Ambulatory cassette polysomnography: findings from a large cohort of drug-free insomnia patients.
Technology for conducting ambulatory polysomnography (APSG) has been available for more than a decade, but relatively few studies have used this technology to study the sleep of subjects in their usual home sleeping environments. Herein we suggest the usefulness of this technology for the study of normal sleepers and insomniacs, and we report our APSG findings with a large cohort (n = 117) of drug-free insomnia outpatients. All patients completed a sleep-history questionnaire, a clinical interview with a sleep-disorders clinician, and one night of APSG in their homes. Most sleep parameters derived were consistent with previously reported laboratory PSG findings for insomniacs, except that values of rapid-eye-movement sleep latencies were generally shorter than typically found in laboratory studies. Moreover, results showed that APSG served to differentiate major age groups and diagnostic subtypes within our larger sample, and patient tolerance for APSG was within acceptable limits. We conclude that APSG is a useful technique for evaluating insomnia complaints.


High-Precision Solvent Vapor Annealing for Block Copolymer Thin Films.
Despite its efficacy in producing well-ordered, periodic nanostructures, the intricate role multiple parameters play in solvent vapor annealing has not been fully established. In solvent vapor annealing a thin polymer film is exposed to a vapor of solvent(s) thus forming a swollen and mobile layer to direct the self-assembly process at the nanoscale. Recent developments in both theory and experiments have directly identified critical parameters that govern this process, but controlling them in any systematic way has proven non-trivial. These identified parameters include vapor pressure, solvent concentration in the film, and the solvent evaporation rate. To explore their role, a purpose-built solvent vapor annealing chamber was designed and constructed. The all-metal chamber is designed to be inert to solvent exposure. Computer-controlled, pneumatically actuated valves allow for precision timing in the introduction and withdrawal of solvent vapor from the film. The mass flow controller-regulated inlet, chamber pressure gauges, in situ spectral reflectance-based thickness monitoring, and low flow micrometer relief valve give real-time monitoring and control during the annealing and evaporation phases with unprecedented precision and accuracy. The reliable and repeatable alignment of polylactide cylinders formed from polystyrene-b-polylactide, where cylinders stand perpendicular to the substrate and span the thickness of the film, provides one illustrative example.


Initial validation of a diagnostic questionnaire for gastroesophageal reflux disease.
Brief, reliable, and valid self-administered questionnaires could facilitate the diagnosis of gastroesophageal reflux disease in primary care. We report the development and validation of such an instrument. Content validity was informed by literature review, expert opinion, and cognitive interviewing of 50 patients resulting in a 22-item survey. For psychometric analyses, primary care patients completed the new questionnaire at enrollment and at intervals ranging from 3 days to 3 wk. Multitrait scaling, test-retest reliability, and responsiveness were assessed. Predictive validity analyses of all scales and items used specialty physician diagnosis as the "gold standard." Iterative factor analyses yielded three scales of four items each including heartburn, acid regurgitation, and dyspepsia. Multitrait scaling criteria including internal consistency, item interval consistency, and item discrimination were 100% satisfied. Test-retest reliability was high in those reporting stable symptoms. Scale scores significantly changed in those reporting a global change. Regressing specialty physician diagnosis on the three scales revealed significant effects for two scales (heartburn and regurgitation). Combining the two significant scales enhanced the strength of the model. Symptom response to self-directed treatment with nonprescription antisecretory medications was highly predictive of the diagnosis also, although the item demonstrated poor validity and reliability. A brief, simple 12-item questionnaire demonstrated validity and reliability and seemed to be responsive to change for reflux and dyspeptic symptoms.


Readability and Quality of Online Patient Education Material on Websites of Breast Imaging Centers.
The purpose of this study was to assess the readability and quality of patient information regarding mammography, tomosynthesis, and breast density on the websites of ACR-designated mammography Breast Imaging Centers of Excellence (BICOEs) in the United States. In this institutional review board-exempt study, websites of mammography BICOEs were identified by state. Websites were assessed for presence of patient education material on screening mammography, tomosynthesis, and breast density. This material was then assessed for readability using five well-established readability metrics (Flesch-Kincaid Reading Ease Index, Flesch-Kincaid Grade Level, Gunning-Fog Score, Coleman-Liau Index, and Simple Measure of Gobbledygook Index) and for quality using the DISCERN instrument. We identified 1,482 BICOE centers, of which 1,451 (98%) had websites; 79% (1,156 of 1,451) of websites had information on screening mammography, 45% (657 of 1,451) on tomosynthesis, and 16% (228 of 1,451) on breast density. Readability analysis showed that the overall average grade level of patient information was 12.4. Average readability grade levels by tested indexes were Flesch-Kincaid Grade Level of 11.5, Gunning-Fog Score of 14.1, Coleman-Liau Index of 14.1, and Simple Measure of Gobbledygook Index of 10.9. The average Flesch-Kincaid Reading Ease score was 45, with 0 being the most difficult and 100 being the easiest text to read. The overall DISCERN score nationally was 2.61 of 5 (with 5 representing the highest quality). Although most BICOEs have patient education material on their websites regarding mammography and some have information regarding tomosynthesis and breast density, the average readability grade level of this material is more than double the nationally recommended readability grade level of 6 for health care information. Additionally, the overall quality of this material is relatively low per established quality metrics.


The overarching influence of the gut microbiome on end-organ function: the role of live probiotic cultures.
At the time of birth, humans experience an induced pro-inflammatory beneficial event. The mediators of this encouraged activity, is a fleet of bacteria that assault all mucosal surfaces as well as the skin. Thus initiating effects that eventually provide the infant with immune tissue maturation. These effects occur beneath an emergent immune system surveillance and antigenic tolerance capability radar. Over time, continuous and regulated interactions with environmental as well as commensal microbial, viral, and other antigens lead to an adapted and maintained symbiotic state of tolerance, especially in the gastrointestinal tract (GIT) the organ site of the largest microbial biomass. However, the perplexing and much debated surprise has been that all microbes need not be targeted for destruction. The advent of sophisticated genomic techniques has led to microbiome studies that have begun to clarify the critical and important biochemical activities that commensal bacteria provide to ensure continued GIT homeostasis. Until recently, the GIT and its associated micro-biometabolome was a neglected factor in chronic disease development and end organ function. A systematic underestimation has been to undervalue the contribution of a persistent GIT dysbiotic (a gut barrier associated abnormality) state. Dysbiosis provides a plausible clue as to the origin of systemic metabolic disorders encountered in clinical practice that may explain the epidemic of chronic diseases. Here we further build a hypothesis that posits the role that subtle adverse responses by the GIT microbiome may have in chronic diseases. Environmentally/nutritionally/and gut derived triggers can maintain microbiome perturbations that drive an abnormal overload of dysbiosis. Live probiotic cultures with specific metabolic properties may assist the GIT microbiota and reduce the local metabolic dysfunctions. As such the effect may translate to a useful clinical treatment approach for patients diagnosed with a metabolic disease for end organs such as the kidney and liver. A profile emerges that shows that bacteria are diverse, abundant, and ubiquitous and have significantly influenced the evolution of the eukaryotic cell.


Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae.
The efficacy of ceftazidime-avibactam-a cephalosporin-β-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE)-compared with colistin remains unknown. Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study. Efficacy, safety, and benefit-risk analyses were performed using intent-to-treat analyses with partial credit and the desirability of outcome ranking approaches. The ordinal efficacy outcome was based on disposition at day 30 after starting treatment (home vs not home but not observed to die in the hospital vs hospital death). All analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). Thirty-eight patients were treated first with ceftazidime-avibactam and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. Bloodstream (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with ceftazidime-avibactam versus colistin, IPTW-adjusted all-cause hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001). In an analysis of disposition at 30 days, patients treated with ceftazidime-avibactam, compared with those treated within colistin, had an IPTW-adjusted probability of a better outcome of 64% (95% confidence interval, 57%-71%). Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin. Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections. These findings require confirmation in a randomized controlled trial.


Stress, energy and psychosocial conditions in different types of call centres.
To identify risk indicators for high stress and low mental energy as well as to describe psychosocial working conditions at different types of call centres. 1183 operators from 28 call centres in Sweden, both external and internal, with different levels of task complexity, ownership and geographical location. A cross sectional questionnaire study. The stress level was moderately high and the energy level fairly high. Stress levels tended to be lower and psychosocial conditions better with increasing level of task complexity. Fourteen per cent of the operators were in a state of high stress/low energy ("worn out") and 47% in high stress/high energy ("committed under pressure"). Operators in a state of low stress/high energy ("committed without pressure") were most likely to report a better health status. High stress and lack of energy was mainly associated with time pressure, low decision latitude, and lack of social and supervisor support. Time pressure in combination with lack of support and influence should be seen as a potential high risk situation for the development of a "worn-out" state among call centre operators. Management should make use of this knowledge in order to promote a long lasting efficient and healthy call centre work.


Risk factors for cesarean delivery following labor induction in multiparous women.
To identify potential risk factors for cesarean delivery following labor induction in multiparous women at term. We conducted a retrospective case-control study. Cases were parous women in whom the induction of labor had resulted in a cesarean delivery. For each case, we used the data of two successful inductions as controls. Successful induction was defined as a vaginal delivery after the induction of labor. The study was limited to term singleton pregnancies with a child in cephalic position. Between 1995 and 2010, labor was induced in 2548 parous women, of whom 80 had a cesarean delivery (3%). These 80 cases were compared to the data of 160 parous women with a successful induction of labor. In the multivariate analysis history of preterm delivery (odds ratio (OR) 5.3 (95% CI 1.1 to 25)), maternal height (OR 0.87 (95% CI 0.80 to 0.95)) and dilatation at the start of induction (OR 0.43 (95% CI 0.19 to 0.98)) were associated with failed induction. In multiparous women, the risk of cesarean delivery following labor induction increases with previous preterm delivery, short maternal height, and limited dilatation at the start of induction.


