Multisensory cueing facilitates naming in aphasia.
Impaired naming is a ubiquitous symptom in all types of aphasia, which often adversely impacts independence, quality of life, and recovery of affected individuals. Previous research has demonstrated that naming can be facilitated by phonological and semantic cueing strategies that are largely incorporated into the treatment of anomic disturbances. Beneficial effects of cueing, whereby naming becomes faster and more accurate, are often attributed to the priming mechanisms occurring within the distributed language network. We proposed and explored two novel cueing techniques: (1) Silent Visuomotor Cues (SVC), which provided articulatory information of target words presented in the form of silent videos, and (2) Semantic Auditory Cues (SAC), which consisted of acoustic information semantically relevant to target words (ringing for "telephone"). Grounded in neurophysiological evidence, we hypothesized that both SVC and SAC might aid communicative effectiveness possibly by triggering activity in perceptual and semantic language regions, respectively. Ten participants with chronic non-fluent aphasia were recruited for a longitudinal clinical intervention. Participants were split into dyads (i.e., five pairs of two participants) and required to engage in a turn-based peer-to-peer language game using the Rehabilitation Gaming System for aphasia (RGSa). The objective of the RGSa sessions was to practice communicative acts, such as making a request. We administered SVCs and SACs in a pseudorandomized manner at the moment when the active player selected the object to be requested from the interlocutor. For the analysis, we compared the times from selection to the reception of the desired object between cued and non-cued trials. Naming accuracy, as measured by a standard clinical scale, significantly improved for all stimuli at each evaluation point, including the follow-up. Moreover, the results yielded beneficial effects of both SVC and SAC cues on word naming, especially at the early intervention sessions when the exposure to the target lexicon was infrequent. This study supports the efficacy of the proposed cueing strategies which could be integrated into the clinic or mobile technology to aid naming even at the chronic stages of aphasia. These findings are consistent with sensorimotor accounts of language processing, suggesting a coupling between language, motor, and semantic brain regions. NCT02928822 . Registered 30 May 2016.


In vitro cell imaging using multifunctional small sized KGdF4:Yb3+,Er3+ upconverting nanoparticles synthesized by a one-pot solvothermal process.
Multifunctional KGdF4:18%Yb(3+),2%Er(3+) nanoparticles with upconversion fluorescence and paramagnetism are synthesized. The average sizes of the nanoparticles capped with branched polyethyleneimine (PEI) and 6-aminocaproic acid (6AA) are ~14 and ~13 nm, respectively. Our KGdF4 host does not exhibit any phase change with the decrease of particle size, which can prevent the detrimental significant decrease in upconversion luminescence caused by this effect observed in the well-known NaYF4 host. The branched PEI and 6AA capping ligands endow our nanoparticles with water-dispersibility and biocompatibility, which can favor internalization of our nanoparticles into the cytoplasm of HeLa cells and relatively high cell viability. The strong upconversion luminescence detected at the cytoplasm of HeLa cells incubated with the branched PEI-capped nanoparticles is probably attributed to the reported high efficiency of cellular uptake. The magnetic mass susceptibility of our nanoparticle is 8.62 × 10(-5) emu g(-1) Oe(-1). This is the highest value ever reported in trivalent rare-earth ion-doped KGdF4 nanoparticles of small size (≤14 nm), and is very close to that of nanoparticles used as T1 contrast agents in magnetic resonance imaging. These suggest the potential of our KGdF4:Yb(3+),Er(3+) nanoparticles as small-sized multifunctional bioprobes.


Aqueous extracts of husks of Plantago ovata reduce hyperglycaemia in type 1 and type 2 diabetes by inhibition of intestinal glucose absorption.
Plantago ovata has been reported to reduce postprandial glucose concentrations in diabetic patients. In the present study, the efficacy and possible modes of action of hot-water extracts of husk of P. ovata were evaluated. The administration of P. ovata (0.5 g/kg body weight) significantly improved glucose tolerance in normal, type 1 and type 2 diabetic rat models. When the extract was administered orally with sucrose solution, it suppressed postprandial blood glucose and retarded small intestinal absorption without inducing the influx of sucrose into the large intestine. The extract significantly reduced glucose absorption in the gut during in situ perfusion of small intestine in non-diabetic rats. In 28 d chronic feeding studies in type 2 diabetic rat models, the extract reduced serum atherogenic lipids and NEFA but had no effect on plasma insulin and total antioxidant status. No effect of the extract was evident on intestinal disaccharidase activity. Furthermore, the extract did not stimulate insulin secretion in perfused rat pancreas, isolated rat islets or clonal beta cells. Neither did the extract affect glucose transport in 3T3 adipocytes. In conclusion, aqueous extracts of P. ovata reduce hyperglycaemia in diabetes via inhibition of intestinal glucose absorption and enhancement of motility. These attributes indicate that P. ovata may be a useful source of active components to provide new opportunities for diabetes therapy.


[Evidence-Based Knowledge Translation: From Scientific Evidence to Clinical Nursing Practice].
In 1992, Gordon Guyatt coined the term "evidence-based medicine", which has since attracted worldwide attention. In 2007, the Institute of Medicine's Roundtable on Evidence-Based Medicine set the goal that 90% of clinical decisions would be supported by accurate, timely, and up-to-date clinical information and would reflect the best available evidence by 2020. However, the chasm between knowing and doing remains palpable. In 2000, the Canadian Institute of Health Research applied the term "knowledge translation" to describe the bridge that is necessary to cross the gap between research knowledge and clinical practice. The present paper outlines the conceptual framework, barriers, and promotion strategies for evidence-based knowledge translation and shares clinical experience related to overcoming the seven layers of leakage (aware, accepted, applicable, able, acted on, agreed, and adhered to). We hope that this paper can enhance the public well-being and strengthen the future health care system.


Recommended prostate-specific antigen testing intervals for the detection of curable prostate cancer.
To evaluate prostate-specific antigen (PSA) testing intervals that maintain the detection of curable cancer and reduce unnecessary testing. Historical prospective study of serial PSA measurements at 2- and 4-year intervals from frozen serum samples of 40 men who eventually developed prostate cancer and 272 men without prostate cancer who were participants in a prospective aging study (Gerontology Research Center of the National Institute on Aging, the Baltimore Longitudinal Study of Aging) and the case series of 389 consecutive men treated surgically for nonpalpable prostate cancer. Probability of a PSA conversion to 4.1 to 5.0 ng/mL and to greater than 5.0 ng/mL at 2 and 4 years and probability of detecting curable prostate cancer by age and PSA level. When the pretreatment PSA level was less than or equal to 4.0 ng/mL, nonpalpable prostate cancers were highly likely (34/36, 94%) to be curable (organ-confined or capsular penetration with Gleason score < 7 and negative margins), and the majority (25/36, 69%) were small cancers (confined tumor < or = 0.5 cm3 with no Gleason pattern 4 or 5). When the pretreatment PSA level was greater than 4.0 ng/mL and less than or equal to 5.0 ng/mL, cancers were highly likely to be curable (32/36, 89%), and a minority were small cancers (12/36, 33%). When the pretreatment PSA level was greater than 5.0 ng/mL, 96 (30%) of 317 cancers were noncurable. The PSA conversion (for cancer cases) to a level at which cure is less likely (> 5.0 ng/mL) is rare (0%) after 2 or 4 years when the initial PSA is less than 2.0 ng/mL. PSA conversion to a range at which cancers are likely to be curable and less likely to be small (4.1-5.0 ng/mL) is rare after 2 years (0%-4%) when the baseline PSA level is less than 2.0 ng/mL but common when the baseline PSA level is between 2.1 and 3.0 ng/mL (27%) or 3.1 and 4.0 ng/mL (36%). These data suggest that for men with no cancer suspected on digital rectal examination, a PSA level of 4.0 to 5.0 ng/mL is an acceptable range for maintaining the detection of curable prostate cancer and a 2-year PSA testing interval is not likely to miss a curable prostate cancer when the initial PSA level is less than 2.0 ng/mL. Recognizing that 70% of a screened population between the ages of 50 years and 70 years have PSA levels less than 2.0 ng/mL, elimination of annual PSA testing for these men would result in large health care cost savings.


