC showing that the drying gas temperature and the fragmentor voltage affected the internal energy distribution, whereas the capillary voltage did not modify the internal energy distribution. A comparison of the internal energy distributions generated by SFC and LC was carried out leading to conclude that SFC led to higher internal energy, i.e. more in-source fragment ions, than LC.


Use of the yeast Saccharomyces cerevisiae as a pre-screening approach for assessment of chemical-induced phototoxicity.
Photoreactive chemicals can induce dermatological reactions when present in the skin exposed to sunlight. Thus, new chemicals absorbing above 290 nm should have their potential phototoxicity tested. In order to screen a large number of molecules with various physico-chemical properties, a microbiological method is helpful. To this end, the yeast Saccharomyces cerevisiae was evaluated for its ability to detect phototoxic compounds. Twelve products known to be phototoxic in vivo and previously used as standards for validating the regulatory test 3T3 NRU were used in this work. Eleven of them could be detected in the yeast assay and, among them, 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP), angelicin and, to a lower extend, tiaprofenic acid induced genetic alterations. Interestingly, a pre-incubation with yeast cells in the dark before exposure decreased the phototoxicity of 5-MOP and 8-MOP but had no effect on this of chlorpromazine and ketoprofen. Saccharomyces cerevisiae and Salmonella typhimurium (strains TA100 and TA102) were compared for the evaluation of 5-MOP and 8-MOP photogenotoxicity; only the yeast assay allowed to perform experiments in exposure conditions close to those encountered in environmental situations. Finally, an application of this experimental approach to the detection of traces of furocoumarins in fragrance materials was developed.


Beta 1- and beta 3-subunits can associate with presynthesized alpha-subunits of Xenopus oocyte Na,K-ATPase.
Oligomerization of newly synthesized alpha- and beta-subunits is a prerequisite for the structural and functional maturation of Na,K-ATPase. In this study, we have tested the competence of presynthesized alpha- and beta-subunits to assemble into functional enzyme complexes. Antisense oligonucleotides complementary to alpha-mRNA were used to inhibit alpha-subunit synthesis in Xenopus oocytes leaving a presynthesized trypsin-sensitive alpha-subunit pool. beta-Subunits expressed in these oocytes from injected cRNA assembled with the preexisting alpha-subunits, rendered them trypsin-resistant, and permitted the expression of more ouabain binding sites at the plasma membrane. Similarly, presynthesized beta 1- or beta 3-subunits produced in Xenopus oocytes by injection of beta-cRNA and later of specific antisense oligonucleotides were stabilized and transported out of the endoplasmic reticulum when alpha-cRNA was injected into oocytes. These data indicate that alpha- and beta-subunits can insert into endoplasmic reticulum membranes independent of each other in an assembly-competent form and retain their ability for oligomerization after synthesis.


Women patients' preference for women physicians is a barrier to colon cancer screening.
The preference of women patients for women physicians has been shown in many specialties. Women patients awaiting a lower endoscopy have been shown to have a preference for women endoscopists. The reasons for this preference and the strength of this preference have not been studied in the primary care setting. A questionnaire was given to female patients who were waiting for primary care appointments at 4 offices. Patients reported sociodemographic characteristics, experiences with colorectal cancer (CRC), barriers to CRC screening, gender preference of their physician, the significance, and reasons for this preference. A total of 202 women patients aged 40 to 70 years (mean 53 years) completed the questionnaire. Of these patients, 43% preferred a woman endoscopist, and of these, 87% would be willing to wait >30 days for a woman endoscopist, and 14% would be willing to pay more for one. The most common reason (in 75%) for this gender preference was embarrassment. Univariate analysis revealed that gender of the primary care physician (PCP), younger patient age, current employment, and no previous history of colonoscopy were predictors of preference for a woman endoscopist. Of these variables, only female gender of the PCP (OR 2.84: 95% CI[1.49, 5.40]) and employment (OR 2.4: 95% CI[1.23, 4.67]) were positive predictors for a woman endoscopist preference by multivariable analysis; 5% stated that they would not undergo a colonoscopy unless guaranteed a woman endoscopist. The sole independent factor associated with adherence to screening was PCP recommendation (OR 2.93: 95% CI[1.63, 5.39]). Women patients frequently prefer a woman endoscopist, and this preference is reported as being strong enough to delay the procedure and to incur personal expense. It is an absolute barrier to endoscopy according to 5% in this subset of women surveyed. Interventions must be made in the primary care setting to address this issue and to increase the participation of women patients in CRC screening.