FDI World Dental Federation: clinical criteria for the evaluation of direct and indirect restorations-update and clinical examples.
In 2007, new clinical criteria were approved by the FDI World Dental Federation and simultaneously published in three dental journals. The criteria were categorized into three groups: esthetic parameters (four criteria), functional parameters (six criteria) and biological parameters (six criteria). Each criterion can be expressed with five scores, three for acceptable and two for non-acceptable (one for reparable and one for replacement). The criteria have been used in several clinical studies since 2007, and the resulting experience in their application has led to a requirement to modify some of the criteria and scores. The two major alterations involve staining and approximal contacts. As staining of the margins and the surface has different causes, both phenomena do not appear simultaneously. Thus, staining has been differentiated into marginal staining and surface staining. The approximal contact now appears under the name "approximal anatomic form" as the approximal contour is a specific, often non-esthetic issue that cannot be integrated into the criterion "esthetic anatomical form". In 2008, a web-based training and calibration tool called e-calib ( www.e-calib.info ) was made available. Clinical investigators and other research workers can train and calibrate themselves interactively by assessing clinical cases of posterior restorations which are presented as high-quality pictures. Currently, about 300 clinical cases are included in the database which is regularly updated. Training for eight of the 16 clinical criteria is available in the program: "Surface lustre"; "Staining (surface, margins)"; "Color match and translucency"; Esthetic anatomical form"; "Fracture of material and retention"; "Marginal adaptation"; "Recurrence of caries, erosion, abfraction"; and "Tooth integrity (enamel cracks, tooth fractures)". Typical clinical cases are presented for each of these eight criteria and their corresponding five scores.


Association Between Colorectal Cancer Mortality and Gradient Fecal Hemoglobin Concentration in Colonoscopy Noncompliers.
To what extent the risk for colorectal cancer (CRC) death among noncompliers of colonoscopy is elevated following positive fecal immunological testing and whether the elevated risk varies with the fecal hemoglobin concentration (f-Hb) and location of CRC have not been researched. We used data on 59 389 individuals (4.0%) among 1 489 937 Taiwanese screenees age 50 to 69 years with f-Hb 20 μg hemoglobin or more per gram of feces from 2004 to 2009. They were classified into 41 995 who received colonoscopy and 10 778 who received no confirmatory examination; the latter was categorized into three risk groups according to f-Hb (20-49, 50-99, and 100+). Mortality from CRC as the primary end point was monitored until December 31, 2012. A 1.64-fold (95% confidence interval [CI] = 1.32 to 2.04) increased risk for CRC death for the noncolonoscopy group as opposed to the colonoscopy group adjusting for differences in baseline characteristics. A gradient relationship was noted between cumulative mortality and age- and sex-adjusted f-Hb categories with 1.31-fold (95% CI = 1.04 to 1.71), 2.21-fold (95% CI = 1.55 to 3.34), and 2.53-fold (95% CI = 1.95 to 3.43) increased risk, respectively, for the 20-49, 50-99, and 100+ risk groups in the noncolonoscopy group compared with the colonoscopy group. The noncolonoscopy group led to a statistically significant 1.75-fold increased risk (95% CI = 1.35 to 2.33) for CRC of the distal colon but a statistically nonsignificant 1.11-fold increased risk (95% CI = 0.70 to 1.75) for the proximal colon, compared with the colonoscopy group. When the comparator was limited to subjects whose colonoscopy was completed to the cecum, the statistically significantly elevated risk for CRC mortality was seen for both distal and proximal colon in the noncolonoscopy group. After a positive fecal immunochemical test, colonoscopy can reduce by about half the number of deaths from CRC. Among colonoscopy noncompliers, higher f-Hb is associated with an increased risk of mortality from CRC in a dose-response manner.


GSK2193874 treatment at heatstroke onset reduced cell apoptosis in heatstroke mice.
Heatstroke is still a potentially fatal threat during summer heat waves, despite improved prevention and treatment. It is reported that the transient receptor potential vanilloid 4 (TRPV4) inhibitor may protect septicemia mice. Many aspects of heatstroke have been defined, from the sepsis-mimic inflammatory response to hyperthermia. Hence, TRPV4 may be a therapeutic target for heatstroke. The results in murine models of heatstroke verified that GSK2193874, as a selected TRPV4 inhibitor, was injected at heatstroke onset, and then reduced the reduction of core temperature, the death rate, wet/dry ratio of the lung, levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, coagulation indicators, the degree of organ injury, and caspase-3/7 activity (P<0.05). But GSK2193874 treatment before heat stress did not improve the symptoms of heatstroke mice. Therefore, TRPV4 should be involved in heatstroke-induced injury. Timely GSK2193874 administration may be useful to reduce heatstroke-induced injury. TRPV4 may be a potential new therapeutic target in fatal heatstroke.


A novel approach to predict the likelihood of specific ovarian tumor pathology based on serum CA-125: a multicenter observational study.
The CA-125 tumor marker has limitations when used to distinguish between benign and malignant ovarian masses. We therefore establish likelihood curves of six subgroups of ovarian pathology based on CA-125 and menopausal status. This cross-sectional study conducted by the International Ovarian Tumor Analysis group involved 3,511 patients presenting with a persistent adnexal mass that underwent surgical intervention. CA-125 distributions for six tumor subgroups (endometriomas and abscesses, other benign tumors, borderline tumors, stage I invasive cancers, stage II-IV invasive cancers, and metastatic tumors) were estimated using kernel density estimation with stratification for menopausal status. Likelihood curves for the tumor subgroups were derived from the distributions. Endometriomas and abscesses were the only benign pathologies with median CA-125 levels above 20 U/mL (43 and 45, respectively). Borderline and invasive stage I tumors had relatively low median CA-125 levels (29 and 81 U/mL, respectively). The CA-125 distributions of stage II-IV invasive cancers and benign tumors other than endometriomas or abscesses were well separated; the distributions of the other subgroups overlapped substantially. This held for premenopausal and postmenopausal patients. Likelihood curves and reference tables comprehensibly show how subgroup likelihoods change with CA-125 and menopausal status. Our results confirm the limited clinical value of CA-125 for preoperative discrimination between benign and malignant ovarian pathology. We have shown that CA-125 may be used in a different way. By using likelihood reference tables, we believe clinicians will be better able to interpret preoperative serum CA-125 results in patients with adnexal masses.


Value of labial salivary gland histopathology for diagnosis of Sjögren's syndrome in patients with anti-centromere antibody positivity.
Although anti-centromere antibody (ACA)+ Sjögren's syndrome (SS) is considered a subtype of SS, it was not included in the recent American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) SS classification criteria. ACA+ patients without anti-SS-A/Ro antibodies require salivary gland histopathology to fulfill the ACR/EULAR criteria for diagnosis of SS. We reviewed salivary gland histology among ACA+ patients referred for the diagnosis of SS using the ACR/EULAR and Japanese criteria which does not require biopsy. Data from 147 ACA+ patients with dry eyes and/or mouth who visited our department were retrospectively analyzed. Clinical, immunological, and histological data were collected and statistically analyzed. Sixty-five patients (44%) had undergone labial salivary gland biopsy. The frequency of dry mouth was higher in ACA+ patients who had undergone labial salivary gland biopsy than in those who had not (P = .046), while there were no differences in biopsy rates between patients with and without sclerodactyly (P = .51). According to the current ACR/EULAR classification criteria, Greenspan grade of 3 or 4 for labial salivary gland histopathology is required in patients without anti-SS-A/Ro antibody for the diagnosis of SS. Four patients with Greenspan grades <3 and anti-SS-A/Ro antibody met the criteria for SS. In 54 patients in which the ACR/EULAR criteria were met, 53 patients were diagnosed with SS using the Japanese criteria. In ACA+/anti-SS-A/Ro- antibody patients, agreement between ACR/EULAR and Japanese criteria sets was excellent. For easily classifying ACA+ patients as SS cases, salivary gland biopsy should be performed in ACA+ patients with dry symptoms to identify ACA+ patients.


Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins.
Many misfolded endoplasmic reticulum (ER) proteins are eliminated by ERAD, a process in which substrates are polyubiquitylated and moved into the cytosol for proteasomal degradation. We have identified in S. cerevisiae distinct ubiquitin-ligase complexes that define different ERAD pathways. Proteins with misfolded ER-luminal domains use the ERAD-L pathway, in which the Hrd1p/Hrd3p ligase forms a near stoichiometric membrane core complex by binding to Der1p via the linker protein Usa1p. This core complex associates through Hrd3p with Yos9p, a substrate recognition protein in the ER lumen. Substrates with misfolded intramembrane domains define a pathway (ERAD-M) that differs from ERAD-L by being independent of Usa1p and Der1p. Membrane proteins with misfolded cytosolic domains use the ERAD-C pathway and are directly targeted to the Doa10p ubiquitin ligase. All three pathways converge at the Cdc48p ATPase complex. These results lead to a unifying concept for ERAD that may also apply to mammalian cells.


