[Breast cancer in Mexico. Is it a young women disease?].
Breast cancer in México has the second place in frequency in general population (10.6%) as well as in females (16.4%). There has been found an increase in mortality from 3.6, in 1985, to 6 x 100,000 inhabitants, in 1994. Breast cancer diagnosis is made in advanced stages (III, IV, N.C.) in two out of three of our patients and a great proportion of them are younger than 50 years old. In order to know if age at diagnosis of breast cancer women in Mexico is similar of that of women of other countries, and in consequence, if breast screening has to be done as they have determined, we analyzed the age at diagnosis of 29,075 mexican women with breast cancer from 1993 to 1996. We found that median age of our patients was 51 years, one decade younger than that of European or white American women (60-64 years), and 45.5% of Mexican women are less than 50 years old at diagnosis of breast cancer, therefore, breast cancer screening indications adopted in Mexico, do not cover, not even theoretically, almost 50% of our women. It is mandatory to determine indications of breast screening according to our reality.


Pediatric weight management programs in Canada: where, what and how?
Our purpose was to conduct a national environmental scan of pediatric weight management programs in Canada. Data were entered by program representatives regarding the history, structure, and function of their weight management programs using an online survey that our team developed in partnership with the Canadian Obesity Network ( www.obesitynetwork.ca ). Of the 18 programs that were identified, all included multidisciplinary teams that take a family-centred, lifestyle/behavioural therapeutic approach; health services were accessed primarily through physician referral. Most programs were launched in the past five years with public funding and enrolled ∼125 clients/year into one-on-one and/or group-based weight management care. Although many participated in research and were affiliated with academic institutions, most did not systematically evaluate their obesity-related programming. Based on these observations, recommendations related to program evaluation, health services delivery, and network collaborations are provided to inform future directions for research and clinical care that have both domestic and international relevance.


Effects of docosahexaenoic acid in an experimental rat model of nonalcoholic steatohepatitis.
Docosahexaenoic acid (DHA) regulates the lipid metabolism and inflammation that is closely associated with oxidative stress. The present study investigated the effects of DHA on the development of nonalcoholic steatohepatitis (NASH). To induce fatty liver, rats were fed choline-deficient high-fat diets (CDHF). The rats were then divided into 4 groups treated over the subsequent 6 weeks as follows: control, CDHF, CDHF+oxidative stress (NASH), and NASH+DHA (1.0 g/kg, p.o.). Rats of the control group were fed MF chow diet only. NASH rats showed severe steatohepatitis and liver fibrosis. Treatment with DHA significantly decreased the n-6/n-3 ratio in the livers and increased plasma SOD like activity compared with NASH rats. In addition, DHA attenuated the liver fibrosis during NASH development. Therefore, a higher DHA ratio in the liver of NASH rats might regulate the inflammatory response through a low n-6 ratio and diminished oxidative stress, effectively inhibiting liver fibrosis during NASH progression. These results suggested that DHA is a novel functional food for the prevention of NASH.


Kinetics of volatile impurity removal from silicon by electron beam melting for photovoltaic applications.
A full domain control model is established for impurity transportation in the liquid phase, gas-liquid interface and gas phase of silicon to analyze the dynamic mechanics of impurity removal. The results show that the overall mass transfer coefficient mainly depends on the temperature and the chamber pressure. Its value increases with the increase of temperature or the decrease of chamber pressure. Under the same melting condition, the order of the overall mass transfer coefficients for P, Al and Ca is kP > kAl > kCa, indicating that P is easier to remove by evaporation. Mass transfer in the gas phase is the rate-controlling step for volatile impurity removal at the temperature above the melting point of silicon. The rate-controlling step transits to evaporation on the gas-liquid interface then to mass transfer in the liquid boundary layer as the temperature increases. During electron beam melting, the removal of P is controlled by both evaporation on the gas-liquid interface and mass transfer in the liquid boundary layer, and the removal of Al and Ca is controlled by evaporation on the gas-liquid interface.


National Surgical Quality Improvement Program surgical risk calculator poorly predicts complications in patients undergoing radical cystectomy with urinary diversion.
To evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Programs (ACS-NSQIP) surgical risk calculator in patients undergoing radical cystectomy (RC) with urinary diversion. Preoperative characteristics of patients who underwent RC with ileal conduit or orthotropic neobladder (ONB) between 2007 and 2016 were entered into the proprietary online ACS-NSQIP calculator to generate 30-day predicted risk profiles. Predicted and observed outcomes were compared by measuring Brier score (BS) and area under the receiver operating characteristic curve (AUC). Of 954 patients undergoing RC, 609 (64%) received ileal conduit and 345 (36%) received ONB. The calculator underestimated most risks by 10%-81%. The BSs exceeded the acceptable threshold of 0.01 and AUC were less than 0.8 for all outcomes in the overall cohort. The mean (standard deviation) predicted vs. observed length of stay was 9 (1.5) vs. 10.6 (7.4) days (Pearson's r = 0.09). Among patients who received ONB, adequate BS (<0.01) was observed for pneumonia, cardiac complications, and death. The receiver operating characteristic curve analysis revealed moderate accuracy of calculator for cardiac complications (AUC = 0.69) and discharge to rehab center (AUC = 0.75) among patients who underwent RC with ONB. The universal ACS-NSQIP calculator poorly predicts most postoperative complications among patients undergoing RC with urinary diversion. A procedure-specific risk calculator is required to better counsel patients in the preoperative setting and generate realistic quality measures.


A Novel Approach for the Manufacturing of Gelatin-Methacryloyl.
Gelatin and its derivatives contain cell adhesion moieties as well as sites that enable proteolytic degradation, thus allowing cellular proliferation and migration. The processing of gelatin to its derivatives and/or gelatin-containing products is challenged by its gelation below 30 ∘C. In this study, a novel strategy was developed for the dissolution and subsequent modification of gelatin to its derivative gelatin-methacryloyl (GelMA). This approach was based on the presence of urea in the buffer media, which enabled the processing at room temperature, i.e., lower than the sol-gel transition point of the gelatin solutions. The degree of functionalization was controlled by the ratio of reactant volume to the gelatin concentration. Hydrogels with tailored mechanical properties were produced by variations of the GelMA concentration and its degree of functionalization. Moreover, the biocompatibility of hydrogels was assessed and compared to hydrogels formulated with GelMA produced by the conventional method. NIH 3T3 fibroblasts were seeded onto hydrogels and the viability showed no difference from the control after a three-day incubation period.


Optical processing of bacterial libraries for directed evolution.
Selection of phenotypically distinct bacterial colonies on a Petri dish is typically performed by one of two methods: chemical or mechanical. Chemical methods (e.g., antibiotic selection) rely on inherent growth advantages of the unique phenotypes desired and thus have limited applicability. Mechanical methods are generally slow and require relatively large colonies (typically hundreds of colonies per plate). Here the use of imaged light to select bacterial colonies is explored, employing either photodynamic therapy agents or a ferrochelatase mutation in combination with porphyrin precursors to sensitize the bacteria to light and a computer-controlled light projection system to illuminate some bacterial colonies while leaving others in the dark. A CCD camera was used to distinguish between bacteria expressing green fluorescent protein (GFP) from nonfluorescent colonies. The fluorescence image from the camera was then used to create a virtual masking image for photoselection. Using a simple commercial projector it was possible to confer a 56-fold selective advantage to colonies expressing GFP. This represents a potentially powerful tool in directed evolution experiments using large libraries.


Pilates and pregnancy.
Pregnancy is associated with a number of musculoskeletal problems. It is important to educate all mothers, as well as those involved in ante- and postnatal care with advice on bras and exercises that are safe in pregnancy (in particular pelvic floor exercises). There is not much that can be done to alter the inevitable physiological and hormonal changes of pregnancy. However, by strengthening the core stabilising muscles around the pelvis and spine, and improving the breathing pattern, it is hoped that one can optimise the body for the challenges it may face. Pilates is based on the principle that a central core is developed and then movements are introduced to challenge this core stability. This philosophy is clearly applicable in pregnancy--a significant test both mentally and physically on the mother's body. By maximising the mother's core stability before and during pregnancy, it should be possible to limit any potential harm. Returning to exercise soon after the birth is important for the mother's physical and mental wellbeing--she looks after her baby's body for nine months, who cares for hers?


Impact of heart failure on quality of sleep.
Chronic heart failure is an important health problem associated with a high mortality and morbidity. Appropriate treatment reduces mortality and leads to improved exercise tolerance but many patients report poor quality of sleep. Sleep studies of patients with heart failure suggest that sleep disordered breathing is experienced in 50% of patients and is a powerful predictor of poor prognosis. Sleep disordered breathing broadly comprises obstructive sleep apnoea, when upper airway instability causes mechanical obstruction to breathing; and central sleep apnoea, characterised by an absence of ventilatory effort. Sleep disordered breathing occurring in patients with heart failure is in most part attributable to central sleep apnoea and reflects uncompensated instability of the ventilatory feedback mechanism.


Brainbow: new resources and emerging biological applications for multicolor genetic labeling and analysis.
Brainbow is a genetic cell-labeling technique where hundreds of different hues can be generated by stochastic and combinatorial expression of a few spectrally distinct fluorescent proteins. Unique color profiles can be used as cellular identification tags for multiple applications such as tracing axons through the nervous system, following individual cells during development, or analyzing cell lineage. In recent years, Brainbow and other combinatorial expression strategies have expanded from the mouse nervous system to other model organisms and a wide variety of tissues. Particularly exciting is the application of Brainbow in lineage tracing, where this technique has been instrumental in parsing out complex cellular relationships during organogenesis. Here we review recent findings, new technical improvements, and exciting potential genetic and genomic applications for harnessing this colorful technique in anatomical, developmental, and genetic studies.


