Carcinoid tumor of the biliary tract: treating a rare cause of bile duct obstruction.
Biliary carcinoids are rare with fewer than 30 cases reported in the English literature. The objective of this report is to describe an additional patient found to have a biliary carcinoid and to define the presentation, diagnosis, and management of patients with this rare biliary tumor. In our case the patient initially presented with clinical jaundice and elevated transaminases. Endoscopic retrograde cholangiogram established a mass suspicious for cholangiocarcinoma (Klatskin tumor). The patient was initially managed with an endostent, which was later removed in favor of a percutaneous transhepatic cholangiogram tube. At the time of surgery successful removal of a firm nodular mass at the area of the ductal bifurcation was achieved and biliary continuity re-established with a Roux-en-Y hepaticojejunostomy. Pathology revealed carcinoid tumor of the bile duct with one lymph node positive for tumor. The patient did not receive any adjuvant radiation or chemotherapy. This case serves to highlight that extrahepatic biliary carcinoids constitute a rare but identifiable subset of bile duct tumors. Diagnostic workup should include US, CT, and cholangiography. Surgical exploration is universally indicated in physiologically fit patients with operative management to include resection and re-establishment of biliary continuity. Data on adjuvant therapy remain investigational; however, available information suggests that patients with biliary carcinoid have an overall favorable prognosis after aggressive surgical management.


Electronic field free line rotation and relaxation deconvolution in magnetic particle imaging.
It has been shown that magnetic particle imaging (MPI), an imaging method suggested in 2005, is capable of measuring the spatial distribution of magnetic nanoparticles. Since the particles can be administered as biocompatible suspensions, this method promises to perform well as a tracer-based medical imaging technique. It is capable of generating real-time images, which will be useful in interventional procedures, without utilizing any harmful radiation. To obtain a signal from the administered superparamagnetic iron oxide (SPIO) particles, a sinusoidal changing external homogeneous magnetic field is applied. To achieve spatial encoding, a gradient field is superimposed. Conventional MPI works with a spatial encoding field that features a field free point (FFP). To increase sensitivity, an improved spatial encoding field, featuring a field free line (FFL) can be used. Previous FFL scanners, featuring a 1-D excitation, could demonstrate the feasibility of the FFL-based MPI imaging process. In this work, an FFL-based MPI scanner is presented that features a 2-D excitation field and, for the first time, an electronic rotation of the spatial encoding field. Furthermore, the role of relaxation effects in MPI is starting to move to the center of interest. Nevertheless, no reconstruction schemes presented thus far include a dynamical particle model for image reconstruction. A first application of a model that accounts for relaxation effects in the reconstruction of MPI images is presented here in the form of a simplified, but well performing strategy for signal deconvolution. The results demonstrate the high impact of relaxation deconvolution on the MPI imaging process.


Cost-effectiveness of novel first-line treatment regimens for tuberculosis.
To evaluate the cost-effectiveness of novel first-line treatment regimens for tuberculosis (TB). Using decision analysis, we projected the costs and effectiveness, from the health care perspective, of treating a patient cohort in the public sector for active TB without known or suspected resistance to first-line drugs. We compared standard (6-month) treatment to hypothetical regimens of equal efficacy, higher cost and shorter duration. For every 100 TB patients treated, replacing standard treatment with shorter-course regimens would avert an estimated 2-4 failures/relapses, 0.2-0.4 deaths and 8-14 disability-adjusted life years (DALYs), or 6-11% of all DALYs suffered. We identified three primary determinants of cost-effectiveness: drug price, continuation phase treatment delivery costs and deaths averted through fewer relapses. In a high treatment cost scenario (similar to Brazil), averted delivery costs outweighed higher drug costs, making novel regimens cost-saving. In a low treatment cost scenario (similar to the Philippines), a 4-month regimen with a drug price of $1/day cost $66 per patient, or $840 per DALY averted, and became cost-saving if the drug price dropped below $0.37/day. Although they avert a small proportion of total DALYs, novel, shorter-course first-line regimens for TB are likely to be cost-effective or cost-saving in most settings.


Inhibition of egg production in zebrafish by fluoxetine and municipal effluents: a mechanistic evaluation.
This study explored the impact of nominal concentrations of ethinylestradiol (EE(2); 10ng/L), fluoxetine (FLU; 0.32, 3.2, 32microg/L), and 1-50% treated municipal effluent on reproduction and liver function in sexually mature female zebrafish over a 7-day period. Compared with the control groups, FLU (32microg/L) and 50% effluent treatment significantly reduced the average eggs spawned by approximately 4.5 and 2 fold, respectively. FLU also decreased ovarian levels of 17beta-estradiol (E(2)) without affecting the gonadosomatic indices of the fish. The expression of ovarian genes involved in the production of prostaglandins, steroid biosynthesis, and gonadotropin receptors were quantified to determine a potential mechanism underlying the reduced egg production in FLU and effluent exposed fish. Quantitative real-time PCR analysis determined that ovarian aromatase, follicle stimulating hormone receptor (FSHr), and luteinizing hormone receptor (LHr) gene expression were significantly reduced by FLU suggesting that disruptions to the synthesis of ovarian steroids and the actions of gonadotropins may underlie the negative influence of FLU on ovarian E(2) and spawning levels. Potential mechanisms involved in the modest effects of the effluent on reproduction remain unknown, but the elevated levels of total ammonia and nitrite in the 50% effluent treatment groups compared with the other treatments should not be discounted. Liver expression of CYP3A65 was significantly induced by all treatments of effluent, while EE(2) caused a reduction in the expression levels of CYP1A1, PXR, and CYP3A65. The results of the present study suggest that SSRI may disrupt reproductive functioning at concentrations greater than those found in receiving environments; yet, more research is warranted into to the possible effects of low levels of synthetic estrogens on liver function in exposed fish, particularly the PXR-CYP3A pathway.


A novel task to assess mood congruent memory bias in non-human animals.
Assessing the affective state of animals is important for a range of research areas, including neuroscience. The use of cognitive judgement and attention biases to determine affective state has been demonstrated in animals, but approaches to assess mood-congruent biases in memory have yet to become established. We describe a novel methodology to investigate memory bias in animals, presenting initial data using the influence of social status to manipulate affective state. The method required laboratory rats to achieve criterion at a working-memory task in an eight-arm radial maze before probing their memory of putative negative, positive or neutral events that occurred in specific arms of the maze. They were tested 2 h and 24 h after experiencing each event to determine how the affective valence of the event influenced task performance. Regardless of social status, rats avoided arms where they had experienced negative events and preferred arms where they had experienced positive events. However, subordinate rats made errors sooner than dominant rats in tests following exposure to the negative event. Furthermore, whilst subordinate individuals made errors earlier in tests following the negative event relative to the neutral or positive event, dominant rats made errors earlier in tests that followed the positive event. Changes in performance thus appeared to reflect social status and associated affective state, confirming a new method for assessing animal affect. This new memory bias task could potentially be used to determine affective state in a range of non-human animal species.


Event-Based Trajectory Prediction Using Spiking Neural Networks.
In recent years, event-based sensors have been combined with spiking neural networks (SNNs) to create a new generation of bio-inspired artificial vision systems. These systems can process spatio-temporal data in real time, and are highly energy efficient. In this study, we used a new hybrid event-based camera in conjunction with a multi-layer spiking neural network trained with a spike-timing-dependent plasticity learning rule. We showed that neurons learn from repeated and correlated spatio-temporal patterns in an unsupervised way and become selective to motion features, such as direction and speed. This motion selectivity can then be used to predict ball trajectory by adding a simple read-out layer composed of polynomial regressions, and trained in a supervised manner. Hence, we show that a SNN receiving inputs from an event-based sensor can extract relevant spatio-temporal patterns to process and predict ball trajectories.


Aircraft noise effects on sleep: application of the results of a large polysomnographic field study.
The Institute of Aerospace Medicine at the German Aerospace Center (DLR) investigated the influence of nocturnal aircraft noise on sleep in polysomnographic laboratory and field studies between 1999 and 2004. The results of the field studies were used by the Regional Council of Leipzig (Germany) for the establishment of a noise protection plan in the official approval process for the expansion of Leipzig/Halle airport. Methods and results of the DLR field study are described in detail. Special attention is given to the dose-response relationship between the maximum sound pressure level of an aircraft noise event and the probability to wake up, which was used to establish noise protection zones directly related to the effects of noise on sleep. These protection zones differ qualitatively and quantitatively from zones that are solely based on acoustical criteria. The noise protection plan for Leipzig/Halle airport is presented and substantiated: (1) on average, there should be less than one additional awakening induced by aircraft noise, (2) awakenings recalled in the morning should be avoided as much as possible, and (3) aircraft noise should interfere as little as possible with the process of falling asleep again. Issues concerned with the representativeness of the study sample are discussed.