Narrative review of strategies by organizations for building evaluation capacity.
Program evaluation is an important source of information to assist organizations to make "evidence-informed" decisions about program planning and development. The objectives of this study were to identify evaluated strategies used by organizations and program developers to build the program evaluation capacity of their workforce, and to describe success factors and lessons learned. Common elements for successful evaluation capacity building (ECB) include: a tailored strategy based on needs assessment, an organizational commitment to evaluation and ECB, experiential learning, training with a practical element, and some form of ongoing technical support within the workplace. ECB is a relatively new field of endeavor, and, while existing studies in ECB are characterized by lower levels of evidence, they suggest the most successful approaches to ECB are likely to be multifaceted. To build the level of evidence in this field, more rigorous study designs need to be implemented in the future.


Replica images of silver-stained gels using direct duplicating film.
A procedure for preparing duplicate images of polyacrylamide gels containing silver-stained proteins using X-ray direct duplicating film is described. Resulting images are shown to be qualitatively and quantitatively faithful representations of the original gel.


Influence of veratridine on [3H]-L-quinuclidinyl benzilate ([3H]QNB) binding in mouse hindbrain.
The neurotoxin veratridine is well known for its ability to open sodium channels in neuronal and muscle tissues in micromolar concentrations. It has also been shown that veratridine is an inhibitor of the potent muscarinic receptor antagonist L-quinuclidinyl benzilate (QNB) at these concentrations. These findings prompted us to examine the relationships between action potential sodium channels and muscarinic receptors in a glass-fiber filtration assay for [3H]QNB binding to mouse hindbrain membranes using agents known to affect interconversion of the affinity states in some muscarinic receptor populations, i.e. guanosine triphosphate (GTP) and magnesium (Mg2+). The actions of the sodium channel antagonist tetrodotoxin (TTX) were also examined. Veratridine inhibited [3H]QNB binding with a Ki value of approximately 2.5 microM. This inhibition exhibited a competitive mechanism at higher concentrations (5-10 microM), while showing an apparent non-competitive action at low concentrations (1 microM). Magnesium caused a parallel shift to the right in the inhibition curve with a 32% increase in the veratridine Ki. GTP caused a non-parallel shift to the left with the greatest displacement occurring at lower veratridine concentrations (2-5 microM). The addition of magnesium to GTP did not alter the action of GTP significantly. TTX (5 microM) caused a parallel shift of the veratridine inhibition curve to the right. In addition, TTX alone inhibited the binding of [3H]QNB. Therefore, it appears that there may be more than one binding site for veratridine which may be linked to the muscarinic system and that these may be action potential sodium channels.


The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age.
Repeated cell divisions and aging impair stem cell function. However, the mechanisms by which this occurs are not fully understood. Here we show that protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, improves haematopoietic stem cell (HSC) activity during aging. Pot1a is highly expressed in young HSCs, but declines with age. In mouse HSCs, Pot1a knockdown increases DNA damage response (DDR) and inhibits self-renewal. Conversely, Pot1a overexpression or treatment with POT1a protein prevents DDR, maintained self-renewal activity and rejuvenated aged HSCs upon ex vivo culture. Moreover, treatment of HSCs with exogenous Pot1a inhibits the production of reactive oxygen species, suggesting a non-telomeric role for Pot1a in HSC maintenance. Consistent with these results, treatment with exogenous human POT1 protein maintains human HSC activity in culture. Collectively, these results show that Pot1a/POT1 sustains HSC activity and can be used to expand HSC numbers ex vivo.Repeated cell divisions induce DNA damage in haematopoietic stem cells (HSC) and telomeres are sensitive to this damage. Here, the authors show in murine HSCs that the telomere binding protein POT1a inhibited the production of reactive oxygen species, and rejuvenated aged HSCs.


Looking for an Objective Parameter to Identify Early Vocal Dysfunctions in Healthy Perceived Singers.
The finding of minimal laryngeal dysfunctions in professional voice users is essential to prevent the onset of organic vocal pathologies. The purpose of this study is to identify an objective parameter that supports the phoniatric evaluation in detecting minimal laryngeal dysfunctions in singers. 54 professional and non-professional singers have been evaluated with laryngostroboscopy, Multi-Dimensional Voice Program (MDVP), Dysphonia Severity Index (DSI), maximum phonation time (TMF), minimum intensity of sound emission (I-min), maximum frequency (F-max), voice handicap index (VHI), singing voice handicap index (SVHI), manual phonogram and audiometric examination. The SVHI of all the "healthy" singers was on average 23.7 ± 22.5, while that of the "dysfunctional" 20.9 ± 18. No statistically significant difference was found between the SVHI scores of the total of healthy singers compared to the scores of the dysfunctional ones on the VSL (p = 0.6). The between-group comparison of the means of individual parameter values of DSI, TMF, F-max, Jitter, Shimmer, NHR, and SPI was not statistically significant (respectively p = 0.315, 0.2, 0.18, 0.09, 0.2, 0.08, 0.3). The only parameter analyzed that was statistically significant was the I-min (p < 0.05). SVHI is a valid instrument for the evaluation after a therapy but in our experience, it is not useful in distinguishing healthy from dysfunctional patients. The minimum intensity of sound emission measured with the sound level meter (I-low2) resulted a reliable parameter to identify minimal laryngeal dysfunctions and a useful tool in supporting the phoniatric diagnostic-therapeutic process in singers.