Assessment of a personalized and distributed patient guidance system.
The MobiGuide project aimed to establish a ubiquitous, user-friendly, patient-centered mobile decision-support system for patients and for their care providers, based on the continuous application of clinical guidelines and on semantically integrated electronic health records. Patients would be empowered by the system, which would enable them to lead their normal daily lives in their regular environment, while feeling safe, because their health state would be continuously monitored using mobile sensors and self-reporting of symptoms. When conditions occur that require medical attention, patients would be notified as to what they need to do, based on evidence-based guidelines, while their medical team would be informed appropriately, in parallel. We wanted to assess the system's feasibility and potential effects on patients and care providers in two different clinical domains. We describe MobiGuide's architecture, which embodies these objectives. Our novel methodologies include a ubiquitous architecture, encompassing a knowledge elicitation process for parallel coordinated workflows for patients and care providers; the customization of computer-interpretable guidelines (CIGs) by secondary contexts affecting remote management and distributed decision-making; a mechanism for episodic, on demand projection of the relevant portions of CIGs from a centralized, backend decision-support system (DSS), to a local, mobile DSS, which continuously delivers the actual recommendations to the patient; shared decision-making that embodies patient preferences; semantic data integration; and patient and care provider notification services. MobiGuide has been implemented and assessed in a preliminary fashion in two domains: atrial fibrillation (AF), and gestational diabetes Mellitus (GDM). Ten AF patients used the AF MobiGuide system in Italy and 19 GDM patients used the GDM MobiGuide system in Spain. The evaluation of the MobiGuide system focused on patient and care providers' compliance to CIG recommendations and their satisfaction and quality of life. Our evaluation has demonstrated the system's capability for supporting distributed decision-making and its use by patients and clinicians. The results show that compliance of GDM patients to the most important monitoring targets - blood glucose levels (performance of four measurements a day: 0.87±0.11; measurement according to the recommended frequency of every day or twice a week: 0.99±0.03), ketonuria (0.98±0.03), and blood pressure (0.82±0.24) - was high in most GDM patients, while compliance of AF patients to the most important targets was quite high, considering the required ECG measurements (0.65±0.28) and blood-pressure measurements (0.75±1.33). This outcome was viewed by the clinicians as a major potential benefit of the system, and the patients have demonstrated that they are capable of self-monitoring - something that they had not experienced before. In addition, the system caused the clinicians managing the AF patients to change their diagnosis and subsequent treatment for two of the ten AF patients, and caused the clinicians managing the GDM patients to start insulin therapy earlier in two of the 19 patients, based on system's recommendations. Based on the end-of-study questionnaires, the sense of safety that the system has provided to the patients was its greatest asset. Analysis of the patients' quality of life (QoL) questionnaires for the AF patients was inconclusive, because while most patients reported an improvement in their quality of life in the EuroQoL questionnaire, most AF patients reported a deterioration in the AFEQT questionnaire. Feasibility and some of the potential benefits of an evidence-based distributed patient-guidance system were demonstrated in both clinical domains. The potential application of MobiGuide to other medical domains is supported by its standards-based patient health record with multiple electronic medical record linking capabilities, generic data insertion methods, generic medical knowledge representation and application methods, and the ability to communicate with a wide range of sensors. Future larger scale evaluations can assess the impact of such a system on clinical outcomes. MobiGuide's feasibility was demonstrated by a working prototype for the AF and GDM domains, which is usable by patients and clinicians, achieving high compliance to self-measurement recommendations, while enhancing the satisfaction of patients and care providers.


Postponed or immediate drainage of infected necrotizing pancreatitis (POINTER trial): study protocol for a randomized controlled trial.
Infected necrosis complicates 10% of all acute pancreatitis episodes and is associated with 15-20% mortality. The current standard treatment for infected necrotizing pancreatitis is the step-up approach (catheter drainage, followed, if necessary, by minimally invasive necrosectomy). Catheter drainage is preferably postponed until the stage of walled-off necrosis, which usually takes 4 weeks. This delay stems from the time when open necrosectomy was the standard. It is unclear whether such delay is needed for catheter drainage or whether earlier intervention could actually be beneficial in the current step-up approach. The POINTER trial investigates if immediate catheter drainage in patients with infected necrotizing pancreatitis is superior to the current practice of postponed intervention. POINTER is a randomized controlled multicenter superiority trial. All patients with necrotizing pancreatitis are screened for eligibility. In total, 104 adult patients with (suspected) infected necrotizing pancreatitis will be randomized to immediate (within 24 h) catheter drainage or current standard care involving postponed catheter drainage. Necrosectomy, if necessary, is preferably postponed until the stage of walled-off necrosis, in both treatment arms. The primary outcome is the Comprehensive Complication Index (CCI), which covers all complications between randomization and 6-month follow up. Secondary outcomes include mortality, complications, number of (repeat) interventions, hospital and intensive care unit (ICU) lengths of stay, quality-adjusted life years (QALYs) and direct and indirect costs. Standard follow-up is at 3 and 6 months after randomization. The POINTER trial investigates if immediate catheter drainage in infected necrotizing pancreatitis reduces the composite endpoint of complications, as compared with the current standard treatment strategy involving delay of intervention until the stage of walled-off necrosis. ISRCTN, 33682933 . Registered on 6 August 2015. Retrospectively registered.


Experimental analysis of the Arabidopsis mitochondrial proteome highlights signaling and regulatory components, provides assessment of targeting prediction programs, and indicates plant-specific mitochondrial proteins.
A novel insight into Arabidopsis mitochondrial function was revealed from a large experimental proteome derived by liquid chromatography-tandem mass spectrometry. Within the experimental set of 416 identified proteins, a significant number of low-abundance proteins involved in DNA synthesis, transcriptional regulation, protein complex assembly, and cellular signaling were discovered. Nearly 20% of the experimentally identified proteins are of unknown function, suggesting a wealth of undiscovered mitochondrial functions in plants. Only approximately half of the experimental set is predicted to be mitochondrial by targeting prediction programs, allowing an assessment of the benefits and limitations of these programs in determining plant mitochondrial proteomes. Maps of putative orthology networks between yeast, human, and Arabidopsis mitochondrial proteomes and the Rickettsia prowazekii proteome provide detailed insights into the divergence of the plant mitochondrial proteome from those of other eukaryotes. These show a clear set of putative cross-species orthologs in the core metabolic functions of mitochondria, whereas considerable diversity exists in many signaling and regulatory functions.


Comorbidities and causes of death in the management of localized T1a kidney cancer.
The objectives of the present study were analyze specific comorbidities associated with survival and actual causes of death for patients with small renal masses, and to suggest a simplified measure associated with decreased overall survival specific to this population. The Surveillance, Epidemiology and End Results-Medicare database (1995-2007) was queried to identify patients with localized T1a kidney cancer undergoing partial nephrectomy, radical nephrectomy or deferring therapy. We explored independent associations of specific comorbidities with causes of death, and developed a simplified cardiovascular index. Cox proportional hazards, and Fine and Gray competing risks regression were used. Of 7177 Medicare beneficiaries in the study population, 754 (10.5%) deferred therapy, 1849 (25.8%) underwent partial nephrectomy and 4574 (63.7%) underwent radical nephrectomy with none of the selected comorbidities identified in 3682 (51.3%) patients. Congestive heart failure, chronic kidney disease, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes and cerebrovascular disease were associated with decreased overall survival. The cardiovascular index provided good survival risk stratification, and reclassified 1427 (41%) patients with a score ≥1 on the Charlson Comorbidity Index to a 0 on the cardiovascular index with minimal concession of 5-year survival. Congestive heart failure, chronic kidney disease, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes and cerebrovascular disease were associated with decreased overall survival among Medicare beneficiaries with small renal masses. The cardiovascular index could serve as a clinically useful prognostic aid when advising older patients that are borderline candidates for surgery or active surveillance.


Retinotopic accommodation responses in myopia.
A reduced sensitivity to retinal image blur has been reported in myopes. Diminished blur detection reduces the error signal to the retinotopic (blur-induced) accommodation system and results in impaired accommodation responses under retinotopic conditions. This study was conducted to investigate retinotopic accommodation responses in emmetropia and myopia under dynamic conditions. Static accommodation responses to a blur-only target with vergences of 0 to 4.5 D were measured with an optometer. Microfluctuations of accommodation were recorded with the subject viewing the target at a vergence of 4 D, and dynamic step responses were measured for step stimuli from 2.5 to 3.5 D and 2.0 to 4.0 D, with the optometer in dynamic recording mode. Measurements were obtained from a group of 32 visually normal emmetropes (EMMs) and subjects with progressing myopia. Stimulus-response curves were not significantly different between the refractive groups. Subjects with late-onset myopia (LOMs) demonstrated significantly larger accommodation microfluctuations compared with emmetropes and subjects with early-onset myopia (EOMs). Fourier analysis revealed that the increase in the magnitude of the fluctuations was mediated by the low-frequency components. Accommodation step responses revealed longer reaction times in LOMs. Further analysis showed that LOMs responded to accommodation step stimuli only between 43% and 64% of the time. In contrast, the other groups showed a response rate of almost 100%. The experiments demonstrate a reduction in retinotopic processing in LOMs, which results in an increased variability in their dynamic accommodation response to stationary near targets and reduced performance for dynamic step tasks. The results demonstrate a reduced blur appreciation under dynamic conditions in these refractive groups that may lead to periods of retinal image blur of varying magnitude during near work.


Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.
Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy. The RAZOR study is a randomised, open-label, non-inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged ≥18 years) had biopsy-proven clinical stage T1-T4, N0-N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non-inferiority established if the lower bound of the one-sided 97·5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than -15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676. Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI 64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in the open cystectomy group (difference 0·7%, 95% CI -9·6% to 10·9%; pnon-inferiority=0·001), indicating non-inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 [35%] in the robotic cystectomy group vs 39 [26%] in the open cystectomy group) and postoperative ileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open cystectomy group). In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types. National Institutes of Health National Cancer Institute.


The LspB protein is involved in the secretion of the LspA1 and LspA2 proteins by Haemophilus ducreyi.
The LspA1 and LspA2 proteins of Haemophilus ducreyi 35000 are two very large macromolecules that can be detected in concentrated culture supernatant fluid. Both of these proteins exhibit homology with the N-terminal region of the Bordetella pertussis filamentous hemagglutinin (FHA), which is involved in secretion of the latter macromolecule. The lspA2 open reading frame is flanked upstream by a gene, lspB, that encodes a predicted protein with homology to the B. pertussis FhaC outer membrane protein that is involved in secretion of FHA across the outer membrane. The H. ducreyi lspB gene encodes a protein with a predicted molecular mass of 66,573 Da. Reverse transcription-PCR analysis suggested that the lspB gene was transcribed together with the lspA2 gene on a single mRNA transcript. Polyclonal H. ducreyi LspB antiserum reacted with a 64-kDa antigen present in the Sarkosyl-insoluble cell envelope fraction of H. ducreyi 35000, which indicated that the LspB protein is likely an outer membrane protein. Concentrated culture supernatant fluids from H. ducreyi lspB and lspA1 lspB mutants did not contain detectable LspA1 and detectable LspA2, respectively. However, complementation of the lspB mutant with the wild-type lspB gene on a plasmid restored LspB protein expression and resulted in release of detectable amounts of the LspA1 protein into culture supernatant fluid. When evaluated in the temperature-dependent rabbit model of infection, the lspB mutant was attenuated in the ability to cause lesions and was never recovered in a viable form from lesions. These results indicated that the H. ducreyi LspB protein is involved in secretion of the LspA1 and LspA2 proteins across the outer membrane.


Shortage of cardiothoracic surgeons is likely by 2020.
Even as the burden of cardiovascular disease in the United States is increasing as the population grows and ages, the number of active cardiothoracic surgeons has fallen for the first time in 20 years. Meanwhile, the treatment of patients with coronary artery disease continues to evolve amid uncertain changes in technology. This study evaluates current and future requirements for cardiothoracic surgeons in light of decreasing rates of coronary artery bypass grafting procedures. Projections of supply and demand for cardiothoracic surgeons are based on analysis of population, physician office, hospital, and physician data sets to estimate current patterns of healthcare use and delivery. Using a simulation model, we project the future supply of cardiothoracic surgeons under alternative assumptions about the number of new fellows trained each year. Future demand is modeled, taking into account patient demographics, under current and alternative use rates that include the elimination of open revascularization. By 2025, the demand for cardiothoracic surgeons could increase by 46% on the basis of population growth and aging if current healthcare use and service delivery patterns continue. Even with complete elimination of coronary artery bypass grafting, there is a projected shortfall of cardiothoracic surgeons because the active supply is projected to decrease 21% over the same time period as a result of retirement and declining entrants. The United States is facing a shortage of cardiothoracic surgeons within the next 10 years, which could diminish quality of care if non-board-certified physicians expand their role in cardiothoracic surgery or if patients must delay appropriate care because of a shortage of well-trained surgeons.


Impaired macrophage function in severe protein-energy malnutrition.
Protein-energy malnutrition induces immunosuppression that predisposes to sepsis, but the mechanisms are unclear. This study examines the role of the macrophage in host defense in the malnourished state. Swiss-Webster mice (N = 300) were randomly allocated to control (24% casein) or low-protein (2.5% casein) diets for 8 weeks. We studied the ability of two populations of macrophages, peritoneal macrophages, and Kupffer cells to produce superoxide anion after in vivo administration of endotoxin or mycobacterium (bacille Calmette-Guérin). Phorbol diester and Candida albicans were used as stimuli. In another group of mice, we evaluated the ability of interferon gamma to up-regulate superoxide anion release and Candida phagocytosis and killing. Mice under protein-energy malnutrition demonstrated decreased mean body weights, serum protein levels, and cell yields. Superoxide anion production in resident and activated (lipopolysaccharide, interferon gamma, bacille Calmette-Guérin infection) peritoneal macrophages was significantly reduced in the malnourished group. Candida phagocytosis and killing were also both depressed in malnourished mice. Kupffer cells failed to generate superoxide anion in all groups. We conclude that severe protein-energy malnutrition significantly impairs macrophage function, which could diminish response to acute and chronic septic challenges. Interferon gamma up regulated peritoneal macrophage and Kupffer cell microbicidal function, which suggests a therapeutic role for this lymphokine in the malnourished septic host.


Altered muscarinic receptor properties and function in the heart in diabetes.
The cardiac cholinergic system was studied in streptozotocin (STZ)-diabetic and age-matched control rats. STZ-diabetic rats (8-10 weeks) were supersensitive to the negative chronotropic effects of acetylcholine, carbamylcholine and bethanechol; inotropic responses to these muscarinic agonists were unaltered. This phenomenon was associated with a decrease in acetylcholinesterase activity but no change in the rate and extent of neuronal choline uptake. [3H]N-methylscopolamine bound to muscarinic receptors in atria from both groups of rats with the same high affinity. The density of [3H]N-methylscopolamine binding sites, however, was 34% lower in atria from STZ-diabetic rats. Agonist binding affinity was lower in diabetes; carbamylcholine had a lower affinity for both the high- and low-affinity receptors. These results indicate that cardiac cholinergic supersensitivity in right atria in diabetes occurs before the development of autonomic neuropathy insofar as neuronal [3H]choline uptake is unaltered at this stage of STZ diabetes. Changes in agonist binding conformation, without a concomitant change in antagonist binding affinity, suggest that supersensitivity of right atria to muscarinic agonist may be a consequence of altered coupling of muscarinic receptor to transduction mechanisms involved in chronotropism in diabetes.


Increase in glutamate as a sensitive indicator of extracellular matrix integrity in peritumoral edema: a 3.0-tesla proton magnetic resonance spectroscopy study.
The authors of previous studies based on diffusion tensor imaging have indicated that there are two types of peritumoral edema-namely, edema with preserved structural integrity of the glial matrix and edema with compromised glial matrix. The authors of this study hypothesized that functionality of the glutamate (Glu)-glutamine shuttle, a vital neuron-glia interaction, may be differentially affected by peritumoral edema. They tested this hypothesis using proton magnetic resonance (MR) spectroscopy on a 3.0-tesla system that is capable of quantifying Glu without need of editing. Twenty-three patients, each with a single brain tumor mass and peritumoral edema (nine high-grade gliomas, eight metastatic brain tumors, and six meningiomas), and nine healthy individuals participated in this study. Single-voxel proton MR imaging targeting the region of peritumoral edema was performed using a 3.0-tesla system. Glutamate levels in the peritumoral edema of nonglial tumors was significantly elevated (p < 0.01) compared with edema associated with glial tumors or normal white matter. The finding confirmed that peritumoral edema in nonglial tumors is distinct from that of glial tumors, as previously indicated in diffusion tensor imaging studies. The authors hypothesized that the former condition represents a compensatory increase in activities of the Glu-glutamine shuttle brought about by simple expansion of the extracellular space due to edema. The assessment of Glu concentrations in peritumoral edema using 3.0-tesla proton MR spectroscopy may be developed into an objective index of the structural integrity of the glial matrix.


Kinetics of dCTP incorporation opposite to 7,8-dihydro-8-oxoguanine with different 5' nearest neighbors by yeast polymerase eta.
Translesion synthesis (TLS), an important mechanism in cells refers to bypassing the DNA damage blockage on replication fork. Yeast TLS polymerase eta (poleta) is able to bypass 7,8-dihydro-8-oxoguanine (8-oxoG) on DNA with high fidelity by incorporation of dCTP opposite 8-oxoG rather than dATP to avoid G to T transversion mutation. We have shown the 5' nearest base next to 8-oxoG affects the G to T mutation by yeast and human poleta previously. In this study, the insertion efficiency of dCTP opposite 8-oxoG in various DNA sequences was kinetically investigated using yeast poleta. Based on K(m) and V(max), we demonstrated that the insertion efficiencies were also influenced by the 5' neighboring nucleotide next to 8-oxoG. The lowest V(max)/K(m) was observed when cytosine was 5' neighbouring base to 8-oxoG, in agreement with previous results in which dCTP incorporation to 8-oxoG was lowest when cytosine is on the 5'-side next to the lesion.


Change in the Prevalence and Social Patterning of First-and Second-Hand Smoking in PORTUGAL: A Repeated Cross-Sectional Study (2005 and 2014).
Between 2005 and 2007, important reinforcements of the tobacco legislation have been implemented in Portugal, which may have affected smoking patterns. The aim of this study was to measure the change in prevalence of first- and second-hand smoking (SHS) among adults, and its socio-demographic patterning in Portugal from 2005 to 2014. Data from the last two Portuguese National Health Interview Surveys (2005 and 2014) were used. The changes in daily smoking and SHS were measured using Poisson regressions, stratifying by sex and survey year. The inequalities were measured using relative inequality indexes (RII). From 2005 to 2014, there was a reduction in SHS (75%-54% among men, and 52%-38% among women), and a reduction in smoking among men (27%-26%), and an increase among women (9%-12%). SHS reduction was more marked among less privileged people. Among Portuguese men, inequalities in daily smoking have increased slightly, while among women the gap favoring low-educated reduced. Between 2005 and 2014, SHS decreased, but not daily smoking, particularly among women. Additionally, socioeconomic inequalities in smoking increased. Future policies should simultaneously tackle smoking and SHS prevalence, and their socioeconomic patterning. More comprehensive policies such as comprehensive national (non-partial) bans, combined with price increases could be more effective.