Role of community pharmacies in prevention of AIDS among injecting drug misusers: findings of a survey in England and Wales.
To determine the current and potential roles of community pharmacists in the prevention of AIDS among misusers of injected drugs. Cross sectional postal survey of a one in four random sample of registered pharmacies in England and Wales. Project conducted in the addiction research unit of the Institute of Psychiatry, London. 2469 Community pharmacies in the 15 regional health authorities in England and Wales. Willingness of pharmacists to sell injecting equipment to known or suspected misusers of drugs; pharmacists' attitudes to syringe exchange schemes, keeping a "sharps" box for use by misusers of drugs, and offering face to face advice and leaflets; and opinions of community pharmacists on their role in AIDS prevention and drug misuse. 1946 Questionnaires were returned, representing a response rate of 79%. This fell short of the target of one in four pharmacies in each family practitioner committee area in England and Wales, and total numbers of respondents were therefore weighted in inverse proportion to the response rate in each area. The findings disclosed a substantial demand for injecting equipment by drug misusers. After weighting of numbers of respondents an estimated 676 of 2434 pharmacies were currently selling injecting equipment and 65 of 2415 (3%) were participating in local syringe exchange schemes; only 94 of 2410 pharmacies (4%) had a sharps box for used equipment. There was a high degree of concern among pharmacists about particular consequences of drug misusers visiting their premises, along with a widespread acceptance that the community pharmacist had an important part to play. Promoting the participation of community pharmacists in the prevention of AIDS among misusers of injected drugs is a viable policy, but several problems would need to be overcome before it was implemented.


De novo assembly of a wild pear (Pyrus betuleafolia) genome.
China is the origin and evolutionary centre of Oriental pears. Pyrus betuleafolia is a wild species native to China and distributed in the northern region, and it is widely used as rootstock. Here, we report the de novo assembly of the genome of P. betuleafolia-Shanxi Duli using an integrated strategy that combines PacBio sequencing, BioNano mapping and chromosome conformation capture (Hi-C) sequencing. The genome assembly size was 532.7 Mb, with a contig N50 of 1.57 Mb. A total of 59 552 protein-coding genes and 247.4 Mb of repetitive sequences were annotated for this genome. The expansion genes in P. betuleafolia were significantly enriched in secondary metabolism, which may account for the organism's considerable environmental adaptability. An alignment analysis of orthologous genes showed that fruit size, sugar metabolism and transport, and photosynthetic efficiency were positively selected in Oriental pear during domestication. A total of 573 nucleotide-binding site (NBS)-type resistance gene analogues (RGAs) were identified in the P. betuleafolia genome, 150 of which are TIR-NBS-LRR (TNL)-type genes, which represented the greatest number of TNL-type genes among the published Rosaceae genomes and explained the strong disease resistance of this wild species. The study of flavour metabolism-related genes showed that the anthocyanidin reductase (ANR) metabolic pathway affected the astringency of pear fruit and that sorbitol transporter (SOT) transmembrane transport may be the main factor affecting the accumulation of soluble organic matter. This high-quality P. betuleafolia genome provides a valuable resource for the utilization of wild pear in fundamental pear studies and breeding.


Recent developments in the medicinal chemistry of single boron atom-containing compounds.
Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.


Prognostic significance of p53 overexpression after hepatic resection of hepatocellular carcinoma.
p53 mutation is the most common genetic abnormality in human cancers. However, although it has been reported that p53 overexpression in hepatocellular carcinoma (HCC) is associated with the aggressive behavior of tumor, the prognostic significance of p53 overexpression in HCC remains controversial. The aims of the present study were to examine the correlations between p53 overexpression and the clinicopathologic parameters of HCCs, and to determine the prognostic significance of p53 overexpression in HCC. Immunohistochemical analysis of p53 overexpression was performed in 105 consecutive cases of HCC who underwent curative hepatic resection. Survival curves were calculated using the Kaplan-Meier method and multivariate analysis of outcome predictors for HCCs was assessed by logistic regression analysis. p53 overexpression was observed in 20 of 105 HCCs (19.0%). Multivariate analysis identified significant correlations between p53 overexpression and microvascular invasion (p=0.027), liver cirrhosis (p=0.035), 1-year survival rate (p=0.016), multiple tumors (p=0.014), and the presence of tumor capsule (p=0.010). The 2-year survival rate was poorer in patients without tumor capsule (p=0.043). Our results show a positive association between p53 overexpression and microvascular invasion in HCC, and indicate that p53 overexpression is a poor prognostic factor of survival, especially within 1 year after liver resection in HCC patients.


Is a Nomogram Able to Predict Postoperative Wound Complications in Localized Soft-tissue Sarcomas of the Extremity?
Postoperative wound complications are challenging in patients with localized extremity soft-tissue sarcomas. Various factors have been associated with wound complications, but there is no individualized predictive model to allow providers to counsel their patients and thus offer methods to mitigate the risk of complications and implement appropriate measures. We used data from multiple centers to ask: (1) What risk factors are associated with postoperative wound complications in patients with localized soft-tissue sarcomas of the extremity? (2) Can we create a predictive nomogram that will assess the risk of wound complications in individual patients after resection for soft-tissue sarcoma? From 2000 to 2016, 1669 patients undergoing limb-salvage resection for a localized primary or recurrent extremity soft-tissue sarcoma with at least 120 days of follow-up at eight participating United States Sarcoma Collaborative institutions were identified. Wound complications included superficial wounds with or without drainage, deep wounds with drainage because of dehiscence, and intentional opening of the wound within 120 days postoperatively. Sixteen variables were selected a priori by clinicians and statisticians as potential risk factors for wound complications. A univariate analysis was performed using Fisher's exact tests for categorical predictors, and Wilcoxon's rank-sum tests were used for continuous predictors. A multiple logistic regression analysis was used to train the prediction model that was used to create the nomogram. The prediction performance of the datasets was evaluated using a receiver operating curve, area under the curve, and calibration plot. After controlling for potential confounding factors such as comorbidities, functional status, albumin level, and chemotherapy use, we found that increasing age (odds ratio 1.02; 95% confidence interval, 1.00-1.03; p = 0.008), BMI (OR 1.05; 95% CI, 1.02-1.09; p = 0.004), lower-extremity location (OR 6; 95% CI, 2.87-12.69; p < 0.001), and neoadjuvant radiation (OR 2; 95% CI, 1.47-3.16; p < 0.001) were associated with postoperative wound complications (area under the curve 69.2% [range 62.8%-75.6%]). We found that age, BMI, tumor location, and timing of radiation are associated with the risk of wound complications. Based on these factors, a validated nomogram has been established that can provide an individualized prediction of wound complications in patients with a resected soft-tissue sarcoma of the extremity. This may allow for proactive management with nutrition and surgical techniques, and help determine the delivery of radiation in patients with a high risk of having these complications. Level III, therapeutic study.


Association Between Endogenous Sex Hormones and Liver Fat in a Multiethnic Study of Atherosclerosis.
Levels of circulating of sex hormones are associated with glucose metabolism and adiposity, but little is known about their association with ectopic fat. We aimed to characterize the association between circulating sex hormones and liver fat. We conducted a cross-sectional analysis by using data from the Multiethnic Study of Atherosclerosis to assess the association of the circulating levels of bioavailable testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG) with fatty liver. Fatty liver was defined as a reduction of ≤40 Hounsfield units, measured by computed tomography, in 2835 postmenopausal women and 2899 men (45-84 years old; white, black, Hispanic, or Chinese) at 6 centers in the United States. Women in the highest tertile of bioavailable testosterone were significantly more likely to have fatty liver than women in the lowest tertile (odds ratio, 1.77; 95% confidence interval, 1.07-2.92). We found an even greater difference for level of estradiol (odds ratio, 2.49; 95% confidence interval, 1.41-4.39) after adjusting for age, race/ethnicity, waist-to-hip ratio, hypertension, total and high-density lipoprotein cholesterol, smoking, insulin sensitivity, and hormone replacement therapy use. Men in the highest tertile of estradiol level were significantly more likely to have fatty liver than men in the lowest tertile (odds ratio, 2.10; 95% confidence level, 1.29-3.40). Men in the highest tertile of SHBG were less likely to have fatty liver than those in the lowest tertile (odds ratio, 0.46; 95% confidence interval, 0.27-0.77). Other associations between hormone levels and fatty liver were not statistically significant. On the basis of a cross-sectional study, postmenopausal women with high levels of bioavailable testosterone are at greater risk for fatty liver. In men, higher levels of SHBG are associated with reduced risk for fatty liver. Higher levels of estradiol are associated with fatty liver in both sexes. This pattern is consistent with the sex-specific associations of sex hormones with other cardiometabolic risk factors.


Breathing Exercises for Patients with Asthma in Specialist Care: A Multicenter Randomized Clinical Trial.
Rationale: Moderate to severe asthma is associated with impaired asthma control and quality of life (QoL) despite access to specialist care and modern pharmacotherapy. Breathing exercises (BrEX) improve QoL in incompletely controlled mild asthma, but impact in moderate to severe asthma is unknown. Objectives: To investigate the effectiveness of BrEX as adjuvant treatment on QoL in patients with uncontrolled moderate to severe asthma. Methods: Adult patients with incompletely controlled asthma attending respiratory specialist clinics were randomized to usual specialist care (UC) or UC and BrEX (UC + BrEX) with three individual physiotherapist-delivered sessions and home exercises. Primary outcome was asthma-related QoL (Mini-Asthma Quality of Life Questionnaire [Mini-AQLQ]) at 6 months on the basis of intention-to-treat analysis. Secondary outcomes: Mini-AQLQ at 12 months, lung function, 6-minute-walk test, physical activity level, Nijmegen Questionnaire, Hospital Anxiety and Depression Scale, and adverse events. Repeated-measures mixed-effects models were used to analyze data. Poisson regression models were used to analyze adverse event incidence rate ratio. Results: A total of 193 participants were allocated to UC + BrEX (n = 94) or UC (n = 99). UC + BrEX was superior in the primary outcome (adjusted mean change difference, 0.35; 95% confidence interval [CI], 0.07 to 0.62). Superiority in Mini-AQLQ was sustained at 12 months (0.38; 95% CI, 0.12 to 0.65). A minor improvement in Hospital Anxiety and Depression Scale depression score at 6 months favoring UC + BrEX (-0.90; 95% CI, -1.67 to -0.14) was observed. Asthma-related adverse events occurred similarly in UC + BrEX and UC participants: 14.9% versus 18.1% (P = 0.38). Conclusions: BrEX as add-on to usual care improve asthma-related QoL in incompletely controlled asthma regardless of severity and with no evidence of harm. Clinical trial registered with www.clinicaltrials.gov (NCT03127059).