A new cytogenetic subgroup in uterine leiomyoma is characterized by a deletion of the long arm of chromosome 3.
Our cytogenetic findings in 175 uterine leiomyomas revealed 52 tumors with clonal chromosome abnormalities, eight of which did not belong to any well-delineated cytogenetic abnormal subgroup. However, an interstitial deletion of the long arm of chromosome 3 was found, as the sole chromosome abnormality, in three cases. We believe that this involvement of 3q is significant enough to consider it as a new cytogenetic subgroup of uterine leiomyoma.


Circulating metabolites and depression: a bidirectional Mendelian randomization.
Studies have shown an association between depression and circulating metabolites, but the causal relationship between them has not been elucidated. The purpose of this study was to elucidate the causal relationship between circulating metabolites and depression and to explore the role of circulating metabolites in depression. In this study, the top single-nucleotide polymorphisms (SNPs) associated with circulating metabolites (n = 24,925) and depression (n = 322,580) were obtained based on the publicly available genome-wide association study using two-sample Mendelian randomization (MR). SNP estimates were summarized through inverse variance weighted, MR Egger, weighted median, MR pleiotropy residual sum and outlier, and "leave-one-out" methods. Apolipoprotein A-I (OR 0.990, 95% CI 981-0.999) and glutamine (OR 0.985, 95% CI 0.972-0.997) had protective causal effects on depression, whereas acetoacetate (OR 1.021, 95% CI 1.009-1.034), glycoproteins (OR 1.005, 95% CI 1.000-1.009), isoleucine (OR 1.013, 95% CI 1.002-1.024), and urea (OR 1.020, 95% CI 1.000-1.039) had an anti-protective effect on depression. Reversed MR showed no effect of depression on the seven circulating metabolites. In this study, MR analysis showed that apolipoprotein A-I and glutamine had a protective effect on depression, and acetoacetate, glycoprotein, isoleucine, glucose, and urea may be risk factors for depression. Therefore, further research must be conducted to translate the findings into practice.


Early clinical evaluation of total hip arthroplasty by three-dimensional gait analysis and muscle strength testing.
As improvement of gait is an important reason for patients to undergo total hip arthroplasty (THA) and they generally tend to evaluate its success based on postoperative walking ability, objective functional evaluation of postoperative gait is important. However, the patient's normal gait before osteoarthritis is unknown and the changes that will occur postoperatively are unclear. We investigated the change in gait and hip joint muscle strength after THA by using a portable gait rhythmograph (PGR) and muscle strength measuring device. The subjects were 46 women (mean age: 65.9 years) with osteoarthritis of the hip. Gait analysis and muscle strength testing were performed before THA, as well as 3 weeks and 3 months after surgery. We measured the walking speed, step length, and gait trajectory using PGR prospectively. PGR is attached to the patient's waist and records signals at a sampling rate of 100 Hz. Isometric torque of hip flexion and abduction were measured by using a hand-held dynamometer. There was no improvement at 3 weeks postoperatively, but the walking speed, stride length and muscle strength were clearly showed improvement at 3 months postoperatively. The walking trajectory was not normal preoperatively, since the trajectory was not symmetrical and did not intersect in the midline or form a butterfly pattern, and abnormality of the trajectory tended to persist postoperative 3 months despite resolution of hip joint pain after surgery. Since postoperative improvement of gait is an important consideration for patients undergoing THA, it seems relevant to evaluate changes in the gait after surgery and three-dimensional analysis with a PGR may be useful for this purpose.


Topical tranexamic acid (TXA) for the management of a bleeding arteriovenous fistula.
Tranexamic acid (TXA) is increasing in use in the Emergency Department (ED). While its topical uses have largely been observed in the management of epistaxis, other applications are utilized. We present a case of an 84 year old male with a bleeding arteriovenous fistula, responsive to topical application of tranexamic acid. This case report demonstrates another novel application of TXA in emergency care.