Group-based intervention program in inflammatory bowel disease patients: effects on quality of life.
Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) have great impact on patients' health-related quality of life (HRQOL). The aim of this study was to develop an integrated medical and psychological/ psychosocial group-based intervention program for IBD patients and to evaluate if such a program could influence the patients' HRQOL and coping abilities. IBD patients in remission or with low disease activity were randomized to intervention or control groups. The intervention comprised nine weekly sessions, alternating lectures, and group therapy sessions. The Inflammatory Bowel Disease Questionnaire (IBDQ) and the Sense of Coherence scale (SOC) were used to measure HRQOL and coping ability at 0, 6, and 12 months. The intervention was evaluated by a visual analog scale (VAS) and written comments by a content analysis. In all, 24 patients were included in the intervention group and 20 in the control group. The mean IBDQ score showed no statistically significant differences before (173.9) or after the intervention at month 6 (175.7) or at month 12 (171.8), or when comparing intervention and controls at month 12. Similarly, there were no statistically significant differences in mean SOC before or after intervention or when comparing groups. The VAS and the content analysis showed that the intervention was well appreciated by the patients. The group-based intervention program was feasible and highly appreciated. There were no statistically significant differences in average IBDQ or SOC over time or in comparison with controls, although a significant increase was seen in patients with short disease duration.


The Reliability and Sensitivity of Performance Measures in a Novel Pace-Bowling Test.
To evaluate the reliability and sensitivity of performance measures in a novel pace-bowling test. Thirteen male amateur-club fast bowlers completed a novel pace-bowling test on 2 separate occasions, 4-7 d apart. Participants delivered 48 balls (8 overs) at 5 targets on a suspended sheet situated behind a live batter, who stood in a right-handed and left-handed stance for an equal number of deliveries. Delivery instruction was frequently changed, with all deliveries executed in a preplanned sequence. Data on ball-release speed were captured by radar gun. A high-speed camera captured the moment of ball impact on the target sheet for assessment of radial error and bivariate variable error. Delivery rating of perceived exertion (0-100%) was collected as a measure of intensity. Intraclass correlation coefficients and coefficients of variation revealed excellent reliability for peak and mean ball-release speed, acceptable reliability for delivery rating of perceived exertion, and poor reliability for mean radial error, bivariate variable error, and variability of ball-release speed. The smallest worthwhile change indicated high sensitivity with peak and mean ball-release speed and lower sensitivity with mean radial error and bivariate variable error. The novel pace-bowling test incorporates improvements in ecological validity compared with its predecessors and can be used to provide a more comprehensive evaluation of pace-bowling performance. Data on the smallest worthwhile change can improve interpretation of pace-bowling research findings and may therefore influence recommendations for applied practice.


Evaluation of the CosmosID Bioinformatics Platform for Prosthetic Joint-Associated Sonicate Fluid Shotgun Metagenomic Data Analysis.
We previously demonstrated that shotgun metagenomic sequencing can detect bacteria in sonicate fluid, providing a diagnosis of prosthetic joint infection (PJI). A limitation of the approach that we used is that data analysis was time-consuming and specialized bioinformatics expertise was required, both of which are barriers to routine clinical use. Fortunately, automated commercial analytic platforms that can interpret shotgun metagenomic data are emerging. In this study, we evaluated the CosmosID bioinformatics platform using shotgun metagenomic sequencing data derived from 408 sonicate fluid samples from our prior study with the goal of evaluating the platform vis-à-vis bacterial detection and antibiotic resistance gene detection for predicting staphylococcal antibacterial susceptibility. Samples were divided into a derivation set and a validation set, each consisting of 204 samples; results from the derivation set were used to establish cutoffs, which were then tested in the validation set for identifying pathogens and predicting staphylococcal antibacterial resistance. Metagenomic analysis detected bacteria in 94.8% (109/115) of sonicate fluid culture-positive PJIs and 37.8% (37/98) of sonicate fluid culture-negative PJIs. Metagenomic analysis showed sensitivities ranging from 65.7 to 85.0% for predicting staphylococcal antibacterial resistance. In conclusion, the CosmosID platform has the potential to provide fast, reliable bacterial detection and identification from metagenomic shotgun sequencing data derived from sonicate fluid for the diagnosis of PJI. Strategies for metagenomic detection of antibiotic resistance genes for predicting staphylococcal antibacterial resistance need further development.


Efficacy of language intervention in the early years.
Oral language skills in the preschool and early school years are critical to educational success and provide the foundations for the later development of reading comprehension. In a randomized controlled trial, 180 children from 15 UK nursery schools (n = 12 from each setting; M(age) = 4;0) were randomly allocated to receive a 30-week oral language intervention or to a waiting control group. Children in the intervention group received 30 weeks of oral language intervention, beginning in nursery (preschool), in three group sessions per week, continuing with daily sessions on transition to Reception class (pre-Year 1). The intervention was delivered by nursery staff and teaching assistants trained and supported by the research team. Following screening, children were assessed preintervention, following completion of the intervention and after a 6-month delay. Children in the intervention group showed significantly better performance on measures of oral language and spoken narrative skills than children in the waiting control group immediately after the 30 week intervention and after a 6 month delay. Gains in word-level literacy skills were weaker, though clear improvements were observed on measures of phonological awareness. Importantly, improvements in oral language skills generalized to a standardized measure of reading comprehension at maintenance test. Early intervention for children with oral language difficulties is effective and can successfully support the skills, which underpin reading comprehension.


Identification of novel mutations in patients with fibrinogen disorders and genotype/phenotype correlations.
Congenital fibrinogen disorders are caused by variants occurring within the fibrinogen gene cluster. We describe ten subjects with disease-causative variants, adding information on such disorders. Ten subjects were referred to our Centre because of likely hypo/dysfibrinogenaemia. We evaluated the function and quantity of fibrinogen, using Clauss and immunoreactive assays, and performed genetic investigations by direct sequencing of alpha, beta and gamma chain-encoding genes. Mutations were analysed using SIFT and Polyphen-2 algorithms. We identified one afibrinogenaemic patient (alpha p.Arg178* homozygote) with bleeding/thrombotic events, three heterozygous patients with hypo/dysfibrinogenaemia (gamma p.Thr47ILeu combined with beta IVS7+1G>T; beta p.Cys95Ser; beta p.Arg196Cys) referred for bleeding or thrombotic episodes and six heterozygous subjects with hypofibrinogenaemia (alpha p.Glu41Lys; gamma p.Gly191Val; beta p.Gly288Ser; gamma p.His333Arg; gamma p.Asp342Glu and p.343-344 duplication; gamma p.Asp356Val), of whom four were symptomatic. Five novel missense changes and one novel duplication variant were found, all in hypofibrinogenaemic subjects: p.Glu41Lys (SIFT score 0, Polyphen-2 score 0.986) was identified in a woman with bleeding after major orthopaedic surgery; p.Gly191Val (SIFT score 0.02, Polyphen-2 score 1) in an asymptomatic woman; p.His333Arg (SIFT score 0, Polyphen-2 score 1) in a woman with a post-partum haemorrhage; and p.Asp342Glu (SIFT score 0.23, Polyphen-2 score 0.931); and an Asn-343 and Asp-344 duplication in a child who developed a haematoma following a fall. All but one of the novel mutations were in symptomatic subjects and are predicted to be deleterious. Our findings shed more light on genotype-phenotype relationships in congenital fibrinogen disorders.


Virtual Dysphagia Evaluation: Practical Guidelines for Dysphagia Management in the Context of the COVID-19 Pandemic.
With encouraging signs of pandemic containment nationwide, the promise of return to a full range of clinical practice is on the horizon. Clinicians are starting to prepare for a transition from limited evaluation of emergent and urgent complaints to resumption of elective surgical procedures and routine office visits within the next few weeks to months. Otolaryngology as a specialty faces unique challenges when it comes to the COVID-19 pandemic due to the fact that a comprehensive head and neck examination requires aerosol-generating endoscopic procedures. Since the COVID-19 pandemic is far from being over and the future may hold other highly communicable infectious threats that may require similar precautions, standard approaches to the clinical evaluation of common otolaryngology complaints will have to be modified. In this communication, we present practical recommendations for dysphagia evaluation with modifications to allow a safe and comprehensive assessment.