[Priority of selenium incorporation into selenoproteins during selenium depletion in rats].
Male weanling Wistar rats were fed with either a basal selenium deficient diet (a Torula yeast based semisynthetic diet, containing Se 0.01 mg/kg) or a selenium sufficient diet supplemented with Se as Na2SeO3 (containing Se 0.5 mg/kg). Rats were killed after different weeks(0,1,2,4,8,12,15,17,19,20 and 24 respectively). Their organs were taken to observe the kinetic change of selenium concentration, the activities of intracellular glutathione peroxidase (cGPX), extracellular glutathione peroxidase (eGPX), and phospholipid hydroperoxide glutathione peroxidase (PHGPX) in different organs. The results showed that selenium levels and the activities of selenoenzyme in testis and pituitary were more resistant to selenium deficiency than other organs. During selenium deficiency, the utilization of selenium by PHGPX and deiodinase was prior to eGPX and cGPX, which suggested that the function of PHGPX and deiodinase were more important than that of eGPX and cGPX.


Secondary free-tissue reconstruction for metachronous tumors of the head and neck: techniques, results, and outcomes.
Malignancies of the head and neck are not uncommon in the Far East due to the habit of betel-nut chewing. The development of a second primary neoplasm is a constant fear for those who have had successful treatment of a primary cancer. A total of 82 patients, treated with microvascular reconstruction after surgical resection of head and neck cancer, were studied retrospectively. Twenty-one patients who had repeated reconstructive microsurgery for a second primary head and neck malignancy were enrolled as the study group. Sixty-one patients treated for the first-diagnosed malignancy were considered as the control group. There were no statistical differences between the two groups, either in terms of operation time, hospital stay, successful rate, or complication rate. The results show that, if required, one should not hesitate to repeat the free-tissue transfer after ablating a second primary neoplasm.


NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation.
BACKGROUND- Reactive oxygen species serve signaling functions in the vasculature, and hypoxia has been associated with increased reactive oxygen species production. NADPH oxidase 4 (Nox4) is a reactive oxygen species-producing enzyme that is highly expressed in the endothelium, yet its specific role is unknown. We sought to determine the role of Nox4 in the endothelial response to hypoxia. Hypoxia induced Nox4 expression both in vitro and in vivo and overexpression of Nox4 was sufficient to promote endothelial proliferation, migration, and tube formation. To determine the in vivo relevance of our observations, we generated transgenic mice with endothelial-specific Nox4 overexpression using the vascular endothelial cadherin promoter (VECad-Nox4 mice). In vivo, the VECad-Nox4 mice had accelerated recovery from hindlimb ischemia and enhanced aortic capillary sprouting. Because endothelial nitric oxide synthase (eNOS) is involved in endothelial angiogenic responses and eNOS is activated by reactive oxygen species, we probed the effect of Nox4 on eNOS. In cultured endothelial cells overexpressing Nox4, we observed a significant increase in eNOS protein expression and activity. To causally address the link between eNOS and Nox4, we crossed our transgenic Nox4 mice with eNOS(-/-) mice. Aortas from these mice did not demonstrate enhanced aortic sprouting, and VECad-Nox4 mice on the eNOS(-/-) background did not demonstrate enhanced recovery from hindlimb ischemia. Collectively, we demonstrate that augmented endothelial Nox4 expression promotes angiogenesis and recovery from hypoxia in an eNOS-dependent manner.


Prognostic variables of papillary and follicular thyroid carcinoma patients with lymph node metastases and without distant metastases.
From 1977 through 1995, 1,013 thyroid carcinoma patients received treatment and were followed up at Chang Gung Medical Center in Taiwan. To evaluate the prognostic variables of papillary and follicular thyroid carcinomas with limited lymph node metastases, a retrospective review of these patients was performed. Of these patients, 910 had papillary or follicular thyroid carcinoma, and 119 patients were categorized as clinical stage 2 with limited neck lymph node metastases only at the time of diagnosis. The patients were categorized into two groups as no recurrence and local recurrence or distant metastasis at the end of 1997. After the operations, radioactive iodide (131I) treatments were performed in 114 patients and external radiotherapy for neck region or distant metastases in 18 patients. The median follow-up period of these patients was 5.4 years. Clinical variables were coded in our computer for statistical analysis. After the treatments, 93 patients remained disease-free; 10 were in stage 2; 5 in stage 3; and 11 aggravated to stage 4. Of the clinical variables, age, post-operative first 1311 uptake scans, and 1-month post-operative thyroglobulin levels revealed statistically significant differences between the group which improved and the group which did not. During the follow-up period, five patients died; three patients died of thyroid cancer and two died of intercurrent diseases. Patients with papillary thyroid carcinoma revealed a higher percentage of lymph node metastases. Although limited lymph node metastases did not influence survival rate, patients with poor prognostic factors need more aggressive treatment to avoid progression of the cancer.


Effects of pharmacological reversal of hyperuricemia on features of the metabolic syndrome in patients with gouty arthritis.
Hyperuricemia has been associated in epidemiological studies with the development of obesity, hypertension, insulin resistance and type 2 diabetes. Nevertheless, it remains unclear whether lowering of serum uric acid (UA) alters any of the features of the metabolic syndrome. In this prospective study (ClinicalTrials.gov identifier: NCT01654276), 24 patients with gouty arthritis and hyperuricemia were treated for 6 months with the xanthine oxidase inhibitor febuxostat to lower serum UA to <6 mg/dL. Measurements of 24 hours ambulatory blood pressure (ABP) and serum and urine markers of the metabolic syndrome were measured at baseline and at the end of 6 months of febuxostat. The study population consisted of 18 men and 6 women, 18 of which completed the baseline and 6 months visits. Serum UA decreased significantly from 8.7±1.5 mg/dL at baseline to 4.4±1.1 mg/dL at 6 months (P<0.0001). During that time frame, there was no significant change in body mass index, systolic or diastolic blood pressure measured by 24 hours ABP monitor, serum glucose, insulin or homeostatic model assessment for insulin resistance, serum total and high-density lipoprotein-cholesterol, serum triglycerides or urine pH (P>0.05 for all). There was no correlation between parameters of the metabolic syndrome and the decline in serum UA or serum UA achieved at study end. In conclusion, in patients with gouty arthritis, UA lowering with febuxostat below 6 mg/dL had no significant impact on features of the metabolic syndrome.


Capillary and venule proliferation in the healing process of Dacron venous grafts in rats.
A woven, noncrimped graft (made of Dacron and coated with an elastomer) that was 1.5 mm in diameter and 15 mm long was capable of replacing the vena cava in rats. The elastomer mixture consisting mainly of silicone rubber was necessary to bond the woven Dacron fibrils of the woven graft to prevent fraying at the anastomoses and bleeding through the interstices of the lightly woven, fairly high porosity (500) conduit. Sequential histologic studies showed that patency was associated with the ingrowth of small venules and the spreading of endothelial cells from each anastomosis toward the center. Small venules appeared in loose connective tissue, forming a pseudointima 12 days after grafting. This process occurred in the midportion of the graft before pannus endothelial growth covered the endothelial surface. Various thicknesses of the external polymer coat were studied for their influence on healing. None of the grafts developed a thrombus in these latter studies, and regardless of the thickness of the external elastomer, endothelial resurfacing was complete at 30 days. However, the graft with the thinnest external elastomer coating had the best-formed vasa vasorum, and the intima at both the anastomoses and midportions of the graft was significantly thinner than intima found in grafts of other composition. We conclude that this woven Dacron polygraft provides a surface resistant to early thrombosis; that healing occurs mainly by pannus ingrowth, but external and interstitial factors are also important; and that properties inherent in the polygraft wall determine the size of the residual lumen.


Foot and ankle injuries related to rock climbing. The role of footwear.
Interest in rock climbing has grown dramatically over the past decade. Although considerable research has been conducted on upper-extremity injuries sustained during rock climbing, there has been no comprehensive evaluation of lower-extremity injuries and related biomechanics. The authors performed a retrospective investigation of rock-climbing injuries using a survey of 104 active rock climbers of varying levels of expertise. The results show that 81% of the respondents have suffered acute or chronic pain or associated pathology in the foot or ankle during or after climbing. The authors propose that this morbidity has biomechanical etiologies related to the common practice among rock climbers of wearing climbing shoes that are smaller than their street shoes.


Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction.
Nimodipine is a 1,4-dihydropyridine derivative that shows a preferential cerebrovascular activity in experimental animals. Clinical data suggest that nimodipine has a beneficial effect on the neurologic outcome of patients suffering an acute ischemic stroke. Our double-blind placebo-controlled multicenter trial was designed to assess the effects of oral nimodipine on the mortality rate and neurologic outcome of patients with an acute ischemic stroke. One hundred sixty-four patients were randomly allocated to receive either nimodipine tablets (30 mg q.i.d.) or identical placebo tablets for 28 days. Treatment was always started less than or equal to 48 hours after the acute event. The Mathew Scale, slightly modified by Gelmers et al, was used for neurologic assessment. Mortality rate and neurologic outcome after 28 days were used as evaluation criteria. We considered 123 patients to be valid for the analysis of efficacy. Mortality rates did not differ significantly between groups. Neurologic outcome after 28 days of therapy did not differ between groups. However, when only those patients most likely to benefit from any intervention (Mathew Scale sum score of less than or equal to 65 at baseline) were analyzed separately in post hoc-defined subgroups, the nimodipine-treated subgroups showed a significantly better neurologic outcome. This result suggests that some patients with acute ischemic stroke will benefit from treatment with nimodipine tablets.