Risk and potential risk reduction in diabetes type 2 patients in Germany.
Avoiding serious complications such as stroke, myocardial infarction, and amputations in diabetes patients is the main interest of long-term treatment. Given the considerable prevalence of diabetes type 2 in industrialized countries this is a major public health concern as well as a burden to health care systems. The present study estimated the current risk of major complications occurring in the German diabetes type 2 population and explored the potential for further risk reduction. Risk reduction can be achieved when physiological and behavioral parameters (HbAlc, blood pressure, cholesterol level, body mass index, smoking) are set to target values recommended in guidelines. To estimate individual risk and potential risk reduction the multifactor disease model Mellibase was employed. Data were obtained from the German Health Survey of 1998, which includes a sample of 7,124 individuals representative of the German population. The survey shows a prevalence rate of 6.3% for diabetes type 2 in persons older than 35 years. The analyses reveal that the overall potential for risk reduction is moderate (e.g., the average reduction potential of the 10-year risk of stroke is 5.7%). A majority of parameter ranges found in the patient population are either already close to the recommended values (HbA1c), are not alarmingly higher than in the general population (blood pressure) or have little impact on risk reduction. In addition nonmodifiable risk factors such as duration of the illness and advanced age constrain possible improvements. However, there is a wide variation in the actual risk between individuals (e.g., the 10-year risk of stroke varies between 2.2% and 79.8%), and thus a wide variation in potential risk reduction (the risk reduction potential for stroke varies between 0% and 53.4%). Intensified treatment should therefore (a) focus on relevant subgroups of patients taking their risk reduction potential into account and (b) aim at improvement in the overall metabolic profile rather than concentrating on single risk factors.


A set of systematic reviews to help reduce inappropriate prescribing to older people: study protocol.
Multimorbidity and polypharmacy are common in older people. Assessment tools or lists of criteria aimed at supporting prescription decisions for older people exist, but have often been based on expert opinion with insufficient consideration of the evidence available. The present paper describes the methods we are using to systematically review the existing evidence on the efficacy and safety of the most commonly prescribed drugs for older people in the management of their chronic medical conditions and to develop recommendations to reduce inappropriate prescriptions for incorporation into the Comprehensive Medication Review (CMR) tool developed by the PRIMA-eDS European project. We selected the 20 most relevant drugs/drug classes in terms of prescription volumes and risk of hospitalisation for older people and the most relevant indications for the most common chronic conditions among older people and a total of 35 distinct drug-indication pairs were chosen. Based on clinical considerations we collapsed some indications together, reducing the 35 pairs to a final total of 22 separate systematic reviews (SR). A common methodology will be used for each individual SR, based on the methodological manuals of the Cochrane collaboration and the PRISMA statement for reporting systematic reviews. Our search strategy will have a staged approach where we initially search for systematic reviews and meta-analyses, but if relevant reviews are not found, then search for individual studies (controlled intervention and observational studies). Our pilot work and initial scoping of the literature suggested that very few, relevant individual trials or existing systematic reviews have researched or reported exclusively on older people. Therefore, sufficient data might not be available to perform meta-analysis but we will provide a narrative synthesis describing characteristics and findings of included studies. The collected evidence will be used to construct recommendations on when not to use or to discontinue a drug, or when to reduce its dose. Recommendations will be developed in team meetings using the GRADE methodology to reflect the strength of the recommendation and the quality of the evidence. Recommendations will be built into the CMR tool. This protocol has been prepared for a series of systematic reviews which will provide research-based evidence to develop recommendations to reduce inappropriate polypharmacy in older people as part of the CMR tool of the PRIMA-eDS project.


Absorption of Phenolic Acids in Rice Kernels after Boiling in Spearmint Aqueous Extracts of Different Concentrations. A Diffusion Study.
In this study, an attempt was made to fortify white milled rice grains with phenolic compounds using a hydrothermal process and spearmint aqueous extracts of different % w/v concentrations. In addition, a mathematical model was acquired in order to simulate the diffusion of specific phenolic acids in rice kernels during boiling inside the extracts. Results showed that the amount of phenolic acids in rice, the potential equilibrium concentration values, as well as the diffusivity of these compounds in rice material were positively affected by the increase in % w/v bulk concentration of the aqueous extract. It was also shown that the diffusion process could be sufficiently described by a Fickian model and the estimated diffusion coefficients ranged from 6.86 × 10-12 to 3.56 × 10-11 m2 /s, with the p-coumaric acid presenting the highest average diffusivity in boiling rice material among all examined compounds. The chemical affinity of each phenolic acid to rice macromolecules was believed to play the most important role concerning their diffusivity in rice during fortification process. PRACTICAL APPLICATION: Consumer's interest for functional food products is constantly growing during the last decades. This study may act as preliminary for the production of fortified rice products, possessing adjusted bioactive content, in industrial scale. The proposed methodology for the production of quick-cooking or ready-to-eat fortified rice may be adopted by rice industries and applied by only making slight modifications in their existing parboiling units.


Holistic Assessment Based On Hepatocyte Mitochondria: Lycopene Repairs Oxidized mtDNA to Alleviate Mitochondrial Stress Induced by Atrazine.
Atrazine (ATZ) is a highly persistent herbicide that harms organism health. Lycopene (LYC) is an antioxidant found in plants and fruits. The aim of this study is to investigate the mechanisms of atrazine-induced mitochondrial damage and lycopene antagonism in the liver. The mice were divided into seven groups by randomization: blank control (Con group), vehicle control (Vcon group), 5 mg/kg lycopene (LYC group), 50 mg/kg atrazine (ATZ1 group), ATZ1+LYC group, 200 mg/kg atrazine (ATZ2 group), and ATZ2+LYC group. The present study performed a holistic assessment based on mitochondria to show that ATZ causes the excessive fission of mitochondria and disrupts mitochondrial biogenesis. However, the LYC supplementation reverses these changes. ATZ causes increased mitophagy and exacerbates the production of oxidized mitochondrial DNA (Ox-mtDNA) and mitochondrial stress. This study reveals that LYC could act as an antioxidant to repair Ox-mtDNA and restore the disordered mitochondrial function caused by ATZ.


Rare locations of metastastatic renal cell carcinoma: a presentation of three cases.
Metastatic renal cell carcinoma (RCC) frequently spreads not only to neighboring lymph nodes, but also to distant organs, including the lungs, liver, bones and brain. We presented three cases of RCC with colon metastasis. In the first, 63-year-old patient, after left nephrectomy followed with lyphadenectomy in paraaortic lymph node, left hemicolectomy was done due to RCC metastasis in rectosigmoid colon. In the second, 35-year-old patient, left radical nephrectomy was followed two years later with partial right nephrectomy, lung metastasectomy, small bowel and coecum resection and right orchiectomy all as separate procedures in different time intervals. The patient died from brain and bone metastases two years after the first surgery. The third, 35-year-old patient, had right nephrectomy followed by repeted lymphadenectomies after 6, 12 and 24 months. Four years later RCC spreaded to coecum and right hemicolectomy was performed. RCC treated with nephrectomy should be carefully followed up with imaging methods as a proper treatment of RCC metastases to distant organs could be important for a patient survival.


Sugar substrates for L-lysine fermentation by Ustilago maydis.
The extracellular production of l-lysine in media with cane sugar, blackstrap molasses, or clarified sugar-cane juice by a previously obtained mutant of Ustilago maydis was studied. Enzymatically inverted clarified juice (medium J-3) gave 2.9 g of lysine per liter under the following conditions: inoculum, 5%; pH 5.8; temperature, 30 C; K(La) in the fermentors, 0.41 mmoles of O(2) per liter per min; fermentation time, 72 hr. The concentrate, obtained by direct evaporation and drying of the fermentation broth, could be used as a possible feed supplement because of its amino-acid and vitamin content.


GDF-8 stimulates trophoblast cell invasion by inducing ALK5-SMAD2/3-mediated MMP2 expression.
Matrix metalloproteinases (MMPs) play a pivotal role in the regulation of cell invasion. Placental trophoblast cell invasion is a precisely regulated event. Dysregulation of MMPs has been linked to various placental diseases. Growth differentiation factor-8 (GDF-8), also known as myostatin, is a member of the transforming growth factor-beta (TGF-β) superfamily. GDF-8 and its putative receptors are expressed in human extravillous cytotrophoblast cells (EVTs). Although the pro-invasive effect of GDF-8 in human EVT cells has been recently reported, the underlying molecular mechanism remains largely unknown. In this study, we investigate the effects of GDF-8 on the expression of the two most important MMPs, MMP2 and MMP9, in the HTR-8/SVneo human EVT cell line. Our results show that GDF-8 significantly upregulates the expression of MMP2. The expression of MMP9 is not affected by GDF-8. Using a siRNA-mediated knockdown approach, we reveal that the stimulatory effect of GDF-8 on MMP2 expression is mediated by the ALK5-SMAD2/3 signaling pathway. Additionally, the knockdown of MMP2 attenuates the GDF-8-induced cell invasiveness. These findings deepen our understanding of the biological roles of GDF-8 in the regulation of human trophoblast cell invasion.


[Use of graded bicycle ergometry as a method for the objective evaluation of the efficacy of reflexotherapy in the early stages of hypertension].
Graded bicycle ergometry was used to evaluate the efficacy of pathogenetic auriculo-paravertebral reflexotherapy (RT) in 24 patients with stages IB and IIA of essential hypertension (EH). After RT was completed the subjective symptomatology, central hemodynamics, and heart work improved. The increment of the minute volume of the circulation in response to graded exercise decreased, especially in patients with stage IB of EH. These patients also showed a reduction in the heart rate. The total peripheral vascular resistance dropped both at rest and after exercise. After RT the patients with stages IB and IIA of EH manifested a decrease in the loading heart index and intensity of the functioning of the structures, with that decrease being more demonstrable in patients with stage IIA EH, which attested to the lowering of heart muscle oxygen consumption. The decreased intensity of the functioning of the structures in patients with stage IB EH points to the diminution of myocardial hyperfunction marking the hyperkinetic circulatory pattern in these patients.