Role of smoking in periodontal disease among diabetic patients.
The objective of the study was to analyse the effect of smoking on periodontal disease in diabetic patients. One hundred and fifty patients participated in the study Fifty patients with Type 1 diabetes mellitus (DM) and periodontal disease were the first group; 50 patients with Type 2 DM and periodontal disease were the second group, and 50 non-diabetic patients with periodontal disease were the third group. After anamnesis was taken, the variable in the analysis was smoker/non-smoker The status of the oral hygiene and periodontal condition was recorded using Plaque index, Supragingival calculus index, Subgingival calculus index, Gingival index, Periodontal Disease Index and Community Periodontal Index of Treatment Needs, by the periodontologist. Except Gingival index, mean values of all investigated indices were higher in smokers in all investigated groups. Periodontal disease is more advanced in diabetic smokers compared to diabetic non-smokers. It can be concluded that smoking negatively affects the course of diabetic periodontal disease and increases the risk of attachment loss. Diabetic smokers are at high risk for poor periodontal prognosis, and they should be included in careful periodontal treatment.


Eicosapentaenoic Acid Reduces Fecal Levels of Calprotectin and Prevents Relapse in Patients With Ulcerative Colitis.
High fecal levels of calprotectin indicate mucosal inflammation and have been shown to predict relapse in patients with ulcerative colitis (UC). Eicosapentaenoic acid (EPA), the major component of n-3 fish oil, has anti-inflammatory properties in patients with chronic inflammatory disorders. We performed a placebo-controlled trial of patients with UC at risk of relapse to determine the ability of the free fatty acid form of EPA (EPA-FFA) to reduce intestinal inflammation, using fecal level of calprotectin as a marker. From June 2014 to May 2016, 60 patients with UC with a partial Mayo score < 2 and fecal calprotectin ≥150 μg/g, in stable therapy for at least the 3 previous months, were randomly assigned to groups (1:1) given either EPA-FFA (500 mg, twice daily) or placebo for 6 months. A colonoscopy was performed at baseline. Clinical assessments and measurements of fecal calprotectin were made at baseline, at study months 3 and 6, or the time of clinical relapse. Patients with a relapse of UC underwent a second colonoscopy. The primary end point was a 100-point reduction in fecal levels of calprotectin at 6 months from the baseline value; the secondary end point was maintenance of clinical remission at 6 months. The primary end point was achieved by 19 of 30 patients (63.3%) in the EPA-FFA group vs 4 of 30 patients (13.3%) in the placebo group (odds ratio, 12.0; 95% CI, 3.12-46.24; P < .001). The secondary end point was achieved by 23 of 30 patients (76.7%) in the EPA-FFA group vs 15 of 30 (50%) patients in the placebo group (OR, 3.29; 95% CI, 1.08-9.95; P = .035). No serious adverse events were observed. In a placebo-controlled trial of 60 patients with UC, we found 6 months' administration of EPA-FFA to reduce fecal levels of calprotectin with no serious adverse events. This agent might be used to induce and maintain symptom-free remission in patients with UC. ClinicalTrials.gov number: NCT02179372.


A screen for genes induced in the suprachiasmatic nucleus by light.
The mechanism by which mammalian circadian clocks are entrained to light-dark cycles is unknown. The clock that drives behavioral rhythms is located in the suprachiasmatic nucleus (SCN) of the brain, and entrainment is thought to require induction of genes in the SCN by light. A complementary DNA subtraction method based on genomic representational difference analysis was developed to identify such genes without making assumptions about their nature. Four clones corresponded to genes induced specifically in the SCN by light, all of which showed gating of induction by the circadian clock. Among these genes are c-fos and nur77, two of the five early-response genes known to be induced in the SCN by light, and egr-3, a zinc finger transcription factor not previously identified in the SCN. In contrast to known examples, egr-3 induction by light is restricted to the ventral SCN, a structure implicated in entrainment.


Inhibition of Tongue Coat and Dental Plaque Formation by Stabilized Chlorine Dioxide Vs Chlorhexidine Mouthrinse: A Randomized, Triple Blinded Study.
Chlorine dioxide (ClO2) is an oxidizing agent with known bactericidal, viricidal and fungicidal properties. Its efficacy in reducing the halitosis has been established by previous literature. However, data evaluating its antiplaque property is scarce. Chlorhexidine (CHX) is considered as the gold standard and an effective adjunctive to mechanical plaque removal. However, it is associated with few reversible side effects. Therefore a study was conducted to assess the antiplaque property of ClO2 containing mouthrinse against CHX mouthrinse. To evaluate the efficacy of stabilized chlorine dioxide containing mouthrinse and CHX containing mouthrinse in inhibition of tongue coat accumulation and dental plaque formation using a four day plaque regrowth model clinically and microbiologically in a healthy dental cohort. A Single Center, Randomized, Triple blinded, Microbiological clinical trial was conducted involving 25 healthy dental students volunteers (11 males, 14 females). Two commercially available mouthrinse: Mouthrinse A - Aqueous based ClO2 mouthrinse Freshchlor(®) and Mouthrinse B - Aqueous based 0.2% CHX mouthrinse Hexidine(®) were selected as the test products. Subjects were asked to rinse and gargle for 1 minute with the allocated mouthrinse under supervision after supragingival scaling, polishing and tongue coat removal. After four hours, smears were taken from the buccal mucosa and tooth surface. On the fifth day from baseline of four day non brushing plaque regrowth model the samples were again taken from buccal mucosa and tooth surface followed by recording of plaque scores by Rastogi Modification of Navy Plaque index, extent of tongue coat by Winkel's tongue coating index and measuring tongue coat wet weight in grams. The samples collected were subjected to microbial analysis and the results were expressed as colony forming units (CFUs) per sample. The Data was analysed using SPSS 16.00 and presented using descriptive statistics. Independent t-test was used for the comparison between mouthrinse A groups & mouthrinse B group. The plaque scores and Winkels tongue coat scores, wet tongue coat weight recorded on the fifth day after the use of the two mouthrinse didn't show a statistically significant difference. The CFU per sample from tooth and mucosa after four hours revealed low bacteria count with respect to mouthrinse B however the CFU obtained on the fifth day did not show a statistically significant difference between the two mouthrinse. The clinical antiplaque efficacy of CHX and ClO2 mouthwash is comparable and so is the efficacy in reducing the oral bacterial load.


Development of a monoclonal antibody to the aP2 protein to identify adipocyte precursors in tumours of adipose differentiation.
aP2 gene product (aP2 protein) expression has been shown to be a useful diagnostic marker for identification of lipoblasts and fetal fat cells in soft tissue tumours. A monoclonal antibody was developed by a mouse spleen cell-myeloma hybridoma technique to an 18 amino acid segment of the aP2 protein and was used to investigate the immunohistochemical expression of this protein in benign and malignant tumours of adipocytic differentiation and a wide variety of other soft tissue tumours. We found that aP2 protein was expressed by lipoblasts in liposarcomas and lipoblastomas and by brown fat cells in hibernomas and normal periadrenal fat. Other benign adipose tissue tumours and benign and malignant soft tissue tumours were distinguished from liposarcoma by absence of staining for aP2 protein. Immunohistochemical identification of the aP2 protein is likely to prove a useful means of distinguishing liposarcoma from other malignant mesenchymal and epithelial neoplasms, some of which contain cells that morphologically resemble lipoblasts.


Effects of cereal and vegetable fiber feeding on potential risk factors for colon cancer.
The effects of two doses of cereal fiber and vegetable fiber on mean transit time, stool weight, fecal pH and fecal bile acids were examined in 34 healthy volunteers. Subjects consumed five diets in random order for 23 days each, consisting of a fiber-free liquid diet and quick breads containing 0 g added dietary fiber, 10 g fiber as wheat bran (WB), 30 g fiber as WB, 10 g fiber as vegetable fiber (VF), and 30 g fiber as VF. Fecal wet and dry weights were 43% and 19% higher, respectively, on WB as compared to VF (P < 0.0001). Fecal pH was lower on WB than on VF (P < 0.0001) and decreased with increased fiber intake (P < 0.005). Transit time was 36% faster with WB than with VF (P < 0.0001). There was no VF dose effect on transit time, but transit time was 23% faster on 30 g WB than on 10 g WB (P = 0.04). Total bile acid concentrations decreased with increased fiber dose (P < 0.0001) but were not significantly different between WB and VF. Daily total bile acid excretion was 14% lower on VF compared to WB (P = 0.01). There was no VF dose effect on total bile acid excretion, but excretion was 13% lower on 30 g WB than on 10 g WB (P = 0.04). These findings are consistent with the capacity of fiber to alter potential risk factors for colon cancer but do not explain differences in epidemiological data between vegetable and cereal intake.