Adrenocortical carcinoma: Single center experience.
Adrenocortical carcinoma is an aggressive endocrine malignancy with an annual incidence of 0.5-2 cases per million. The most important factors that determine prognosis are tumor stage at the time of diagnosis and the success of surgery. However, advanced age, large tumor size, hormone secretion, high Ki-67 index (>10%), tumor necrosis and high mitotic activity are other factors associated with poor prognosis. In the present study, we aimed to evaluate the contribution of the patient and treatment- related factors to the prognosis in adrenocortical carcinoma. We included 15 adrenocortical carcinoma patients who were followed in our center between 2005 and 2015. The effects of age, gender, tumor size, type of operation, postoperative resection status and adjuvant treatment on disease-free survival and overall survival were analyzed. Disease-free survival was 23.32±3.69 months and overall survival was 36.60±10.78 months. Gender, tumor size, tumor stage, type of operation, hormonal activity, presence of necrosis, recurrence and development of metastasis were not found to be associated with disease-free survival and overall survival (p>0.05). Postoperatively applied adjuvant treatments including mitotane, chemotherapy and radiotherapy did not significantly affect disease-free survival in our study, but statistically significant increase in overall survival was observed in patients getting adjuvant treatments (p=0.006). Adrenocortical carcinoma has poor prognosis and short overall survival, and in its clinical course, recurrence and development of metastasis can be commonly observed even after complete resection of the tumor. Therefore, the patients should be evaluated carefully while determining the surgical procedure during the preoperative period, and the operation and post-operative follow-up should be performed in experienced centers. However, due to the positive effects of adjuvant treatments on survival, all patients should be evaluated postoperatively for the necessity of adjuvant treatments, especially mitotane.


Chondrons from articular cartilage. V. Immunohistochemical evaluation of type VI collagen organisation in isolated chondrons by light, confocal and electron microscopy.
The pericellular microenvironment around articular cartilage chondrocytes must play a key role in regulating the interaction between the cell and its extracellular matrix. The potential contribution of type VI collagen to this interaction was investigated in this study using isolated canine tibial chondrons embedded in agarose monolayers. The immunohistochemical distribution of an anti-type VI collagen antibody was assessed in these preparations using fluorescence, peroxidase and gold particle probes in combination with light, confocal and transmission electron microscopy. Light and confocal microscopy both showed type VI collagen concentrated in the pericellular capsule and matrix around the chondrocyte with reduced staining in the tail region and the interconnecting segments between adjacent chondrons. Minimal staining was recorded in the territorial and interterritorial matrices. At higher resolution, type VI collagen appeared both as microfibrils and as amorphous deposits that accumulated at the junction of intersecting capsular fibres and microfibrils. Electron microscopy also showed type VI collagen anchored to the chondrocyte membrane at the articular pole of the pericellular capsule and tethered to the radial collagen network through the tail at the basal pole of the capsule. We suggest that type VI collagen plays a dual role in the maintenance of chondron integrity. First, it could bind to the radial collagen network and stabilise the collagens, proteoglycans and glycoproteins of the pericellular microenvironment. Secondly, specific cell surface receptors exist, which could mediate the interaction between the chondrocyte and type VI collagen, providing firm anchorage and signalling potentials between the pericellular matrix and the cell nucleus. In this way type VI collagen could provide a close functional interrelationship between the chondrocyte, its pericellular microenvironment and the load bearing extracellular matrix of adult articular cartilage.


Carcinogenic effects of circadian disruption: an epigenetic viewpoint.
Circadian rhythms refer to the endogenous rhythms that are generated to synchronize physiology and behavior with 24-h environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all cells. Disruption of circadian rhythms, which is called circadian disruption, affects many biological processes within the body and results in different long-term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modifications and the formation of circadian epigenomes. Aberrant epigenetic modifications, such as hypermethylation, due to circadian disruption may be involved in the transformation of normal cells into cancer cells. Several studies have indicated an epigenetic basis for the carcinogenic effects of circadian disruption. In this review, I first discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modifications that result in circadian disruption. In addition, I explain the carcinogenic effects of circadian disruption and highlight its potential role in different human cancers using an epigenetic viewpoint. Finally, the importance of chronotherapy in cancer treatment is highlighted.


Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer.
Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.


Prostaglandin E2 Antagonizes TGF-β Actions During the Differentiation of Monocytes Into Dendritic Cells.
Inflammatory dendritic cells (DCs) are a distinct subset of DCs that derive from circulating monocytes infiltrating injured tissues. Monocytes can differentiate into DCs with different functional signatures, depending on the presence of environment stimuli. Among these stimuli, transforming growth factor-beta (TGF-β) and prostaglandin E2 (PGE2) have been shown to modulate the differentiation of monocytes into DCs with different phenotypes and functional profiles. In fact, both mediators lead to contrasting outcomes regarding the production of inflammatory and anti-inflammatory cytokines. Previously, we have shown that human semen, which contains high concentrations of PGE2, promoted the differentiation of DCs into a tolerogenic profile through a mechanism dependent on signaling by E-prostanoid receptors 2 and 4. Notably, this effect was induced despite the huge concentration of TGF-β present in semen, suggesting that PGE2 overrides the influence exerted by TGF-β. No previous studies have analyzed the joint actions induced by PGE2 and TGF-β on the function of monocytes or DCs. Here, we analyzed the phenotype and functional profile of monocyte-derived DCs differentiated in the presence of TGF-β and PGE2. DC differentiation guided by TGF-β alone enhanced the expression of CD1a and abrogated LPS-induced expression of IL-10, while differentiation in the presence of PGE2 impaired CD1a expression, preserved CD14 expression, abrogated IL-12 and IL-23 production, stimulated IL-10 production, and promoted the expansion of FoxP3+ regulatory T cells in a mixed lymphocyte reaction. Interestingly, DCs differentiated in the presence of TGF-β and PGE2 showed a phenotype and functional profile closely resembling those induced by PGE2 alone. Finally, we found that PGE2 inhibited TGF-β signaling through an action exerted by EP2 and EP4 receptors coupled to cyclic AMP increase and protein kinase A activity. These results indicate that PGE2 suppresses the influence exerted by TGF-β during DC differentiation, imprinting a tolerogenic signature. High concentrations of TGF-β and PGE2 are usually found in infectious, autoimmune, and neoplastic diseases. Our observations suggest that in these scenarios PGE2 might play a mandatory role in the acquisition of a regulatory profile by DCs.


Unusual presentation of renal vein thrombosis with pulmonary artery embolism.
A young 23-year-old male patient presented with a two-day history of right flank pain. He had no history of any significant illnesses in the past. His investigations showed nephrotic range proteinuria with hypoalbuminemia. The patient developed cough and shortness of breath after having a left kidney biopsy. He did not respond to regular respiratory tract infection treatment. The kidney biopsy revealed membranoproliferative glomerulonephritis. Further investigations for the cough showed thromboembolism of the posterior and lateral basal segments of the right lower lobe. Moreover he was found to have thrombosis of the right upper pole renal vein. The patient was started on full anticoagulation along with three days pulse steroid, followed by 1 mg/kg oral steroid. Clinical improvement was noticed within 48 h. After eight weeks the proteinuria decreased from 8.5 gm/day to 1.1 gm/day. The kidney function was normal with eGFR 145 mL/min through the course of the disease. This case represent one of the unusual presentation of nephrotic syndrome with pulmonary and renal vascular thromboembolic events. The response to the combination of anticoagulation and steroid was remarkable.


Dual-recognition-based determination of ctDNA via the clamping function of peptide nucleic acid and terminal protection of small-molecule-linked DNA.
A new dual-recognition fluorescent biosensor for circulating tumor DNA (ctDNA) detection has been developed, which combines the clamping function of peptide nucleic acid (PNA) and terminal protection of small-molecule-linked DNA (TPSMLD). Taking the tumor-specific E542K mutation and methylation of the PIK3CA gene as the target ctDNA, a low detection limit of 0.3161 pM ctDNA is achieved with good selectivity. This study not only offers a sensitive, selective and accurate ctDNA detection method, but can also be used to detect the target in complex biological samples.


Nonlinear current-voltage characteristics and enhanced negative differential conductance in graphene field effect transistors.
Recent observations of the negative differential conductance (NDC) phenomenon in graphene field-effect transistors (FET) open up new opportunities for their application in graphene-based fast switches, frequency multipliers and, most importantly, in high frequency oscillators up to the terahertz regime. Unlike conventional two-terminal NDC devices that rely on resonant tunneling and inter-valley transferring, in the present work, it has been shown that the universal NDC phenomenon of graphene-based FETs originates from their intrinsic nonlinear carrier transport under a strong electric field. The operation of graphene-NDC devices depends strongly on the interface between graphene and dielectric materials, the scattering-limited carrier mobility, and on the saturation velocity. To reveal such NDC behavior, the output characteristics of GFET are investigated rigorously, with both an analytical model and self-consistent transport equation, and with a multi-electrical parameter simulation. It is demonstrated that the contact-induced doping effect plays an important role in the operational efficiency of graphene-based NDC devices, rather than the ambipolar behavior associated with the competition between electron and hole conductances. In the absence of a NDC regime or beyond one, ambipolar transport starts at Vds > 2Vgs at the drain end, and as the dielectric layer begins to thin down, the kink-like saturation output characteristic is enhanced by the quantum capacitance contribution. These observations reveal the intrinsic mechanism of the NDC effect and open up new opportunities for the performance improvement of GFETs in future high-frequency applications, beyond the current paradigm based on two-terminal diodes.