Can toxin warfare against fungal parasitism influence short-term Dolichospermum bloom dynamics? - A field observation.
Cyanobacterial blooms often consist of numerous co-existing cyanobacterial species, with predominant taxa dynamically varying intra-annually. Parasitism by fungi (chytrids) has come into focus as an important factor driving short-term bloom dynamics. Using microscopic analysis, Illumina sequencing and cyanobacterial toxin analyses, we monitored the seasonal succession of Dolichospermum blooms in a reservoir along with environmental parameters. We identified two consecutive Dolichospermum blooms that were characterized by a straight and a coiled morphotype, separated by a complete bloom collapse. Phylotyping provided evidence for three putative Dolichospermum amplicon sequence variants (ASVs); i.e. Dolichospermum1 & 2 in the first bloom (straight filaments) and Dolichospermum3 in the second bloom (coiled filaments). Morphotype succession as well as total filament concentration did not correlate with any of the measured environmental parameters. Fungal parasitism by the chytrid Rhizosiphon crassum occurred in straight Dolichospermum filaments only. Coiled filaments showed no infection despite ambient presence of chytrids, deduced from fungal ASVs, throughout the entire observation period. Toxin concentrations (microcystins (MCs) and anabaenopeptins) correlated significantly with the abundance of the straight Dolichospermum morphotype. Enhanced cyanotoxin biosynthesis in the straight Dolichospermum morphotype, interpreted as a defensive reaction to fungal parasitism, appeared to come at the expense of lowered competitiveness with the co-occurring coiled morphotype. Our findings support the hypothesis that selective parasitism by chytrids is an important factor driving short-term morphotype and toxin dynamics within cyanobacterial blooms.


Efficient Microwave-assisted One-pot Three-component Synthesis of 2,3-Disubstituted Benzofurans under Sonogashira Conditions.
An efficient one-pot method for the synthesis of 2,3-disubstituted benzo[b]furans from commercially available 2-iodophenols, terminal acetylenes and aryl iodides has been developed utilizing Sonogashira reaction conditions. After an initial Sonogashira coupling of the 2-iodophenol with the terminal alkyne, cyclization involving the aryl iodide provides the 2,3-disubstituted benzo[b]furan in good to excellent yields. The use of microwave irradiation shortens the reaction times and minimizes the side products. This methodology is especially useful for the construction of libraries of highly substituted benzo[b]furans and their analogues.


Structural basis of the amidase ClbL central to the biosynthesis of the genotoxin colibactin.
Colibactin is a genotoxic natural product produced by select commensal bacteria in the human gut microbiota. The compound is a bis-electrophile that is predicted to form interstrand DNA cross-links in target cells, leading to double-strand DNA breaks. The biosynthesis of colibactin is carried out by a mixed NRPS-PKS assembly line with several noncanonical features. An amidase, ClbL, plays a key role in the pathway, catalyzing the final step in the formation of the pseudodimeric scaffold. ClbL couples α-aminoketone and β-ketothioester intermediates attached to separate carrier domains on the NRPS-PKS assembly. Here, the 1.9 Å resolution structure of ClbL is reported, providing a structural basis for this key step in the colibactin biosynthetic pathway. The structure reveals an open hydrophobic active site surrounded by flexible loops, and comparison with homologous amidases supports its unusual function and predicts macromolecular interactions with pathway carrier-protein substrates. Modeling protein-protein interactions supports a predicted molecular basis for enzyme-carrier domain interactions. Overall, the work provides structural insight into this unique enzyme that is central to the biosynthesis of colibactin.


Management of dental care of patients on immunosuppressive drugs for chronic immune-related inflammatory diseases: a survey of French dentists' practices.
The aim of the study was to provide an overview of the practices of French general dentists (GDs) and specialists (SDs) concerning the management of patients with inflammatory bowel diseases (IBDs), rheumatic inflammatory diseases (IRDs), and vasculitis on biologic disease-modifying antirheumatic drugs (bDMARDs), conventional DMARDs, or immunosuppressants (ISs). An online national cross-sectional survey with 53 questions was developed by a multidisciplinary team including rheumatologists, gastroenterologists and dentists based on their clinical experience. It was refined following a test with nine dentists in private practice and in hospital before being disseminated to the members of French scientific societies and colleges of dentistry teachers over 3 months. Responses of general dentists versus specialists were compared with respect to their experience in managing patients with IRDs or IBDs, knowledge/training, type of invasive procedure performed, management of medical treatment, perioperative oral-care protocols, and frequency of postoperative complications after invasive dental care procedures. In total, 105 practitioners fully completed the survey (participation rate 11.1%). SDs more frequently performed invasive surgical procedures and were more aware of the recommendations of learned societies than GDs. They encountered more post-operative complications for patients on bDMARDs. For both SDs and GDs, most patients were managed without stopping treatment and pre- and postoperative antibiotics were prescribed to more than 75% of patients. When medical treatment was stopped, the decision was made by the prescribing physician. Complications were reported more frequently by SDs when highly invasive procedures were performed on patients under active drug therapy. Certain common procedures, such as scaling and root planing, appear to be safe, regardless of treatment management. However, adapted guidelines for the practice of dentistry are needed to standardize the management of patients on bDMARDS, conventional DMARDs, or ISs. French dentists perform a wide range of oral procedures on patients on bDMARDS, conventional DMARDs, or ISs under antibiotic coverage and antiseptic mouthwashes. SDs reported more postoperative complications after extensive invasive procedures for patients under active drug therapy, despite their greater knowledge of recommendations on how to manage such patients.


