Study protocol for the SOFIA project: Swallowing function, Oral health, and Food Intake in old Age: a descriptive study with a cluster randomized trial.
Extensive studies have shown that older people are negatively impacted by impaired eating and nutrition. The abilities to eat, enjoy food, and participate in social activities associated with meals are important aspects of health-related quality of life (HRQoL) and recovery after illness. This project aims to (i) describe and analyze relationships between oral health and oral HRQoL, swallowing ability, eating ability, and nutritional risk among older individuals admitted to short-term care; (ii) compare the perceptions that older individuals and staff report on care quality related to oral hygiene and eating; and (iii) study the feasibility and effects of a training program for people with impaired swallowing (i.e., dysphagia). This project consists of two parts, which will be performed in five Swedish counties. It will include approximately 400 older individuals and 200 healthcare professionals. Part 1 is a cross-sectional, descriptive study of older people admitted to short-term care. Subjects will be assessed by trained professionals regarding oral health status, oral HRQoL, eating and nutritional risk, and swallowing ability. Swallowing ability will be measured with a teaspoon test and a swallowing capacity test (SCT). Furthermore, subjects and staff will complete a questionnaire regarding their perceptions of care quality. Part 2 is a cluster randomized intervention trial with controls. Older participants with dysphagia (i.e., SCT <10 ml/s, measured in part 1) will be recruited consecutively to either the intervention or control group, depending on where they were admitted for short-term care. At baseline, all subjects will be assessed for oral health status, oral HRQoL, eating and nutritional risk, swallowing ability, and swallowing-related QoL. Then, the intervention group will receive 5 weeks of training with an oral screen for neuromuscular training focused on orofacial and pharyngeal muscles. After completing the intervention, and at six months post-intervention, all assessments will be repeated in both study groups. The results will make important contributions to rehabilitation knowledge, including approaches for improving swallowing function, oral health, and food intake and for improving the quality of oral care for older people. This trial was retrospectively registered at ClinicalTrials.gov, on July 4, 2016, identifier: NCT02825927 .


Zn-Doped Cu(100) facet with efficient catalytic ability for the CO2 electroreduction to ethylene.
Electrochemically converting CO2 into fuels and chemicals is an appealing strategy to create energy rich products. The highly demanded product ethylene has been preferably produced on Cu-based catalysts with abundant exposed Cu(100) facets. However, the performance is still limited by the large energy barrier for the C-C dimerization. Here, to lower the energy barrier, we tailor the electronic structure of Cu(100) by doping a series of transition metals using the density functional theory (DFT) method. The zinc-doped Cu(100) surface has shown a superior catalytic performance. Mechanistic study further reveals that doping with Zn alters the electronic structure around Cu, adjusts the atomic arrangement in the active sites and makes the catalyst surface electronegative, which is conducive to the activation of acidic molecular CO2 and the reduction of the energy barrier for C-C dimerization. This work reveals that the doping of Cu with transition metals has great potential in promoting the electrochemical CO2-to-C2H4 conversion. This work also provides deep insights into the formation mechanisms of C2H4, thus guiding the design of Cu-based bimetallic catalysts for its effective production.


Measure accurately, Act rapidly, and Partner with patients: An intuitive and practical three-part framework to guide efforts to improve hypertension control.
Hypertension is the leading cause of cardiovascular disease in the United States and worldwide. It also provides a useful model for team-based chronic disease management. This article describes the M.A.P. checklists: a framework to help practice teams summarize best practices for providing coordinated, evidence-based care to patients with hypertension. Consisting of three domains-Measure Accurately; Act Rapidly; and Partner With Patients, Families, and Communities-the checklists were developed by a team of clinicians, hypertension experts, and quality improvement experts through a multistep process that combined literature review, iterative feedback from a panel of internationally recognized experts, and pilot testing among a convenience sample of primary care practices in two states. In contrast to many guidelines, the M.A.P. checklists specifically target practice teams, instead of individual clinicians, and are designed to be brief, cognitively easy to consume and recall, and accessible to healthcare workers from a range of professional backgrounds.


The zebrafish reference genome sequence and its relationship to the human genome.
Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.


The influence of protein solubilisation, conformation and size on the burst release from poly(lactide-co-glycolide) microspheres.
Encapsulation of proteins in poly(lactide-co-glycolide) microspheres via emulsion is known to cause insoluble protein aggregates. Following protein emulsification and encapsulation in PLGA microspheres, we used circular dichroism to show that the recoverable soluble protein fraction also suffers subtle conformational changes. For a panel of proteins selected on the basis of molecular size and structural class, conformational stability measured by chemical denaturation was not indicative of stability during emulsion-encapsulation. Partial loss of structure was observed for alpha-helical proteins released from freeze-dried microspheres in aqueous buffer, with dramatic loss of structure for a beta-sandwich protein. The addition of sucrose (a lyoprotectant) did not prevent the loss of protein conformation upon encapsulation. Therefore, the conformational changes seen for the released soluble protein fraction originates during emulsification rather than microsphere freeze-drying. Analysis of the burst release for all proteins in buffer containing denaturant or surfactant showed that the degree of protein solubilisation was the dominant factor in determining the initial rate and extent of release. Our data for protein release into increasing concentrations of denaturing buffer suggest that the emulsion-denatured protein fraction remains insoluble; this fraction may represent the protein loss encountered upon comparison of protein encapsulated versus protein released.


The reach and effectiveness of SIPsmartER when implemented by rural public health departments: a pilot dissemination and implementation trial to reduce sugar-sweetened beverages.
SIPsmartER is a theory-based, 6-month, multi-component health literacy intervention shown to improve sugar-sweetened beverages (SSB) behaviors among adults in rural, southwest Virginia. The objective of this pilot trial was to understand the reach and effectiveness of SIPsmartER when delivered by existing staff in public health practice settings. This pre-post research design was conducted in partnership with four medically underserved southwest Virginia Department of Health (VDH) districts. Validated measures and standardized data collection techniques were used. Analyses included descriptive statistics and multilevel mixed-effects linear regressions models. Of 928 individuals screened, 586 (63%) were eligible and 117 (20% of eligible) enrolled in SIPsmartER (79% retained). The sample was majority female (71%) and white (94%) and had ≤high school education (59%) and an annual income of approximately $12,500. Relative to the county population, the enrolled study sample was representative for age and race, yet underrepresented for men and overrepresented for low income and low educational attainment. Significant improvements from baseline to 6 months were observed for the primary SSB outcome (-403 [confidence interval [CI] = -528, -278] SSB kcals/day) (p < .001). SSB-related attitudes, perceived behavioral control, behavioral intentions, and media literacy also significantly improved (all p < .05). SIPsmartER appears to be promising for VDH and potentially other health departments in medically underserved areas. When compared to the previous effectiveness trial, existing VDH staff achieved similar reach and effectiveness for some, but not all, outcomes. Future work is needed on methods to support health departments in developing strategies to reach new participants and to integrate SIPsmartER into sustained practice.


Extracorporeal shockwave therapy and therapeutic exercise for supraspinatus and biceps tendinopathies in 29 dogs.
Supraspinatus tendinopathy (ST) and biceps tendinopathy (BT) are common causes of forelimb lameness in large-breed dogs and have historically been treated with conservative management or surgery. Extracorporeal shockwave therapy (ESWT) and therapeutic exercise (TE) are thought to be treatment options for these conditions. The objectives of this study were to report the clinical presentations of dogs treated with ESWT for shoulder tendinopathies, to determine the association between shoulder lesion severity identified on ultrasonography or MRI and outcome, and to compare the outcomes of dogs treated with ESWT with and without TE. Medical records of 29 dogs diagnosed with shoulder tendinopathies and treated with ESWT were reviewed, and 24 dogs were diagnosed with either unilateral BT or BT and ST. None were found to have unilateral ST. Five dogs were diagnosed with bilateral disease. Eighty-five per cent of dogs had good or excellent outcomes determined by owner assessment 11-220 weeks after therapy. Outcomes were found to be better as tendon lesion severity increased (P=0.0497), regardless if ESWT was performed with or without TE (P=0.92). ESWT should be considered a safe primary therapeutic option for canine shoulder tendinopathies. Larger controlled prospective studies are needed to adequately assess these findings.


Quantitative Radiographic Evaluation of Elbow Incongruity in Labrador and Golden Retrievers with Confirmed Medial Coronoid Disease.
The purpose of this study was to objectively estimate humeroradial (HR), humeroulnar (HU) and radioulnar (RU) congruity on mediolateral elbow radiographs of Labrador and Golden Retrievers without and with medial coronoid disease (MCD), and to determine the correlation between traditional and modified RU-step assessment techniques. Extended mediolateral elbow radiographs of Labrador and Golden Retrievers without MCD (control group) and with confirmed MCD (diseased group) were investigated. Absolute and average HR and HU distances were determined and standardized by the radius of the corresponding humeral condyle. Traditional RU-step was measured, and a modified procedure of RU-step assessment was generated. The correlation between the two RU-step assessment procedures was tested. A total of 131 (197 elbows) Labrador and Golden Retrievers met the criteria for inclusion in the control and diseased groups. The normalized HR and HU distances increased significantly (p ≤ 0.002) in dogs with MCD. There was a significant increase (p < 0.0001) in the traditional and modified RU-step in dogs with MCD. A significant correlation (r s = 0.74, p < 0.0001) was identified between traditional and modified RU-step calculated for control and diseased elbows. Dogs with confirmed MCD had quantitative radiographic evidences of elbow incongruity. Modified RU-step procedure may be an alternative to the traditional technique and can be utilized during routine quantification of HR and HU congruity. Validation of the reported measurements is, however, warranted.