Transcatheter Coil Embolization of Iatrogenic Aorto-Right Atrial Fistula.
Coronary artery fistula (CAF) is a rare complication following coronary artery bypass grafting (CABG). True incidence is unknown, as at least 50% are asymptomatic. CAF can be either congenital or acquired. Congenital CAF is either an isolated finding or seen with other congenital cardiac anomalies or structural heart defects. Acquired CAF is seen in relation with trauma, infection, or iatrogenic injury. We report a rare case of a 58-year-old man with iatrogenic aorto-right atrial fistula following inadvertent saphenous vein grafting (SVG) implantation to a right coronary vein with persistent angina following CABG and resolution of symptoms following successful obliteration of large, hemodynamically significant, fistulae by coil embolization when medical management failed.


Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): a randomized study of finerenone vs. eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease.
To investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction. The MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7 days of emergency presentation to hospital for worsening chronic HF to receive finerenone (one of five doses in the range 2.5-20.0 mg once daily) or eplerenone (25 mg every second day to 50 mg once daily for 90 days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 90 ± 2) of different oral doses of finerenone compared with eplerenone. Other objectives are to assess the effects of finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline. ARTS-HF is the first phase 2b clinical trial to investigate the effects of finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.


Comparative Genome analysis of the Genus Curvibacter and the Description of Curvibacter microcysteis sp. nov. and Curvibacter cyanobacteriorum sp. nov., Isolated from Fresh Water during the Cyanobacterial Bloom Period.
The three Gram-negative, catalase- and oxidase-positive bacterial strains RS43T, HBC28, and HBC61T, were isolated from fresh water and subjected to a polyphasic study. Comparison of 16S rRNA gene sequence initially indicated that strains RS43T, HBC28, and HBC61T were closely related to species of genus Curvibacter and shared the highest sequence similarity of 98.14%, 98.21%, and 98.76%, respectively, with Curvibacter gracilis 7-1T. Phylogenetic analysis based on genome sequences placed all strains within the genus Curvibacter. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between the three strains and related type strains supported their recognition as two novel genospecies in the genus Curvibacter. Comparative genomic analysis revealed that the genus possessed an open pangenome. Based on KEGG BlastKOALA analyses, Curvibacter species have the potential to metabolize benzoate, phenylacetate, catechol, and salicylate, indicating their potential use in the elimination of these compounds from the water systems. The results of polyphasic characterization indicated that strain RS43T and HBC61T represent two novel species, for which the name Curvibacter microcysteis sp. nov. (type strain RS43T =KCTC 92793T=LMG 32714T) and Curvibacter cyanobacteriorum sp. nov. (type strain HBC61T =KCTC 92794T =LMG 32713T) are proposed.


Characterization of polymerized impurities in cefoxitin sodium for injection by two-dimensional chromatography coupled with time-of-flight mass spectrometry.
Polymerized impurities in β-lactam antibiotics can induce allergic reactions, which seriously threaten the health of patients. In order to study the polymerized impurities in cefoxitin sodium for injection, a novel approach based on the use of two-dimensional liquid chromatography coupled with time-of-flight mass spectrometry (2D-LC-TOF MS) was applied. In the 1st dimension, high performance size exclusion chromatography (HPSEC) with a TSK-G2000SWxl column was employed. Column switching was applied for the desalination of the mobile phase used to separate polymerized impurities in the 1st dimension before they were transferred to the 2nd dimension which utilized reversed phase liquid chromatography (RP-LC) and TOF MS for further structural characterization. The structures of four polymerized impurities (which were all previously unknown) in cefoxitin sodium for injection were deduced based on the MS2 data. One novel polymerized impurity (PI-I), with 2H less than the molecular weight of two molecules of cefoxitin (Mr. 852.09), was found to be the most abundant (>50 %) in almost all the samples examined and could be regarded as the marker polymer of cefoxitin sodium for injection. This work also showed the great potential of the 2D-LC-TOF MS approach in structural characterization of unknown impurities separated with a mobile phase containing non-volatile phosphate in the 1st dimension.


Age at diagnosis and age at death in familial prostate cancer.
A family history of prostate cancer is associated with a higher risk for prostate cancer to first-degree relatives. If greater surveillance of men at familial risk is considered to be useful, population-based estimates of the differences in the age at diagnosis between familial and sporadic prostate cancer cases are needed. The men in the nationwide Swedish Family-Cancer Database were classified according to the number and type of affected first-degree relatives (father or brother) and according to the relative's age at diagnosis. The cumulative incidence of prostate cancer and cumulative prostate cancer-specific mortality were estimated using a stratified Cox model. The cumulative incidence was highest for men with multiple affected first-degree relatives, and it was higher for brothers than for sons of prostate cancer patients. The age to reach the same cumulative incidence as the general population at age 55 years decreased with decreasing age at diagnosis of the relative, ranging from 48.7 years (father diagnosed before 60 years of age) to 53.7 years (father diagnosed after 82 years of age). Prostate cancer-specific mortality was also related to the number and type of affected relatives but there was no clear evidence for a dependency on the age at diagnosis of the relative. Men with a father or a brother affected by prostate cancer are diagnosed and die at earlier ages than men without a family history of prostate cancer. This study should encourage further analysis in order to assess the risks and benefits of screening for prostate cancer in men at higher risk.


Association of socioeconomic position with insulin resistance among children from Denmark, Estonia, and Portugal: cross sectional study.
To examine the association between socioeconomic position and insulin resistance in children from three countries in northern Europe (Denmark), eastern Europe (Estonia), and southern Europe (Portugal) that have different physical, economic, and cultural environments. Cross sectional study. 3189 randomly selected schoolchildren aged 9 and 15 years from Denmark (n = 933), Estonia (n = 1103), and Portugal (n = 1153). Insulin resistance (homoeostasis model assessment). Family income and parental education were inversely associated with insulin resistance in Danish children but were positively associated with insulin resistance in Estonian and Portuguese children. Among Danish children, insulin resistance was 24% lower (95% confidence interval -38% to -10%) in those whose fathers had the most education compared with those with the least education. The equivalent results were 15% (2% to 28%) higher for Estonia and 19% (2% to 36%) higher for Portugal. These associations remained after adjustment for a range of covariates: -20% (-36% to -5%) for Denmark, 10% (-4% to 24%) for Estonia, and 18% (-1% to 31%) for Portugal. Strong statistical evidence supported differences between the associations in Denmark and those in the other two countries in both unadjusted and adjusted models (all P < 0.03). Among Danish children, those with the most educated and highest earning parents had least insulin resistance, whereas the opposite was true for children from Estonia and Portugal.


[Clinical trials in Dakar: survey on knowledge, attitudes and practices of key actors on the period from 2003 to 2007].
The general objective of this study was to agree an inventory of fixtures of clinical trials done in Dakar, in order to make recommendations to improve the quality of clinical trials in Senegal. We have done a survey from mars to may 2007, with investigators of the two biggest Senegalese university teaching hospitals and to the pharmacy management and the ethical committee. Our key results showed: 1) a small participation rate of teachers to clinical trials (11 on 37 interviewed); 2) that the principal sponsor is pharmaceutical industry; 3) that most of investigators have not degree in clinical trials; 4) that most pathologies concerned were malaria and AIDS; 5) that there are regulations related to clinical trials in Senegal. This study shows the necessity to integrate, in Senegal, clinical trials in the curricula of students training.


Method for studying kinetics of light-induced transport across membranes.
A technique based on phase spectrophotometry is described for studying the rates of elementary processes associated with the light-driven transport of ions and molecules across membranes. The light-induced pumping of protons by bacteriorhodopsin reconstituted into phospholipid vesicles and by chloroplast thylakoids has been studied to illustrate the potential of this technique. The exciting light is modulated by a mechanical chopper over the frequency range 5 Hz to 2 kHz. The internal pH of the membrane vesicles is modulated at the same frequency as the exciting light but differs in phase because of the finite rate of proton pumping. Measurement of this phase difference or of the frequency dispersion of the amplitude of the internal pH modulation is accomplished by use of a lock-in amplifier. The results can be interpreted in terms of relaxation times characterizing the chemical steps in proton pumping. The shortest relaxation time that can be measured is about 50 microseconds, although the time resolution could be easily extended by use of faster light chopping techniques. At pH 8.0, two relaxation processes are associated with proton pumping by bacteriorhodopsin reconstituted into phospholipid vesicles; the relaxation times are 2 and 28 msec. Two relaxation processes also were found with chloroplast thylakoids at pH 7.8, with relaxation times of 2 and 16 msec. The former can be associated with photosystem II and the latter, with photosystem I.


Chemistry and multibeneficial bioactivities of carvacrol (4-isopropyl-2-methylphenol), a component of essential oils produced by aromatic plants and spices.
Aromatic plants produce organic compounds that may be involved in the defense of plants against phytopathogenic insects, bacteria, fungi, and viruses. One of these compounds, called carvacrol, which is found in high concentrations in essential oils such as oregano, has been reported to exhibit numerous bioactivities in cells and animals. This integrated overview surveys and interprets our present knowledge of the chemistry and analysis of carvacrol and its beneficial bioactivities. These activities include its antioxidative properties in food (e.g., lard, sunflower oil) and in vivo and the inhibition of foodborne and human antibiotic-susceptible and antibiotic-resistant pathogenic bacteria, viruses, pathogenic fungi and parasites, and insects in vitro and in human foods (e.g., apple juice, eggs, leafy greens, meat and poultry products, milk, oysters) and food animal feeds and wastes. Also covered are inhibitions of microbial and fungal toxin production and the anti-inflammatory, analgesic, antiarthritic, antiallergic, anticarcinogenic, antidiabetic, cardioprotective, gastroprotective, hepatoprotective, and neuroprotective properties of carvacrol as well as metabolic, synergistic, and mechanistic aspects. Areas for future research are also suggested. The collated information and suggested research might contribute to a better understanding of agronomical, biosynthetic, chemical, physiological, and cellular mechanisms of the described health-promoting effects of carvacrol, and facilitate and guide further studies needed to optimize the use of carvacrol as a multifunctional food in pure and encapsulated forms, in edible antimicrobial films, and in combination with plant-derived and medical antibiotics to help prevent or treat animal and human diseases.