Cutaneous microcirculation in patients with peripheral arterial occlusive disease: Comparison of capillary blood circulation in the nail fold of finger and toe.
In patients with peripheral arterial occlusive disease (PAOD) a restricted circulation in cutaneous microvessels has been reported. In this study the velocity of erythrocytes (very) in finger nailfold capillaries - a vascular area without upstream macroangiopathy - and also in toe nailfold capillaries - a post-stenotic area -was investigated using capillary microscopy in apparently healthy subjects and patients with PAOD. Already in finger nailfold capillaries very of patients with PAOD under resting conditions was significantly lower than in capillaries of healthy subjects. This was also true for the circulation in toe capillaries. In addition, the erythrocyte velocities under resting conditions in the toe capillaries were significantly lower than in the finger capillaries. Similar results were found for the duration and the maximum velocity of postocclusive hyperemia. It is concluded that the resting blood flow in the skin microcirculation is impaired in PAOD patients, both under resting conditions and during postocclusive hyperemia in finger as well in toe nailfold capillaries.


How to analyze continuous and discrete repeated measures in small-sample cross-over trials?
To optimize the use of data from a small number of subjects in rare disease trials, an at first sight advantageous design is the repeated measures cross-over design. However, it is unclear how these within-treatment period and within-subject clustered data are best analyzed in small-sample trials. In a real-data simulation study based upon a recent epidermolysis bullosa simplex trial using this design, we compare non-parametric marginal models, generalized pairwise comparison models, GEE-type models and parametric model averaging for both repeated binary and count data. The recommendation of which methodology to use in rare disease trials with a repeated measures cross-over design depends on the type of outcome and the number of time points the treatment has an effect on. The non-parametric marginal model testing the treatment-time-interaction effect is suitable for detecting between group differences in the shapes of the longitudinal profiles. For binary outcomes with the treatment effect on a single time point, the parametric model averaging method is recommended, while in the other cases the unmatched generalized pairwise comparison methodology is recommended. Both provide an easily interpretable effect size measure, and do not require exclusion of periods or subjects due to incompleteness.


Cancer translocations in human cells induced by zinc finger and TALE nucleases.
Chromosomal translocations are signatures of numerous cancers and lead to expression of fusion genes that act as oncogenes. The wealth of genomic aberrations found in cancer, however, makes it challenging to assign a specific phenotypic change to a specific aberration. In this study, we set out to use genome editing with zinc finger (ZFN) and transcription activator-like effector (TALEN) nucleases to engineer, de novo, translocation-associated oncogenes at cognate endogenous loci in human cells. Using ZFNs and TALENs designed to cut precisely at relevant translocation breakpoints, we induced cancer-relevant t(11;22)(q24;q12) and t(2;5)(p23;q35) translocations found in Ewing sarcoma and anaplastic large cell lymphoma (ALCL), respectively. We recovered both translocations with high efficiency, resulting in the expression of the EWSR1-FLI1 and NPM1-ALK fusions. Breakpoint junctions recovered after ZFN cleavage in human embryonic stem (ES) cell-derived mesenchymal precursor cells fully recapitulated the genomic characteristics found in tumor cells from Ewing sarcoma patients. This approach with tailored nucleases demonstrates that expression of fusion genes found in cancer cells can be induced from the native promoter, allowing interrogation of both the underlying mechanisms and oncogenic consequences of tumor-related translocations in human cells. With an analogous strategy, the ALCL translocation was reverted in a patient cell line to restore the integrity of the two participating chromosomes, further expanding the repertoire of genomic rearrangements that can be engineered by tailored nucleases.


An open-label study of the effects of a 24-day regimen of gestodene 60 microg/ethinylestradiol 15 microg on endometrial histological findings in healthy women.
This open-label, non-comparative study was conducted at a single center to evaluate the effects on the endometrium of a 24-day regimen of a combined oral contraceptive containing gestodene (GTD) 60 microg and ethinylestradiol (EE) 15 microg. Healthy parous women who were > or = 18 years old and had had regular menstrual cycles for the prior 3 months were randomly assigned to one of two groups. Subjects in group A underwent endometrial biopsies during the late luteal phase of the pretreatment cycle and between days 15 and 24 of cycle 6. Subjects in group B had biopsies between days 15 and 24 of cycle 3 and during the late luteal phase of the post-treatment cycle. GTD 60 microg/EE 15 microg was taken for the first 24 days of a 28-day cycle, followed by placebo pills for 4 days, for a total of six cycles. Data from 27 women were included in the analyses. Eleven of the 13 evaluable baseline biopsies were classified as secretory. Three of nine subjects with evaluable biopsies at cycle 3 and four of nine subjects with evaluable biopsies at cycle 6 had an atrophic endometrium. Post-treatment biopsies showed a typical secretory endometrium in seven of 11 subjects with evaluable biopsies. The results of this study show that the 24-day regimen of GTD 60 microg/EE 15 microg produced effective endometrial suppression.


Coexisting chronic conditions associated with mortality and morbidity in adult patients with asthma.
Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma. In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n = 25 975, follow-up 3.0 ± 1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV and heart failure) and four conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates. HIV followed by alcoholism and mental disorders among 18-45-years old, and heart failure, diabetes, IHD and cancer among those ≥ 65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18-45 years old, and chronic sinusitis, mental disorder and IHD among those ≥ 65-years old. GERD was associated with decreased risk for asthma exacerbation in all ages. Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.


Unusual case of cholecystocolonic fistula secondary to megabowel.
Cholecystocolonic fistula with associated idiopathic megabowel (megacolon and megarectum) is a rare presentation as acute large bowel obstruction. Frequently presenting with chronic constipation, acute bowel obstruction is rarely encountered in the presence of concomitant cholecystocolonic fistula. This presents diagnostic and management difficulties with no consensus on appropriate surgical approach. This case highlights the outcomes following emergency total colectomy and subtotal cholecystectomy as a single-stage procedure for a 68-year-old man presenting with cholecystocolonic fistula secondary to idiopathic megabowel as acute large bowel obstruction.


Singing for Lung Health-a systematic review of the literature and consensus statement.
There is growing interest in Singing for Lung Health (SLH), an approach where patients with respiratory disease take part in singing groups, intended to improve their condition. A consensus group was convened in early 2016 to address issues including: the specific features that make SLH distinct from other forms of participation in singing; the existing evidence base via a systematic review; gaps in the evidence base including the need to define value-based outcome measures for sustainable commissioning of SLH; defining the measures needed to evaluate both individuals' responses to SLH and the quality of singing programmes. and core training, expertise and competencies required by singing group leaders to deliver high-quality programmes. A systematic review to establish the extent of the evidence base for SLH was undertaken. Electronic databases, including Pubmed, OVID Medline and Embase, Web of Science, Cochrane central register of controlled trials and PEDro, were used. Six studies were included in the final review. Quantitative data suggest that singing has the potential to improve health-related quality of life, particularly related to physical health, and levels of anxiety without causing significant side effects. There is a significant risk of bias in many of the existing studies with small numbers of subjects overall. Little comparison can be made between studies owing to their heterogeneity in design. Qualitative data indicate that singing is an enjoyable experience for patients, who consistently report that it helps them to cope with their condition better. Larger and longer-term trials are needed.


Foraging behavior of Melipona rufiventris Lepeletier (Apinae; Meliponini) in Ubatuba, SP, Brazil.
This study describes how the foraging activity of Melipona rufiventris is influenced by the environment and/or by the state of a colony. Two colonies were studied in Ubatuba, SP (44 degrees 48 W and 23 degrees 22 S) from July/2000 to June/2001. These colonies were classified as strong (Colony 1) and intermediate (Colony 2) according to their general conditions: population and brood comb size and number of food pots. The bees were active from dawn to dusk. The number of pollen loads presented a positive correlation with relative humidity (r(s) = 0.401; p <0.01) and was highest between 70 and 90%. However, it was negatively correlated with temperature (r(s) = -0.228; p <0.01) showing a peak between 18 and 23 degrees C. The number of nectar loads presented a positive correlation with temperature (r(s) = 0.244; p <0.01) and light intensity (r(s) = 0.414; p <0.01); it was greater between 50 and 90% of relative humidity and 20 and 30 degrees C of temperature. They collected more nectar than pollen throughout the day, and were more active between 6 and 9 hours. Workers from Colony 1 (strong) collected nectar in greater amounts and earlier than those from Colony 2 (intermediate). The number of pollen, nectar and resin loads varied considerably between the study days. Peaks of pollen collection occurred earlier in months with longer days and in a hotter and more humid climate. The foraging behavior of M. rufiventris is probably affected by the state of the colony and by environmental conditions, notably temperature, relative humidity, light intensity and length of the day.