Mutual inhibition among neural command systems as a possible mechanism for behavioral choice in crayfish.
Mutual inhibition among behavioral command systems frequently has been suggested as a possible mechanism for switching between incompatible behaviors. Several neural circuits in crayfish that mediate incompatible behaviors have been found to interact through inhibition; this accounts for increased stimulus threshold of one behavior (e.g., escape tailflip) during performance of others (eating, walking, defense). To determine whether mutual inhibition between command systems can provide a mechanism that produces adaptive behavior, I developed a model crayfish that uses this mechanism to govern its behavioral choices in a simulated world that contains a predator, a shelter, and a food source. The crayfish uses energy that must be replaced by eating while it avoids capture by the predator. The crayfish has seven command systems (FORAGE, EAT, DEFENSE, RETREAT, ESCAPE, SWIM, HIDE) that compete through mutual inhibition for control of its behavior. The model crayfish was found to respond to changing situations by making adaptive behavioral choices at appropriate times. Choice depends on internal and external stimuli, and on recent history, which determines the pattern of those stimuli. The model's responses are unpredictable: small changes in the initial conditions can produce unexpected patterns of behavior that are appropriate alternate responses to the stimulus conditions. Despite this sensitivity, the model is robust; it functions adaptively over a large range of internal and external parameter values.


Colocalization of F-actin and talin during Fc receptor-mediated phagocytosis in mouse macrophages.
We have studied the distribution of talin in J774 cells and mouse peritoneal macrophages undergoing Fc receptor-mediated phagocytosis. At early stages of phagocytosis, talin accumulates in the cells' cortical cytoplasm adjacent to the forming phagosome and extends into pseudopods that are encircling the particle. Talin colocalizes with F-actin at these sites. After particle ingestion is completed, F-actin and talin are no longer concentrated adjacent to phagosomes. Thus, talin and F-actin undergo dynamic and coordinate changes in their cytoplasmic location during Fc receptor-mediated phagocytosis.


Service delivery during the COVID-19 pandemic: Experience from The Oxford Bone Tumour and Soft Tissue Sarcoma service.
The COVID-19 (Coronavirus disease 2019) pandemic has caused an unprecedented strain on healthcare systems across the globe. Apart from being a major hurdle to delivery of basic healthcare services, this may be associated with potential harm for cancer patients. Usually being immunocompromised, cancer patients are at a higher risk of contracting the disease and with hospitals being a potential source of the infection, an urgent need to reorganise the structure of delivery of cancer care is essential. Cancer departments must balance patient care whilst also minimising transmission among patients and healthcare professionals. The Oxford Sarcoma Service was re-structured based on the guidelines issued by the National Health Service (NHS) and the British Orthopaedic Oncology Society (BOOS) to deliver unhindered care to patients. Prioritising patients who needed urgent surgery, weighing the risk-benefit ratio while delivering adjuvant treatments and conducting regular virtual multi-disciplinary team (MDT) meetings combined with personal protection equipment (PPE) usage by all involved healthcare workers were salient features in terms of ensuring the delivery of effective care during the COVID-19 pandemic. Our new model of modus operandi during this global crisis was effective in delivering high standard of care to patients and might serve as a guide to similar units managing bone and soft tissue tumours.


Oxidative stress and reduced responsiveness of challenged circulating leukocytes following pulmonary instillation of metal-rich particulate matter in rats.
Welding fume is an exposure that consists of a mixture of metal-rich particulate matter with gases (ozone, carbon monoxide) and/or vapors (VOCs). Data suggests that welders are immune compromised. Given the inability of pulmonary leukocytes to properly respond to a secondary infection in animal models, the question arose whether the dysfunction persisted systemically. Our aim was to evaluate the circulating leukocyte population in terms of cellular activation, presence of oxidative stress, and functionality after a secondary challenge, following welding fume exposure. Rats were intratracheally instilled (ITI) with PBS or 2 mg of welding fume collected from a stainless steel weld. Rats were sacrificed 4 and 24 h post-exposure and whole blood was collected. Whole blood was used for cellular differential counts, RNA isolation with subsequent microarray and Ingenuity Pathway Analysis, and secondary stimulation with LPS utilizing TruCulture technology. In addition, mononuclear cells were isolated 24 h post-exposure to measure oxidative stress by flow cytometry and confocal microscopy. Welding fume exposure had rapid effects on the circulating leukocyte population as identified by relative mRNA expression changes. Instillation of welding fume reduced inflammatory protein production of circulating leukocytes when challenged with the secondary stimulus LPS. The effects were not related to transcription, but were observed in conjunction with oxidative stress. These findings support previous studies of an inadequate pulmonary immune response following a metal-rich exposure and extend those findings showing leukocyte dysfunction occurs systemically.


Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial.
Exacerbations of asthma cause a substantial global illness burden. Adults with uncontrolled persistent asthma despite maintenance treatment require additional therapy. Since macrolide antibiotics can be used to treat persistent asthma, we aimed to assess the efficacy and safety of oral azithromycin as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator. We did a randomised, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in adults (≥18 years) with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Patients were randomly assigned (1:1) to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Patients were centrally allocated using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Primary efficacy endpoints were the rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analysed on an intention-to-treat basis. The trial is registered at the Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235. Between June 12, 2009, and Jan 31, 2015, 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). Azithromycin reduced asthma exacerbations (1·07 per patient-year [95% CI 0·85-1·29]) compared with placebo (1·86 per patient-year [1·54-2·18]; incidence rate ratio [IRR] 0·59 [95% CI 0·47-0·74]; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 [61%] patients in the placebo group vs 94 [44%] patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 [95% CI 0·21-0·52]; p=0·001). Diarrhoea was more common in azithromycin-treated patients (72 [34%] vs 39 [19%]; p=0·001). Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma. National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust.


Random Walk Graph Laplacian-Based Smoothness Prior for Soft Decoding of JPEG Images.
Given the prevalence of joint photographic experts group (JPEG) compressed images, optimizing image reconstruction from the compressed format remains an important problem. Instead of simply reconstructing a pixel block from the centers of indexed discrete cosine transform (DCT) coefficient quantization bins (hard decoding), soft decoding reconstructs a block by selecting appropriate coefficient values within the indexed bins with the help of signal priors. The challenge thus lies in how to define suitable priors and apply them effectively. In this paper, we combine three image priors-Laplacian prior for DCT coefficients, sparsity prior, and graph-signal smoothness prior for image patches-to construct an efficient JPEG soft decoding algorithm. Specifically, we first use the Laplacian prior to compute a minimum mean square error initial solution for each code block. Next, we show that while the sparsity prior can reduce block artifacts, limiting the size of the overcomplete dictionary (to lower computation) would lead to poor recovery of high DCT frequencies. To alleviate this problem, we design a new graph-signal smoothness prior (desired signal has mainly low graph frequencies) based on the left eigenvectors of the random walk graph Laplacian matrix (LERaG). Compared with the previous graph-signal smoothness priors, LERaG has desirable image filtering properties with low computation overhead. We demonstrate how LERaG can facilitate recovery of high DCT frequencies of a piecewise smooth signal via an interpretation of low graph frequency components as relaxed solutions to normalized cut in spectral clustering. Finally, we construct a soft decoding algorithm using the three signal priors with appropriate prior weights. Experimental results show that our proposal outperforms the state-of-the-art soft decoding algorithms in both objective and subjective evaluations noticeably.


Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012.
In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.


Can arginine and ornithine support gut functions?
Arginine and ornithine are precursors of nitric oxide and polyamines, respectively. These metabolites intimately participate in permeability and adaptive responses of the gut. The liver possesses high arginase activity as an intrinsic part of urea synthesis and would consume most of the portal supply of dietary arginine. The gut reduces this possibility by converting dietary arginine to citrulline, which effectively bypass the liver and is resynthesized to arginine in the kidney. Dietary ornithine supplementation, in the form of ornithine alpha-ketoglutarate (OKG) can be considered as an arginine precursor. Several supplement studies have shown both amino acids to promote growth hormone and insulin secretion with anabolic effects in postoperative patients. Their intermediary metabolites (for example, glutamine, proline) may also be of benefit in trauma metabolism. Specific effects of either amino acid on the gut are poorly reported. One recent animal study showed improved morphology after OKG administration, perhaps through increased polyamine secretion. Generation of nitric oxide from arginine has two facets. Excess production from high dose arginine potentiated the effects of experimentally induced sepsis, whereas low doses improved survival. These considerations suggest that the role of enteral diet supplementation with arginine or OKG should be urgently examined for any benefits it may have on mucosal barrier function.