Electric field strength and focality in electroconvulsive therapy and magnetic seizure therapy: a finite element simulation study.
We present the first computational study comparing the electric field induced by various electroconvulsive therapy (ECT) and magnetic seizure therapy (MST) paradigms. Four ECT electrode configurations (bilateral, bifrontal, right unilateral, and focal electrically administered seizure therapy) and three MST coil configurations (circular, cap, and double cone) were modeled. The model incorporated a modality-specific neural activation threshold. ECT (0.3 ms pulse width) and MST induced the maximum electric field of 2.1-2.5 V cm⁻¹ and 1.1-2.2 V cm⁻¹ in the brain, corresponding to 6.2-7.2 times and 1.2-2.3 times the neural activation threshold, respectively. The MST electric field is more confined to the superficial cortex compared to ECT. The brain volume stimulated was much larger with ECT (up to 100%) than with MST (up to 8.2%). MST with the double-cone coil was the most focal, and bilateral ECT was the least focal. Our results suggest a possible biophysical explanation of the reduced side effects of MST compared to ECT. Our results also indicate that the conventional ECT pulse amplitude (800-900 mA) is much higher than necessary for seizure induction. Reducing the ECT pulse amplitude should be explored as a potential means of diminishing side effects.


The role of Notch receptor expression in bile duct development and disease.
Mutations in the Jagged1 gene, a ligand for the Notch signalling pathway, have been implicated in the pathogenesis of Alagille syndrome (AGS), resulting in bile duct paucity. Recently, a mouse model for AGS suggested that abnormalities of the Notch2 receptor, as well as of Jagged1, may be present. Expression patterns of Notch receptors have not been described in the developing human liver or in paediatric liver. The expression of Notch receptors and ligands was examined in fetal, paediatric normal, and diseased human liver by RT-PCR and immunohistochemistry. RT-PCR showed Notch1-4 mRNA expression to be present. In fetal liver, Notch3 protein was expressed on mesenchymal cells, closely adjacent to ductal plate cells that expressed Jagged1. In paediatric normal liver, Notch1 and Notch2 were present on mature bile duct cells. Notch expression was altered in disease, with distinct differences in AGS from extrahepatic biliary atresia (EHBA) and alpha1-anti-trypsin deficiency (alpha1AT). In AGS, where extensive ductular reaction was present, Jagged1 was expressed on ductular reactive cells (DRCs), along with marked Notch2 and Notch3 staining. Where there was ductular paucity, Notch2 and Notch3 were not expressed on remaining biliary epithelial cells. In EHBA and alpha1AT, Notch receptor expression was not seen on DRCs. Instead, Notch2 and Notch3 were expressed by stromal cells. In all diseases, Notch3 was expressed on neovessels in portal tracts and cirrhotic fibrous septa. In conclusion, Notch3 is expressed in close proximity to Jagged1 at the time of ductal plate formation, suggesting that Notch3 is important for bile duct development. The expression of both Notch2 and Notch3 in AGS on DRCs confirms that these receptors may be important in the pathogenesis of this disease. Further studies are required to investigate the presence of Notch2 and Notch3 at other periods in liver development and to clarify the role of Notch signalling in paediatric cholestases.


The Temperature Dependence of Kinetics Associated with Drug Block of hERG Channels Is Compound-Specific and an Important Factor for Proarrhythmic Risk Prediction.
Current mandated preclinical tests for drug-induced proarrhythmia are very sensitive, but not sufficiently specific. This has led to concern that there is a high attrition rate of potentially safe drugs that could have been beneficial to patients. The comprehensive in vitro proarrhythmia initiative has proposed new metrics based around in silico risk predictions, which are informed, among other things, by measures of human ether-à-go-go-related gene channel (hERG) block kinetics. However, high-throughput patch-clamp systems set to collect these data largely operate at ambient temperature, whereas the simulations for risk prediction are carried out at physiologic temperature. The aims of this study were to: 1) determine to what degree kinetics of drug block of hERG are temperature-dependent, 2) assess the impact of any temperature dependence of drug binding kinetics on repolarization in silico, and 3) identify whether a common set of Q10 scalars can be used to extrapolate kinetic data gathered at ambient to physiologic temperatures for use in in silico proarrhythmic risk prediction. We show that, for a range of drugs, kinetics of block are temperature-dependent and, furthermore, that the degree of temperature dependence is different for each drug. As a result, no common set of Q10 scalars could describe the observed range of temperature dependencies. These results suggest that if accurate physiologic temperature models of the kinetics of drug binding are important for in silico risk prediction, the in vitro data should be acquired at physiologic temperature.


Fizeau interferometer for measuring the flatness of optical surfaces.
A Fizeau interferometer is described with which to test the flatness of optical surface up to 240-mm diam. A mercury mirror of suitable diameter is used as a flatness standard. A simple 240-mm diam lens is sufficient. For easy testing of the surfaces of wedge-shaped glass plates without adjustment difficulties the illumination and photographic arrangement, mounted in the same frame, can be tipped on an axis, going through the test surface. The influence of the aberration of the simple lens is discussed. Experimental results of the measurement of an optical flat are presented.


Evidence of hepatitis in patients receiving transfusions of blood components containing antibody to hepatitis C.
When hepatitis C virus antibody (anti-HCV) enzyme immunoassay (EIA1) testing became available in 1990, we tested samples from previously transfused blood units, traced the recipients of reactive units, and evaluated the recipients for HCV infection during the 12 months after transfusion. Ten of 42 recipients of EIA1-reactive blood were anti-HCV reactive on follow-up by EIA1 and 12 were reactive by a second-generation assay (EIA2). Reverse transcriptase-polymerase chain reaction (RT-PCR) detected HCV RNA in 5 seronegative recipients. In all, 17 of 42 recipients (40%) of EIA1-reactive blood had evidence of HCV infection. In comparison, 54 surgery patients, who received either no transfusion or autologous EIA1-nonreactive blood, remained EIA1 nonreactive and RT-PCR negative for 1 year; 1 patient (1.8%) became EIA2 reactive (P < or = .01). Of the recipients of anti-HVC reactive blood transfusions (reactive by both EIA1 and a supplemental 4-antigen strip immunoblot assay [RIBA2]), 14 (93%) of the recipients had evidence of HCV infection compared with only 3 of 27 recipients (11%) of EIA1-reactive, RIBA2-nonreactive blood (P < or = .01). Thus, blood components reactive for anti-HCV EIA1 may have transmitted HCV up to 40% of the time, but blood components found reactive by both EIA1 and RIBA2 may transmit HCV with a frequency of greater than 90%.


Use of the Russell-Taylor reconstruction nail in femoral shaft fractures.
Of 242 patients with injuries treated by locked intramedullary nailing of the femur, 52 (22 percent) were considered suitable for insertion of the reconstruction nail. The Russell-Taylor reconstruction nail was found to be useful in a greater variety of fractures than those for which it was originally designed. In addition to ipsilateral neck and shaft fractures, the Russell-Taylor reconstruction nail proved successful in high-energy comminuted subtrochanteric fractures, elderly subtrochanteric fractures and pathological lesions. In two cases, problems were encountered due to the relative straightness of the nail, but in the remaining patients there were no technical problems. In the 43 elderly patients and those with pathological lesions, seven complications occurred: a number which compares favourably with published reports for extramedullary devices. There were no cases of implant failure and in all patients the device supported the fracture to union or death.