Suppression of B16 melanoma lung colonization by syngeneic monoclonal antibodies.
Syngeneic monoclonal antibodies (MAbs) were produced to B16 melanoma by hybridization of spleen cells from B16-F1 or B16-F10 tumor-bearing C57BL/6J mice. Two antigens were identified by the immunofluorescence reactions of anti-F1 MAbs, 2G10 (IgG1) and 3C10 (IgM). Both antigens are membrane associated in 97-99% of fixed F1 and F10 cells and are cross-reactive with normal syngeneic thymocytes, and other normal and transformed cultured mouse cells. An anti-F10 Mab, 3E9 (IgG3), reacts with a membrane antigen found in about 40% of F1 and F10 cells and in all transformed mouse cells tested, but was not found in normal cells. The 3C10 and 3E9 antigens are shed into the medium of cultured cells. 125I-Labeled membrane components of Mr 48,000 and 40,000 (3C10) and 25,000 (3E9) were immunoprecipitated. Some 3C10 immunoprecipitates also contained components of Mr 25,000 and 15,000. The three MAbs were tested for suppression of lung colonization by B16-F1 and B16-F10 metastatic variants in C57BL/6J mice. MAbs were injected 1 day prior to and 1 week after injection of tumor cells. 2G10 was highly suppressive for both B16-F1 and B16-F10 cells. 3C10 and 3E9 were suppressive for B16-F10 cells but were nonsuppressive and enhancing for B16-F1 cells (P less than or equal to 0.05). A novel immunotherapy model was tested. Delayed hypersensitivity was selectively induced to the 3C10 MAb in C57BL/6J mice by sensitization with lipid-conjugated purified MAb. Sensitized mice were injected with B16 cells and MAb to determine whether a cellular reaction with cell bound MAb in vivo could be suppressive for tumor cells. The treatment was suppressive for B16-F1 lung colonies, but caused augmentation of lung colonies from B16-F10 cells (P less than or equal to 0.05).


Geographical differences in bacteria detected in endodontic infections using polymerase chain reaction.
The polymerase chain reaction (PCR) is an innovative nucleic acid-based assay that has the highest sensitivity of any microbiological technique for the detection of bacteria. The purpose of this study was to use PCR to detect the presence of specific species of bacteria in samples collected from two geographical locations. Microbial samples from abscesses of endodontic origin were collected from patients in Portland, Oregon, and Rio de Janeiro, Brazil. PCRs with species-specific oligonucleotide primers for the 16S ribosomal RNA gene were used for detection of the bacteria after DNA extraction from each clinical sample. Statistical analysis revealed that there was a significant difference in detection of the bacteria between the two geographical locations for Prevotella intermedia, Prevotella nigrescens, Prevotella tannerae, Fusobacterium nucleatum, and Porphyromonas gingivalis, but not for Porphyromonas endodontalis, Fusobacterium necrophorum, and Enterococcus faecalis. These results suggest that differences in bacteria detected or cultured in studies can be associated with geographical location.


A conserved domain of previously unknown function in Gap1 mediates protein-protein interaction and is required for biogenesis of a serine-rich streptococcal adhesin.
Fap1-like serine-rich proteins are a new family of bacterial adhesins found in a variety of streptococci and staphylococci that have been implicated in bacterial pathogenesis. A gene cluster encoding glycosyltransferases and accessory Sec components is required for Fap1 glycosylation and biogenesis in Streptococcus parasanguinis. Here we report that the glycosylation-associated protein, Gap1, contributes to glycosylation and biogenesis of Fap1 by interacting with another glycosylation-associated protein, Gap3. Gap1 shares structural homology with glycosyltransferases. The gap1 mutant, like the gap3 mutant, produced an aberrantly glycosylated Fap1 precursor and failed to produce mature Fap1, suggesting that Gap1 and Gap3 might function in concert in the Fap1 glycosylation and biogenesis. Indeed, Gap1 interacted with Gap3 in vitro and in vivo. A Gap1 N-terminal motif, within a highly conserved domain of unknown function (DUF1975) identified in many bacterial glycosyltransferases, was required for the Gap1-Gap3 interaction. Deletion of one, four and nine amino acids within the conserved motif gradually inhibited the Gap1-Gap3 interaction and diminished production of mature Fap1 and concurrently increased production of the Fap1 precursor. Consequently, bacterial adhesion to an in vitro tooth model was also reduced. These data demonstrate that the Gap1-Gap3 interaction is required for Fap1 biogenesis and Fap1-dependent bacterial adhesion.


[Intraosseous blocks in the treatment of symmetrical distal diabetic polyneuropathy].
To evaluate the efficiency of intraosseous blocks (IOB) in the combination treatment of patients with painful diabetic symmetrical distal polyneuropathy (DSDP) of the lower limbs. Seventy-eight patients with painful DSDP were examined. Its diagnosis was verified by neurological examination, assessments of the data of the neuropathic pain diagnostic (DN4) questionnaire and electroneuromyography (ENMG). The pain syndrome was evaluated with a combined visual analogue scale (VAS). The degree of DSDP was estimated using the total symptoms score (TSS) and the neuropathy impairment scale-lower limbs (NIS-LL) scale. The Spielberger questionnaire was used to evaluate reactive and trait anxiety and the Beck inventory was employed to estimate the level of depression. A study group comprised 40 patients receiving IOB as part of the standard treatment. A control group consisted of 38 patients taking oral amitriptyline as a component of the standard treatment. Therapeutic effectiveness was evaluated, by changing the neurological status, trends in VAS, TSS, and NIS-LL scores, and data of psychological questionnaires and ENMG before and after the course of therapy and 1, 3, and 6 months after treatment. IOB was found to be highly effective in pain syndrome, affective disorders, and other manifestations of DSDP; moreover, the therapeutic effect persisted within 6 months after treatment.


Genetic loci associated with an earlier age at onset in multiplex schizophrenia.
An earlier age at onset (AAO) has been associated with greater genetic loadings in schizophrenia. This study aimed to identify modifier loci associated with an earlier AAO of schizophrenia. A genome-wide association analysis (GWAS) was conducted in 94 schizophrenia probands with the earliest AAO and 91 with the latest AAO. Candidate single nucleotide polymorphisms (SNPs) were then genotyped in the co-affected siblings and unrelated probands. Multi-SNP genetic risk scores (GRS) composed of the candidate loci were used to distinguish patients with an early or late AAO. The 14-SNP GRS could distinguish the co-affected siblings (n = 90) of the earliest probands from those (n = 91) of the latest probands. When 132 patients with an earlier AAO and 158 patients with a later AAO were included, a significant trend in the 14-SNP GRS was detected among those unrelated probands from 4 family groups with the earliest, earlier, later, and latest AAO. The overall effect of the 14 SNPs on an AAO in schizophrenia was verified using co-affected siblings of the GWAS probands and trend effect across unrelated patients. Preliminary network analysis of these loci revealed the involvement of PARK2, a gene intensively reported in Parkinson's disease and schizophrenia research.


Thermal rearrangements of spiro[2.4]hepta-1,4,6-trienes.
Thermolysis of spiro[2.4]hepta-1,4,6-triene (1a) at 50 degrees C yielded bicyclo[3.2.0]hepta-1,3,6-triene (5), which dimerized in two different fashions to form cyclobutanes. The 1,2-dimethyl and 1-propyl derivatives of 1a also rearranged at 50 degrees C, but at a faster rate, each yielding a pair of cyclobutane dimers. The structures of these symmetrical dimers were investigated by 1D and 2D NMR and NOE difference spectroscopy. Ab initio calculations indicated that the two strained olefins 1a and 5 had comparable energies about 50 kcal/mol lower than norborna-1(7),2,5-triene, which was thus excluded as a reaction intermediate.


Artificial cranial deformation and fossil Australians revisited.
Based on cranial characters shared by Homo erectus in Java and Homo sapiens in Australia, Australasia is widely considered the strongest case for a regional origin of modern humans. However, artificial vault deformation has been suggested to be the cause of "archaic" characters such as frontal recession in key fossil Australian crania. We use log-log plots of cranial arc versus chord measurements and we score nonmetric traits often thought to be associated with artificial deformation to make systematic comparisons across groups and deformation types to identify universal consequences of artificial deformation. Based on our large comparative sample (n = 588) apparatus-deformed crania have flatter frontals and occipitals and usually more angulated parietals in the sagittal plane than undeformed crania, regardless of deformation type. Fossil Australian samples exhibit evidence of both undeformed and deformed individuals. The sample from Coobool Creek provides evidence that undeformed individuals had more rounded frontals than recent Australians. However, many individuals from Coobool Creek, Kow Swamp, and Nacurrie exhibit modification of one or more cranial contours. The Kow Swamp individuals in particular plot with deformed crania from all regions. In addition, the frequency of hyperostotic traits such as bregmatic eminence, metopic and sagittal keels in H. sapiens is influenced by both artificial deformation and pathological hypervascularity/hyperostosis. Thus it is unwise to use cranial contours and these nonmetric traits to infer genetic relatedness between Fossil Australians and Indonesian H. erectus.


[Biological effects of vitamin K and concentration of vitamin K in Norwegian food].
Vitamin K has several biological effects and dietary intake seems to be more important than previously believed because of low bioavailability of the vitamins from the colon. Data from the literature were identified on PubMed, and data from NORKOST II (a dietary study from 1997 based on a nation-wide sample of respondents) were used to calculate dietary intake of vitamin K. The dietary intake of vitamin K in Norway seems to be < 50% of what is recommended. The stores of vitamin K are small and T/2 in the body is approximately 1-1.5 day. Vitamin K executes its effects by carboxylation of proteins and as ligand (vitamin K2) for a nuclear transcription factor. Biological effects beyond coagulation include bone formation, neural functioning and blood vessel calcification. Anticoagulation with warfarin inhibits vitamin K-dependent reactions and may have detrimental effects on bone formation. It is possible that the high incidence of osteoporosis in Norway may be due to the low dietary intake of vitamin K, hence it is suggested that the intake of vitamin K should be increased and vitamin K antagonists be replaced with specific thrombin inhibitors. New technology allows measurements of plasma concentration of vitamin K in relation to malabsorption, insufficient diet, and osteoporosis.