Antibacterial activities of the methanol extracts, fractions and compounds from Harungana madagascariensis Lam. ex Poir. (Hypericaceae).
Harungana madagascariensis Lam. ex Poir. (Hypericaceae) is used in folk medicine to treat a variety of human ailments, mainly antibacterial, antifungal, antiviral and viral infections. In the present study, the methanol extract from the leaves (HML) and bark (HMB) of this plant as well as fractions (HMBa-c), sub-fractions (HMBa1-5) and compounds isolated from HMBa and HMBb namely betulinic acid (1), madagascin (2), ferruginin A (3) and Kaempferol-3-O-β-d-glucopyranoside (4) were tested for their antimicrobial activities against a panel of 28 g-negative bacteria including multidrug resistant (MDR) phenotypes. The broth microdilution method was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of the above samples; column chromatography was used for the fractionation and purification of the bark extract whilst the chemical structures of compounds were determined using spectroscopic techniques. Crude extract HMB together with fraction HMBa and sub-fraction HMBa3 were active on the 28 tested bacterial strains. HML as well as fractions HMBb, HMBc and sub-fractions HMBa1, HMBa2, HMBa4 and HMBa5 were selectively active. MIC values below or equal to 1024µg/mL were recorded with these samples on 92.9% (for HML and HMBa 4), 82.1% (for HMBb), 78.6% (for HMBa2), 50.0% (for HMBa5) and 42.9% (for HMBc) tested bacteria. For crude material, the lowest MIC value below 8µg/mL was obtained with HMB against Escherichia coli ATCC10536 and W3110 strains, and with sub-fraction HMBa3 against Klebsiella pneumoniae K2 strains. MIC values below 10µg/mL were recorded with compound 3 against E. coli ATCC10536, Enterobacter aerogenes ATCC13048 and EA294, Pseudomonas aeruginosa PA01, K. pneumoniae K2 and Kp55 and Enterobacter cloacae BM67. Harungana madagascariensis is a potential source of antimicrobial drugs to fight against MDR bacteria. The anthranol 3 is the main antibacterial constituents of the bark of the plant. HMB and compound 3 deserve further investigations to develop natural drug to combat Gram-negative bacteria and otherwise MDR phenotypes.


Acute glutamate toxicity in cultured cerebellar granule cells: agonist potency, effects of pH, Zn2+ and the potentiation by serum albumin.
Cell death was due to activation of the receptor responsive to N-methyl-D-aspartate (NMDA). Even during a 30-min incubation, glutamate toxicity was unaffected by 5 microM CNQX and was greater than 90% blocked by 160 nM MK-801, a specific antagonist of the NMDA receptor. The extent of toxicity was dependent on the age of the cultured cells, the concentration of KCl, which determined membrane polarization, the duration of exposure to, and the concentration of, glutamate. Toxicity was critically pH-dependent, increasing from a minimal effect at pH 7.0 to an extremely high level at pH 8.0. Among a number of acidic amino acids tested, glutamate showed the highest potency. Aspartate, cysteine sulfinate and homocysteate reached the same maximal toxicity, but at a 25 times higher concentration. Cysteate and quinolinate were of very low potency. Zn2+, at 0.5 microM, attenuated glutamate toxicity considerably. At concentrations above 5 microM the metal ion showed strong toxicity on its own. Dialysed serum and serum albumin strongly potentiated glutamate and NMDA toxicity in presence and absence of Mg2+. A concentration of 2 mg/ml bovine serum albumin caused maximal potentiation; fatty acid-free bovine serum albumin and human serum albumin were all about equipotent. To be effective, the serum albumin had to act simultaneously with glutamate. Among a number of proteins and other polymers, only casein showed an ability to potentiate glutamate toxicity, similar to serum albumin. It is concluded that minor effects of glutamate toxicity could be considerably aggravated by the potentiating activity of serum albumin, also in pathological situations in vivo.