Atraumatic nonaneurysmal sulcal subarachnoid hemorrhages: a diagnostic workup based on a case series.
Atraumatic and nonaneurysmal sulcal subarachnoid hemorrhage (sSAH) is a rare type of cerebrovascular disease with various etiologies previously reported in small case reports. In this study, we propose to analyze clinical presentations, imaging patterns and etiologies in a large case series of such patients in order to propose a diagnostic workup. We retrospectively analyzed clinical and radiological data of consecutive patients with a diagnosis of atraumatic and nonaneurysmal sSAH, admitted to our institution between 2008 and 2011. All patients had both computed tomography (CT) and magnetic resonance imaging (MRI) as a part of their initial evaluation. 30 patients (18 women and 12 men, mean age: 60 years) were identified. The main clinical symptoms at presentation were focal and transient neurological deficit (n = 22) and thunderclap headache (n = 10). Four patients had progressive headache and 4 other had partial or generalized epileptic seizures. MRI abnormalities associated with sSAH were prior hemorrhages, microbleeds, severe leukoencephalopathy and hemosiderosis suggesting cerebral amyloid angiopathy (CAA; n = 9), vasogenic edema in parieto-occipital areas compatible with a posterior reversible encephalopathy syndrome (PRES; n = 3), cortical venous thrombosis (n = 2) and concomitant acute cortical stroke (n = 3). Other underlying causes of sSAH, not diagnosed on MRI, were reversible cerebral vasoconstriction syndrome (RCVS) based on clinical criteria and conventional angiography (n = 4), angiitis diagnosed by skin biopsy (n = 1), vascular malformation diagnosed on CT and digital subtraction angiographies (n = 3), and overanticoagulation (n = 1). Four cases remained unresolved. This study confirmed that sSAH is a rare condition related to a wide spectrum of etiologies. Combination of brain MRI and magnetic resonance angiography and eventually digital subtraction angiography allowed the identification of an underlying etiology for 87% of patients. CAA, RCVS and PRES represented more than 50% of the etiological mechanisms. Among older patients, sSAH was mainly related to CAA while in younger patients, RCVS represented the most frequent etiology.


Use of a driving simulator to improve on-road driving performance and cognition in persons with Parkinson's disease: A pilot study.
The use of simulators as an assessment and intervention tool for driving is an emerging field in occupational therapy. We investigated the potential usefulness of a driving simulator to improve on-road skills and cognitive functions in drivers with Parkinson's disease (PD). Fifteen participants with PD, and Hoehn and Yahr stages between 2 and 3 participated in this pre-post comparison study. Twelve of the 15 individuals (median age (Q1-Q3), 68 (63.5-72.5); 10 men) completed 10 hours of training in a high-fidelity driving simulator. A practical road test as well as off-road cognitive and simulator tests were administered at pre-training and post-training. Nine participants, who passed the road test before training, passed at post-training. Furthermore, all three participants who initially failed the on-road test passed after training. Participants' performance improved significantly from pre- to post-training on two cognitive tests: (i) the Montreal Cognitive Assessment and (ii) Dot Cancellation test. This pilot study demonstrates the potential usefulness of a simulator to improve on-road driving and driving-related cognitive skills in PD. Adequately powered randomized controlled trials are needed to further expand this field of study.


Holistic Facial Composite Creation and Subsequent Video Line-up Eyewitness Identification Paradigm.
The paradigm detailed in this manuscript describes an applied experimental method based on real police investigations during which an eyewitness or victim to a crime may create from memory a holistic facial composite of the culprit with the assistance of a police operator. The aim is that the composite is recognized by someone who believes that they know the culprit. For this paradigm, participants view a culprit actor on video and following a delay, participant-witnesses construct a holistic system facial composite. Controls do not construct a composite. From a series of arrays of computer-generated, but realistic faces, the holistic system construction method primarily requires participant-witnesses to select the facial images most closely meeting their memory of the culprit. Variation between faces in successive arrays is reduced until ideally the final image possesses a close likeness to the culprit. Participant-witness directed tools can also alter facial features, configurations between features and holistic properties (e.g., age, distinctiveness, skin tone), all within a whole face context. The procedure is designed to closely match the holistic manner by which humans' process faces. On completion, based on their memory of the culprit, ratings of composite-culprit similarity are collected from the participant-witnesses. Similar ratings are collected from culprit-acquaintance assessors, as a marker of composite recognition likelihood. Following a further delay, all participants--including the controls--attempt to identify the culprit in either a culprit-present or culprit-absent video line-up, to replicate circumstances in which the police have located the correct culprit, or an innocent suspect. Data of control and participant-witness line-up outcomes are presented, demonstrating the positive influence of holistic composite construction on identification accuracy. Correlational analyses are conducted to measure the relationship between assessor and participant-witness composite-culprit similarity ratings, delay, identification accuracy, and confidence to examine which factors influence video line-up outcomes.


Arabidopsis MAP kinase 4 regulates salicylic acid- and jasmonic acid/ethylene-dependent responses via EDS1 and PAD4.
Arabidopsis MPK4 has been implicated in plant defense regulation because mpk4 knockout plants exhibit constitutive activation of salicylic acid (SA)-dependent defenses, but fail to induce jasmonic acid (JA) defense marker genes in response to JA. We show here that mpk4 mutants are also defective in defense gene induction in response to ethylene (ET), and that they are more susceptible than wild-type (WT) to Alternaria brassicicola that induces the ET/JA defense pathway(s). Both SA-repressing and ET/JA-(co)activating functions depend on MPK4 kinase activity and involve the defense regulators EDS1 and PAD4, as mutations in these genes suppress de-repression of the SA pathway and suppress the block of the ET/JA pathway in mpk4. EDS1/PAD4 thus affect SA-ET/JA signal antagonism as activators of SA but as repressors of ET/JA defenses, and MPK4 negatively regulates both of these functions. We also show that the MPK4-EDS1/PAD4 branch of ET defense signaling is independent of the ERF1 transcription factor, and use comparative microarray analysis of ctr1, ctr1/mpk4, mpk4 and WT to show that MPK4 is required for induction of a small subset of ET-regulated genes. The regulation of some, but not all, of these genes involves EDS1 and PAD4.


Rating the urgency of coronary angiography: results of an expert panel process. Ontario Coronary Angiography Panel.
To rate the urgency of coronary angiography for patients with ischemic heart disease. Ratings were made for patients with varying degrees of symptoms and noninvasive cardiac test results. A panel of 10 cardiologists rated 354 case scenarios which presented varying combinations of clinical factors that may affect urgency. The case scenarios were rated by each panelist on a waiting time scale consisting of six categories which ranged from the requirement for emergency angiography to a delay of up to three months. A seventh category represented the lack of urgent need for angiography. The contribution of each clinical factor to urgency of coronary angiography was determined. Symptom class as defined by a modification to the Canadian Cardiovascular Society grading scale for angina pectoris, results of exercise stress tests and results of imaging studies were the major determinants of urgency. In cases of unstable angina, rest electrocardiography is of importance. These factors explained at least 95% of the variance in the case urgency scores. There was agreement by at least five of the panelists on urgency score in 84% of cases. The assigned urgency varied from 6.7, representing no urgent need for angiography, for minimally asymptomatic angina with no positive noninvasive test results, to immediate angiography for cardiogenic shock. Other factors had minimal or negligible effects on urgency. The urgency of need for coronary angiography was addressed by an explicit method incorporating the judgements of a panel of expert cardiologists, permitting derivation of a scoring system for rating priority of individual patients in the face of waiting lists. These methods illustrate an approach to problems presented by procedure waiting lists.


Stiffness can mediate balance between hydrodynamic forces and avidity to impact the targeting of flexible polymeric nanoparticles in flow.
We report computational investigations of deformable polymeric nanoparticles (NPs) under colloidal suspension flow and adhesive environment. We employ a coarse-grained model for the polymeric NP and perform Brownian dynamics (BD) simulations with hydrodynamic interactions and in the presence of wall-confinement, particulate margination, and wall-adhesion for obtaining NP microstructure, shape, and anisotropic and inhomogeneous transport properties for different NP stiffness. These microscopic properties are utilized in solving the Fokker-Planck equation to obtain the spatial distribution of NP subject to shear, margination due to colloidal microparticles, and confinement due to a vessel wall. Comparing our computational results for the amount of NP margination to the near-wall adhesion regime with those of our binding experiments in cell culture under shear, we found quantitative agreement on shear-enhanced binding, the effect of particulate volume fraction, and the effect of NP stiffness. For the experimentally realized polymeric NP, our model predicts that the shear and volume fraction mediated enhancement in targeting has a hydrodynamic transport origin and is not due to a multivalent binding effect. However, for ultrasoft polymeric NPs, our model predicts a substantial increase in targeting due to multivalent binding. Our results are also in general agreement with experiments of tissue targeting measurements in vivo in mice, however, one needs to exercise caution in extending the modeling treatment to in vivo conditions owing to model approximations. The reported combined computational approach and results are expected to enable fine-tuning of design and optimization of flexible NP in targeted drug delivery applications.


Organosulfur Compounds: A Review of Their Anti-inflammatory Effects in Human Health.
Phytonutrients are widely recognized for providing protective human health benefits. Among the phytonutrients, epidemiological and experimental studies show that dietary organosulfur compounds (OSC) play a significant role in preventing various human pathological progressions, including chronic inflammation, by decreasing inflammatory mediators such as nitric oxide (NO), prostaglandin (PG)E2, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-17, which are all typical hallmarks of inflammation. Evidence supports OSC in reducing the expression of these markers, thereby attenuating chronic inflammatory processes. Nuclear factor-kappa B (NF-κB) is a key regulating factor during inflammation, and novel evidence shows that OSC downregulates this transcriptional factor, thus contributing to the anti-inflammatory response. In vitro and in vivo studies show that inflammation is mechanistically linked with acute and chronic pathological conditions including cancer, diabetes, obesity, neural dysfunction, etc. Furthermore, a considerable number of experiments have demonstrated that the anti-inflammatory properties of OSC occur in a dose-dependent manner. These experiments also highlight indirect mechanisms as well as potent co-functions for protective roles as antioxidants, and in providing chemoprotection and neuroprotection. In this brief review, we provided an overview of the anti-inflammatory effects of OSC and elucidated probable mechanisms that are associated with inflammation and chronic disorders.


Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker.
Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG-moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL-11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti-PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti-PEG antibodies exclusively. Pre-existing anti-PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS-linker were predominantly detected during induction (50% IgG; 42% IgM). Anti-asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment.


A cluster of Nocardia keratitis after LASIK.
To report a cluster of Nocardia asteroides keratitis cases after LASIK. Retrospective review of the history and examination of three patients (four eyes) operated on the same day at a single center who developed postoperative keratitis. All patients underwent lifting of the superficial flap for microbiologic evaluation of the corneal scrapings. The operating surgeon was contacted to identify the possible source of contamination. Two patients underwent simultaneous bilateral LASIK; however, only one developed postoperative keratitis in both eyes. One patient had unilateral surgery and developed keratitis in the operated eye. Microscopic examination of smears from all eyes revealed thin, branching, acid-fast, filamentous bacteria that were identified as Nocardia asteroides after culture. The infiltrates resolved with topical administration of amikacin sulphate (2.5%) and topical and oral trimethoprim-sulfamethoxazole. Final visual acuity ranged between 20/25 and 20/80. The operating surgeon had used the same blade and microkeratome in all patients. Nocardia, a relatively unusual organism, can cause an epidemic of infection after LASIK.


Continuous-Trait Probabilistic Model for Comparing Multi-species Functional Genomic Data.
A large amount of multi-species functional genomic data from high-throughput assays are becoming available to help understand the molecular mechanisms for phenotypic diversity across species. However, continuous-trait probabilistic models, which are key to such comparative analysis, remain under-explored. Here we develop a new model, called phylogenetic hidden Markov Gaussian processes (Phylo-HMGP), to simultaneously infer heterogeneous evolutionary states of functional genomic features in a genome-wide manner. Both simulation studies and real data application demonstrate the effectiveness of Phylo-HMGP. Importantly, we applied Phylo-HMGP to analyze a new cross-species DNA replication timing (RT) dataset from the same cell type in five primate species (human, chimpanzee, orangutan, gibbon, and green monkey). We demonstrate that our Phylo-HMGP model enables discovery of genomic regions with distinct evolutionary patterns of RT. Our method provides a generic framework for comparative analysis of multi-species continuous functional genomic signals to help reveal regions with conserved or lineage-specific regulatory roles.


Reversible cerebral vasoconstriction syndrome and bilateral vertebral artery dissection presenting in a patient after cesarean section.
Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by sudden-onset thunderclap headache and focal neurologic deficits. Once thought to be a rare syndrome, more advanced non-invasive imaging has led to an increase in RCVS diagnosis. Unilateral vertebral artery dissection has been described in fewer than 40% of cases of RCVS. Bilateral vertebral artery dissection has rarely been reported. We describe the case of a patient with RCVS and bilateral vertebral artery dissection presenting with an intramedullary infarct treated successfully with medical management and careful close follow-up. This rare coexistence should be recognized as the treatment differs.


Kahweol Found in Coffee Inhibits IL-2 Production Via Suppressing the Phosphorylations of ERK and c-Fos in Lymphocytic Jurkat Cells.
Interleukin-2 (IL-2) is a cytokine involved in the development and maturation of the subsets of T cells, critically associated with the progression of several immune-related diseases (e.g. liver disease, bowel disease). Interestingly, a recent study suggests that coffee may contain several compounds to inhibit IL-2 expression in activated T-lymphocytic cells. However, there is little information about the potential effects of several coffee compounds (e.g. kahweol, cafestol, trigonelline, niacin and chlorogenic acids) on IL-2 expression in activated T-lymphocytic cells. Therefore, in this paper, their effects on IL-2 expression were evaluated in PHA/PMA-activated lymphocytic Jurkat cells. Among the tested compounds, only kahweol and cafestol were able to reduce IL-2 production significantly in the cells (p < 0.05). However, the inhibition of kahweol was a bit stronger than cafestol. Therefore, the molecular mechanism underlying the IL-2 inhibition was investigated using kahweol. Kahweol (≤ 20 µM) was able to inhibit the phosphorylations of ERK and c-Fos (p < 0.05) with little effects on p38 and JNK phosphorylations in the Jurkat cells. Subsequently, the inhibition of ERK/c-Fos led to the reduction of IL-2 mRNA expression in the Jurkat cells. In summary, the data suggest that kahweol may be a potential coffee compound to reduce IL-2 production via inhibiting the phosphorylations of ERK/c-Fos in PHA/PMA-activated lymphocytic Jurkat cells.


Peripheral arterial disease: the evolving role of non-invasive imaging.
Peripheral arterial disease is usually secondary to stenotic or occlusive atherosclerosis and is both common and increasing in western society. The majority of symptomatic patients have intermittent claudication and only a minority (<2% and typically those with diabetes mellitus or renal failure) progress to critical limb ischaemia, heralded by the onset of rest pain and/or tissue loss. Imaging is largely reserved for patients with disabling symptoms in whom revascularisation is planned. In these patients, accurate depiction of the vascular anatomy is critical for clinical decision making as the distribution and severity of disease are key factors determining whether revascularisation should be by endovascular techniques or open surgery. Driven by advances in technology, non-invasive vascular imaging has recently undergone significant refinement and has replaced conventional digital subtraction angiography for many clinical indications. In this review, the relative merits and limitations of duplex ultrasound, CT angiography, and magnetic resonance angiography are discussed, emerging imaging techniques are described, and complications relating to the use of intravascular contrast agents are highlighted.


Globally optimal co-segmentation of three-dimensional pulmonary ¹H and hyperpolarized ³He MRI with spatial consistence prior.
Pulmonary imaging using hyperpolarized (3)He/(129)Xe gas is emerging as a new way to understand the regional nature of pulmonary ventilation abnormalities in obstructive lung diseases. However, the quantitative information derived is completely dependent on robust methods to segment both functional and structural/anatomical data. Here, we propose an approach to jointly segment the lung cavity from (1)H and (3)He pulmonary magnetic resonance images (MRI) by constraining the spatial consistency of the two segmentation regions, which simultaneously employs the image features from both modalities. We formulated the proposed co-segmentation problem as a coupled continuous min-cut model and showed that this combinatorial optimization problem can be solved globally and exactly by means of convex relaxation. In particular, we introduced a dual coupled continuous max-flow model to study the convex relaxed coupled continuous min-cut model under a primal and dual perspective. This gave rise to an efficient duality-based convex optimization algorithm. We implemented the proposed algorithm in parallel using general-purpose programming on graphics processing unit (GPGPU), which substantially increased its computational efficiency. Our experiments explored a clinical dataset of 25 subjects with chronic obstructive pulmonary disease (COPD) across a wide range of disease severity. The results showed that the proposed co-segmentation approach yielded superior performance compared to single-channel image segmentation in terms of precision, accuracy and robustness.


The Effects of Rhodiola rosea L. Extract on Anxiety, Stress, Cognition and Other Mood Symptoms.
This trial evaluated the impact of a Rhodiola rosea L. extract on self-reported anxiety, stress, cognition, and other mood symptoms. Eighty mildly anxious participants were randomized into two different groups of either Rhodiola rosea L (2 × 200 mg dose Vitano®, 1 tablet taken before breakfast and 1tablet before lunch) or a control condition (no treatment). Self-report measures and cognitive tests were completed at four testing sessions over a period of 14 days. Relative to the controls, the experimental group demonstrated a significant reduction in self-reported, anxiety, stress, anger, confusion and depression at 14 days and a significant improvements in total mood. No relevant differences in cognitive performance between the groups were observed. Rhodiola rosea L (Vitano®) presented a favourable safety tolerability profile. Although this was a non-placebo controlled trial, it is unlikely that the findings were the result of placebo effects as changes appeared gradual and were specific to certain psychological measures. However, we cannot determine a causal relationship; further investigations are recommended to support the effects of Rhodiola rosea L. extract on stress related symptoms.


Cytochrome P4501A1 is required for vascular dysfunction and hypertension induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
National Health and Nutrition Examination Survey data show an association between hypertension and exposure to dioxin-like halogenated aromatic hydrocarbons (HAHs). Furthermore, chronic exposure of mice to the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces reactive oxygen species (ROS), endothelial dysfunction, and hypertension. Because TCDD induces cytochrome P4501A1 (CYP1A1) and CYP1A1 can increase ROS, we tested the hypothesis that TCDD-induced endothelial dysfunction and hypertension are mediated by CYP1A1. CYP1A1 wild-type (WT) and knockout (KO) mice were fed one control or TCDD-containing pill (180 ng TCDD/kg, 5 days/week) for 35 days (n = 10-14/genotype/treatment). Blood pressure was monitored by radiotelemetry, and liver TCDD concentration, CYP1A1 induction, ROS, and aortic reactivity were measured at 35 days. TCDD accumulated to similar levels in livers of both genotypes. TCDD induced CYP1A1 in endothelium of aorta and mesentery without detectable expression in the vessel wall. TCDD also induced superoxide anion production, measured by NADPH-dependent lucigenin luminescence, in aorta, heart, and kidney of CYP1A1 WT mice but not KO mice. In contrast, TCDD induced hydrogen peroxide, measured by amplex red assay, to similar levels in aorta of CYP1A1 WT and KO mice but not in heart or kidney. TCDD reduced acetylcholine-dependent vasorelaxation in aortic rings of CYP1A1 WT mice but not in KO mice. Finally, TCDD steadily increased blood pressure after 15 days, which plateaued after 25 days (+20 mmHg) in CYP1A1 WT mice but failed to alter blood pressure in KO mice. These results demonstrate that CYP1A1 is required for TCDD-induced cardiovascular superoxide anion production, endothelial dysfunction, and hypertension.