Determinants of compliance with anticoagulation: A case-control study.
The number of patients for whom long-term anticoagulation is indicated has increased dramatically over the past decade. Good patient compliance is necessary to safely realize the benefits of anticoagulation, yet barriers to compliance with anticoagulation therapy have not been studied. We conducted a case-control study in the Anticoagulation Therapy Unit (ATU) at Massachusetts General Hospital. Forty-three patients who had been discharged from the ATU for noncompliance (cases) and 89 randomly selected compliant ATU controls were interviewed. Noncompliant cases had self-discontinued warfarin or were taking warfarin with inadequate monitoring of international normalized ratio (INR) levels. Telephone interviews assessed sociodemographic features, indication for anticoagulation, patient satisfaction, and health beliefs. Noncompliant cases were more likely to be younger (mean 53.7 years versus 68.7 years, P < 0.0001), male (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.5, 8.2) and nonwhite (OR 6.4, 95% CI 1.9, 21.9), and less likely to have had a stroke or transient ischemic attack (OR 0.2, 95% CI 0.1, 0.7). In open-ended questioning, cases were more likely to report that they did not know why warfarin had been prescribed (OR 4.4, 95% CI 1.4, 14.2). Noncompliant cases were more likely not to have a regular physician (OR 11.1, 95% CI 3.6, 50.0); among patients with a regular physician, noncompliant cases were more likely to feel dissatisfied. Examination of health beliefs revealed that noncompliant cases felt more burdened by taking warfarin, and perceived fewer health benefits. Patients who are noncompliant with warfarin share distinctive clinical characteristics. Notably, younger, male patients who have not experienced a thromboembolic event are more likely to forego INR testing or to stop anticoagulation therapy completely. Improved patient education, physician involvement, and ease of monitoring may improve compliance, particularly among younger male patients.


A major trichinellosis outbreak suggesting a high endemicity of Trichinella infection in northern Laos.
Trichinellosis is an important and under-recognized food-borne zoonosis in Southeast Asia. After 30 years of no reports, a small outbreak was described in Central Lao PDR (Laos) in 2003. Here we report a large outbreak of at least 650 estimated patients in Udomxay (northern Laos) in June 2005. Trichinella ELISA assays on serum from 133 patients and Western blot assays on 16 patients were positive in 67.6% and 81.2%, respectively. No deaths were recorded. Consumption of uncooked or fermented pork at funeral and wedding ceremonies was the main source of infection. Larvae of Trichinella spiralis were found in 1 of 11 local pigs not involved in this outbreak. The results suggest that trichinellosis may be an under-recognized but important endemic disease in Laos and reinforces the need to urgently implement veterinary and educational programs.


Rectal diazepam gel for treatment of acute repetitive seizures in adults.
To evaluate the efficacy and tolerability of diazepam (DZP) rectal gel (Diastat; Elan Pharmaceuticals, Dublin, Ireland) for the treatment of acute repetitive seizures in adult patients in 2 multicenter, double-blind, placebo-controlled parallel studies. Ninety-six adults 18 years or older with acute repetitive seizures, 70 of whom received treatment, were randomized into the 2 studies. Active and placebo medications were supplied in prefilled, identical-appearing delivery systems. In study 001, patients received a second dose 4 hours after the initial treatment. Patients in study 003 received only 1 treatment. Patients were observed for 12 hours after the first dose. There was a significant reduction in seizure frequency in patients who received DZP compared with the placebo group. The median number of seizures per hour in the group treated with DZP rectal gel was 0.00, vs 0.13 in the placebo group (P =.002). In addition, significantly more DZP rectal gel-treated patients remained seizure-free during the 12-hour observation period (71% [22/31] vs 28% [11/39]). Using Kaplan-Meier life-table analysis, time to the next seizure was found to be significantly longer in DZP rectal gel-treated than placebo-treated patients (P<.001). Global assessment as provided by the caregivers was in favor of DZP rectal gel for both study 001 (P =.17) and study 003 (P =.02). Dizziness and somnolence were the only central nervous system adverse events that occurred more frequently in patients receiving DZP rectal gel than in those receiving placebo. In adults, rectal DZP formulated as Diastat significantly reduced the likelihood of seizure recurrence during an episode of acute repetitive seizures, with minimal safety concerns.


Bactericidal activity of soymilk fermentation broth by in vitro and animal models.
Soybean fermentation broth (SFB) exhibits potent antibacterial activity against different species of bacteria in in vitro assays and animal models. Four isoflavone compounds-daidzin, genistin, genistein, and daidzein-of SFB were analyzed and quantified by high-performance liquid chromatography. In the in vitro test, daidzin and daidzein had more potent antibacterial activity than genistin. The minimum inhibition concentration values for these bacteria of SFB ranged from 1.25% to 5%, and the minimum bactericidal concentration values of strains ranged from 2.5% to 10%, depending on the species or strain. Vancomycin-resistant Entercoccus faecalis (VRE) strains were also tested for susceptibility to SFB in two species of animal model: the Sprague-Dawley rat and the BALB/c mouse. SFB-fed Sprague-Dawley rats showed excellent elimination efficiency against VRE, close to 99% compared with the phosphate-buffered saline-fed control group. In the BALB/c mouse model, SFB antibacterial activity was 65-80% against VRE compared with the control. In conclusion, SFB contains natural antibacterial substances such as daidzin, genistin, and daidzein that inhibit bacterial growth.


Simvastatin and atorvastatin reduce the mechanical properties of tendon constructs in vitro and introduce catabolic changes in the gene expression pattern.
Treatment with lipid-lowering drugs, statins, is common all over the world. Lately, the occurrence of spontaneous tendon ruptures or tendinosis have suggested a negative influence of statins upon tendon tissue. But how statins might influence tendons is not clear. In the present study, we investigated the effect of statin treatment on mechanical strength, cell proliferation, collagen content and gene expression pattern in a tendon-like tissue made from human tenocytes in vitro. Human tendon fibroblasts were grown in a 3D tissue culture model (tendon constructs), and treated with either simvastatin or atorvastatin, low or high dose, respectively, for up to seven days. After seven days of treatment, mechanical testing of the constructs was performed. Collagen content and cell proliferation were also determined. mRNA levels of several target genes were measured after one or seven days. The maximum force and stiffness were reduced by both statins after 7 days (p<0.05), while the cross sectional area was unaffected. Further, the collagen content was reduced by atorvastatin (p = 0.01) and the cell proliferation rate was decreased by both types of statins (p<0.05). Statin treatment also introduced increased mRNA levels of MMP-1, MMP-3, MMP-13, TIMP-1 and decreased levels of collagen type 1 and 3. In conclusion, statin treatment appears to have a negative effect on tendon matrix quality as seen by a reduced strength of the tendon constructs. Further, activated catabolic changes in the gene expression pattern and a reduced collagen content indicated a disturbed balance in matrix production of tendon due to statin administration.


Abundant tissue butyrylcholinesterase and its possible function in the acetylcholinesterase knockout mouse.
We have described recently an acetylcholinesterase (AChE) knockout mouse. While comparing the tissue distribution of AChE and butyrylcholinesterase (BChE), we found that extraction buffers containing Triton X-100 strongly inhibited mouse BChE activity. In contrast, buffers with Tween 20 caused no inhibition of BChE. Conventional techniques grossly underestimated BChE activity by up to 15-fold. In Tween 20 buffer, the intestine, serum, lung, liver, and heart had higher BChE than AChE activity. Only brain had higher AChE than BChE activity in AChE +/+ mice. These findings contradict the dogma, based mainly on observations in Triton X-100 extracts, that BChE is a minor cholinesterase in animal tissues. AChE +/- mice had 50% of normal AChE activity and AChE -/- mice had none, but all mice had similar levels of BChE activity. BChE was inhibited by Triton X-100 in all species tested, except rat and chicken. Inhibition was reversible and competitive with substrate binding. The active site of rat BChE was unique, having an arginine in place of leucine at position 286 (human BChE numbering) in the acyl-binding pocket of the active site, thus explaining the lack of inhibition of rat BChE by Triton X-100. The generally high levels of BChE activity in tissues, including the motor endplate, and the observation that mice live without AChE, suggest that BChE has an essential function in nullizygous mice and probably in wild-type mice as well.


'Poking the skunk': Ethical and medico-legal concerns in research about patients' experiences of medical injury.
Improving how health care providers respond to medical injury requires an understanding of patients' experiences. Although many injured patients strongly desire to be heard, research rarely involves them. Institutional review boards worry about harming participants by asking them to revisit traumatic events, and hospital staff worry about provoking lawsuits. Institutions' reluctance to approve this type of research has slowed progress toward responses to injuries that are better able to meet patients' needs. In 2015-2016, we were able to surmount these challenges and interview 92 injured patients and families in the USA and New Zealand. This article explores whether the ethical and medico-legal concerns are, in fact, well-founded. Consistent with research about trauma-research-related distress, our participants' accounts indicate that the pervasive fears about retraumatization are unfounded. Our experience also suggests that because being heard is an important (but often unmet) need for injured patients, talking provides psychological benefits and may decrease rather than increase the impetus to sue. Our article makes recommendations to institutional review boards and researchers. The benefits to responsibly conducted research with injured patients outweigh the risks to participants and institutions.