Taxonomy and abundance of epibenthic Prorocentrum (Dinophyceae) species from the tropical and subtropical Southwest Atlantic Ocean including a review of their global diversity and distribution.
In the tropical and subtropical South Atlantic Ocean, studies on the taxonomy and abundance of benthic harmful algae are scarce and the region has been largely under investigated. In this study, morphological descriptions, molecular (LSU rDNA and ITS region) and abundance data of benthic Prorocentrum species from the tropical and subtropical Southwest Atlantic and three oceanic islands are presented. Moreover, a review of global benthic Prorocentrum species richness and distribution is presented. Eleven benthic Prorocentrum species were found in Brazil. Morphological and molecular data on P. borbonicum, P. hoffmannianum, P. lima species complex and P. rhathymum were provided. Prorocentrum panamense, P. cf. caipirignum, P. cf. concavum, P. cf. norrisianum, P. emarginatum/fukuyoi/sculptile complex and two not identified species were observed using scanning electron and/or light microscopy, and morphological descriptions are presented. Prorocentrum lima species complex was found at all investigated sites, in abundances up to 2 × 104 cells g-1 FW at the Northeast Brazil, while maximum abundance of all the remaining species did not exceed 1 × 103 cells g-1 FW. The Fernando de Noronha archipelago can be considered a hotspot of benthic Prorocentrum species diversity, with ten species registered. Data compiled in the literature review shows a clear latitudinal gradient with higher species richness in tropical and subtropical regions relative to temperate areas. It is also evident that there is a bias caused by taxonomic impediment and an uneven sampling effort, with many regions still to be investigated using a combined morphological and molecular effort. Therefore, the current knowledge on the global distribution of benthic Prorocentrum species is likely underestimated.


The importance of surgical margins in renal cell and urothelial carcinomas.
This chapter reviews the prevalence, outcomes, and management of positive surgical margins for patients with either renal cell or urothelial carcinomas. Though renal cell carcinoma tends to be resistant to conventional radio- or chemotherapy, kidney cancer patients with positive surgical margins can often be managed with close surveillance with acceptable outcomes. On the other hand, urothelial tumors tend to be more aggressive, and positive surgical margins after radical cystectomy often requires adjuvant therapy.


Hybrid purity assessment in Eucalyptus F1 hybrids using microsatellite markers.
The worldwide expansion of hybrid breeding and clonal forestry is to meet the demands of paper pulp and bioenergy. Although India was one of the pioneers in hybrid production of eucalypts only recently the hybrid clonal forestry is gaining momentum. Inter-specific hybrids are being produced to exploit the hybrid vigor of F1 individuals. Quality control genotyping for hybrid purity and parentage confirmation at the early stage is one of the essential criteria for clonal propagation and field trails for the assessment of growth performance. Eucalyptus being a obligatory outcrossed species with potential to self pollination, possibilities of pollen contamination are high. Hence, in the present study, Eucalyptus camaldulensis × E. tereticornis inter-specific hybrids were genotyped using 25 fluorescent labeled microsatellite markers available in public domain. Multiplex loading of PCR products was performed successfully for most of the microsatellite loci. Hybrid purity index was calculated and parentage was confirmed. Hybrid purity values ranged from 85 to 100 % showed the efficiency of controlled pollination techniques. A subset of six fully informative simple sequence repeats was identified for routine quality control genotyping for these hybrids. Detection of non-essential genotypes observed among the hybrid seedlings proved the significance of hybrid purity tests and the false hybrids were removed at the seedling stage. The hybrids with proven hybridity will be used for generation of genetic linkage, discovery of quantitative trait loci and the individuals with high productivity can enter into mass clonal multiplication.