Male fidelity expressed through rapid testosterone suppression of ultrasonic vocalizations to novel females in the monogamous California mouse.
The steroid hormone testosterone (T) is a well-known mediator of male sexual behavior in vertebrates. However, less is known about T's rapid effects on sexual behavior, particularly those involving ultrasonic vocalizations (USVs), a mode of communication that can influence mate acquisition in rodents. Using the monogamous California mouse, Peromyscus californicus, we tested whether T rapidly alters male USV production by giving T or saline injections to non-paired (sexually naïve) males and paired (paternally experienced and pair-bonded) males immediately prior to a brief exposure to an unrelated, novel female. Among non-paired males, no differences in the total number of USVs were observed; however, T increased the proportion of simple sweeps produced. Among paired males, T decreased the number of USVs produced, and this change was driven by a reduction in simple sweeps. These results suggest a differential rapid effect of T pulses between non-paired and paired males upon exposure to a novel female. Additionally, we observed a positive correlation in the production of USVs made between males and novel females, and this relationship was altered by T. Given the importance of USVs in sexual communication, our study supports an essential concept of monogamy in that mate fidelity is reinforced by decreased responsiveness to prospective mates outside of the pair bond. The central mechanism in pair bonded males that decreases their responsiveness to novel females appears to be one that T can trigger. This is among the first studies to demonstrate that T can inhibit sexually related behaviors and do so rapidly.


Recent advances in affinity capillary electrophoresis.
Use of the specificity of (bio)interactions can effectively overcome the selectivity limitation faced in capillary electrophoresis (CE), and the resulting technique usually is referred to as affinity capillary electrophoresis (ACE). Despite the high selectivity of ACE, several important problems still need to be addressed. A major issue in all CE separations, including ACE, is the concentration detection limit. Using UV detection, this is usually in the order of 10(-6) M whereas laser-induced fluorescence (LIF) detection can provide detection limits down to the sub-10(-10) M range. However, a marked disadvantage of LIF is that labeling of the analytes is usually required, which might change the interaction behavior of the solutes under investigation. Additionally, labeling reactions at sub-10(-10) M concentration levels are certainly not trivial and often difficult to perform quantitatively. Alternative and universal detection approaches, particularly mass spectrometric (MS) detection, look very promising but (A) CE-MS techniques are still far from routine application. Important future progress in sensitive detection strategies is likely to increase the use of ACE in the future.


Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies.
Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p<0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p<0·0001). Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. No funding.


De Novo Transcriptome Assembly and Characterization for the Widespread and Stress-Tolerant Conifer Platycladus orientalis.
Platycladus orientalis, of the family Cupressaceae, is a widespread conifer throughout China and is extensively used for ecological reforestation, horticulture, and in medicine. Transcriptome assemblies are required for this ecologically important conifer for understanding genes underpinning adaptation and complex traits for breeding programs. To enrich the species' genomic resources, a de novo transcriptome sequencing was performed using Illumina paired-end sequencing. In total, 104,073,506 high quality sequence reads (approximately 10.3 Gbp) were obtained, which were assembled into 228,948 transcripts and 148,867 unigenes that were longer than 200 nt. Quality assessment using CEGMA showed that the transcriptomes obtained were mostly complete for highly conserved core eukaryotic genes. Based on similarity searches with known proteins, 62,938 (42.28% of all unigenes), 42,158 (28.32%), and 23,179 (15.57%) had homologs in the Nr, GO, and KOG databases, 25,625 (17.21%) unigenes were mapped to 322 pathways by BLASTX comparison against the KEGG database and 1,941 unigenes involved in environmental signaling and stress response were identified. We also identified 43 putative terpene synthase (TPS) functional genes loci and compared them with TPSs from other species. Additionally, 5,296 simple sequence repeats (SSRs) were identified in 4,715 unigenes, which were assigned to 142 motif types. This is the first report of a complete transcriptome analysis of P. orientalis. These resources provide a foundation for further studies of adaptation mechanisms and molecular-based breeding programs.


'Subarachnoid cyst' after evacuation of chronic subdural hematoma: Case report of an unusual postoperative morbidity.
Burr-hole drainage of chronic subdural hematomas are routine operative procedures done by neurosurgical residents. Common postoperative complications include acute epidural and/or subdural bleeding, tension pneumocephalus, intracranial hematomas and ischemic cerebral infarction. We report an interesting post-operative complication of a 'subarachnoid cyst' after burr-hole evacuation of a chronic subdural hematoma. The authors hypothesize that the 'cyst' is likely secondary to the splitting of the adjacent neomembrane within its arachnoid-brain interface by iatrogenic irrigation of the subdural space. Over time, this 'cyst' develops into an area of gliosis which eventually causes long-term scar epilepsy in the patient. As far as we are aware, this is the first complication of such a 'subarachnoid cyst' post burr-hole drainage reported in the literature.


Getting no respect: barriers to mammography for a group of Swedish women.
Mammography screening is a highly sensitive and specific method to detect breast cancer at an early stage. If screening campaigns are to be cost effective, compliance is valuable. However, many women do not attend when called for mammography screening. Our aim in this study is to understand and explain why women become nonattenders. A sample of 16 nonattending women, aged between 43 and 73 years, participated in this qualitative study, by interviews or written comments. The core category discovered in the data was "getting no respect." The informants did not feel respected from either the society or the health care system. Below this core category, two categories were identified: the mammography examination and affecting circumstances. The performance and its effects comprised the content of the category of mammography examination. The category affecting circumstances included knowledge about risk factors, prevention, and practical or emotional arguments.


Cytochrome a,a3 reoxidation. Early indicator of metabolic recovery from hemorrhagic shock in rats.
To assess the metabolic recovery of mitochondria after injury, we have monitored, in vivo and noninvasively, changes in the redox state of cytochrome (cyt) a,a3 in 35 rats after tissue hypoxia induced by rapid exsanguination to a mean arterial pressure of 30-35 mmHg. This level of mean arterial pressure was maintained for a shorter period of time in group I (n = 17) and a longer period of time in group II (n = 18), then the shed blood was returned by infusion. The surviving animals were observed for 2 more h before terminating the experiments. During exsanguination, reinfusion and recovery intervals brain tissue parameters of blood oxygenation, relative blood volume, and cyt a,a3 redox state were monitored continuously by spectrophotometry through the closed skull and intact skin. Group I had a high survival rate while group II had a very low survival rate. In both groups, with the onset of hypotension, there was a prompt rapid shift, followed by a slow continued progressive shift, of cyt a,a3 toward a more reduced state. The extent of recovery of cyt a,a3 following reinfusion was different in each group. In group I there was a rapid reoxidation of cyt a,a3 to a level above the base line (16 +/- 12%, mean +/- SEM). In contrast, the extent of reoxidation of cyt a,a3 in group II was significantly lower and stayed 31 +/- 6% below the base-line level. To further evaluate the mechanisms responsible for these observations, another related experiment was performed. 12 rats were subjected to shock and resuscitation as outlined for groups I and II. After death or killing of the animal, we measured, in vitro, oxygen consumption of cerebral cortical slices. Oxygen consumption of cortical tissue slices in subgroup I was significantly higher than in subgroup II. We conclude that, under these experimental conditions, the oxidative response of cyt a,a3 correlates closely with survival or death in the two groups. If in group I animals the greater oxidation of cyt a,a3, in vivo after resuscitation, reflects greater oxygen utilization, as is suggested by the in vitro observations in subgroup I, then we may be observing a useful adaptive response to tissue injury leading to preserved organ function and enhanced survival. Therefore, noninvasively measured cyt a,a3 redox state, reflecting intracellular metabolic activity, seems to indicate both the overall cerebral cellular response to injury and the likelihood of survival.