IFNγ induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma.
Programmed death-ligand 1 (PD-L1) acts as an immune checkpoint inhibitor in various cancers. PD-L1 is known to be more frequently expressed in EBV (+) gastric cancer (GC). However, the mechanisms underlying the regulation of PD-L1 expression in EBV (+) GC remain unclear. We investigated the basal and inducible PD-L1 expressions in GC cells. PD-L1 expression was upregulated upon treatment with IFNγ in both EBV (-) and EBV (+) GC cells. Upon stimulation with the same concentration of IFNγ for 24 h, EBV (+) SNU-719 cells showed dramatically higher PD-L1 expression levels by activating JAK2/STAT1/IRF-1 signaling than those of EBV (-) AGS cells. PD-L1 promoter assays, chromatin immunoprecipitation, and electrophoretic mobility shift assays revealed that IFNγ-inducible PD-L1 overexpression is primarily mediated by the putative IRF-1α site of the PD-L1 promoter in EBV (+) SNU-719 cells. Moreover, EBNA1 knockdown reduced both constitutive and IFNγ-inducible PD-L1 promoter activity by decreasing the transcript and protein levels of JAK2 and subsequently STAT1/IRF-1/PD-L1 signaling. EBNA1 is suggested to be moderately enhance both constitutive and IFNγ-inducible PD-L1 expression in EBV (+) GC cells. Thus, the signaling proteins and EBNA1 that regulate PD-L1 expression are potential therapeutic targets in EBV (+) GC.


Associations between community health workers' home visits and education-based inequalities in institutional delivery and perinatal mortality in rural Uttar Pradesh, India: a cross-sectional study.
India's National Health Mission has trained community health workers called Accredited Social Health Activists (ASHAs) to visit and counsel women before and after birth. Little is known about the extent to which exposure to ASHAs' home visits has reduced perinatal health inequalities as intended. This study aimed to examine whether ASHAs' third trimester home visits may have contributed to equitable improvements in institutional delivery and reductions in perinatal mortality rates (PMRs) between women with varying education levels in Uttar Pradesh (UP) state, India. Cross-sectional survey data were collected from a representative sample of 52 615 women who gave birth in the preceding 2 months in rural areas of 25 districts of UP in 2014-2015. We analysed the data using generalised linear modelling to examine the associations between exposure to home visits and education-based inequalities in institutional delivery and PMRs. Third trimester home visits were associated with higher institutional delivery rates, in particular public facility delivery rates (adjusted risk ratio (aRR) 1.32, 95% CI 1.30 to 1.34), and to a lesser extent private facility delivery rates (aRR 1.09, 95% CI 1.04 to 1.13), after adjusting for confounders. Associations were stronger among women with lower education levels. Having no compared with any third trimester home visits was associated with higher perinatal mortality (aRR 1.18, 95% CI 1.09 to 1.28). Having any versus no visits was more highly associated with lower perinatal mortality among women with lower education levels than those with the most education, and most notably among public facility births. The results suggest that ASHAs' home visits in the third trimester contributed to equitable improvements in institutional deliveries and lower PMRs, particularly within the public sector. Broader strategies must reinforce the role of ASHAs' home visits in reaching the sustainable development goals of improving maternal and newborn health and leaving no one behind.


Identification of a SRC-like tyrosine kinase gene, FRK, fused with ETV6 in a patient with acute myelogenous leukemia carrying a t(6;12)(q21;p13) translocation.
The SRC family of kinases is rarely mutated in primary human tumors. We report the identification of a SRC-like tyrosine kinase gene, FRK (Fyn-related kinase), fused with ETV6 in a patient with acute myelogenous leukemia carrying t(6;12)(q21;p13). Both reciprocal fusion transcripts, ETV6/FRK and FRK/ETV6, were expressed. In ETV6/FRK, exon 4 of ETV6 was fused in-frame to exon 3 of FRK, producing a chimeric protein consisting of the entire oligomerization domain of ETV6 and the kinase domain of FRK. The ETV6/FRK protein was shown to be constitutively autophosphorylated on its tyrosine residues. ETV6/FRK phosphorylated histones H2B and H4 in vitro to a greater extent than did FRK, suggesting it had elevated kinase activity. ETV6/FRK could transform both Ba/F3 cells and NIH3T3 cells, which depended on its kinase activity. Moreover, ETV6/FRK inhibited ETV6-mediated transcriptional repression in a dominant-negative manner. This report provides the first evidence that a SRC-like kinase gene, FRK fused with ETV6, could directly contribute to leukemogenesis by producing an oncoprotein, ETV6/FRK, with dual functions: constitutive activation of the ETV6/FRK tyrosine kinase and dominant-negative modulation of ETV6-mediated transcriptional repression.


Communities' perceptions of health hazards induced by climate change in Mount Darwin district, Zimbabwe.
Climate change contributes toward many global challenges, such as increases in diseases in some communities, thereby accelerating health hazards to disasters. Establishing the extent to which local communities understand and perceive climate change and related health hazards is important for effective disaster risk management strategies. The objective of this study was to investigate communities' perceptions of health hazards induced by climate change in Mount Darwin district of Zimbabwe. This was in the light that besides the visible indications that climate is changing, the local people still perceive the climate change phenomenon as mystical or even a non-event. The study was situated within the social capital theory contextualised within the climate change, disaster management and the knowledge and perception realm constructed through social relationships, networks and interactions. A mixed-method research approach was used to assess the extent of knowledge and perceptions related to climate change and climate change-related health hazards. A semi-structured questionnaire was used to survey 204 participants from 10 wards in Mount Darwin, Zimbabwe. Respondents were purposively selected as they were mostly characterised by high vulnerability levels. While 38% of the respondents were not aware of climate change, 7% correctly identified climate change as caused by both natural and man-made forces. Most (89%) of the respondents stated that hazards occur mainly because of meteorological and hydrological causes. The study therefore recommended further education and awareness programmes to deepen community understanding of climate change. Despite the communities having some knowledge gaps and lacking an in-depth understanding of how climate change alters disease, there was some vital information within the Mount Darwin community that could have been used in local disaster risk management initiatives.


Moving further upstream: from toxics reduction to the precautionary principle.
Early policies to reduce the amount of toxic waste in the environment focused on cleaning up downstream sources of pollution, such as toxic disposal sites. Public attention in the 1980s encouraged both industry and government to develop an alternative to this command-and-control approach. This article describes the emergence of that alternative-pollution prevention-and its application in Massachusetts through the 1989 Toxics Use Reduction Act. Pollution prevention focuses on the sources of pollution, both metaphorically and physically, more upstream than its predecessors. The success of the Toxics Use Reduction Act in Massachusetts helped create an opportunity where an alternative pollution prevention paradigm could develop. That paradigm, the precautionary principle, is popular among environment activists because it focuses further upstream than pollution prevention by calling attention to the role the social construction of risk plays in decisions regarding the use of hazardous substances. The authors examine the evolution of the precautionary principle through an investigation of three major pathways in its development and expansion. The article concludes with a discussion of the increased potential for protecting public health and the environment afforded by this new perspective.


[Changes in the clinical presentation of Influenza A H1N1pdm09 after the pandemic].
After the 2009 influenza pandemic the H1N1pdm09 strain circulate seasonally. In 2015, Puerto Montt Hospital in Chile faced a simultaneous outbreak of both seasonal H3N2 and H1N1pdm09 influenza A (IA). To evaluate the clinical differences between the two viral strains and recent changes in the behavior of H1N1pdm09 IA. We set up a retrospective study including every adult hospitalized in Puerto Montt Hospital in 2015 due to IA, confirmed by reverse transcription polymerase chain reaction. We compared epidemiological data, clinical presentation, complications, and the outcome of patients with H1N1pdm09 versus those with seasonal influenza. In parallel, we compared 62 cases of thatH1N1 IA from 2015 with 100 cases who were hospitalized and analyzed in 2009. Between July and October 2015, 119 adults with confirmed IA were hospitalized. From 2009 to 2015, the mean age of patients with IAH1N1pdm09 increased from 40.4 ± 17 to 58.8 ± 16 years (p < 0.01). Pneumonia as the cause of hospitalization decreased from 75 to 58% of patients, (p = 0.04). Likewise, the presence of comorbidities increased from 53 to 74%, (p < 0.01). Compared with seasonal H3N2, patients with IAH1N1pdm09 IA were more likely to require intensive care (p < 0.01) and mechanical ventilation (p < 0.01) and developed septic shock (p = 0.03). Their mortality was non-significantly higher (13 and 5% respectively). The clinical presentation of H1N1pdm09 IA has varied over time and now affects an older population, with a greater number of comorbidities. It also appears to be adopting the clinical behavior of a classic seasonal influenza virus.


Role of stem cells in fertility preservation: current insights.
While improvements made in the field of cancer therapy allow high survival rates, gonadotoxicity of chemo- and radiotherapy can lead to infertility in male and female pre- and postpubertal patients. Clinical options to preserve fertility before starting gonadotoxic therapies by cryopreserving sperm or oocytes for future use with assisted reproductive technology (ART) are now applied worldwide. Cryopreservation of pre- and postpubertal ovarian tissue containing primordial follicles, though still considered experimental, has already led to the birth of healthy babies after autotransplantation and is performed in an increasing number of centers. For prepubertal boys who do not produce gametes ready for fertilization, cryopreservation of immature testicular tissue (ITT) containing spermatogonial stem cells may be proposed as an experimental strategy with the aim of restoring fertility. Based on achievements in nonhuman primates, autotransplantation of ITT or testicular cell suspensions appears promising to restore fertility of young cancer survivors. So far, whether in two- or three-dimensional culture systems, in vitro maturation of immature male and female gonadal cells or tissue has not demonstrated a capacity to produce safe gametes for ART. Recently, primordial germ cells have been generated from embryonic and induced pluripotent stem cells, but further investigations regarding efficiency and safety are needed. Transplantation of mesenchymal stem cells to improve the vascularization of gonadal tissue grafts, increase the colonization of transplanted cells, and restore the damaged somatic compartment could overcome the current limitations encountered with transplantation.