MetA (Rv3341) from Mycobacterium tuberculosis H37Rv strain exhibits substrate dependent dual role of transferase and hydrolase activity.
The metA (Rv3341) gene from Mycobacterium tuberculosis H37Rv strain encodes a homoserine-acetyltransferase (HAT) enzyme, also called MetA. This enzyme plays a key role in the biosynthetic pathway of methionine and is a potential target for the development of antimicrobial drugs. Purified MetA showed 40 kDa molecular mass on SDS-PAGE. Manual docking was performed with substrates acetyl-CoA, l-homoserine, and p-nitrophenylacetate using crystal structure coordinates of MetA (PDB ID 6PUX) from M. tuberculosis. Multiple sequence alignment indicated that catalytic triad residues Ser157, Asp320, His350 were conserved across species in acetyltransferases, esterases, and hydrolases. As a conserved pentapeptide, GXSMG belongs to α/β hydrolase superfamily and it shares similarity with esterases and hydrolases from different sources. Hydrolase activity of MetA was tested using (PNPA), N-acetylglycine, N-acetylmethionine and Phe-Gly as substrate. LC-MS confirmed that MetA possessed HAT activity, but no homoserine-succinyltransferase (HST) and serine-acetyltransferase (SAT) activities. Replacing acetyl-CoA with PNPA as acetyl group donor showed a drastic reduction in transferase activity, arising due to the interaction of R227 of the enzyme with PNPA. This could prevent the binding of the second substrate in the right orientation and results in the preferential transfer of the acetyl group to water, thus exhibiting hydrolase rather than transferase activity. In this paper, we report that MetA has both transferase and hydrolase activity depending on the correct orientation of the second substrate and the availability of the amino acids involved in enzyme-substrate interaction.


Evaluation of methods for the assessment of attention while driving.
The ability to assess the current attentional state of the driver is important for many aspects of driving, not least in the field of partial automation for transfer of control between vehicle and driver. Knowledge about the driver's attentional state is also necessary for the assessment of the effects of additional tasks on attention. The objective of this paper is to evaluate different methods that can be used to assess attention, first theoretically, and then empirically in a controlled field study and in the laboratory. Six driving instructors participated in all experimental conditions of the study, delivering within-subjects data for all tested methods. Additional participants were recruited for some of the conditions. The test route consisted of 14km of motorway with low to moderate traffic, which was driven three times per participant per condition. The on-road conditions were: baseline, driving with eye tracking and self-paced visual occlusion, and driving while thinking aloud. The laboratory conditions were: Describing how attention should be distributed on a motorway, and thinking aloud while watching a video from the baseline drive. The results show that visual occlusion, especially in combination with eye tracking, was appropriate for assessing spare capacity. The think aloud protocol was appropriate to gain insight about the driver's actual mental representation of the situation at hand. Expert judgement in the laboratory was not reliable for the assessment of drivers' attentional distribution in traffic. Across all assessment techniques, it is evident that meaningful assessment of attention in a dynamic traffic situation can only be achieved when the infrastructure layout, surrounding road users, and intended manoeuvres are taken into account. This requires advanced instrumentation of the vehicle, and subsequent data reduction, analysis and interpretation are demanding. In conclusion, driver attention assessment in real traffic is a complex task, but a combination of visual occlusion, eye tracking and thinking aloud is a promising combination of methods to come further on the way.


Ankyrin and spectrin associate with voltage-dependent sodium channels in brain.
The segregation of voltage-dependent sodium channels to specialized regions of the neuron is crucial for propagation of an action potential. Studies of their lateral mobility indicate that sodium channels are freely mobile on the neuronal cell body but are immobile at the axon hillock, presynaptic terminal and at focal points along the axon. To elucidate the mechanisms that regulate sodium channel topography and mobility, we searched for specific proteins from the brain that associate with sodium channels. Here we show that sodium channels labelled with 3H-saxitoxin (STX) are precipitated in the presence of exogenous brain ankyrin by anti-ankyrin antibodies and that 125I-labelled ankyrin binds with high affinity to sodium channels reconstituted into lipid vesicles. The cytoplasmic domain of the erythrocyte anion transporter competes for the latter interaction. Neither the neuronal GABA (gamma-aminobutyric acid) receptor channel complex nor the dihydropyridine (DHP) receptor bind brain ankyrin. The results indicate that brain ankyrin links the voltage-dependent sodium channel to the underlying cytoskeleton and may help to maintain axolemmal membrane heterogeneity and control sodium channel mobility.


Nanocrystals of Novel Valerolactam-Fenbendazole Hybrid with Improved in vitro Dissolution Performance.
Valero-fenbendazole (VAL-FBZ) is a novel hybrid compound with in vitro anthelmintic activity, designed and synthesized to address the global problem of resistance to anthelmintic compounds. This new molecule derives from fenbendazole (FBZ), a well-known commercially available benzimidazole used in veterinary medicine despite its poor water solubility. In this work, we report for the first time a strategy to solve the solubility problems of FBZ and VAL-FBZ by means of self-dispersible nanocrystals (SDNC). Nanocrystals were prepared by media milling followed by a spray-drying step, and a comprehensive and exhaustive structural and physicochemical characterization was carried out, in order to understand the systems and their behavior. The formulation poloxamer 188 (P188):FBZ 1:1 turned out with the best process yield (53%) and re-dispersability properties, particle size average of 258 nm, and polydispersity index of 0.2 after redispersion in water. The dissolution profile showed a markedly increased dissolution rate compared with the simple mixture of the components (80% FBZ dissolved in 15 min from the SDNC vs 14% from the control formulation). FTIR spectroscopy, thermal analysis, and X-Ray Powder Diffraction (XRPD) studies showed no chemical interactions between components and an extensive confocal Raman microscopy analysis of the formulations showed very homogeneous spatial distribution of components in the SDNC samples. This manufacturing process was then successfully transferred for preparing and characterizing VAL-FBZ:P188 (1:1) SDNC with similar results, suggesting the promising interest of a novel anthelmintic with improved biopharmaceutical behavior. In conclusion, new FBZ and VAL-FBZ SDNC with improved dissolution rate were successfully prepared and characterized. Graphical abstract.


Three-dimensional hydrodynamic focusing in a microfluidic Coulter counter.
Electrical impedance-based particle detection or Coulter counting, offers a lab-on-chip compatible method for flow cytometry. Developments in this area will produce devices with greater portability, lower cost, and lower power requirements than fluorescence-based flow cytometry. Because conventional Coulter apertures are prone to clogging, hydrodynamic focusing improves the device by creating fluid-walled channels with variable width to increase sensitivity without the associated risk of blocking the channel. We describe a device that focuses the sample in three dimensions, creating a narrow sample stream on the floor of the channel for close interaction with sensing electrodes. The key to this design is a stepped outlet channel fabricated in a single layer with soft lithography. In contrast to previous impedance-based designs, the new design requires minimal alignment with the substrate. Three-dimensional focusing maximizes the sensitivity of the device to cell-size particles within much larger channels. Impedance-based particle sensing experiments within this device show an increase in percentage conductivity change by a factor of 2.5 over devices that only focus the sample in the horizontal direction.


Anticancer drugs induce increased mitochondrial cytochrome c expression that precedes cell death.
Recent studies have demonstrated that cytochrome c plays an important role in cell death. In the present study, we report that teniposide and various other chemotherapeutic agents induced a dose-dependent increase in the expression of the mitochondrial respiratory chain proteins cytochrome c, subunits I and IV of cytochrome c oxidase, and the free radical scavenging enzyme manganous superoxide dismutase. The teniposide-induced increase of cytochrome c was inhibited by cycloheximide, indicating new protein synthesis. Elevated cytochrome c levels were associated with enhanced cytochrome c oxidase-dependent oxygen uptake using TMPD/ascorbate as the electron donor, suggesting that the newly synthesized proteins were functional. Cytochrome c was released into the cytoplasm only after maximal levels had been reached in the mitochondria, but there was no concomitant decrease in mitochondrial membrane potential or caspase activation. Our results suggest that the increase in mitochondrial protein expression may play a role in the early cellular defense against anticancer drugs.


MICROSCALE SERUM EXTRACTION METHOD FOR THE SIMULTANEOUS ANALYSIS OF CORTICOSTERONE AND LIPIDS.
Corticosterone is an important steroid for the regulation of metabolism and stress response. Existing methods for the measurement of corticosterone include radioimmunoassay (RIA), enzyme linked immunosorbent assay (ELISA), and liquid chromatography-mass spectrometry (LC-MS). While each of these approaches have their advantages, RIAs use radioactive isotopes that necessitate specially regulated usage and disposal. Furthermore, both ELISAs and RIAs require expensive kits and can only measure a single analyte. In this study, we establish a new sample preparation technique based on a modified Folch extraction that allows for the simultaneous isolation of corticosterone and lipids from serum. The extract is then analyzed by LC-MS. Using only 5 µL of serum, quantification of corticosterone was achieved with coefficients of variation at 3% or less and a detection limit of 0.12 µM. Overall, the results of this study should be beneficial to the measurement of circulating corticosterone and lipids for a variety of studies using small volumes of samples.


levels and sociodemographic correlates of accelerometer-based physical activity in Irish children: a cross-sectional study.
The aim of this study was to explore levels and sociodemographic correlates of physical activity (PA) over 1 week using accelerometer data. Accelerometer data was collected over 1 week from 1075 8-11-year-old children in the cross-sectional Cork Children's Lifestyle Study. Threshold values were used to categorise activity intensity as sedentary, light, moderate or vigorous. Questionnaires collected data on demographic factors. Smoothed curves were used to display minute by minute variations. Binomial regression was used to identify factors correlated with the probability of meeting WHO 60 min moderate to vigorous PA guidelines. Overall, 830 children (mean (SD) age: 9.9(0.7) years, 56.3% boys) were included. From the binomial multiple regression analysis, boys were found more likely to meet guidelines (probability ratio 1.17, 95% CI 1.06 to 1.28) than girls. Older children were less likely to meet guidelines than younger children (probability ratio 0.91, CI 0.87 to 0.95). Normal weight children were more likely than overweight and obese children to meet guidelines (probability ratio 1.25, CI 1.16 to 1.34). Children in urban areas were more likely to meet guidelines than those in rural areas (probability ratio 1.19, CI 1.07 to 1.33). Longer daylight length days were associated with greater probability of meeting guidelines compared to shorter daylight length days. PA levels differed by individual factors including age, gender and weight status as well as by environmental factors including residence and daylight length. Less than one-quarter of children (26.8% boys, 16.2% girls) meet guidelines. Effective intervention policies are urgently needed to increase PA.