Activity of serotonin-containing neurons in nucleus raphe magnus in freely moving cats.
Serotonergic neurons were recorded in the nucleus raphe magnus in freely moving cats and were initially identified on-line by their characteristic slow and regular spontaneous activity during quiet waking (3.42 +/- 0.33 spikes/s; mean +/- SE). Discharge rates of these serotonergic neurons were highest during active waking (4.49 +/- 0.40 spikes/s), intermediate during slow-wave sleep (middle: 2.14 +/- 0.23 spikes/s), and lowest during REM sleep (0.20 +/- 0.03 spikes/s). Although these cells fired at a rate 31.3% higher during active waking than during quiet waking, their activity displayed no correlation with phasic elevations of the nuchal EMG or overt body movements. In addition, no relationship was observed between the activity of these neurons during slow-wave sleep and the occurrence of sleep spindles in the cortical EEG or pontogeniculooccipital waves recorded from the lateral geniculate nucleus. Serotonergic neurons of nucleus raphe magnus were also relatively unresponsive to phasic auditory and visual stimuli, with about half of the cells examined showing weak excitatory responses. These neurons did respond, however, to the administration of a small dose of the serotonin specific agonist, 5-methoxy-N,N-dimethyltryptamine (250 micrograms/kg, i.m.) with a mean decrease in unit activity of 73.6 +/- 4.5%. The results of this study are compared with those previously reported for serotonergic neurons in the dorsal raphe nucleus, nucleus centralis superior, and nucleus raphe pallidus of freely moving cats.


Advances in the study of molecularly targeted agents to treat hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a severe form of liver cancer that is found worldwide. Treatments such as liver transplantation and surgical resection and local-regional therapies such as transarterial chemoembolization have progressed considerably and play a prominent role in HCC management. After those treatments, though, systematic drug intervention is required to deal with tumor metastasis in its early stages and the high frequency of tumor recurrence and/or metastasis. The approval of sorafenib, an agent that targets receptor tyrosine kinases (RTKs), as the first effective drug for systemic treatment of HCC represents a milestone in the treatment of this disease. In addition to sorafenib, a number of agents that target various RTKs or intracellular signal transduction molecules, such as mTOR, are currently being investigated as monotherapy or combination therapy for HCC. This article reviews advances in the study of molecularly targeted agents to treat HCC.


Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer.
Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC). Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points. In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment. In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.


Reduced occurrence of childhood cancer in twins compared to singletons: protection but by what mechanism?
Several small studies combined have suggested that twins develop fewer childhood cancers than singletons. The national Swedish Family-Cancer Database contains information on a large population of multiple births providing an unbiased dataset for the estimation of cancer risk in twins. Lifelong cancer incidence in these twins has already been reported as similar to that in singleton births. In contrast, the present paper presents robust estimates of a significantly reduced childhood cancer risk in twins to age 15. Standardised incidence ratios (SIR) were used to measure cancer risk for twins, taking the corresponding rates for singletons as reference. Rates were adjusted for age, sex, period of birth, and residential area. Follow up data cover the period 1958-2002. Overall childhood cancer risk was significantly reduced in all twins (SIR 0.81 [95% CI: 0.69-0.94]) as was the risk for Wilms tumour (SIR 0.34 [95% CI: 0.09-0.88]). These significant reductions in risk were both driven by effects in same sex twins (overall cancer SIR 0.77 [95% CI: 0.64-0.93], Wilms tumour 0.12 [95% CI: 0.00-0.71]). Leukaemia risk was also significantly reduced for same sex twins (SIR 0.69 [95% CI: 0.47-0.97]). Our study provides the evidence that twins experience less childhood cancer than singletons. The risk reduction is most marked for Wilms tumour but may, to a varying extent, be true for a number of childhood neoplasms.


FS-HGR: Few-Shot Learning for Hand Gesture Recognition via Electromyography.
This work is motivated by the recent advances in Deep Neural Networks (DNNs) and their widespread applications in human-machine interfaces. DNNs have been recently used for detecting the intended hand gesture through the processing of surface electromyogram (sEMG) signals. Objective: Although DNNs have shown superior accuracy compared to conventional methods when large amounts of data are available for training, their performance substantially decreases when data are limited. Collecting large datasets for training may be feasible in research laboratories, but it is not a practical approach for real-life applications. The main objective of this work is to design a modern DNN-based gesture detection model that relies on minimal training data while providing high accuracy. Methods: We propose the novel Few-Shot learning- Hand Gesture Recognition (FS-HGR) architecture. Few-shot learning is a variant of domain adaptation with the goal of inferring the required output based on just one or a few training observations. The proposed FS-HGR generalizes after seeing very few observations from each class by combining temporal convolutions with attention mechanisms. This allows the meta-learner to aggregate contextual information from experience and to pinpoint specific pieces of information within its available set of inputs. Data Source & Summary of Results: The performance of FS-HGR was tested on the second and fifth Ninapro databases, referred to as the DB2 and DB5, respectively. The DB2 consists of 50 gestures (rest included) from 40 healthy subjects. The Ninapro DB5 contains data from 10 healthy participants performing a total of 53 different gestures (rest included). The proposed approach for the Ninapro DB2 led to 85.94% classification accuracy on new repetitions with few-shot observation (5-way 5-shot), 81.29% accuracy on new subjects with few-shot observation (5-way 5-shot), and 73.36% accuracy on new gestures with few-shot observation (5-way 5-shot). Moreover, the proposed approach for the Ninapro DB5 led to 64.65% classification accuracy on new subjects with few-shot observation (5-way 5-shot).


Peri-operative interventions, but not inflammatory mediators, increase risk of acute kidney injury after cardiac surgery: a prospective cohort study.
Cardiopulmonary bypass (CPB)-related inflammatory response might be one mechanism by which cardiac surgery associated acute kidney injury (CS-AKI) occurs. Interventions that may attenuate inflammation, including glucocorticoids or phosphodiesterase inhibitors, could therefore have a role in its prevention. We aimed to determine the role of inflammatory mediators in CS-AKI in children and the efficacy of commonly used peri-operative interventions to reduce CS-AKI risk. We prospectively studied 109 children undergoing heart surgery. Using regression modeling (adjusting for covariates), we (1) evaluated the association between inflammatory mediators [interleukin (IL)-6, IL-8, C-reactive protein, and tumor necrosis factor-α levels] and CS-AKI, and (2) evaluated risk/prevention factors for CS-AKI including glucocorticoid and milrinone administration. CS-AKI was defined based on pRIFLE methods. CS-AKI occurred in 68% of children. No inflammatory mediator measured had an independent association with CS-AKI. Higher pre-operative glomerular filtration rate (GFR), sustained decrease in mean arterial pressure during CPB, post-operative single ventricle physiology, deep hypothermic circulatory arrest, and milrinone use at 24 h post-operatively were significant independent predictors of CS-AKI. Intra-operative steroid administration had no effect on the rate of CS-AKI. Although inflammatory mediators are up-regulated following CPB, we found no association between levels of inflammatory cytokines and CS-AKI. CS-AKI has complex pathophysiology and the observation that milrinone was associated with increased AKI risk (and that higher GFR predicts more injury) suggests that mechanisms beyond inflammation play a significant role. Intra-operative administration of glucocorticoid does not appear to be an effective intervention for reducing the risk of CS-AKI.


Inductive differentiation of two neural lineages reconstituted in a microculture system from Xenopus early gastrula cells.
Neural induction of ectoderm cells has been reconstituted and examined in a microculture system derived from dissociated early gastrula cells of Xenopus laevis. We have used monoclonal antibodies as specific markers to monitor cellular differentiation from three distinct ectoderm lineages in culture (N1 for CNS neurons from neural tube, Me1 for melanophores from neural crest and E3 for skin epidermal cells from epidermal lineages). CNS neurons and melanophores differentiate when deep layer cells of the ventral ectoderm (VE, prospective epidermis region; 150 cells/culture) and an appropriate region of the marginal zone (MZ, prospective mesoderm region; 5-150 cells/culture) are co-cultured, but not in cultures of either cell type on their own; VE cells cultured alone yield epidermal cells as we have previously reported. The extent of inductive neural differentiation in the co-culture system strongly depends on the origin and number of MZ cells initially added to culture wells. The potency to induce CNS neurons is highest for dorsal MZ cells and sharply decreases as more ventrally located cells are used. The same dorsoventral distribution of potency is seen in the ability of MZ cells to inhibit epidermal differentiation. In contrast, the ability of MZ cells to induce melanophores shows the reverse polarity, ventral to dorsal. These data indicate that separate developmental mechanisms are used for the induction of neural tube and neural crest lineages. Co-differentiation of CNS neurons or melanophores with epidermal cells can be obtained in a single well of co-cultures of VE cells (150) and a wide range of numbers of MZ cells (5 to 100). Further, reproducible differentiation of both neural lineages requires intimate association between cells from the two gastrula regions; virtually no differentiation is obtained when cells from the VE and MZ are separated in a culture well. These results indicate that the inducing signals from MZ cells for both neural tube and neural crest lineages affect only nearby ectoderm cells.


ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system.
The sequestration of damaged mitochondria within double-membrane structures termed autophagosomes is a key step of PINK1/Parkin mitophagy. The ATG4 family of proteases are thought to regulate autophagosome formation exclusively by processing the ubiquitin-like ATG8 family (LC3/GABARAPs). We discover that human ATG4s promote autophagosome formation independently of their protease activity and of ATG8 family processing. ATG4 proximity networks reveal a role for ATG4s and their proximity partners, including the immune-disease protein LRBA, in ATG9A vesicle trafficking to mitochondria. Artificial intelligence-directed 3D electron microscopy of phagophores shows that ATG4s promote phagophore-ER contacts during the lipid-transfer phase of autophagosome formation. We also show that ATG8 removal during autophagosome maturation does not depend on ATG4 activity. Instead, ATG4s can disassemble ATG8-protein conjugates, revealing a role for ATG4s as deubiquitinating-like enzymes. These findings establish non-canonical roles of the ATG4 family beyond the ATG8 lipidation axis and provide an AI-driven framework for rapid 3D electron microscopy.


Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors.
Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.


Crystal structures of the wild type and the Glu376Gly/Thr255Glu mutant of human medium-chain acyl-CoA dehydrogenase: influence of the location of the catalytic base on substrate specificity.
Crystal structures of the wild type human medium-chain acyl-CoA dehydrogenase (MCADH) and a double mutant in which its active center base-arrangement has been altered to that of long chain acyl-CoA dehydrogenase (LCADH), Glu376Gly/Thr255Glu, have been determined by X-ray crystallography at 2.75 and 2.4 A resolution, respectively. The catalytic base responsible for the alpha-proton abstraction from the thioester substrate is Glu376 in MCADH, while that in LCADH is Glu255 (MCADH numbering), located over 100 residues away in its primary amino acid sequence. The structures of the mutant complexed with C8-, C12, and C14-CoA have also been determined. The human enzyme structure is essentially the same as that of the pig enzyme. The structure of the mutant is unchanged upon ligand binding except for the conformations of a few side chains in the active site cavity. The substrate with chain length longer than C12 binds to the enzyme in multiple conformations at its omega-end. Glu255 has two conformations, "active" and "resting" forms, with the latter apparently stabilized by forming a hydrogen bond with Glu99. Both the direction in which Glu255 approaches the C alpha atom of the substrate and the distance between the Glu255 carboxylate and the C alpha atom are different from those of Glu376; these factors are responsible for the intrinsic differences in the kinetic properties as well as the substrate specificity. Solvent accessible space at the "midsection" of the active site cavity, where the C alpha-C beta bond of the thioester substrate and the isoalloxazine ring of the FAD are located, is larger in the mutant than in the wild type enzyme, implying greater O2 accessibility in the mutant which might account for the higher oxygen reactivity.


Population Structure and Local Adaptation of MAC Lung Disease Agent Mycobacterium avium subsp. hominissuis.
Mycobacterium avium subsp. hominissuis (MAH) is one of the most common nontuberculous mycobacterial species responsible for chronic lung disease in humans. Despite increasing worldwide incidence, little is known about the genetic mechanisms behind the population evolution of MAH. To elucidate the local adaptation mechanisms of MAH, we assessed genetic population structure, the mutual homologous recombination, and gene content for 36 global MAH isolates, including 12 Japanese isolates sequenced in the present study. We identified five major MAH lineages and found that extensive mutual homologous recombination occurs among them. Two lineages (MahEastAsia1 and MahEastAsia2) were predominant in the Japanese isolates. We identified alleles unique to these two East Asian lineages in the loci responsible for trehalose biosynthesis (treS and mak) and in one mammalian cell entry operon, which presumably originated from as yet undiscovered mycobacterial lineages. Several genes and alleles unique to East Asian strains were located in the fragments introduced via recombination between East Asian lineages, suggesting implication of recombination in local adaptation. These patterns of MAH genomes are consistent with the signature of distribution conjugative transfer, a mode of sexual reproduction reported for other mycobacterial species.


Regulation of blood glucose homeostasis during prolonged exercise.
The maintenance of normal blood glucose levels at rest and during exercise is critical. The maintenance of blood glucose homeostasis depends on the coordination and integration of several physiological systems, including the sympathetic nervous system and the endocrine system. During prolonged exercise increased demand for glucose by contracting muscle causes to increase glucose uptake to working skeletal muscle. Increase in glucose uptake by working skeletal muscle during prolonged exercise is due to an increase in the translocation of insulin and contraction sensitive glucose transporter-4 (GLUT4) proteins to the plasma membrane. However, normal blood glucose level can be maintained by the augmentation of glucose production and release through the stimulation of liver glycogen breakdown, and the stimulation of the synthesis of glucose from other substances, and by the mobilization of other fuels that may serve as alternatives. Both feedback and feedforward mechanisms allow glycemia to be controlled during exercise. This review focuses on factors that control blood glucose homeostasis during prolonged exercise.


Cost effectiveness of ovarian reserve testing in in vitro fertilization: a Markov decision-analytic model.
To compare the cost effectiveness of ovarian reserve testing in in vitro fertilization (IVF). A Markov decision model based on data from the literature and original patient data. Decision analytic framework. Computer-simulated cohort of subfertile women aged 20 to 45 years who are eligible for IVF. [1] No treatment, [2] up to three cycles of IVF limited to women under 41 years and no ovarian reserve testing, [3] up to three cycles of IVF with dose individualization of gonadotropins according to ovarian reserve, and [4] up to three cycles of IVF with ovarian reserve testing and exclusion of expected poor responders after the first cycle, with no treatment scenario as the reference scenario. Cumulative live birth over 1 year, total costs, and incremental cost-effectiveness ratios. The cumulative live birth was 9.0% in the no treatment scenario, 54.8% for scenario 2, 70.6% for scenario 3 and 51.9% for scenario 4. Absolute costs per woman for these scenarios were €0, €6,917, €6,678, and €5,892 for scenarios 1, 2, 3, and 4, respectively. Incremental cost-effectiveness ratios (ICER) for scenarios 2, 3, and 4 were €15,166, €10,837, and €13,743 per additional live birth. Sensitivity analysis showed the model to be robust over a wide range of values. Individualization of the follicle-stimulating hormone dose according to ovarian reserve is likely to be cost effective in women who are eligible for IVF, but this effectiveness needs to be confirmed in randomized clinical trials.


First detection of porcine circovirus type 3 on commercial pig farms in Poland.
Porcine circovirus type 3 (PCV3) is a novel circovirus species recently discovered in USA and China in cases of porcine dermatitis and nephropathy syndrome, reproductive failure, respiratory disease and multisystemic inflammation. This study reports on the first identification of PCV3 in Europe, in serum from pigs from Polish farms. A total of 1,050 serum samples were collected between 2014 and 2017 from sows and 3-20 weeks old pigs from 14 commercial farms representing different regions of Poland, different size and health status. The samples were pooled by 4-6 and tested with real-time PCR for PCV3. PCV3 DNA was detected in 12 of 14 farms (85.7%). On the PCV3-positive farms, the virus was detected in 5.9% to 65% serum pools. PCV3 was most common among weaned pigs and finishers (26.1% and 28.0% of serum pools, respectively). Sequence analysis of 359 nucleotide fragment of ORF2 showed highest identity of 99.7% to PCV3-US/SD2016 from USA. Our results indicate that PCV3 is a common virus among Polish pigs but no links to unexplained disease conditions were established.


Preparation and characterization of alkylated poly(vinyl alcohol) hydrogels using alkyl halides.
A poly(vinyl alcohol) hydrogel coated onto polyethylene was partially alkylated by reaction with an alkylhalide (C4, C8, or C18) in the presence of a deprotonating agent (sodium ethoxide or potassium tert-butoxiDATE Surface coverage determined by X-ray photoelectron spectroscopy (XPS) was respectively approximately 34, 25, and approximately 8% for the C4, C8, and C18 modified surfaces. Statistically significant differences were observed in the fraction of C8 and C18 grafted alkyl groups as a function of depth (i.e. take-off angle) indicating the presence of a verticle composition gradient. All three surfaces showed maximal surface coverage of alkyl groups after 1 h reaction. At this reaction time, no further coverage was observed beyond a base/PVA ratio twenty times greater than the stoichiometric ratio. The advancing contact angle data exhibited an increase in hydrophobicity that correlated with the degree of coverage obtained by XPS: 90 +/- 1, 83 +/- 0.5, and 71 +/- 1 deg for C4, C8 and C18 alkylated PVA, and 55 +/- 2 deg for PVA respectively. Large contact angle hysteresis was observed on all three surfaces consistent with surface heterogeneity.