The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus.
Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer's disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer's disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p < 0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: - 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥.


Membrane activity detection in cultured cells using phase-sensitive plasmonics.
Despite the existence of various neural recording and mapping techniques, there is an open territory for the emergence of novel techniques. The current neural imaging and recording techniques suffer from invasiveness, a time-consuming labeling process, poor spatial/ temporal resolution, and noisy signals. Among others, neuroplasmonics is a label-free and nontoxic recording technique with no issue of photo-bleaching or signal-averaging. We introduced an integrated plasmonic-ellipsometry platform for membrane activity detection with cost-effective and high-quality grating extracted from commercial DVDs. With ellipsometry technique, one can measure both amplitude (intensity) and phase difference of reflected light simultaneously with high signal to noise ratio close to surface plasmon resonances, which leads to the enhancement of sensitivity in plasmonic techniques. We cultured three different types of cells (primary hippocampal neurons, neuroblastoma SH-SY5Y cells, and human embryonic kidney 293 (HEK293) cells) on the grating surface. By introducing KCl solution as a chemical stimulus, we can differentiate the neural activity of distinct cell types and observe the signaling event in a label-free, optical recording platform. This method has potential applications in recording neural signal activity without labeling and stimulation artifacts.


NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation.
Platelet-leukocyte interactions on activated endothelial cells play an important role during microvascular occlusion under oxidative stress conditions. However, it remains poorly understood how neutrophil-platelet interactions are regulated during vascular inflammation. By using intravital microscopy with mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their bone marrow chimera, we demonstrated that NOX2 from both hematopoietic and endothelial cells is crucial for neutrophil-platelet interactions during tumor necrosis factor alpha-induced venular inflammation. Platelet NOX2-produced reactive oxygen species (ROS) regulated P-selectin exposure upon agonist stimulation and the ligand-binding function of glycoprotein Ibα. Furthermore, neutrophil NOX2-generated ROS enhanced the activation and ligand-binding activity of αMβ2 integrin following N-formyl-methionyl-leucyl phenylalanine stimulation. Studies with isolated cells and a mouse model of hepatic ischemia/reperfusion injury revealed that NOX2 from both platelets and neutrophils is required for cell-cell interactions, which contribute to the pathology of hepatic ischemia/reperfusion injury. Platelet NOX2 modulated intracellular Ca(2+) release but not store-operated Ca(2+) entry (SOCE), whereas neutrophil NOX2 was crucial for SOCE but not intracellular Ca(2+) release. Different regulation of Ca(2+) signaling by platelet and neutrophil NOX2 correlated with differences in the phosphorylation of AKT, ERK, and p38MAPK. Our results indicate that platelet and neutrophil NOX2-produced ROS are critical for the function of surface receptors essential for neutrophil-platelet interactions during vascular inflammation.


Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer.
To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.


Imiquimod enhances the systemic immunity attained by local cryosurgery destruction of melanoma lesions.
Melanoma lesions can be frozen in vivo, resulting in necrotic death of malignant cells and in tumor antigen release suitable for cross-presentation by professional antigen-presenting cells. Imiquimod is a small molecule with adjuvant pro-inflammatory effects that can be topically delivered as a cream. Local cryosurgery of B16/ovalbumin (OVA)-derived subcutaneous tumor nodules leads to curative destruction of the lesions. If imiquimod is repeatedly applied on the cryo-treated lesion, a conspicuous, leukocyte-rich inflammatory infiltrate appears during the days following treatment. Mice treated by cryosurgery plus imiquimod rejected rechallenges of B16/OVA in 90% of the cases, whereas cryosurgery alone failed to prevent tumor grafting in 70% of the cases. The combination treatment of B16/OVA tumors was also able to protect 60% of the mice against outgrowth of a lethal dose of non-transfected B16 tumor cells. Addition of imiquimod to cryosurgery results in increases of the cellular immune response against tumor antigens as measured by in vitro IFN-gamma production and T-cell proliferation in response to OVA. The potent memory response is not only directed against the OVA epitope, but also toward a broader range of B16 antigens. Our data indicate that these combined treatments turn the treated tumor lesion into an autologous tumor vaccine, which is even able to cause vitiligo in several cases. These preclinical data and the simplicity of the procedures warrant the design of a pilot clinical trial.


GASTRIC TWIST AFTER SLEEVE GASTRECTOMY: A PROPOSAL FOR ENDOSCOPIC CLASSIFICATION.
The twisting of the gastric tube is one of the main causes of persistent reflux and food intolerance after sleeve gastrectomy (SG). To date, there is no classification for gastric twist after SG. This study aimed to propose an endoscopic classification for this condition and outline the clinical profile of these patients with sleeve gastrectomy. Patients in the postoperative period of SG presenting endoscopic findings of gastric twist were included. All patients underwent an esophagogastroduodenoscopy 12 months after SG. The classification proposed consists of three degrees: degree I: mild rotation of the staple line without relevant shrinkage of the gastric lumen; degree II: moderate rotation of the staple line, leading to a focal area of fixed narrowing that requires additional maneuvers for its transposition; and degree III: severe rotation of the staple line leading to stenosis, with increased difficulty for transposition or complete blockage. Out of 2,723 patients who underwent SG, 45 (1.6%) presented gastric twist. Most patients were female (85%), with mean age of 39±10.4 years. In all, 41 (91.1%) presented degree I, 3 (6.7%) presented degree II, and 1 (2.2%) had degree III. Most patients were asymptomatic (n=26). Vomiting was the most prevalent symptom (15.5%). Statistically significant correlation of twisting degrees was not observed for both the presence of symptoms and the degrees of esophagitis. Gastric twist after SG is rare, with generally mild and asymptomatic presentation. The endoscopic classification was not statistically related to clinical presentation but set the ground for further analysis.


Long-term outcomes after Gamma Knife surgery for vestibular schwannomas: a 10-year experience.
The authors sought to assess the results of Gamma Knife surgery (GKS) in patients with vestibular schwannomas (VSs). Seventy-four consecutive patients (33 men and 41 women) were evaluated by means of serial imaging studies, clinical examinations, and questionnaires. Nineteen patients had undergone resection of their VS. Facial nerve function was normal in 63 patients (85.1%) before GKS, and 63.5% of them had useful hearing. The prescription peripheral dose varied between 10 and 14 Gy (mean 12.27 +/- 0.96 Gy); the corresponding central dose was 21 to 30 Gy (mean 24.9 +/- 2.18 Gy). The mean volume of the tumor at GKS was 10.79 +/- 5.52 ml (range 0.11-27.8 ml). A mean of eight isocenters (range 3-17) was used for treating these lesions. At a median follow-up period of 68.3 months (range 30-122 months), tumor shrinkage was observed in 60 patients (81.1%), and the tumor size was stable in 11 (14.8%). Persistent neuroimaging demonstrated evidence of progression in only three patients (4.1%): two underwent repeated GKS after an interval of 18 months and one continues to be observed. Five patients experienced trigeminal dysfunction: in three the dysfunction was transient and in the other two the dysfunction persists. Three patients suffered facial palsy. Useful hearing was preserved in 34 patients. Thirteen patients experienced some degree of hearing improvement. Deterioration of hearing was found in 13 of 62 patients who had Class I or II hearing before treatment. Gamma Knife surgery prevents tumor growth; it achieves excellent neurological function preservation and produces few treatment-related complications.


Oxidized CaMKII: a "heart stopper" for the sinus node?
Each normal heart beat is triggered by an electrical impulse emitted from a group of specialized cardiomyocytes that together form the sinoatrial node (SAN). In this issue of the JCI, Swaminathan and colleagues demonstrate a new molecular mechanism that can disrupt the normal beating of the heart: angiotensin II - typically found in increased levels in heart failure and hypertension - oxidizes and activates Ca2+/calmodulin-dependent kinase II via NADPH oxidase activation, causing SAN cell death. The loss of SAN cells produces an electrical imbalance termed the "source-sink mismatch," which may contribute to the SAN dysfunction that affects millions of people later in life and complicates a number of heart diseases.


Affinity-labeling-based introduction of a reactive handle for natural protein modification.
A new chemical method to site-specifically modify natural proteins without the need for genetic manipulation is described. Our strategy involves the affinity-labeling-based attachment of a unique reactive handle at the surface of the target protein, and the subsequent selective transformation of the reactive handle by a bioorthogonal reaction to introduce a variety of functional probes into the protein. To demonstrate this approach, we synthesized labeling reagents that contain: 1) a benzenesulfonamide ligand that directs specifically to bovine carbonic anhydrase II (bCA), 2) an electrophilic epoxide group for protein labeling, 3) an exchangeable hydrazone bond linking the ligand and the epoxide group, and 4) an iodophenyl or acetylene handle. By incubating the labeling reagent with bCA, the reactive handle was covalently attached at the surface of bCA through epoxide ring opening. Either after or before removing the ligand by a hydrazone/oxime-exchange reaction, which restores the enzymatic activity, the reactive handle incorporated could be derivatized by Suzuki coupling or Huisgen cycloaddition reactions. This method is also applicable to the target-specific multiple modification in a protein mixture. The availability of various (photo)affinity-labeling reagents and bioorthogonal reactions should extend the flexibility of this strategy for the site-selective incorporation of many functional molecules into proteins.