Mechanism underlying the reversal of contractility dysfunction in experimental colitis by cyclooxygenase-2 inhibition.
Inflammatory bowel diseases are associated with reduced colonic contractility and induction of cyclooxygenase-2. In this study a possible role of cyclooxygenase-2 in and the underlying mechanism of the reduced contractility were investigated in experimental colitis. The effects of meloxicam, a cyclooxygenase-2 selective inhibitor were examined on colonic contractility and MAP kinase p38 and ERK(1/2) expression. Colitis was induced in Sprague-Dawley male rats by intra-colonic instillation of trinitrobenzenesulphonic acid (TNBS; 40 mg/rat in 50 ethanol). The animals were divided into three groups. Group 1 (n=9) received meloxicam (3 mg/kg-day) gavage 1 h before and 1 day (Group 2) after induction of colitis. Group 3 (n=9) received phosphate buffered saline (PBS) in a similar manner and served as colitic control. The non colitic control animals received meloxicam in a similar manner. The animals were sacrificed after 5 days of treatment, colon was cleaned with PBS and colonic smooth muscle was obtained which was used in this study. Meloxicam treatment given 1 h before or 1 day after administration of colitis restored the reduced colonic contractility without affecting the sensitivity to carbachol. The levels of colonic smooth muscle IL-1beta mRNA, PGE(2), ERK(1/2), p38, malondialdehyde, myeloperoxidase activity and colonic mass were increased, whereas the body weight was decreased due to TNBS. The changes except colonic muscle mass and p38 expression were reversed by meloxicam treatment. These findings indicate that restoration of reduced colonic contractility by meloxicam is mediated by ERK(1/2), and that ERK(1/2) may serve as an important anti inflammatory target for treatment of colitis.


A handy and solventless direct route to primary 3-[3-aryl)-1,2,4-oxadiazol-5-yl]propionamides using microwave irradiation.
A one-step, simple and straightforward synthesis of the title amides from the corresponding carboxylic acids, urea and imidazole under microwave irradiation is described.


The role of psychological risk factors in recovery from borderline personality disorder.
This study examined the role of psychological risk factors in recovery from borderline personality disorder (BPD). A lifetime BPD group (n = 13) was composed of female subjects who had met the criteria for BPD in the past but no longer did so in the present. The comparison group was a sample with active BPD (n = 26). Psychological risk factors were measured by a developmental interview, which scored childhood sexual abuse (CSA) and its parameters, childhood physical abuse (PA), and separation or loss, as well as by the Parental Bonding Index (PBI). Subjects from the active BPD group showed a trend toward higher rates of CSA, and had a significantly higher CSA severity score. The results suggest that a history of severe CSA may adversely influence recovery from BPD.


Efficacy and safety of pentoxifylline for chronic venous leg ulcers: study protocol for a multicenter randomized controlled trial in China (ESPECT study).
Venous leg ulcers (VLUs) are the most severe manifestation of chronic venous disease, with long healing time and a high recurrence rate. It imposes a heavy burden on patients, their families, and the health care system. Chronic inflammation triggered by sustained venous hypertension is now recognized as the hallmark of chronic venous disease. The anti-inflammatory effect of pentoxifylline may offer a promising avenue to treat VLUs. However, current evidence of pentoxifylline for VLUs is relatively small and of low quality. The aim of this study is to evaluate the efficacy and safety of pentoxifylline for VLUs in the Chinese population. This is a randomized, double-blinded, double-dummy, multi-center, placebo-controlled clinical trial. A total of 240 patients will be randomized to receive pentoxifylline (400 mg, twice daily) or placebo for 24 weeks. All participants will receive diosmin treatment and standard care of VLUs and other comorbidities. The primary outcome is the difference in the wound healing rate within 12 weeks between pentoxifylline and placebo. Secondary outcomes include (1) percent wound size changes at 12 weeks, (2) the levels of TNF-α and IL-6, (3) venous clinical severity score and chronic venous insufficiency quality of life score, and (4) ulcer recurrence within 24 weeks. This study would evaluate the efficacy and safety of pentoxifylline for VLUs in the Chinese population. If confirmed, it wound offer another effective and safe therapeutic option for treatment of VLUs. The trial was registered at the Chinese Clinical Trial Registry (No. ChiCTR-2100053053). Registered on 10 November, 2021, https://www.chictr.org.cn/showproj.aspx?proj=137010.


Loss calculation and thermal analysis of ultra-high speed permanent magnet motor.
The ultra-high speed permanent magnet motor (UHSPM) for hydrogen fuel cell air compressor is characterized by high speed, high motor power density, small size, and high reliability. Compared to the conventional motor, the loss per unit volume is increased and therefore the calculation of the temperature field is more important than that of conventional motors. In this paper, a UHSPM with a rated speed of 90000 r/min is designed. Firstly, a finite element (FE) model of the UHSPM is established and the losses of each part of the high-speed motor are calculated, and the calculated losses are introduced into the fluid field in the form of a heat source for motor temperature analysis. The calculated losses were introduced into the fluid field in the form of a heat source and used in the motor temperature analysis. The temperature rise was then calculated for the unidirectional and bidirectional magneto-thermal coupling (MTC) respectively. The results show that the bidirectional magneto- thermal coupling (BMTC) simulation results are about 2-3 °C smaller than the experimental measured values, which can more accurately predict the motor temperature. The measurement results verify the accuracy of BMTC, and provide basic theoretical support for the subsequent cooling optimization scheme of high-speed motor.