Inhibition of notch signaling in combination with Paclitaxel reduces platinum-resistant ovarian tumor growth.
Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a γ-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy. Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p < 0.05), as well as in one of three platinum-sensitive tumors (p = 0.04). The combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of P/C in platinum-sensitive tumors. Interestingly, although the response of each tumor to chronic GSI exposure did not correlate with its endogenous level of Notch expression, GSI did negatively affect Notch signaling in an acute setting. Inhibiting the Notch signaling cascade with a GSI reduces primary human xenograft growth in vivo. GSI synergized with conventional cytotoxic chemotherapy only in the platinum-resistant OvCa models with single agent paclitaxel. These findings suggest inhibition of the Notch pathway in concert with taxane therapy may hold promise for treatment of platinum-resistant OvCa.


Modeling the Complete Catalytic Cycle of Aspartoacylase.
The complete catalytic cycle of aspartoacylase (ASPA), a zinc-dependent enzyme responsible for cleavage of N-acetyl-l-aspartate, is characterized by the methods of molecular modeling. The reaction energy profile connecting the enzyme-substrate (ES) and the enzyme-product (EP) complexes is constructed by the quantum mechanics/molecular mechanics (QM/MM) method assisted by the molecular dynamics (MD) simulations with the QM/MM potentials. Starting from the crystal structure of ASPA complexed with the intermediate analogue, the minimum-energy geometry configurations and the corresponding transition states are located. The stages of substrate binding to the enzyme active site and release of the products are modeled by MD calculations with the replica-exchange umbrella sampling technique. It is shown that the first reaction steps, nucleophilic attack of a zinc-bound nucleophilic water molecule at the carbonyl carbon and the amide bond cleavage, are consistent with the glutamate-assisted mechanism hypothesized for the zinc-dependent hydrolases. The stages of formation of the products, acetate and l-aspartate, and regeneration of the enzyme are characterized for the first time. The constructed free energy diagram from the reactants to the products suggests that the enzyme regeneration, but not the nucleophilic attack of the catalytic water molecule, corresponds to the rate-determining stage of the full catalytic cycle of ASPA.


Myogenic responsiveness in rat hindquarter vessels during constant-flow and constant-pressure perfusion in vitro; effects of various potassium concentrations and of endothelial nitrous oxide blockade.
An in vitro constant-flow, alternatively constant-pressure, perfusion method for studying microvascular myogenic responsiveness in otherwise intact rat hindquarters was used to explore how three types of influences affect the pressure-flow induced enhancements of myogenic tone: (1) Changes of potassium concentration over the range 2-50 mmol; (2) Whether myogenic responsiveness, which is fairly weak during these conditions of high shear rates, is enhanced by blockade of endothelial prostacyclin and nitrous oxide formation; (3) Whether some of the drawbacks of the constant-flow technique, like rapid edema formation, is offset by a constant-pressure variant. The result can be summed up as follows. (1) Myogenic responsiveness is also during in vitro conditions markedly influenced by even modest potassium concentration changes around the physiological resting level, e.g. showing a fourfold difference between potassium concentrations of 2.5-4.5 mmol. It was entirely suppressed above 7-8 mmol potassium concentration but also when potassium concentration values above 20 mmol increasingly depolarize and constrict the resistance vessels. (2) While blockade of prostacyclin synthesis was without effect, suppression of endothelial nitrous oxide production could increase myogenic responsiveness up to fourfold, suggesting that shear-stress dependent release of this agent serves to suppress myogenic activity. These effects were, however, quite variable suggesting that also other endothelial inhibitory influences are involved. (3) The constant-pressure variant reduces some of the methodological drawbacks, particularly the oedema formation which can be further reduced by increasing perfusate colloid osmotic pressure. However, interferences by the mentioned, partly unknown endothelial mechanisms still tend to suppress myogenic responsiveness to a varying extent, which hampers quantitative analyses particularly of other inhibitory influences.


A Comprehensive Assessment of Informal Caregivers of Patients in a Primary Healthcare Home-Care Program.
Studies of the characteristics of informal caregivers and associated factors have focused on care-receiver disease or caregiver social and psychological traits; however, an integral description may provide better understanding of informal caregivers' problems. A multicenter cross-sectional study in primary healthcare centers was performed in Barcelona (Spain). Participants were a random sample of informal caregivers of patients in a home-care program. Primary outcomes were health-related quality of life and caregiver burden, and related factors were sociodemographic data, clinical and risk factors, social support and social characteristics, use of healthcare services, and care receivers' status. In total, 104 informal caregivers were included (mean age 68.25 years); 81.73% were female, 54.81% were retired, 58.65% had high comorbidity, and 48.08% of care receivers had severe dependence. Adjusted multivariate regression models showed health-related quality of life and the caregivers' burden were affected by comorbidity, age, time of care, and dependency of care receiver, while social support and depression also showed relative importance. Aging, chronic diseases, and comorbidity should be included when explaining informal caregivers' health status and wellbeing. The effectiveness of interventions to support informal caregivers should comprehensively evaluate caregivers when designing programs, centering interventions on informal caregivers and not care receivers' conditions.


Exposure of a Dengue Vector to Tea and Its Waste: Survival, Developmental Consequences, and Significance for Pest Management.
Dengue mosquitoes are evolving into a broader global public health menace, with relentless outbreaks and the rise in number of Zika virus disease cases as reminders of the continued hazard associated with Aedes vectors. The use of chemical insecticides-the principal strategy against mosquito vectors-has been greatly impeded due to the development of insecticide resistance and the shrinking spectrum of effective agents. Therefore, there is a pressing need for new chemistries for vector control. Tea contains hundreds of chemicals, and its waste, which has become a growing global environmental problem, is almost as rich in toxicants as green leaves. This paper presents the toxic and sublethal effects of different crude extracts of tea on Aedes albopictus. The survival rates of larvae exposed to tea extracts, especially fresh tea extract (FTE), were markedly lower than those in the control treatment group. In addition to this immediate toxicity against different developmental stages, the extracts tested caused a broad range of sublethal effects. The developmental time was clearly longer in containers with tea, especially in those with young larvae (YL) and FTE. Among the survivors, pupation success was reduced in containers with tea, which also produced low adult emergence rates with increasing tea concentration. The production of eggs tended to be reduced in females derived from the tea treatment groups. These indirect effects of tea extracts on Ae. albopictus exhibited different patterns according to the exposed larval stage. Taken together, these findings indicate that tea and its waste affect most key components of Ae. albopictus vectorial capacity and may be useful for dengue control. Reusing tea waste in vector control could also be a practical solution to the problems associated with its pollution.


Cerebrovascular, Cardiovascular, and Mortality Events in New Users of Selective Serotonin Reuptake Inhibitors and Serotonin Norepinephrine Reuptake Inhibitors: A Propensity Score-Matched Population-Based Study.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are widely prescribed for mood and anxiety disorders. However, it is not clear whether SNRIs are more strongly associated with cardiovascular and cerebrovascular events than SSRIs. This was a propensity score-matched, population-based, cohort study of Manitobans who started an SSRI or SNRI between April 1, 1998, and March 31, 2014. The primary outcome was a composite of acute myocardial infarction (AMI), stroke, or cardiovascular-related hospitalization within 1 year of drug initiation. Each component of the primary outcome and death were analyzed separately in secondary analyses. A total of 225,504 and 54,635 patients initiated treatment on an SSRI and SNRI, respectively. After propensity score matching, a higher risk was observed for the primary outcome among SNRI users (weighted hazards ratio [HR], 1.13; 95% confidence interval [CI], 1.06-1.21). Secondary analyses showed that the risk of nonfatal stroke was higher among SNRI users (weighted HR, 1.20; 95% CI, 1.08-1.33). The risk of death was higher among SNRI users without mood and/or anxiety disorders (weighted HR, 1.17; 95% CI; 1.03-1.32). No differences were observed in the risk of AMI or fatal stroke between SSRI and SNRI use. New SNRI use was associated with a higher risk of nonfatal stroke relative to SSRI use. Further investigation is warranted regarding the higher risk of death observed in our subgroup analysis among incident SNRI users without mood and/or anxiety disorders.


Relationship between perlecan and tropoelastin gene expression and cell replication in the developing rat pulmonary vasculature.
Smooth-muscle-cell (SMC) replication and extracellular matrix protein expression are two vital and interrelated processes necessary for normal development of the vasculature. To understand better the nature of this relationship in the developing rat lung, we investigated the relationship between SMC proliferation and the expression of perlecan, a basement membrane (BM) heparan sulfate proteoglycan implicated in the control of SMC growth and differentiation, and tropoelastin (TE), a structural matrix protein not known to influence directly the replicative state of SMCs. Using bromodeoxyuridine (BrdU) incorporation to assess DNA synthesis, we first established the time course of SMC proliferation in the hilar pulmonary artery (PA) from embryonic to adult life. We found a labeling index of > 80% during the embryonic period (embryonic Day 13 [e13] to fetal Day 18 [f18]), a dramatic decline to approximately 40% during the fetal period of development, and a steady decrease in proliferation rates following birth such that, by 30 d of age, a labeling index of < 2% was noted. Using in situ hybridization, we found that although peak expression of both perlecan and TE messenger RNA (mRNA) occurred in the fetal and early postnatal periods following the major decrease in cell replication, TE mRNA expression was clearly observed in the PA as early as embryonic Day 14, whereas perlecan transcripts were virtually undetectable until fetal Day 19. Therefore, to evaluate further the relationship between cell replication and perlecan and/or TE gene expression, we used a combined in situ hybridization/BrdU immunohistochemistry technique and demonstrated that, on an individual cell basis, perlecan message was predominantly expressed by nonreplicating (BrdU-negative) PA, whereas TE mRNA was equally expressed in replicating and nonreplicating PA SMCs. Interestingly, a very similar pattern of replication and relationship to perlecan and TE mRNA expression was noted in airway SMCs and epithelial cells. Thus, in the lung as a whole, maximal expression of both the BM protein perlecan and the interstitial matrix protein TE occurs coordinately and follows the period of maximal SMC proliferation. However, in individual SMCs, perlecan mRNA expression varies inversely with DNA synthesis, whereas TE mRNA expression appears independent of the proliferative state of the cell.