ZnS nanocrystal cytotoxicity is influenced by capping agent chemical structure and duration of time in suspension.
As a result of their characteristic physical and optical properties, including their size, intense fluorescence, broad excitation, narrow emission and resistance to photobleaching, semiconductor nanocrystals are potentially useful for a variety of biological applications including molecular imaging, live-cell labeling, photodynamic therapy and targeted drug delivery. In this study, zinc sulfide (ZnS) semiconductor nanocrystals were synthesized in the 3 to 4 nm size range with selected capping agents intended to protect the nanocrystal core and increase its biological compatibility. We show that the biocompatibility of ZnS nanocrystals with primary murine splenocytes is influenced by the chemical structure of the outer capping agent on the nanocrystal. Additionally, the cytotoxicity of ZnS nanocrystals increases markedly as a function of time spent in suspension in phosphate-buffered saline (PBS). These data suggest that the potential therapeutic and/or biological use of ZnS nanocrystals is inherently dependent upon the proper choice of capping agent, as well as the conditions of nanocrystal preparation and storage.


High-resolution structure of an HIV-1 quasispecies: identification of novel coding sequences.
To characterize an HIV-1 quasispecies in vivo at high resolution (1%) in order to determine its genetic structure. The first coding exon of tat was amplified by polymerase chain reaction from uncultured peripheral blood mononuclear cells of an HIV-1-infected patient. The products were cloned into M13mp18 RF, and 106 clones were sequenced. Thirty-one different Tat protein variants were found. Amongst these, five major forms with frequencies of 44, 11, 8 and 5% were identified. All of the remaining 26 sequences were unique, 15 of which were defective. Within the variant spectrum a small number of genomes encoded novel open reading frames, for example, a tat-vpu fusion product. Some of the myriad proviruses present in an individual harbour novel coding sequences. While these are probably of little importance for AIDS pathogenesis they emphasize the ability of HIV to explore a huge range of genetic configurations.


Potential role of peroxisome proliferator-activated receptor-alpha in the modulation of glucose-stimulated insulin secretion.
In this review, we discuss the influence of peroxisome proliferator-activated receptor (PPAR)-alpha on islet insulin secretion and develop the hypothesis that modulation of PPAR-alpha function may be important for the regulation of compensatory insulin secretion. We have attempted to analyze the role of PPAR-alpha-linked fatty acid metabolism in islet function in health and in insulin-resistant states linked to lifestyle factors, in particular pregnancy and a diet inappropriately high in saturated fat. We have emphasized the potential for both actions of PPAR-alpha on insulin sensitivity that may be relayed systemically to the islet, leading to modulation of the insulin response in accordance with changes in insulin sensitivity, and direct effects of PPAR-alpha action on the islet itself. Finally, we have developed the concept that compensatory insulin secretion may have a function not only in glucoregulation but also in liporegulation. Thus, augmented insulin secretion may reflect a requirement for lipid lowering as well as for increased glucose disposal and is perceived to aim to compensate for impaired suppression of islet lipid delivery by insulin. This introduces the possibility of a continuum between liporegulation with islet compensation and lipodysregulation leading to islet decompensation in the development of type 2 diabetes.


[Fluid intake and overweight risk in children].
The global prevalence of overweight and obesity in children is growing. A number of eating patterns have been associated with different risks of overweight. Sugar sweetened beverages have received considerable attention as potential sources of energy in liquid form that could be responsible for body weight gain. Evaluate the association between fluid intake and overweight in schoolchildren. The final sample of the study includes 1675 children schools between 5 and 10 years old, after excluding dietary misreporting and questionnaires with incomplete information. After parental written consent, children's height and weight were measured according to international standards, and body mass index was calculated. The definition of overweight was based on average centiles according to the International Obesity Task Force cutoffs. We administered a questionnaire to parents that included information about physical activity, dietary intake (food frequency questionnaire that included information on milk, vegetable soup, cola, ice-tea and other sugar-sweetened beverages) and socio-demographic information. Adjusted odds ratios were computed using logistic regression. We found a high prevalence of overweight (including obesity) being 36,6% for girls, and 38,8% for boys. In girls the probability of being overweight increased significantly for those having low consumption of vegetable soup (equal or lower tan the median) compared to those with high consumption (higher than the median), even after adjusting for confounders (OR = 0,68, CI 95% 0,48-0,96, p = 0,030). We didn't find any significant association between sugar sweetened beverages and milk intake with overweight in both genders. In girls, high vegetable soup consumption significantly decreased the probability of being overweight, independently of other characteristics.


The role of CX₃CL1/CX₃CR1 in pulmonary angiogenesis and intravascular monocyte accumulation in rat experimental hepatopulmonary syndrome.
Hepatopulmonary syndrome (HPS), classically attributed to intrapulmonary vascular dilatation, occurs in 15-30% of cirrhotics and causes hypoxemia and increases mortality. In experimental HPS after common bile duct ligation (CBDL), monocytes adhere in the lung vasculature and produce vascular endothelial growth factor (VEGF)-A and angiogenesis ensues and contribute to abnormal gas exchange. However, the mechanisms for these events are unknown. The chemokine fractalkine (CX(3)CL1) can directly mediate monocyte adhesion and activate VEGF-A and angiogenesis via its receptor CX(3)CR1 on monocytes and endothelium during inflammatory angiogenesis. We explored whether pulmonary CX(3)CL1/CX(3)CR1 alterations occur after CBDL and influence pulmonary angiogenesis and HPS. Pulmonary CX(3)CL1/CX(3)CR1 expression and localization, CX(3)CL1 signaling pathway activation, monocyte accumulation, and development of angiogenesis and HPS were assessed in 2- and 4-week CBDL animals. The effects of a neutralizing antibody to CX(3)CR1 (anti-CX(3)CR1 Ab) on HPS after CBDL were evaluated. Circulating CX(3)CL1 levels and lung expression of CX(3)CL1 and CX(3)CR1 in intravascular monocytes and microvascular endothelium increased in 2- and 4-week CBDL animals as HPS developed. These events were accompanied by pulmonary angiogenesis, monocyte accumulation, activation of CX(3)CL1 mediated signaling pathways (Akt, ERK) and increased VEGF-A expression and signaling. Anti-CX(3)CR1 Ab treatment reduced monocyte accumulation, decreased lung angiogenesis and improved HPS. These events were accompanied by inhibition of CX(3)CL1 signaling pathways and a reduction in VEGF-A expression and signaling. Circulating CX(3)CL1 levels and pulmonary CX(3)CL1/CX(3)CR1 expression and signaling increase after CBDL and contribute to pulmonary intravascular monocyte accumulation, angiogenesis and development of experimental HPS.


Geographic risk factors for inter-river dispersal of Gyrodactylus salaris in fjord systems in Norway.
Gyrodactylus salaris has been recorded in 46 Norwegian rivers since 1975 and is considered a threat to Atlantic salmon stocks. The primary introductions of G. salaris (primary infected rivers) have been accounted for by specific events, as reported in the literature. The parasite has subsequently dispersed to adjacent localities (secondary infected rivers). The objective of this paper is to address the occurrence of secondary infections by examining the hypothesis of inter-river dispersal of G. salaris. A dispersal model for the secondary river infections via migrating infected fish is proposed. Due to the limited tolerance of G. salaris to salinity, both freshwater inflow to dispersal pathways and dispersal distance were expected to influence the probability of inter-river dispersal. Eighteen rivers were categorised as primary infected rivers, 28 as secondary infected rivers, and 54 as rivers at risk. Four risk factors: the log10 freshwater inflow; the dispersal distance; the time at risk; and the salmon harvest were combined in a multi-variable logistic regression model of the probability of secondary infection. The final multi-variable model included log10 freshwater inflow (Wald chi-square = 9.93) and dispersal distance (Wald chi-square = 6.48). Receiver operating characteristic analyses of the final model supported freshwater inflow as a strong predictor of G. salaris infection status. The strong influence of the freshwater inflow on the probability of secondary infection adds further support to the hypothesis of inter-river dispersal of G. salaris through fjords.


Small cell carcinoma of the urinary bladder--histogenesis, genetics, diagnosis, biomarkers, treatment, and prognosis.
Small cell carcinoma of the urinary bladder is a rare but highly aggressive malignancy with a dismal prognosis. Most patients present with advanced disease at the time of diagnosis. Hematuria is the most frequent presenting symptom. Histologically, small cell carcinoma of the urinary bladder is indistinguishable from its pulmonary counterpart. Coexistence with other types of carcinoma is common. Histogenesis is uncertain; there are several competing theories, including origin from stem cells, from urothelial cells, and from neuroendocrine cells in normal or metaplastic urothelium. The molecular pathogenesis remains unclear. Immunohistochemical staining can be extremely helpful in establishing the diagnosis, and in investigating the use of potential therapeutic strategies. Currently, combinations of surgical resection, chemotherapy, and radiation therapy represent the main treatment options. The recent observation of c-kit and epidermal growth factor receptor expression in more than 25% of patients with urinary bladder small cell carcinoma opens new avenues for further investigation. Improvement in survival may depend upon the identification of new molecular markers to facilitate earlier diagnosis and the development of novel targeted therapies. In this paper, we review general aspects of small cell carcinoma of the urinary bladder, focusing on the ways in which our understanding of this entity has been positively influenced by studies of the histopathologic and immunohistochemical findings, and by investigations of genetic alterations in this disease.