A quercetin containing supplement reduces niacin-induced flush in humans.
Coronary artery disease is associated with increased serum levels of cholesterol, triglycerides and LDL, but low levels of HDL. The most potent agent capable of reversing this trend is the vitamin nicotinic acid (niacin). However, compliance even with extended-release preparations and addition of acetylsalicylic acid (ASA) is hampered by the development of a feeling of erythema and burning ("flush"), especially on the face. We recently showed that the natural flavonoids quercetin and luteolin can eliminate "flush", as well as inhibit both niacin-induced plasma prostaglandin D2 (PGD2) and serotonin increase in an animal model. We conducted a pilot clinical study in humans. Four normal male subjects received (a) 1 g immediate release niacin either alone or after (b) the dietary formulation (Algonot-plus) containing 150 mg quercetin per capsule. Subjects completed a visual scale (1 = no, 5 = worst response) symptom assessment. Erythema and burning sensation scores were both 4.75+/-0.50 and lasted for 3.63+/-1.11 hours. After Algonot-plus administration, both scores were reduced to 2.5+/-0.58 and lasted only for 1.68+/-0.70 hours. Quercetin also inhibited methylnicotinate-induced human mast cell PGD2 release. These preliminary results suggest that quercetin could reduce niacin-induced "flush" in humans.


CAVER Analyst 2.0: analysis and visualization of channels and tunnels in protein structures and molecular dynamics trajectories.
Studying the transport paths of ligands, solvents, or ions in transmembrane proteins and proteins with buried binding sites is fundamental to the understanding of their biological function. A detailed analysis of the structural features influencing the transport paths is also important for engineering proteins for biomedical and biotechnological applications. CAVER Analyst 2.0 is a software tool for quantitative analysis and real-time visualization of tunnels and channels in static and dynamic structures. This version provides the users with many new functions, including advanced techniques for intuitive visual inspection of the spatiotemporal behavior of tunnels and channels. Novel integrated algorithms allow an efficient analysis and data reduction in large protein structures and molecular dynamic simulations. CAVER Analyst 2.0 is a multi-platform standalone Java-based application. Binaries and documentation are freely available at www.caver.cz. Supplementary data are available at Bioinformatics online.


Cell count ratio: new criterion of diagnostic peritoneal lavage for detection of hollow organ perforation.
Diagnostic peritoneal lavage (DPL) had been widely used in evaluating patients with suspected intraperitoneal injuries due to its high sensitivity. If the positive criteria are strictly followed, however, the incidence of nontherapeutic laparotomies will be unacceptably high. This realization has become more important recently with the popularization of nonoperative treatment for blunt solid organ injuries. For these patients, the early diagnosis of an associated hollow organ perforation is mandatory. Three hundred and twenty patients undergoing DPL over an 18-month period were retrospectively reviewed to evaluate the usefulness of "cell count ratio" in diagnosing hollow organ perforation. The cell count ratio was defined as the ratio between white blood cell count and red blood cell count in the lavage fluid divided by the ratio of the same parameters in the peripheral blood. Two hundred twelve patients were diagnosed as having a positive DPL according to the classic criteria. Forty-four patients (21%) had a cell count ratio of greater than or equal to 1. The diagnosis at laparotomy was small bowel perforation in 31 patients, colon perforation in eight patients, diaphragmatic hernia in one patient, pancreatic transection in two patients, and liver laceration in two patients. None of the patients with a cell count ratio of less than I sustained hollow organ perforation. The average interval from injury to DPL was 5 hours, with the shortest being 1.5 hours. A cell count ratio of greater than or equal to 1 predicted hollow organ perforation with a specificity of 97% and a sensitivity of 100%. The selective use of the cell count ratio has improved the probability of early diagnosis of bowel perforation without increasing the cost of care. Nonoperative management can be applied more confidently to those patients sustaining a blunt solid viscus injury of the abdomen if the cell count ratio is low. We conclude that the cell count ratio of DPL effluent is a very sensitive and specific indicator of hollow organ perforation. In the treatment of blunt abdominal injuries, if the cell count ratio is positive, nonoperative treatment should be abandoned and a laparotomy undertaken.


Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes.
Leucine-rich repeat kinase 2 (LRRK2) variants associated with Parkinson's disease (PD) and Crohn's disease lead to increased phosphorylation of its Rab substrates. While it has been recently shown that perturbations in cellular homeostasis including lysosomal damage can increase LRRK2 activity and localization to lysosomes, the molecular mechanisms by which LRRK2 activity is regulated have remained poorly defined. We performed a targeted siRNA screen to identify regulators of LRRK2 activity and identified Rab12 as a novel modulator of LRRK2-dependent phosphorylation of one of its substrates, Rab10. Using a combination of imaging and immunopurification methods to isolate lysosomes, we demonstrated that Rab12 is actively recruited to damaged lysosomes and leads to a local and LRRK2-dependent increase in Rab10 phosphorylation. PD-linked variants, including LRRK2 R1441G and VPS35 D620N, lead to increased recruitment of LRRK2 to the lysosome and a local elevation in lysosomal levels of pT73 Rab10. Together, these data suggest a conserved mechanism by which Rab12, in response to damage or expression of PD-associated variants, facilitates the recruitment of LRRK2 and phosphorylation of its Rab substrate(s) at the lysosome.


Transient ischaemic attack (TIA) knowledge in general practice: a cross-sectional study of Western Adelaide general practitioners.
With evidence to support early assessment and management of TIAs, the role of the general practitioner (GP) needs to be considered in developing a TIA service in Western Adelaide. We thus aimed to determine GP knowledge of TIA assessment and management and identify perceived barriers, in order to tailor subsequent GP education and engage primary care in the co-ordinated care of TIA patients. A self-administered questionnaire was mailed to all GPs (n = 202) in the Adelaide Western General Practice Network. Response frequencies were calculated for all variables, and associations examined by univariate analysis.32 GPs responded. All respondents correctly identified early risk of stroke following a TIA. Difficulty accessing neurological expertise was identified as a barrier (40.6 %), as was a lack of GP knowledge (18.8 %). Areas for improvement included access to neurologists (36.7 %), relevant guidelines and education (43.3 %). Diagnosis of TIA is difficult and this study highlights the need for further education and practical guidelines for GPs. With this training, GPs could be better equipped to assess and manage TIAs effectively in the community in consultation with stroke physicians.


Competency-based training: who benefits?
Competency based training describes progression through training referenced to the demonstrated ability to perform certain tasks. In recent years, this has become the dominant curriculum model. We seek to examine who benefits from a competency based approach to medical education. For the regulators and service, the apparent advantage is in terms of apparent measurable accountability and flexibility. For assessors, the promise of competence based assessments in the workplace to provide a reliable and objective measurement of a trainee's performance has not been demonstrated in practice. For the doctor in training, there is very little evidence to show benefit from competency based training. Competency based training places emphasis on individual skills rather than overall learning experience thus risks diminishing the role of the trainee in the workplace. Any form of medical education that devalues workplace based learning will ultimately harm the profession and, in turn, patient care.


Platelet-activating factor mediates pancreatic function derangement in caerulein-induced pancreatitis in rats.
1. We have assessed the role of platelet-activating factor in caerulein-induced acute pancreatitis (four subcutaneous injections of caerulein at a dose of 20 micrograms/kg) by measuring platelet-activating factor levels in portal blood, pancreatic tissue and peritoneal exudate in rats with and without pancreatitis. 2. We have also observed the effect of the platelet-activating factor antagonist, BN-52021, on the hyperamylasaemia and exocrine pancreatic secretion impairment associated with pancreatitis. 3. In rats with pancreatitis the basal pancreatic flow rate was increased (1.63 +/- 0.41 versus 0.25 +/- 0.03 microliters/min). Total protein output was similar in both untreated (5.98 +/- 1.93 micrograms/min) and caerulein-injected (6.5 +/- 2.0 micrograms/min) animals. Amylase output was lower in rats with pancreatitis (19.6 +/- 4.8 mu-units/min) than in controls (39.4 +/- 16.6 mu-units/min). 4. Caerulein-treated animals had significantly higher serum amylase levels than untreated animals. BN-52021 significantly reduced the caerulein-induced hyperamylasaemia. 5. Portal blood platelet-activating factor levels increased in rats with pancreatitis and in rats infused with cholecystokinin. Rats injected with caerulein and BN-52021 had portal blood levels of platelet-activating factor that were lower than those with pancreatitis. 6. Morphological derangements associated with pancreatitis (inflammatory infiltration and cell vacuolization) were also markedly reduced in BN-52021-treated animals. 7. The results of this study suggest that platelet-activating factor is involved in the development of caerulein-induced acute pancreatitis in rats.


Spontaneous emission enhancement at a photonic wire miniband edge.
In a multimode photonic-crystal waveguide, we observe strong enhancement of the photoluminescence of embedded quantum dots at the edges of the so-called mini-stopband that were opened by Bragg diffraction between two guided modes. Taking into account light collection, we relate this observation to the singular photon density of states that is characteristic of a one-dimensional photon system. Furthermore, we quantify by how much the radiation losses smooth the divergence. For the first time to our knowledge, a clear account of the control of spontaneous emission in a one-dimensional system is thus demonstrated.