Multiple relapses of Plasmodium vivax malaria acquired from West Africa and association with poor metabolizer CYP2D6 variant: a case report.
Plasmodium vivax transmission in West Africa, dominant for the Duffy-negative blood group, has been increasingly recognized from both local residents as well as international travelers who contracted P. vivax malaria there. However, the relapsing pattern and sensitivity to antimalarial treatment of P. vivax strains originated from this region are largely unknown. There is evidence that the efficacy of primaquine for radical cure of relapsing malaria depends on host factors such as the hepatic enzyme cytochrome P450 (CYP) 2D6. A 49-year-old Chinese man was admitted to the Shanglin County Hospital in Guangxi Province, China, on December 19, 2016, 39 days after he returned from Ghana, where he stayed for one and a half years. He was diagnosed by microscopy as having uncomplicated P. vivax malaria. Treatment included 3 days of intravenous artesunate (420 mg total), and 3 days of chloroquine (1550 mg total), and 8 days of primaquine (180 mg total). Although parasites and symptoms were cleared rapidly and he was malaria-negative for almost two months, he suffered four relapses with relapse intervals ranging from 58 to 232 days. The last relapse occurred at 491 days from his first vivax attack. For the first three relapses, he was treated similarly with chloroquine and primaquine, sometimes supplemented with additional artemisinin combination therapies (ACTs). For the last relapse, he was treated with intravenous artesunate, 3 days of an ACT, and 7 days of azithromycin, and had remained healthy for 330 days. Molecular studies confirmed P. vivax infections for all the episodes. Although this patient was diagnosed to have normal glucose-6-phosphate dehydrogenase (G6PD) activity, his CYP2D6 genotype corresponded to a *2A/*36 allele variant suggesting of an impaired primaquine metabolizer phenotype. This clinical case suggests that P. vivax malaria originating from West Africa may produce multiple relapses extending beyond one year. The failures of primaquine as an anti-relapse therapy may be attributed to the patient's impaired metabolizer phenotype of the CYP2D6. This highlights the importance of knowing the host G6PD and CYP2D6 activities for effective radical cure of relapsing malaria by primaquine.


When is the optimal time to deliver late preterm IUGR fetuses with abnormal umbilical artery Dopplers?
To determine the optimal timing of delivery in late preterm intrauterine growth restriction (IUGR) fetuses with abnormal umbilical artery Doppler (UAD) indices. A decision-analytic model was built to determine the optimal gestational age (GA) of delivery in a theoretic cohort of 10 000 IUGR fetuses with elevated UAD systolic/diastolic ratios diagnosed at 34 weeks. All inputs were derived from the literature. Strategies involving expectant management accounted for the probabilities of stillbirth, spontaneous delivery and induction of labor for UAD absent or reversed end-diastolic flow (AREDF) at each successive week. Outcomes included short- and long-term neonatal morbidity and mortality with quality-adjusted life years (QALYs) generated based on these outcomes. Base case, sensitivity analyses and a Monte Carlo simulation were performed. The optimal GA for delivery is 35 weeks, which minimized perinatal deaths and maximized total QALYs. Earlier delivery became optimal once the risk of stillbirth was threefold our baseline assumption; our model was also robust until the risk of AREDF at 35 weeks was half our baseline assumption, after which delivery at 36 weeks was preferred. Delivery at 35 weeks was the optimal strategy in 77% of trials in Monte Carlo multivariable sensitivity analysis. Weighing the risks of iatrogenic prematurity against the poor outcomes associated with AREDF, the ideal GA to deliver late preterm IUGR fetuses with elevated UAD indices is 35 weeks.


Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma.
NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity. Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways. We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells. Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions.


A qualitative study of stress in individuals self-employed in solo businesses.
This qualitative study involved 54 individuals who were self-employed in a variety of solo businesses. All participants were administered a semistructured interview that inquired into various aspects of their work experience with the data subject to reliability and validity checks. The study identified stressful incidents, coping strategies, and emotional strains arising from those stressful incidents. Uncertainty about income was a common background stressor. Recent specific stressors included dramatic slowdowns in business, reputational threat, betrayal, unreasonable customers, and medical problems. Commonly occurring strains included apprehension/anxiety, frustration, anger, and sadness/depression. The self-employed used problem-focused coping much more often than emotion-focused coping. We also identified a third kind of coping that we labeled humanitarian coping. A number of questions/hypotheses for future research emerged, including identifying (a) a tipping point bearing on when the psychological benefits of self-employment (e.g., autonomy) are overtaken by business losses outside the individual's control and (b) the coping strategies that are most useful in managing work-related stressors.


Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants.
Duchenne muscular dystrophy (DMD) is characterised by progressive muscle weakness. It has recently been reported that single nucleotide polymorphisms (SNPs) located in the SPP1 and LTBP4 loci can account for some of the inter-individual variability observed in the clinical disease course. The validation of genetic association in large independent cohorts is a key process for rare diseases in order to qualify prognostic biomarkers and stratify patients in clinical trials. Duchenne patients from five European neuromuscular centres were included. Information about age at wheelchair dependence and steroid use was gathered. Melting curve analysis of PCR fragments or Sanger sequencing were used to genotype SNP rs28357094 in the SPP1 gene in 336 patients. The genotype of SNPs rs2303729, rs1131620, rs1051303 and rs10880 in the LTBP4 locus was determined in 265 patients by mass spectrometry. For both loci, a multivariate analysis was performed, using genotype/haplotype, steroid use and cohort as covariates. We show that corticosteroid treatment and the IAAM haplotype of the LTBP4 gene are significantly associated with prolonged ambulation in patients with DMD. There was no significant association between the SNP rs28357094 in the SPP1 gene and the age of ambulation loss. This study underlines the importance of replicating genetic association studies for rare diseases in large independent cohorts to identify the most robust associations. We anticipate that genotyping of validated genetic associations will become important for the design and interpretation of clinical trials.


Sources of activity-related social support and adolescents' objectively measured after-school and weekend physical activity: gender and age differences.
To progress physical activity (PA) social support research using objective measures of PA, attention should be turned to specific segments of the day (eg, after school or weekends) in which young people spend the majority of their time with parents or friends. Furthermore, the majority of previous research has focused on the influence of parents and peers. The current study examined gender and age differences in 5 sources of activity-related social support and their relationship with objectively measured after-school and weekend PA among adolescents. 328 adolescents aged 12-16 years (57% boys) wore an accelerometer for 7 days and completed a questionnaire assessing support for PA. After-school and weekend PA were extracted. Adolescents perceived more support from their peers compared with other sources and boys perceived more peer support than girls. Younger adolescents perceived greater amounts of family support and explicit modeling from both mother and father; however, logistic support appeared constant throughout adolescence. After controlling for gender and age, peer support was a significant influence on after-school MVPA. Findings suggest that there may be benefit in encouraging adolescents to participate in PA in the after-school period with their peers.


The ABMS MOC Part III Examination: Value, Concerns, and Alternative Formats.
This article describes the presentations and discussions at a conference co-convened by the Council on Medical Education of the American Medical Association (AMA) and by the American Board of Medical Specialties (ABMS). The conference focused on the ABMS Maintenance of Certification (MOC) Part III Examination. This article, reflecting the conference agenda, covers the value of and evidence supporting the examination, as well as concerns about the cost of the examination, and-given the current format-its relevance. In addition, the article outlines alternative formats for the examination that four ABMS member boards are currently developing or implementing. Lastly, the article presents contrasting views on the approach to professional self-regulation. One view operationalizes MOC as a high-stakes, pass-fail process while the other perspective holds MOC as an organized approach to support continuing professional development and improvement. The authors hope to begin a conversation among the AMA, the ABMS, and other professional stakeholders about how knowledge assessment in MOC might align with the MOC program's educational and quality improvement elements and best meet the future needs of both the public and the physician community.


Practical issues in implementation of WMA's draft Declaration of Helsinki.
The working group of the World Medical Association (WMA) has published a revised draft of the Declaration of Helsinki for public consultation till June 15, 2013. There are many positive changes in the document with respect to compensation, education of investigators, informed consent in the case of stored samples, etc. The changes represent a step forward for ethics. However, there may be certain points of concern regarding the implementation of the Declaration.