Application of Artificial Intelligence and Machine Learning in Drug Discovery.
Machine Learning (ML) and Deep Learning (DL) are two subclasses of Artificial Intelligence (AI), that, in this day and age of big data provides significant opportunities to pharmaceutical discovery research and development by translating data to information and ultimately to knowledge. Machine Learning or AI is not really new but over last few years, application of better methods have emerged and they have been successfully applied for drug discovery and development. This chapter would provide an overview of these methods and how they have been applied across various work streams, e.g., generative chemistry, ADMET prediction, retrosynthetic analysis, etc. within drug discovery process. This chapter would also attempt to provide caution and pit falls in utilizing these methods blindly while summarizing challenges and limitations.


Urinary concentrations of acrylamide (AA) and N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and associations with demographic factors in the South Korean population.
Acrylamide (AA) and N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) are important urinary biomarkers of acrylamide exposure in human biomonitoring, because AA is classified as a probable carcinogen in humans. In this study, urinary AA and AAMA were assessed in the South Korean adult population aged 18-69, based on the Korean National Human Biomonitoring Survey conducted in 2009. Urinary metabolites in samples were analyzed with LC-MS/MS system. Relying on data from 1873 representative South Korean adults, the population-weighted geometric means of urinary AA and AAMA concentrations were 6.8 ng/ml (95% CI: 6.4-7.3), and 30.0 ng/ml (95% confidence interval (CI): 28.2-31.8), respectively. The creatinine-adjusted geometric means of AA and AAMA were 6.2 μg/g creatinine (95% CI: 5.8-6.7) and 26.4μg/g creatinine (95% CI: 24.9-28.0), respectively. When covariates for predictors of urinary metabolites were adjusted simultaneously in a log-linear multiple regressions, the strongest predictors of urinary AA were education (OR=1.08-1.28; 95% CI: 1.11-1.48; p=0.0024) and age (OR=0.66-0.84; 95% CI: 0.54-0.97; p=0.0003), and those of urinary AAMA were smoking status (OR=1.16-2.63; 95% CI: 0.98-3.08; p=0.001) and education (OR=1.12-1.19; 95% CI: 1.02-1.38; p=0.0425). The ratio of current/never smokers for urinary AA was 1.3, whereas the same ratio for urinary AAMA was 3.0. These findings suggested that most South Koreans had detectable levels of AA and AAMA (98.7% and 99.4%, respectively) in their urine and that the body burden of AA and AAMA varied according to demographic, geographic, and lifestyle (smoking) factors.


Liquid chromatographic resolution of vigabatrin and its analogue gamma-amino acids on chiral stationary phases based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid.
Racemic vigabatrin, an anticonvulsant drug used for the treatment of epilepsy, and its analogue gamma-amino acids were resolved without derivatization on liquid chromatographic chiral stationary phases (CSPs) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Between the two CSPs which contain 3 methylene-unit or 11 methylene-unit spacer group, the latter was found to be greater than the former in the resolution of vigabatrin and its analogue gamma-amino acids, the separation, alpha, and the resolution factor, RS, for the resolution of vigabatrin on the latter being 1.91 and 4.57, respectively. The chromatographic behaviors for the resolution of vigabatrin and its analogue gamma-amino acids on the two CSPs were found to be dependent on the type and the content of organic and acidic modifiers in aqueous mobile phase.


Postlunch smoking for pleasure seeking or arousal maintenance?
Interactions between smoking and eating might be expected, since the craving to smoke increases after a meal, since smokers tend to have a lower body weight and since they have also been suggested to differ from nonsmokers with respect to metabolism. Further, both eating and smoking have been reported to affect mental performance. In the first experiment the influences of a heavy meal, a light meal and no meal on smoking behavior and subjective ratings were compared in 15 subjects. Whereas puffing behavior was not affected by the meal conditions, craving and smoking enjoyment increased after the meals. In the second experiment the effects of smoking on postlunch performance and concomitant central and peripheral physiology were investigated. Postlunch smoking (compared to postlunch no smoking) distinctly showed the usual increases in heart rate, peripheral vasoconstriction and electrocortical arousal, but it failed to affect rapid information processing performance and its concomitant event-related EEG potentials as well as several indices of metabolic activity. It appears, thus, that under the conditions of the present experiments, pleasure seeking may be a more important factor in postmeal smoking than the effects on performance, EEG or metabolism.