Multiple somatotopic representations of heat and mechanical pain in the operculo-insular cortex: a high-resolution fMRI study.
Whereas studies of somatotopic representation of touch have been useful to distinguish multiple somatosensory areas within primary (SI) and secondary (SII) somatosensory cortex regions, no such analysis exists for the representation of pain across nociceptive modalities. Here we investigated somatotopy in the operculo-insular cortex with noxious heat and pinprick stimuli in 11 healthy subjects using high-resolution (2 × 2 × 4 mm) 3T functional magnetic resonance imaging (fMRI). Heat stimuli (delivered using a laser) and pinprick stimuli (delivered using a punctate probe) were directed to the dorsum of the right hand and foot in a balanced design. Locations of the peak fMRI responses were compared between stimulation sites (hand vs. foot) and modalities (heat vs. pinprick) within four bilateral regions of interest: anterior and posterior insula and frontal and parietal operculum. Importantly, all analyses were performed on individual, non-normalized fMRI images. For heat stimuli, we found hand-foot somatotopy in the contralateral anterior and posterior insula [hand, 9 ± 10 (SD) mm anterior to foot, P < 0.05] and in the contralateral parietal operculum (SII; hand, 7 ± 10 mm lateral to foot, P < 0.05). For pinprick stimuli, we also found somatotopy in the contralateral posterior insula (hand, 9 ± 10 mm anterior to foot, P < 0.05). Furthermore, the response to heat stimulation of the hand was 11 ± 12 mm anterior to the response to pinprick stimulation of the hand in the contralateral (left) anterior insula (P < 0.05). These results indicate the existence of multiple somatotopic representations for pain within the operculo-insular region in humans, possibly reflecting its importance as a sensory-integration site that directs emotional responses and behavior appropriately depending on the body site being injured.


Class I major histocompatibility complexes loaded by a periodate trigger.
Class I major histocompatibility complexes (MHCs) present peptide ligands on the cell surface for recognition by appropriate cytotoxic T cells. The unstable nature of unliganded MHC necessitates the production of recombinant class I complexes through in vitro refolding reactions in the presence of an added excess of peptides. This strategy is not amenable to high-throughput production of vast collections of class I complexes. To address this issue, we recently designed photocaged MHC ligands that can be cleaved by a UV light trigger in the MHC bound state under conditions that do not affect the integrity of the MHC structure. The results obtained with photocaged MHC ligands demonstrate that conditional MHC ligands can form a generally applicable concept for the creation of defined peptide-MHCs. However, the use of UV exposure to mediate ligand exchange is unsuited for a number of applications, due to the lack of UV penetration through cell culture systems and due to the transfer of heat upon UV irradiation, which can induce evaporation. To overcome these limitations, here, we provide proof-of-concept for the generation of defined peptide-MHCs by chemical trigger-induced ligand exchange. The crystal structure of the MHC with the novel chemosensitive ligand showcases that the ligand occupies the expected binding site, in a conformation where the hydroxyl groups should be reactive to periodate. We proceed to validate this technology by producing peptide-MHCs that can be used for T cell detection. The methodology that we describe here should allow loading of MHCs with defined peptides in cell culture devices, thereby permitting antigen-specific T cell expansion and purification for cell therapy. In addition, this technology will be useful to develop miniaturized assay systems for performing high-throughput screens for natural and unnatural MHC ligands.


Factors that influence primary cilium length.
Almost all mammalian cells carry one primary cilium that functions as a biosensor for chemical and mechanical stimuli. Genetic damages that compromise cilia formation or function cause a spectrum of disorders referred to as ciliapathies. Recent studies have demonstrated that some pharmacological agents and extracellular environmental changes can alter primary cilium length. Renal injury is a well-known example of an environmental insult that triggers cilia length modification. Lithium treatment causes primary cilia to extend in several cell types including neuronal cells;this phenomenon is likely independent of glycogen synthase kinase-3β inhibition. In renal epithelial cell lines, deflection of the primary cilia by fluid shear shortens them by reducing the intracellular cyclic AMP level, leading to a subsequent decrease in mechanosensitivity to fluid shear. Primary cilium length is also influenced by the dynamics of actin filaments and microtubules through the levels of soluble tubulin in the cytosol available for primary cilia extension. Thus, mammalian cells can adapt to the extracellular environment by modulating the primary cilium length, and this feedback system utilizing primary cilia might exist throughout the mammalian body. Further investigation is required concerning the precise molecular mechanisms underlying the control of primary cilium length in response to environmental factors.


Combined QTL and selective sweep mappings with coding SNP annotation and cis-eQTL analysis revealed PARK2 and JAG2 as new candidate genes for adiposity regulation.
Very few causal genes have been identified by quantitative trait loci (QTL) mapping because of the large size of QTL, and most of them were identified thanks to functional links already known with the targeted phenotype. Here, we propose to combine selection signature detection, coding SNP annotation, and cis-expression QTL analyses to identify potential causal genes underlying QTL identified in divergent line designs. As a model, we chose experimental chicken lines divergently selected for only one trait, the abdominal fat weight, in which several QTL were previously mapped. Using new haplotype-based statistics exploiting the very high SNP density generated through whole-genome resequencing, we found 129 significant selective sweeps. Most of the QTL colocalized with at least one sweep, which markedly narrowed candidate region size. Some of those sweeps contained only one gene, therefore making them strong positional causal candidates with no presupposed function. We then focused on two of these QTL/sweeps. The absence of nonsynonymous SNPs in their coding regions strongly suggests the existence of causal mutations acting in cis on their expression, confirmed by cis-eQTL identification using either allele-specific expression or genetic mapping analyses. Additional expression analyses of those two genes in the chicken and mice contrasted for adiposity reinforces their link with this phenotype. This study shows for the first time the interest of combining selective sweeps mapping, coding SNP annotation and cis-eQTL analyses for identifying causative genes for a complex trait, in the context of divergent lines selected for this specific trait. Moreover, it highlights two genes, JAG2 and PARK2, as new potential negative and positive key regulators of adiposity in chicken and mice.


Fluorescent Imaging for In Situ Measurement of Drug Target Engagement and Cell Signaling Pathways.
Successful cancer treatment continues to elude modern medicine and its arsenal of therapeutic strategies. Therapy resistance is driven by significant tumor heterogeneity, complex interactions between malignant, microenvironmental and immune cells and cross talk between signaling pathways. Advances in molecular characterization technologies such as next generation sequencing have helped unravel this network of interactions and identify druggable therapeutic targets. Tyrosine kinase inhibitors (TKI) are a class of drugs seeking to inhibit signaling pathways critical to sustaining proliferative signaling, resisting cell death, and the other hallmarks of cancer. While tumors may initially respond to TKI therapy, disease progression is near universal due to mechanisms of acquired resistance largely involving cellular signaling pathway reprogramming. With the ultimate goal of improved TKI therapeutic efficacy our group has developed intracellular paired agent imaging (iPAI) to quantify drug target interactions and oligonucleotide conjugated antibody (Ab-oligo) cyclic immunofluorescence (cycIF) imaging to characterize perturbed signaling pathways in response to therapy. iPAI uses spectrally distinct, fluorescently labeled targeted and untargeted drug derivatives, correcting for non-specific drug distribution and facilitating quantitative assessment of the drug binding before and after therapy. Ab-oligo cycIF exploits in situ hybridization of complementary oligonucleotides for biomarker labeling while oligonucleotide modifications facilitate signal removal for sequential rounds of fluorescent tagging and imaging. Ab-oligo CycIF is capable of generating extreme multi-parametric images for quantifying total and phosphorylated protein expression to quantify protein activation, expression, and spatial distribution. Together iPAI and Ab-oligo cycIF can be applied to interrogate drug uptake and target binding as well as changes to heterogenous cell populations within tumors that drive variable therapeutic responses in patients.


Herbal medicine: current status and the future.
The number of patients seeking alternate and herbal therapy is growing exponentially. Herbal medicines are the synthesis of therapeutic experiences of generations of practicing physicians of indigenous systems of medicine for over hundreds of years. Herbal medicines are now in great demand in the developing world for primary health care not because they are inexpensive but also for better cultural acceptability, better compatibility with the human body and minimal side effects. However, recent findings indicate that all herbal medicines may not be safe as severe consequences are reported for some herbal drugs. Most herbal products on the market today have not been subjected to drug approval process to demonstrate their safety and effectiveness. Thousand years of traditional use can provide us with valuable guidelines to the selection, preparation and application of herbal formulation. To be accepted as viable alternative to modern medicine, the same vigorous method of scientific and clinical validation must be applied to prove the safety and effectiveness of a therapeutical product. In the present review we attempted to describe the present scenario and project the future of herbal medicine.


The incident user design in comparative effectiveness research.
Comparative effectiveness research includes cohort studies and registries of interventions. When investigators design such studies, how important is it to follow patients from the day they initiated treatment with the study interventions? Our article considers this question and related issues to start a dialogue on the value of the incident user design in comparative effectiveness research. By incident user design, we mean a study that sets the cohort's inception date according to patients' new use of an intervention. In contrast, most epidemiologic studies enroll patients who were currently or recently using an intervention when follow-up began. We take the incident user design as a reasonable default strategy because it reduces biases that can impact non-randomized studies, especially when investigators use healthcare databases. We review case studies where investigators have explored the consequences of designing a cohort study by restricting to incident users, but most of the discussion has been informed by expert opinion, not by systematic evidence.


Mouse models and induced pluripotent stem cells in researching psychiatric disorders.
Psychiatric disorders are a problem for society both on a micro level involving patients and their families as well as on a macro level involving global economic costs. For years, scientists have relied on mouse models for research, but these have shortcomings that greatly hinder efforts to understand the pathophysiology and genetic factors of psychiatric disorders. Induced pluripotent stem cells (iPSCs) have shown potential to overcome obstacles that mouse models face and can provide patient-specific cells that allow for better understanding of genetic effects on psychiatric disorders. This review explores the current progress using iPSCs to model psychiatric disorders, specifically bipolar disorder and schizophrenia, while discussing remaining issues with iPSC use and how these issues can be resolved in the future.