The effect of remifentanil on the middle latency auditory evoked response and haemodynamic measurements with and without the stimulus of orotracheal intubation.
Changes in the middle latency auditory evoked response following the administration of opioids have been shown. However, it remains unclear as to whether these changes are due to a direct depressant effect of opioids on the middle latency auditory evoked response itself, or an indirect effect on account of their action in attenuating central nervous system arousal associated with noxious stimuli. By comparing changes in the middle latency auditory evoked response in intubated and non-intubated patients, receiving saline or remifentanil in different doses, this study attempts to answer this question. Fifty-four patients were anaesthetized with isoflurane and nitrous oxide (0.9 MAC) and randomized to 1-6 groups. Groups 1-3 received a bolus injection of either saline 0.9%, low-dose remifentanil (1 microg kg(-1)) or high-dose remifentanil (3 microg kg(-1)) prior to intubation of the trachea. Groups 4-6 were not intubated following the bolus injection. Pa and Nb amplitudes of the middle latency auditory evoked response increased by 82% and 79% with intubation in the saline group (P < 0.005) and these changes were not seen in the patients given remifentanil. There was a significant linear trend for the reduction in Pa and Nb amplitude with increasing remifentanil dose (P < 0.05). In the absence of endotracheal intubation remifentanil had no effect on either the amplitudes or latencies of the waves Pa and Nb and there was no effect of dose. For the haemodynamic measurements remifentanil attenuated the pressor response to intubation (P < 0.001) and had a significant dose-related effect (P < 0.001) in the absence of intubation. We demonstrated an effect of remifentanil on both the middle latency auditory evoked response and haemodynamic changes to endotracheal intubation. For the non-intubated patients there was only an effect of remifentanil on the haemodynamic measurements. This suggests that remifentanil has an effect on the middle latency auditory evoked response in attenuating the arousal associated with intubation of the trachea but has no effect in the absence of a stimulus.


Proximity to the US-Mexico border: a key to explaining geographic variation in US methamphetamine, cocaine and heroin purity.
Although illicit drug purity is a widely discussed health risk, research explaining its geographic variation within a country is rare. This study examines whether proximity to the US-Mexico border, the United States' primary drug import portal, is associated with geographic variation in US methamphetamine, heroin and cocaine purity. Distances (proximity) between the US-Mexico border and locations of methamphetamine, cocaine and heroin seizures/acquisitions (n = 239,070) recorded in STRIDE (System to Retrieve Information from Drug Evidence) were calculated for the period of 1990-2004. The association of drug purity with these distances and other variables, including time and seizure/acquisition size, was examined using hierarchical multivariate linear modeling (HMLM). Coterminous United States. Methamphetamine, cocaine and heroin purity generally decreased with distance from the US-Mexico border. Heroin purity, however, after initially declining with distance, turned upwards-a U-shaped association. During 2000-04, methamphetamine purity also had a U-shaped association with distance. For each of the three drugs, temporal changes in the purity of small acquisitions (<10 g) were typically more dynamic in areas closer to the US-Mexico border. Geographic variance in methamphetamine, cocaine and heroin purity throughout the coterminous United States was associated with US-Mexico border proximity. The U-shaped associations between border-distance and purity for heroin and methamphetamine may be due to imports of those drugs via the eastern United States and southeast Canada, respectively. That said, areas closer to the US-Mexico border generally had relatively high illicit drug purity, as well as more dynamic change in the purity of small ('retail level') drug amounts.


Predicting Patients' Satisfaction With Mental Health Drug Treatment Using Their Reviews: Unified Interchangeable Model Fusion Approach.
After the COVID-19 pandemic, the conflict between limited mental health care resources and the rapidly growing number of patients has become more pronounced. It is necessary for psychologists to borrow artificial intelligence (AI)-based methods to analyze patients' satisfaction with drug treatment for those undergoing mental illness treatment. Our goal was to construct highly accurate and transferable models for predicting the satisfaction of patients with mental illness with medication by analyzing their own experiences and comments related to medication intake. We extracted 41,851 reviews in 20 categories of disorders related to mental illnesses from a large public data set of 161,297 reviews in 16,950 illness categories. To discover a more optimal structure of the natural language processing models, we proposed the Unified Interchangeable Model Fusion to decompose the state-of-the-art Bidirectional Encoder Representations from Transformers (BERT), support vector machine, and random forest (RF) models into 2 modules, the encoder and the classifier, and then reconstruct fused "encoder+classifer" models to accurately evaluate patients' satisfaction. The fused models were divided into 2 categories in terms of model structures, traditional machine learning-based models and neural network-based models. A new loss function was proposed for those neural network-based models to overcome overfitting and data imbalance. Finally, we fine-tuned the fused models and evaluated their performance comprehensively in terms of F1-score, accuracy, κ coefficient, and training time using 10-fold cross-validation. Through extensive experiments, the transformer bidirectional encoder+RF model outperformed the state-of-the-art BERT, MentalBERT, and other fused models. It became the optimal model for predicting the patients' satisfaction with drug treatment. It achieved an average graded F1-score of 0.872, an accuracy of 0.873, and a κ coefficient of 0.806. This model is suitable for high-standard users with sufficient computing resources. Alternatively, it turned out that the word-embedding encoder+RF model showed relatively good performance with an average graded F1-score of 0.801, an accuracy of 0.812, and a κ coefficient of 0.695 but with much less training time. It can be deployed in environments with limited computing resources. We analyzed the performance of support vector machine, RF, BERT, MentalBERT, and all fused models and identified the optimal models for different clinical scenarios. The findings can serve as evidence to support that the natural language processing methods can effectively assist psychologists in evaluating the satisfaction of patients with drug treatment programs and provide precise and standardized solutions. The Unified Interchangeable Model Fusion provides a different perspective on building AI models in mental health and has the potential to fuse the strengths of different components of the models into a single model, which may contribute to the development of AI in mental health.


Evidence for a multistep pathogenesis of a myelodysplastic syndrome.
Somatic cell genetic approaches utilizing the cellular mosaicism present in women heterozygous for glucose-6-phosphate dehydrogenase (G6PD) have provided information relevant to the pathogenesis of some neoplastic disorders. With these techniques, we studied a 61-year-old woman with a myelodysplastic syndrome. GdB/GdA heterozygosity was demonstrated in skin and cultured T lymphocytes, which exhibited both A and B type G6PD. In contrast, erythrocytes, platelets, granulocytes, and marrow nucleated cells displayed almost exclusively G6PD type B. In addition, 21 of 24 Epstein-Barr virus-transformed B lymphoblastoid lines that expressed a single immunoglobulin light chain showed only type B G6PD, suggesting that the stem cells involved by this disease were clonal and could differentiate to B lymphocytes as well as to mature granulocytes, erythrocytes , and platelets. Cultured skin fibroblasts and phytohemagglutinin-stimulated lymphocytes were karyotypically normal, but two independent abnormalities were found in marrow--47,XX, +8 and 46,XX,del(11)(q23). None of 14 type B G6PD lymphoblastoid lines analyzed in detail contained these karyotypic abnormalities, which strongly suggests that a visible chromosomal alteration is not the sole step in the development of this disease. We hypothesize that at least two events are involved in the pathogenesis of this patient's myelodysplasia: one causing proliferation of a clone of genetically unstable pluripotent stem cells and another inducing chromosomal abnormalities in its descendants.


Prevention and reversal by a retinoid of 3,4-benzpyrene- and cigarette smoke condensate-induced hyperplasia and metaplasia of rodent respiratory epithelia in organ culture.
The influence of an aromatic analog of vitamin A, etretinate, on the effects of 3,4-benzpyrene and cigarette smoke condensate has been investigated in fetal mouse lung and neonatal rat tracheas grown in organ culture. In both tissues, 3,4-benzpyrene as well as cigarette smoke condensate induces a striking increase of epithelial mitosis within 12--14 days of treatment. The increase is associated with a loss of secretory activity and of ciliary function. These changes persist in the absence of benzpyrene or smoke condensate in explants transferred to control medium. Treatment with etretinate alone does not affect the normal epithelial growth rate or normal differentiation. If combined with either benzpyrene or smoke condensate, the aromatic compound inhibits the increase in cell division and prevents the loss of secretory activity or ciliary function. In explants pretreated with 3,4-benzpyrene or cigarette smoke condensate, etretinate reduces the carcinogen- or smoke condensate-induced increase in mitotic activity to normal levels and restores secretory differentiation and ciliary function. The mechanism of action involved in the anticarcinogenic activity of the retinoid is discussed.


Aspergillus protein degradation pathways with different secreted protease sets at neutral and acidic pH.
Aspergillus fumigatus grows well at neutral and acidic pH in a medium containing protein as the sole nitrogen source by secreting two different sets of proteases. Neutral pH favors the secretion of neutral and alkaline endoproteases, leucine aminopeptidases (Laps) which are nonspecific monoaminopeptidases, and an X-prolyl dipeptidase (DppIV). Acidic pH environment promotes the secretion of an aspartic endoprotease of pepsin family (Pep1) and tripeptidyl-peptidases of the sedolisin family (SedB and SedD). A novel prolyl peptidase, AfuS28, was found to be secreted in both alkaline and acidic conditions. In previous studies, Laps were shown to degrade peptides from their N-terminus until an X-Pro sequence acts as a stop signal. X-Pro sequences can be then removed by DppIV, which allows Laps access to the following residues. We have shown that at acidic pH Seds degrade large peptides from their N-terminus into tripeptides until Pro in P1 or P'1 position acts as a stop for these exopeptidases. However, X-X-Pro and X-X-X-Pro sequences can be removed by AfuS28 thus allowing Seds further sequential proteolysis. In conclusion, both alkaline and acidic sets of proteases contain exoprotease activity capable of cleaving after proline residues that cannot be removed during sequential digestion by nonspecific exopeptidases.