Predictors of discharge to acute care after inpatient rehabilitation in severely affected stroke patients.
This study aimed to determine the predictors of discharge to acute care after inpatient rehabilitation in severely affected stroke patients. This was a retrospective study using data from the Uniform Data System for Medical Rehabilitation (UDSMR) between 2008 and 2009. The main outcome variable was discharge location, which included discharge to acute care or discharge to the community after inpatient rehabilitation. The study sample included 223 of the most severely affected stroke patients (Case-Mix Group 0110 of Medicare reimbursement classification), of whom 86 were discharged to acute care from after the inpatient medical rehabilitation setting; 137 similarly classified stroke patients were discharged to the community after inpatient medical rehabilitation. The variables examined were Functional Independence Measure ratings, co-morbid medical conditions, and four groups of stroke-related neurologic deficits (hemiparesis, dysphagia, language deficits, and other stroke-related neurologic deficits). The groups were devised based on International Classification of Diseases, 9th Revision codes. There were no significant demographic differences between the two groups-those discharged to the acute care hospital and those discharged to the community. There was a difference in admission Functional Independence Measure ratings, whereby patients discharged to acute care were significantly lower (P < 0.05) on admission motor and cognitive function than were patients discharged to the community. When controlling for 19 groups of co-morbid medical conditions and 4 groups of stroke-related neurologic deficits, there was no significant difference between patients being discharged to an acute care hospital and those discharged to the community. In the current study, controlling for impairment (stroke), severity of condition, demographic variables, inpatient rehabilitation admission day of the week and discharge day of the week, prehospitalization living setting, prehospitalization living with (alone, family, other), payer (secondary insurance coverage), onset days, co-morbid medical conditions, and classification of stroke-related neurologic deficits, the only variable predictive of discharge to the acute care hospital from an inpatient rehabilitation facility is function at admission, mainly the admission motor Functional Independence Measure rating. If clinicians routinely assess the functional status of patients during the preadmission screening process, it may aid in identifying whether the patient is at an increased risk of being readmitted to the acute care hospital.


Carcinogenicity of mercury and mercury compounds.
Mercury and mercury compounds are widely used in modern society, but only sparse data are available on their carcinogenicity. Methylmercury chloride causes kidney tumors in male mice. Mercury chloride has shown some carcinogenic activity in male rats, but the evidence for female rats and male mice is equivocal. Other mercury compounds and metallic mercury have not been tested adequately in experimental animals. Epidemiologic data are available for chloralkali workers, dentists and dental nurses, and nuclear weapons workers, three groups occupationally exposed to low levels of mercury and its compounds, but those highly exposed in the past, such as miners, or populations which have suffered massive environmental exposure have not been adequately studied. However, the sparse epidemiologic data point toward the possibility of a risk of lung, kidney, and central nervous system tumors. Better data are needed on the carcinogenicity of mercury and mercury compounds in humans and experimental animals.


A prospective cohort study to investigate risk factors for horse falls in UK hurdle and steeplechase racing.
Equine fatalities during racing continue to be a major welfare concern and falls at fences are responsible for a proportion of all equine fatalities recorded on racecourses. To identify and quantify risk factors for horse falls in National Hunt (NH) racing and to report the frequency of falling and falling-associated fatalities. A prospective cohort study was conducted on 2879 horse starts in hurdle and steeplechase races on 6 UK racecourses. Any horse that suffered a fall at a steeplechase or hurdle fence during the race was defined as a case. Data were obtained by interview and observations in the parade ring and from commercial databases. Multivariable logistic regression models, allowing for clustering at the level of the track, were used to identify the relationship between variables and the risk of falling. There were 124 falling cases (32 in hurdling and 92 in steeplechasing) identified. The injury risk of fallers was 8.9% and fatality risk 6.5%. Duration of journey to the racecourse, behaviour in the parade ring and weather at the time of the race were associated with falling in both hurdle and steeplechase racing. Age, amount of rainfall and going were also associated with falling in steeplechase racing. Falls at fences are significant contributors to equine fatalities during NH racing. Potentially modifiable risk factors identified were the condition of track surfaces and journey time to the racecourse. It is hoped that information from this study may be used in future interventions to improve horse and jockey safety in racing. The study has also identified areas requiring further research, such as equine behaviour and its effect on racing performance, and the effect of light conditions on jumping ability.


A Ketogenic Diet in Rodents Elicits Improved Mitochondrial Adaptations in Response to Resistance Exercise Training Compared to an Isocaloric Western Diet.
Purpose: Ketogenic diets (KD) can facilitate weight loss, but their effects on skeletal muscle remain equivocal. In this experiment we investigated the effects of two diets on skeletal muscle mitochondrial coupling, mitochondrial complex activity, markers of oxidative stress, and gene expression in sedentary and resistance exercised rats. Methods: Male Sprague-Dawley rats (9-10 weeks of age, 300-325 g) were fed isocaloric amounts of either a KD (17 g/day, 5.2 kcal/g, 20.2% protein, 10.3% CHO, 69.5% fat, n = 16) or a Western diet (WD) (20 g/day, 4.5 kcal/g, 15.2% protein, 42.7% CHO, 42.0% fat, n = 16) for 6 weeks. During these 6 weeks animals were either sedentary (SED, n = 8 per diet group) or voluntarily exercised using resistance-loaded running wheels (EXE, n = 8 per diet group). Gastrocnemius was excised and used for mitochondrial isolation and biochemical analyses. Results: In the presence of a complex II substrate, the respiratory control ratio (RCR) of isolated gastrocnemius mitochondria was higher (p < 0.05) in animals fed the KD compared to animals fed the WD. Complex I and IV enzyme activity was higher (p < 0.05) in EXE animals regardless of diet. SOD2 protein levels and GLUT4 and PGC1α mRNA expression were higher (p < 0.05) in EXE animals regardless of diet. Conclusion: Our data indicate that skeletal muscle mitochondrial coupling of complex II substrates is more efficient in chronically resistance trained rodents fed a KD. These findings may provide merit for further investigation, perhaps on humans.


A time-course analysis of changes in cerebral metal levels following a controlled cortical impact.
Traumatic brain injury (TBI) is complicated by a sudden and dramatic change in brain metal levels, including iron (Fe), copper (Cu) and zinc (Zn). Specific 'metallo-pathological' features of TBI include increased non-heme bound Fe and the liberation of free Zn ions, both of which may contribute to the pathogenesis of TBI. To further characterise the metal dyshomeostasis that occurs following brain trauma, we performed a quantitative time-course survey of spatial Fe, Cu and Zn distribution in mice receiving a controlled cortical impact TBI. Images of brain metal levels produced using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) in the upper quadrant of the ipsilateral hemisphere were compared to the corresponding contralateral hemisphere, together with regional areas radiating toward the center of the brain from the site of lesion. Significant regional and time point specific elevations in Fe, Zn and Cu were detected immediately and up to 28 days after TBI. The magnitude and timeframe of many of these changes suggest that TBI results in a pronounced and sustained alteration in normal metal levels within the brain. Such alterations are likely to play a role in both the short- and long-term consequences of head trauma and suggest that pharmacological modulation to normalize these metal levels may be efficacious in improving functional outcome.


Evidence for the interaction of peroxiredoxin-4 with the store-operated calcium channel activator STIM1 in liver cells.
Ca2+ entry through store-operated Ca2+ channels (SOCs) in the plasma membrane (PM) of hepatocytes plays a central role in the hormonal regulation of liver metabolism. SOCs are composed of Orai1, the channel pore protein, and STIM1, the activator protein, and are regulated by hormones and reactive oxygen species (ROS). In addition to Orai1, STIM1 also interacts with several other intracellular proteins. Most previous studies of the cellular functions of Orai1 and STIM1 have employed immortalised cells in culture expressing ectopic proteins tagged with a fluorescent polypeptide such as GFP. Little is known about the intracellular distributions of endogenous Orai1 and STIM1. The aims are to determine the intracellular distribution of endogenous Orai1 and STIM1 in hepatocytes and to identify novel STIM1 binding proteins. Subcellular fractions of rat liver were prepared by homogenisation and differential centrifugation. Orai1 and STIM1 were identified and quantified by western blot. Orai1 was found in the PM (0.03%), heavy (44%) and light (27%) microsomal fractions, and STIM1 in the PM (0.09%), and heavy (85%) and light (13%) microsomal fractions. Immunoprecipitation of STIM1 followed by LC/MS or western blot identified peroxiredoxin-4 (Prx-4) as a potential STIM1 binding protein. Prx-4 was found principally in the heavy microsomal fraction. Knockdown of Prx-4 using siRNA, or inhibition of Prx-4 using conoidin A, did not affect Ca2+ entry through SOCs but rendered SOCs susceptible to inhibition by H2O2. It is concluded that, in hepatocytes, a considerable proportion of endogenous Orai1 and STIM1 is located in the rough ER. In the rough ER, STIM1 interacts with Prx-4, and this interaction may contribute to the regulation by ROS of STIM1 and SOCs.