Adjunct ultrasonography for breast cancer screening in women at average risk: a systematic review.
Screening with mammography has the ability to detect breast cancer at an early stage but misses some cancers. Supporters of adjunct ultrasonography to the screening regimen argue that it might be a safe and inexpensive approach to reduce the false-negative rates of screening. Critics are concerned that adjunct ultrasonography will also increase the rate of false-positive findings and can lead to unnecessary biopsies and treatments in women at average risk. The purpose of this review was to systematically assess the comparative benefits and harms of mammography with adjunct breast ultrasonography and mammography only in breast cancer screening. We searched multiple electronic databases and the Cochrane Breast Cancer Group's Specialised Register (from 1995 to February 2012). To detect ongoing or unpublished studies, we searched trial registries and multiple sources of grey literature. Two researchers independently reviewed all abstracts and full-text articles against pre-defined eligibility criteria. We dually rated the risk of bias of studies and the strength of evidence based on established guidance. We did not detect any controlled studies that provide evidence for (or against) the use of adjunct ultrasonography for screening in women at average risk for breast cancer. Extrapolations of results from women at elevated risk for breast cancer indicate that the false-positive rates in women at average risk who were recalled because of positive ultrasonographies will exceed 98%. In women with dense or very dense breast tissue, the evidence regarding the use of adjunct ultrasonography is not conclusive. No methodologically sound evidence is available justifying the routine use of ultrasonography as an adjunct screening tool in women at average risk for breast cancer. Clinicians should not use ultrasonography as a screening tool for breast cancer screening on a routine basis. The use should be limited to women with dense breasts for whom the accuracy of mammography is low, or for diagnostic purposes.


Cervical Microbiota Associated with Higher Grade Cervical Intraepithelial Neoplasia in Women Infected with High-Risk Human Papillomaviruses.
It is increasingly recognized that microbes that reside in and on human body sites play major roles in modifying the pathogenesis of several diseases, including cancer. However, specific microbes or microbial communities that can be mechanistically linked to cervical carcinogenesis remain largely unexplored. The purpose of the study was to examine the association between cervical microbiota and high-grade cervical intraepithelial neoplasia (CIN 2+) in women infected with high-risk (HR) human papillomaviruses (HPV) and to assess whether the cervical microbiota are associated with oxidative DNA damage as indicated by the presence of cervical cells positive for 8-hydroxy-2'-deoxyguanosine. The study included 340 women diagnosed with CIN 2+ (cases) and 90 diagnosed with CIN 1 (non-cases). Microbiota composition was determined by Illumina sequencing of the 16S rRNA gene amplified from DNA extracted from cervical mucus samples. Measures of alpha/beta-diversity were not associated with either CIN severity or oxidative DNA damage. However, a cervical mucosal community type (CT) dominated by L. iners and unclassified Lactobacillus spp was associated with CIN 2+ (OR = 3.48; 95% CI, 1.27-9.55). Sequence reads mapping to Lactobacillaceae, Lactobacillus, L. reuteri, and several sub-genus level Lactobacillus operational taxonomic units were also associated with CIN 2+ when examined independently (effect size >2.0; P < 0.05). Our 16S rRNA sequencing results need confirmation in independent studies using whole-genome shotgun sequencing and that would allow sharpening the suggested associations at finer taxonomic levels. Our results provide little evidence that DNA oxidative damage mediates the effect of the microbiome on the natural history of HPV infection and CIN severity. Cancer Prev Res; 9(5); 357-66. ©2016 AACR.


Becoming more oneself? Changes in personality following DBS treatment for psychiatric disorders: Experiences of OCD patients and general considerations.
Does DBS change a patient's personality? This is one of the central questions in the debate on the ethics of treatment with Deep Brain Stimulation (DBS). At the moment, however, this important debate is hampered by the fact that there is relatively little data available concerning what patients actually experience following DBS treatment. There are a few qualitative studies with patients with Parkinson's disease and Primary Dystonia and some case reports, but there has been no qualitative study yet with patients suffering from psychiatric disorders. In this paper, we present the experiences of 18 patients with Obsessive-Compulsive Disorder (OCD) who are undergoing treatment with DBS. We will also discuss the inherent difficulties of how to define and assess changes in personality, in particular for patients with psychiatric disorders. We end with a discussion of the data and how these shed new light on the conceptual debate about how to define personality.


Climatic drivers of hemispheric asymmetry in global patterns of ant species richness.
Although many taxa show a latitudinal gradient in richness, the relationship between latitude and species richness is often asymmetrical between the northern and southern hemispheres. Here we examine the latitudinal pattern of species richness across 1003 local ant assemblages. We find latitudinal asymmetry, with southern hemisphere sites being more diverse than northern hemisphere sites. Most of this asymmetry could be explained statistically by differences in contemporary climate. Local ant species richness was positively associated with temperature, but negatively (although weakly) associated with temperature range and precipitation. After contemporary climate was accounted for, a modest difference in diversity between hemispheres persisted, suggesting that factors other than contemporary climate contributed to the hemispherical asymmetry. The most parsimonious explanation for this remaining asymmetry is that greater climate change since the Eocene in the northern than in the southern hemisphere has led to more extinctions in the northern hemisphere with consequent effects on local ant species richness.


[The influence of alcohol drinking on medical care expenditures among National Health Insurance beneficiaries].
Heavy alcohol drinking is an important risk factor for some lifestyle-related diseases. However, the relationship between drinking habits and medical care expenditures has not been elucidated in a Japanese general population. We examined this relationship in a 9-year cohort study. Study participants were 2039 National Health Insurance beneficiaries aged 40-69 years living in a rural Japanese community. The baseline survey, with medical check-up, was performed in 1989 or 1990 and the subjects' drinking habits were estimated by questionnaire. Medical care use and costs were monitored by linkage with the National Health Insurance claim history files at baseline survey through the end of March 2000. Men who were daily heavy drinkers (ethanol intake > or =69 g per day) had significantly higher medical costs compared to participants who drank less, within 5 years after baseline. This difference was 2000 yen per month after adjusting for age, body mass index, smoking, systolic blood pressure, glycosuria, serum total cholesterol and alanine aminotransferase. Daily heavy male drinkers also had a higher hazard ratio for total mortality compared to occasional drinkers, by the Cox proportional hazard model (hazard ratio: 1.81), although it did not reach statistical significance (P = 0.153). In women, medical costs were almost the same for occasional and daily drinkers. Total medical costs among Japanese men aged 20 years and over may be decreased by about 8400 billon yen per year if we assume a 20% decrease in daily heavy drinkers. To reduce national medical costs, it is important to promote a program for heavy drinkers, as described in the "Health Japan 21" initiative, the Japanese national health promotion guidelines for the first 10 years of the 21st century.


The human laminin receptor is a member of the integrin family of cell adhesion receptors.
A receptor for the adhesive basement membrane protein, laminin, was isolated from human glioblastoma cells by affinity chromatography on laminin. This receptor has a heterodimeric structure similar to that of receptors for other extracellular matrix proteins such as fibronectin and vitronectin. Incorporation of the laminin receptor into liposomal membranes makes it possible for liposomes to attach to surfaces coated with laminin. The receptor liposomes also attached to some extent to surfaces coated with fibronectin, but not with other matrix proteins. These properties identify the laminin receptor as a member of the integrin family of cell adhesion receptors.


Childhood-onset schizophrenia. Progressive ventricular change during adolescence.
There is controversy about progression in brain abnormalities in later-onset schizophrenia. This study looked for more striking progression in brain abnormalities during adolescence in a chronically ill, treatment-refractory sample of patients with childhood-onset schizophrenia who had had more prepsychotic developmental disturbance, but clinical and neurobiological characteristics similar to those of patients with treatment-refractory adult-onset schizophrenia who have poor outcome. Anatomic brain magnetic resonance images were obtained for 16 children and adolescents with onset of schizophrenia by 12 years of age and 24 temporally yoked, age- and sex-matched healthy controls. Subjects were scanned on initial admission and rescanned after 2 years with the identical equipment and measurement methods. Childhood schizophrenics showed a significantly greater increase in ventricular volume than did controls, for whom ventricles did not increase significantly (analysis of variance, diagnosis x time, F = 16.1, P < .001). A significant decrease in midsagittal thalamic area was also seen for the schizophrenics (P = .03), which was unchanged at rescan for controls. These differential brain changes correlated significantly with each other and tended to be predicted by both prepsychotic developmental abnormality (Premorbid Assessment Scale, P = .06) and Brief Psychiatric Rating Scale at follow-up (P = .07). More consistent progressive ventricular enlargement was seen during adolescence for this childhood-onset sample than has been reported for adult-onset populations. The brain imaging results support other clinical data showing both early and late deviations in brain development for at least this rare subgroup of treatment-refractory, very-early-onset schizophrenic patients.