Incidental catch of loggerhead sea turtles (Caretta caretta) along the Sicilian coasts by longline fishery.
It has been estimated that 44,000 Caretta caretta turtles die every year due to anthropomorphic activity in the Mediterranean Sea, and that longline fishing is one of the most significant causes of mortality. A total of 482 specimens of C. caretta were rescued from different parts of the Sicilian coast (Mediterranean Sea) from 2014 to 2016. The most numerous stranding was recorded during the spring and summer seasons, mainly along the north and eastern coasts of Sicily. The curved carapace length for all the specimens ranged from between 19 and 95 cm and most of these were young or sub adults. The highest number of strandings was recorded in 2014 and 2015, with 206 and 169 individuals, respectively. A total of 66 live specimens out of 239 were successfully rehabilitated and released after surgery or drug therapy; fishing hooks were found in 129 specimens in different parts of the digestive tract with greater frequency in the oesophagus (47.3%) followed by the gut (24.8%), stomach (14.7%), and mouth (13.2%). This paper will highlight the incidence of the incidental catch by longline fishing of C. caretta along the Sicilian coasts and also relate the size of ingested hooks to the size of examined specimens.


Early life body size, growth and risks of systemic lupus erythematosus - A large Danish observational cohort study.
Adult obesity may increase the risks of systemic lupus erythematosus (SLE), and there are genetic links between adult height and SLE. Thus, it is plausible that size earlier in life may be important in the aetiology of SLE as well. We investigated whether birthweight, childhood body mass index (BMI; [kg/m2]), height and growth are associated with risks of adult SLE. The study included 346,627 children from the Copenhagen School Health Records Register, born 1930-1996 with measured weights and heights from 7-13 years. Birthweight information was available from 1936. Linkages were made to the Danish National Patient Register for information on registrations of SLE. During follow-up, 435 individuals (366 women) were registered with SLE. Cox proportional hazards regressions were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI). No differences by sex were detected in any of the associations. Birthweight was not associated with SLE risks. Childhood BMI and height were positively and linearly associated with SLE risks. For BMI at age 7, the HR was 1.11 (95% CI: 1.01-1.23) per z-score. For height at age 7, the HR was 1.13 (95% CI: 1.02-1.24) per z-score. The estimates were similar in magnitude across all childhood ages for BMI and height. There were limited indications that change in BMI or growth in height during childhood influence the risks of SLE in adulthood. Childhood body size is associated with risks of adult SLE, which supports the hypothesis that early life factors are important in SLE aetiology.


Motor skill interventions to improve fundamental movement skills of preschoolers with developmental delay.
Preschoolers with developmental delay (DD) are at risk for poor fundamental movement skills (FMS), but a paucity of early FMS interventions exist. The purpose of this review was to critically appraise the existing interventions to establish direction for future trials targeting preschoolers with DD. A total of 11 studies met the inclusion criteria. Major findings were summarized based on common subtopics of overall intervention effect, locomotor skill outcomes, object-control outcomes, and gender differences. Trials ranged from 8 to 24 weeks and offered 540-1700 min of instruction. The majority of trials (n = 9) significantly improved FMS of preschoolers with DD, with a large intervention effect (η(2) = 0.57-0.85). This review supports the utility of interventions to improve FMS of preschoolers with DD. Future researchers are encouraged to include more robust designs, a theoretical framework, and involvement of parents and teachers in the delivery of the intervention.


Cellular and subcellular distribution of a cAMP-regulated prestalk protein and prespore protein in Dictyostelium discoideum: a study on the ontogeny of prestalk and prespore cells.
We have analyzed a developmentally and spatially regulated prestalk-specific gene and a prespore-specific gene from Dictyostelium. The prestalk gene, pst-cathepsin, encodes a protein highly homologous to the lysosomal cysteine proteinases cathepsin H and cathepsin B. The prespore gene encodes a protein with some homology to the anti-bacterial toxin crambin and has been designated beejin. Using the lambda gtll system, we have made polyclonal antibodies directed against a portion of the protein encoded by pst-cathepsin and other antibodies directed against the beejin protein. Both antibodies stain single bands on Western blots. By immunofluorescence and Western blots, pst-cathepsin is not present in vegetative cells or developing cells during the first approximately 10 h of development. It then appears with a punctate distribution in a subset of developing cells. Beejin is detected only after approximately 15 h of development, also in a subset of cells. Pst-cathepsin is distributed in the anterior approximately 1/10 of migrating slugs and on the peripheral posterior surfaces of slugs. Beejin is distributed in the posterior region of slugs. Expression of both pst-cathepsin and beejin can be induced in subsets of isolated cultured cells by a combination of conditioned medium and extracellular cAMP in agreement with the regulation of the mRNAs encoding these proteins. We have used the antibodies as markers for cell type to examine the ontogeny and the spatial distribution of prestalk and prespore cells throughout multicellular development. Our findings suggest that prestalk cell differentiation is independent of position within the aggregate and that the spatial localization of prestalk cells within the multicellular aggregate arises from sorting of the prestalk cells after their induction. We have also found a class of cell in developing aggregates that contains neither the prestalk nor the prespore markers.


Surface Analyses of PVDF/NMP/[EMIM][TFSI] Solid Polymer Electrolyte.
Thermal treatment conditions of solid polymer polymer electrolyte (SPE) were studied with respect to their impact on the surface morphology, phase composition and chemical composition of an imidazolium ionic-liquid-based SPE, namely PVDF/NMP/[EMIM][TFSI] electrolyte. These investigations were done using scanning electron microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry as well as X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectroscopy. A thoroughly mixed blend of polymer matrix, ionic liquid and solvent was deposited on a ceramic substrate and was kept at a certain temperature for a specific time in order to achieve varying crystallinity. The morphology of all the electrolytes consists of spherulites whose average diameter increases with solvent evaporation rate. Raman mapping shows that these spherulites have a semicrystalline structure and the area between them is an amorphous region. Analysis of FTIR spectra as well as Raman spectroscopy showed that the β-phase becomes dominant over other phases, while DSC technique indicated decrease of crystallinity as the solvent evaporation rate increases. XPS and ToF-SIMS indicated that the chemical composition of the surface of the SPE samples with the highest solvent evaporation rate approaches the composition of the ionic liquid.


Synthesis of a base-free hafnium nitride from N2 cleavage: a versatile platform for dinitrogen functionalization.
The synthesis and characterization of a metastable, base-free isocyanato dihafnocene μ-nitrido complex from CO-induced dinitrogen cleavage is described. The open coordination site at hafnium suggested the possibility of functionalization of the nitrogen atom by cycloaddition and insertion chemistry. Addition of the strained, activated alkyne, cyclooctyne, resulted in N-C bond formation by cycloaddition. The alkyne product is kinetically unstable engaging the terminal hafnocene isocyanate and promoting deoxygenation and additional N-C bond formation resulting in a substituted cyanamide ligand. Group transfer between hafnium centers was observed upon treatment with Me3SiCl resulting in bridging carbodiimidyl ligands. Amidinato-type ligands, [NC(R)N](3-) were prepared by addition of either cyclohexyl or isobutyronitrile to the base free dihafnocene μ-nitrido complex, which also engages in additional N-C bond formation with the terminal isocyanate to form bridging ureate-type ligands. Heterocummulenes also proved reactive as exposure of the nitride complex to CO2 resulted in deoxygenation and N-C bond formation to form isocyanate ligands. With substituted isocyanates, cycloaddition to the dihafnocene μ-nitrido was observed forming ureate ligands, which upon thermolysis isomerize to bridging carbodiimides. Taken together, these results establish the base free dihafnocene μ-nitrido as a versatile platform to synthesize organic molecules from N2 and carbon monoxide.


Fungal bioremediation of polyethylene: Challenges and perspectives.
Plastics have become ubiquitous in both their adoption as materials and as environmental contaminants. Widespread pollution of these versatile, man-made and largely petroleum-derived polymers has resulted from their long-term mass production, inappropriate disposal and inadequate end of life management. Polyethylene (PE) is at the forefront of this problem, accounting for one-third of plastic demand in Europe in part due to its extensive use in packaging. Current recycling and incineration processes do not represent sustainable solutions to tackle plastic waste, especially once it becomes littered, and the development of new waste-management and remediation technologies are needed. Mycoremediation (fungal-based biodegradation) of PE has been the topic of several studies over the last two decades. The utility of these studies is limited by an inconclusive definition of biodegradation and a lack of knowledge regarding the biological systems responsible. This review highlights relevant features of fungi as potential bioremediation agents, before discussing the evidence for fungal biodegradation of both high- and low-density PE. An up-to-date perspective on mycoremediation as a future solution to PE waste is provided.