Endothelin signalling mediates experience-dependent myelination in the CNS.
Experience and changes in neuronal activity can alter CNS myelination, but the signalling pathways responsible remain poorly understood. Here we define a pathway in which endothelin, signalling through the G protein-coupled receptor endothelin receptor B and PKC epsilon, regulates the number of myelin sheaths formed by individual oligodendrocytes in mouse and zebrafish. We show that this phenotype is also observed in the prefrontal cortex of mice following social isolation, and is associated with reduced expression of vascular endothelin. Additionally, we show that increasing endothelin signalling rescues this myelination defect caused by social isolation. Together, these results indicate that the vasculature responds to changes in neuronal activity associated with experience by regulating endothelin levels, which in turn affect the myelinating capacity of oligodendrocytes. This pathway may be employed to couple the metabolic support function of myelin to activity-dependent demand and also represents a novel mechanism for adaptive myelination.


Combined signature of G protein-coupled receptors and tumor microenvironment provides a prognostic and therapeutic biomarker for skin cutaneous melanoma.
G protein-coupled receptors (GPCRs) have been shown to have an important role in tumor development and metastasis, and abnormal expression of GPCRs is significantly associated with poor prognosis of tumor patients. In this study, we analyzed the GPCRs-related gene (GPRGs) and tumor microenvironment (TME) in skin cutaneous melanoma (SKCM) to construct a prognostic model to help SKCM patients obtain accurate clinical treatment strategies. SKCM expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differential expression analysis, LASSO algorithm, and univariate and multivariate cox regression analysis were used to screen prognosis-related genes (GPR19, GPR146, S1PR2, PTH1R, ADGRE5, CXCR3, GPR143, and OR2I1P) and multiple prognosis-good immune cells; the data set was analyzed according to above results and build up a GPR-TME classifier. The model was further subjected to immune infiltration, functional enrichment, tumor mutational load, immunotherapy prediction, and scRNA-seq data analysis. Finally, cellular experiments were conducted to validate the functionality of the key gene GPR19 in the model. The findings indicate that high expression of GPRGs is associated with a poor prognosis in patients with SKCM, highlighting the significant role of GPRGs and the tumor microenvironment (TME) in SKCM development. Notably, the group characterized by low GPR expression and a high TME exhibited the most favorable prognosis and immunotherapeutic efficacy. Furthermore, cellular assays demonstrated that knockdown of GPR19 significantly reduced the proliferation, migration, and invasive capabilities of melanoma cells in A375 and A2058 cell lines. This study provides novel insights for the prognosis evaluation and treatment of melanoma, along with the identification of a new biomarker, GPR19.


Power generation from water flowing through three-dimensional graphene foam.
Three-dimensional graphene foam (GF) is synthesized by CVD. When water flows through GF, electricity is induced. The direction of the induced current is dominated by the flow direction of water; the value of induced current is related to the flow velocity but has no relationship with the flow direction and external bias voltage.


Effects of different anticoagulant drugs on the prevention of complications in patients after arthroplasty: A network meta-analysis.
After arthroplasty treatment, some complications commonly occur, such as early revision, infection/dislocation, and venous thromboembolism (VTE). This study aims to use a network meta-analysis to compare effects of 9 anticoagulant drugs (edoxaban, dabigatan, apixaban, rivaroxaban, warfarin, heparin, bemiparin, ximelagatran, and enoxaparin) in preventing postoperative complications in arthroplasty patients. After retrieving PubMed, Embase, and Cochrane Library database from the inception to November 2016, randomized controlled trials were enrolled. The integration of direct and indirect evidences was performed to calculate odd ratios and the surface under the cumulative ranking curves. Nineteen eligible randomized controlled trials were included. The network meta-analysis results showed that compared with warfarin, edoxaban, apixaban, and rivaroxaban had a lower incidence rate in asymptomatic deep venous thrombosis, which indicated that edoxaban, apixaban, and rivaroxaban had better effects on prevention. Similarly, in comparison to enoxaparin, edoxaban and rivaroxaban had better effect; rivaroxaban was better than ximelagatran in preventive effects. Compared with apixaban, edoxaban, dabigatan, rivaroxaban, and enoxaparin had a higher incidence rate in clinically relevant non-major bleeding, which showed that preventive effects were relatively poor. In addition, the results of the surface under the cumulative ranking curves showed that rivaroxaban and bemiparin worked best on symptomatic deep venous thrombosis and pulmonary embolism. In terms of bleeding, apixaban and warfarin had better preventive effects. Our findings suggested that rivaroxaban may work better in terms of symptomatic deep venous thrombosis and pulmonary embolism, whereas apixaban had better preventive effects in bleeding.


A Multivariate Functional Connectivity Approach to Mapping Brain Networks and Imputing Neural Activity in Mice.
Temporal correlation analysis of spontaneous brain activity (e.g., Pearson "functional connectivity," FC) has provided insights into the functional organization of the human brain. However, bivariate analysis techniques such as this are often susceptible to confounding physiological processes (e.g., sleep, Mayer-waves, breathing, motion), which makes it difficult to accurately map connectivity in health and disease as these physiological processes affect FC. In contrast, a multivariate approach to imputing individual neural networks from spontaneous neuroimaging data could be influential to our conceptual understanding of FC and provide performance advantages. Therefore, we analyzed neural calcium imaging data from Thy1-GCaMP6f mice while either awake, asleep, anesthetized, during low and high bouts of motion, or before and after photothrombotic stroke. A linear support vector regression approach was used to determine the optimal weights for integrating the signals from the remaining pixels to accurately predict neural activity in a region of interest (ROI). The resultant weight maps for each ROI were interpreted as multivariate functional connectivity (MFC), resembled anatomical connectivity, and demonstrated a sparser set of strong focused positive connections than traditional FC. While global variations in data have large effects on standard correlation FC analysis, the MFC mapping methods were mostly impervious. Lastly, MFC analysis provided a more powerful connectivity deficit detection following stroke compared to traditional FC.


A trace display and editing program for data from fluorescence based sequencing machines.
'Ted' (Trace editor) is a graphical editor for sequence and trace data from automated fluorescence sequencing machines. It provides facilities for viewing sequence and trace data (in top or bottom strand orientation), for editing the base sequence, for automated or manual trimming of the head (vector) and tail (uncertain data) from the sequence, for vertical and horizontal trace scaling, for keeping a history of sequence editing, and for output of the edited sequence. Ted has been used extensively in the C.elegans genome sequencing project, both as a stand-alone program and integrated into the Staden sequence assembly package, and has greatly aided in the efficiency and accuracy of sequence editing. It runs in the X windows environment on Sun workstations and is available from the authors. Ted currently supports sequence and trace data from the ABI 373A and Pharmacia A.L.F. sequencers.


Effects of cholinergic and adrenergic nerve stimulations on amylase release from superfused small segment of rat parotid gland.
The effects of the cholinergic and adrenergic nerve stimulations on amylase release from the segment isolated from the rat parotid gland were investigated, employing the combined techniques of electrical field stimulation (FS) and tyramine application with automated fluorescence method for measuring amylase. The maximum amylase release in response to FS for a short period (1 min) was attained at 16 Hz frequency, 2 ms pulse width and 8 V strength stimulation in the absence of any autonomic antagonist. Periodic short-lasting FS using these parameters at intervals of about 15 min could reproduce similar sizes of amylase release for about 2 h. Continuous long-lasting FS (3 V, 2 ms, 16 Hz) caused a transient sharp increase in amylase release followed by a sustained one. The FS-evoked amylase release was completely abolished by tetrodotoxin (TTX) (10(-7) g/ml) and markedly reduced by atropine (7 X 10(-6) M) or by propranolol (10(-5) M), while it was scarcely affected by hexamethonium (3 X 10(-4) M) and phentolamine (10(-5) M). The maximum stimulus frequency of short-lasting FS for amylase release in the presence of propranolol was similar to that (16 Hz) in the control, but it was higher (32 Hz) in the presence of atropine. Reduced response in amylase release to FS by propranolol was completely restored by the superimposed addition of dibutyryl cyclic AMP (10(-4) M). Application of tyramine (5 X 10(-4) M) evoked amylase release in the presence of atropine, which was blocked mostly by propranolol and partly by phentolamine, while tyramine was ineffective in the tissue segment from rats pretreated with 6-hydroxydopamine. From these results the following were suggested; that the intrinsic cholinergic neurotransmitter activates a muscarinic receptor of the acinar cell, while the adrenergic neurotransmitter stimulates mainly a beta-adrenergic and partly an alpha-adrenergic receptor, resulting in amylase release.


A new automatic method for tracking rats in the Morris water maze.
Morris water maze (MWM) test is widely used to evaluate the learning and memory deficits in rodents. Image processing and pattern recognition can be used to analyse videos and recognize automatically the tracking in MWM. There are several commercial and free access software that allows analyzing the behavioral tasks although they also have limitations such as automation, cost, user intervention among other things. The aim of this paper was to develop a new image processing technique to automatically analyse the track of the rat in the MWM, which we called RatsTrack. The MWM test was performed with an animal model for Alzheimer, and the videos were recorded to measure the distance, time, and speed. The segmentation method based on the projection of the video frames was made for pool identification, eliminating the rat, while conserving the shape of the pool. Then, the Hough transformation was used to recognize the position and radius of the pool. Finally, the frame in which the rat is released into the pool was established automatically using mathematical morphology techniques and added as a plugin on free access ImageJ software. The new image processing technique, RatsTrack, successfully detected and located the pool and rat without user intervention, significantly decreasing operational time and providing results for distance, time, speed, and acceleration parameters of the MWM test. Alzheimer's rats compared with the control group presented significant data measured with the RatsTrack. RatsTrack is a plugin of ImageJ software and will be made freely available for public use.