Help-seeking from clergy and spiritual counselors among veterans with depression and PTSD in primary care.
Little is known about the prevalence or predictors of seeking help for depression and PTSD from spiritual counselors and clergy. We describe openness to and actual help-seeking from spiritual counselors among primary care patients with depression. We screened consecutive VA primary care patients for depression; 761 Veterans with probable major depression participated in telephone surveys (at baseline, 7 months, and 18 months). Participants were asked about (1) openness to seeking help for emotional problems from spiritual counselors/clergy and (2) actual contact with spiritual counselors/clergy in the past 6 months. At baseline, almost half of the participants, 359 (47.2%), endorsed being "very" or "somewhat likely" to seek help for emotional problems from spiritual counselors; 498 (65.4%) were open to a primary care provider, 486 (63.9%) to a psychiatrist, and 409 (66.5%) to another type of mental health provider. Ninety-one participants (12%) reported actual spiritual counselor/clergy consultation. Ninety-five (10.3%) participants reported that their VA providers had recently asked them about spiritual support; the majority of these found this discussion helpful. Participants with current PTSD symptoms, and those with a mental health visit in the past 6 months, were more likely to report openness to and actual help-seeking from clergy. Veterans with depression and PTSD are amenable to receiving help from spiritual counselors/clergy and other providers. Integration of spiritual counselors/clergy into care teams may be helpful to Veterans with PTSD. Training of such providers to address PTSD specifically may also be desirable.


Readability assessment of online patient resources for breast augmentation surgery.
Patients increasingly rely on Internet resources for medical information. Well-informed patients are more likely to be active participants in their health care, contributing to higher satisfaction and better overall outcomes. Access to online patient material, however, can be limited by inadequate functional health literacy. The National Institutes of Health and the American Medical Association recommend that educational content be written at a sixth-grade reading level. This study aims to assess the readability of online patient resources for breast augmentation surgery. A Web search for "breast implant surgery" was performed using the largest public search engine. After sponsored results were excluded, the 12 most accessed sites were identified. Patient-directed information from all relevant articles immediately linked from the main site was downloaded and formatted into plain text. The readability of 110 articles was evaluated using 10 established analyses, both overall and by Web site. The overall average readability of the 12 most popular Internet resources for breast augmentation was at a thirteenth-grade reading level (Coleman-Liau, 13.4; Flesch-Kincaid, 12.7; FORCAST, 11.3; Fry, 13; New Dale-Chall, 12.9; New Gunning Fog, 13.8; Raygor Estimate, 15; and Simple Mesaure of Gobbledygook Formula, 14.3). The Flesch Reading Ease index was 41, which falls into a "difficult" reading category. No individual article or Web site was at the recommended sixth-grade level. Online resources for breast augmentation are above recommended reading levels. This may potentially serve as a barrier to patients seeking this type of surgery. Plastic surgeons should be aware of potential gaps in understanding and direct patients toward more appropriate resources.


Knowledge Guided Disambiguation for Large-Scale Scene Classification With Multi-Resolution CNNs.
Convolutional neural networks (CNNs) have made remarkable progress on scene recognition, partially due to these recent large-scale scene datasets, such as the Places and Places2. Scene categories are often defined by multi-level information, including local objects, global layout, and background environment, thus leading to large intra-class variations. In addition, with the increasing number of scene categories, label ambiguity has become another crucial issue in large-scale classification. This paper focuses on large-scale scene recognition and makes two major contributions to tackle these issues. First, we propose a multi-resolution CNN architecture that captures visual content and structure at multiple levels. The multi-resolution CNNs are composed of coarse resolution CNNs and fine resolution CNNs, which are complementary to each other. Second, we design two knowledge guided disambiguation techniques to deal with the problem of label ambiguity: 1) we exploit the knowledge from the confusion matrix computed on validation data to merge ambiguous classes into a super category and 2) we utilize the knowledge of extra networks to produce a soft label for each image. Then, the super categories or soft labels are employed to guide CNN training on the Places2. We conduct extensive experiments on three large-scale image datasets (ImageNet, Places, and Places2), demonstrating the effectiveness of our approach. Furthermore, our method takes part in two major scene recognition challenges, and achieves the second place at the Places2 challenge in ILSVRC 2015, and the first place at the LSUN challenge in CVPR 2016. Finally, we directly test the learned representations on other scene benchmarks, and obtain the new state-of-the-art results on the MIT Indoor67 (86.7%) and SUN397 (72.0%). We release the code and models at https://github.com/wanglimin/MRCNN-Scene-Recognition.


Cubilin maintains blood levels of HDL and albumin.
Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL3 particles (density>1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.


A molecular and structural characterization of senescing Arabidopsis siliques and comparison of transcriptional profiles with senescing petals and leaves.
Senescence of plant organs is a genetically controlled process that regulates cell death to facilitate nutrient recovery and recycling, and frequently precedes, or is concomitant with, ripening of reproductive structures. In Arabidopsis thaliana, the seeds are contained within a silique, which is itself a photosynthetic organ in the early stages of development and undergoes a programme of senescence prior to dehiscence. A transcriptional analysis of the silique wall was undertaken to identify changes in gene expression during senescence and to correlate these events with ultrastructural changes. The study revealed that the most highly up-regulated genes in senescing silique wall tissues encoded seed storage proteins, and the significance of this finding is discussed. Global transcription profiles of senescing siliques were compared with those from senescing Arabidopsis leaf or petal tissues using microarray datasets and metabolic pathway analysis software (MapMan). In all three tissues, members of NAC and WRKY transcription factor families were up-regulated, but components of the shikimate and cell-wall biosynthetic pathways were down-regulated during senescence. Expression of genes encoding ethylene biosynthesis and action showed more similarity between senescing siliques and petals than between senescing siliques and leaves. Genes involved in autophagy were highly expressed in the late stages of death of all plant tissues studied, but not always during the preceding remobilization phase of senescence. Analyses showed that, during senescence, silique wall tissues exhibited more transcriptional features in common with petals than with leaves. The shared and distinct regulatory events associated with senescence in the three organs are evaluated and discussed.


Arsenic: toxicity, oxidative stress and human disease.
Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)-mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione-depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO•), the superoxide radical, singlet oxygen, hydroxyl radical (OH•) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant-induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (α-tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic-induced oxidative stress.


Novel pathways associated with bypassing cellular senescence in human prostate epithelial cells.
Cellular senescence forms a barrier that inhibits the acquisition of an immortal phenotype, a critical feature in tumorigenesis. The inactivation of multiple pathways that positively regulate senescence are required for immortalization. To identify these pathways in an unbiased manner, we performed DNA microarray analyses to assess the expression of 20,000 genes in human prostate epithelial cells (HPECs) passaged to senescence. These gene expression patterns were then compared with those of HPECs immortalized with the human Papillomavirus 16 E7 oncoprotein. Senescent cells display gene expression patterns that reflect their nonproliferative, differentiated phenotype and express secretory proteases and extracellular matrix components. A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes: the chemokine BRAK, DOC1, and a member of the insulin-like growth factor axis, IGFBP-3. Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts, and previously, their inactivation was documented in tumor samples. Thus, these genes may function in novel pathways that regulate senescence and are inactivated during immortalization. These changes may be critical not only in allowing cells to bypass senescence in vitro but in the progression of prostate cancer in vivo.


Influence of hormonal functional status on survival in adrenocortical carcinoma: systematic review and meta-analysis.
Objective Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis. Many publications in ACC report on risk factors for a poor outcome; one risk factor studied is hormonal hypersecretion (cortisol, sex-hormones, steroid precursors or aldosterone). The aim of this systematic review was to study the association between hormonal secretion and recurrence or mortality in ACC. Design Systematic review and meta-analysis. We searched PubMed, EMBASE and The Cochrane library (January 2018) for cohort studies examining the association between hormonal secretion on overall or recurrence-free survival in ACC. Methods A random-effects model meta-analysis was performed to obtain a weighted relative risk comparing cortisol-secreting and/or androgen-secreting ACCs to non-secreting tumours regarding overall and recurrence-free survival. Risk of bias assessment was performed for all studies included. Results Nineteen publications were included representing a total of 3814 patients. Most studies were generally considered low/intermediate risk of bias. Meta-analysis showed higher mortality risk for cortisol-secreting ACCs, weighted relative risk 1.71 (95% CI: 1.18-2.47) combining studies that adjusted for tumour stage; also a higher recurrence risk was found for cortisol producing ACCs, relative risk 1.43 (95% CI: 1.18-1.73). Androgen secretion was not clearly associated with survival (RR: 0.82, 95% CI: 0.60-1.12). Conclusion This systematic review and meta-analysis show that cortisol-secreting ACCs are associated with a worse overall survival; future research is needed to establish whether this association points to negative effects of cortisol action, whether it signifies a more aggressive ACC subtype or whether cortisol is merely a prognostic marker.


Mesothelioma associated with the shipbuilding industry in coastal Virginia.
A case-control study was undertaken to clarify reasons for a four-fold increased incidence of mesothelioma discovered among white males in coastal Tidewater, Va., from 1972 to 1978. Sixty-one cases were identified. Interviews with next of kin revealed that the excess was linked to employment in area shipyards. Three-fourths of the cases had been employed in the shipbuilding industry, nearly all beginning employment prior to 1950. Most were career employees, but an increased risk was also found among those who worked only temporarily, mainly during World War II, and were reportedly exposed to asbestos. More of the cases than controls were pipecoverers or pipefitters, but cases were reported to work in a variety of shipyard trades. Few of the mesothelioma cases were heavy smokers, a trend that may be related in part to the competing risks for fatal diseases caused by the interactions of smoking and asbestos exposure. Information obtained by interview for five of the six white females diagnosed with mesothelioma revealed that the husband of four had been employed in the shipbuilding industry.