Variable Accuracy of Wearable Heart Rate Monitors during Aerobic Exercise.
Athletes and members of the public increasingly rely on wearable HR monitors to guide physical activity and training. The accuracy of newer, optically based monitors is unconfirmed. We sought to assess the accuracy of five optically based HR monitors during various types of aerobic exercise. Fifty healthy adult volunteers (mean ± SD age = 38 ± 12 yr, 54% female) completed exercise protocols on a treadmill, a stationary bicycle, and an elliptical trainer (±arm movement). Each participant underwent HR monitoring with an electrocardiogaphic chest strap monitor (Polar H7), forearm monitor (Scosche Rhythm+), and two randomly assigned wrist-worn HR monitors (Apple Watch, Fitbit Blaze, Garmin Forerunner 235, and TomTom Spark Cardio), one on each wrist. For each exercise type, HR was recorded at rest, light, moderate, and vigorous intensity. Agreement between HR measurements was assessed using Lin's concordance correlation coefficient (rc). Across all exercise conditions, the chest strap monitor (Polar H7) had the best agreement with ECG (rc = 0.996) followed by the Apple Watch (rc = 0.92), the TomTom Spark (rc = 0.83), and the Garmin Forerunner (rc = 0.81). Scosche Rhythm+ and Fitbit Blaze were less accurate (rc = 0.75 and rc = 0.67, respectively). On treadmill, all devices performed well (rc = 0.88-0.93) except the Fitbit Blaze (rc = 0.76). While bicycling, only the Garmin, Apple Watch, and Scosche Rhythm+ had acceptable agreement (rc > 0.80). On the elliptical trainer without arm levers, only the Apple Watch was accurate (rc = 0.94). None of the devices was accurate during elliptical trainer use with arm levers (all rc < 0.80). The accuracy of wearable, optically based HR monitors varies with exercise type and is greatest on the treadmill and lowest on elliptical trainer. Electrode-containing chest monitors should be used when accurate HR measurement is imperative.


Groundwater intrusion into leaky sewer systems.
Vast volumes of groundwater are drained by urban sewer systems. This unwanted flow component intrudes into sewer systems through leaky joints or connected house drains. However, unlike urban storm drainage, it has a high seasonal variation corresponding to groundwater storage and long slow recessions similar to baseflow in rivers also fed by shallow groundwater exfiltrating into the surface waters. By applying the nonlinear reservoir algorithm as used for baseflow separation from total flow in a river, groundwater flow is separated from daily measured influents to treatment plants in Lower Saxony and Baden-Württemberg, Germany and in the Terkos Lake watershed near Istanbul, Turkey. While waste water flows vary only moderately within a year, separated intruded groundwater flows show recessions and seasonal variations correlated to baseflow in neighbouring rivers. It is possible to conclude that recession characteristics of treatment plant influents allow quantification and prediction of groundwater intrusion into sewer systems.


Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin.
The integrin alpha v beta 6 is only expressed in epithelial cells. In healthy adult epithelia, this receptor is barely detectable, but expression is rapidly induced following epithelial injury. Mice homozygous for a null mutation in the gene encoding the beta 6 subunit had juvenile baldness associated with infiltration of macrophages into the skin, and accumulated activated lymphocytes around conducting airways in the lungs. Beta 6-/- mice also demonstrated airway hyperresponsiveness to acetylcholine, a hallmark feature of asthma. These results suggest that the epithelial integrin alpha v beta 6 participates in the modulation of epithelial inflammation. Genetic or acquired alterations in this integrin could thus contribute to the development of inflammatory diseases of epithelial organs, such as the lungs and skin.


Use of Micropatterned Thin Film Nitinol in Carotid Stents to Augment Embolic Protection.
Stenting is an alternative to endarterectomy for the treatment of carotid artery stenosis. However, stenting is associated with a higher risk of procedural stroke secondary to distal thromboembolism. Hybrid stents with a micromesh layer have been proposed to address this complication. We developed a micropatterned thin film nitinol (M-TFN) covered stent designed to prevent thromboembolism during carotid intervention. This innovation may obviate the need or work synergistically with embolic protection devices. The proposed double layered stent is low-profile, thromboresistant, and covered with a M-TFN that can be fabricated with fenestrations of varying geometries and sizes. The M-TFN was created in multiple geometries, dimensions, and porosities by sputter deposition. The efficiency of various M-TFN to capture embolic particles was evaluated in different atherosclerotic carotid stenotic conditions through in vitro tests. The covered stent prevented emboli dislodgement in the range of 70%-96% during 30 min duration tests. In vitro vascular cell growth study results showed that endothelial cell elongation, alignment and growth behaviour silhouettes significantly enhance, specifically on the diamond-shape M-TFN, with the dimensions of 145 µm × 20 µm and a porosity of 32%. Future studies will require in vivo testing. Our results demonstrate that M-TFN has a promising potential for carotid artery stenting.


In vitro/in vivo biocompatibility and mechanical properties of bioactive glass nanofiber and poly(epsilon-caprolactone) composite materials.
In this study, a poly(epsilon-caprolactone) (PCL)/bioactive glass (BG) nanocomposite was fabricated using BG nanofibers (BGNFs) and compared with an established composite fabricated using microscale BG particles. The BGNFs were generated using sol-gel precursors via the electrospinning process, chopped into short fibers and then incorporated into the PCL organic matrix by dissolving them in a tetrahydrofuran solvent. The biological and mechanical properties of the PCL/BGNF composites were evaluated and compared with those of PCL/BG powder (BGP). Because the PCL/BG composite containing 20 wt % BG showed the highest level of alkaline phosphatase (ALP) activity, all evaluations were performed at this concentration except for that of the ALP activity itself. In vitro cell tests using the MC3T3 cell line demonstrated the enhanced biocompatibility of the PCL/BGNF composite compared with the PCL/BGP composite. Furthermore, the PCL/BGNF composite showed a significantly higher level of bioactivity compared with the PCL/BGP composite. In addition, the results of the in vivo animal experiments using Sprague-Dawley albino rats revealed the good bone regeneration capability of the PCL/BGNF composite when implanted in a calvarial bone defect. In the result of the tensile test, the stiffness of the PCL/BG composite was further increased when the BGNFs were incorporated. These results indicate that the PCL/BGNF composite has greater bioactivity and mechanical stability when compared with the PCL/BG composite and great potential as a bone regenerative material.


Aster-free spindle poles in insect spermatocytes: evidence for chromosome-induced spindle formation?
Tipulid spermatocytes form normally functioning bipolar spindles after one of the centrosomes is experimentally dislocated from the nucleus in late diakinesis (Dietz, R., 1959, Z. Naturforsch., 14b:749-752; Dietz, R., 1963, Zool. Anz. Suppl., 23:131-138; Dietz, R., 1966, Heredity, 19:161-166). The possibility that dissociated pericentriolar material (PCM) is nevertheless responsible for the formation of the spindle in these cells cannot be ruled out based on live observation. In studying serial sections of complete cells and of lysed cells, it was found that centrosome-free spindle poles in the crane fly show neither pericentriolar-like material nor aster microtubules, whereas the displaced centrosomes appear complete, i.e., consist of a centriole pair, aster microtubules, and PCM. Exposure to a lysis buffer containing tubulin resulted in an increase of centrosomal asters due to aster microtubule polymerization. Aster-free spindle poles did not show any reaction, also indicating the absence of PCM at these poles. The results favor the hypothesis of chromosome-induced spindle pole formation at the onset of prometaphase and the dispensability of PCM in Pales.


Coherent Dynamics Enhanced by Uncorrelated Noise.
Synchronization is a widespread phenomenon observed in physical, biological, and social networks, which persists even under the influence of strong noise. Previous research on oscillators subject to common noise has shown that noise can actually facilitate synchronization, as correlations in the dynamics can be inherited from the noise itself. However, in many spatially distributed networks, such as the mammalian circadian system, the noise that different oscillators experience can be effectively uncorrelated. Here, we show that uncorrelated noise can in fact enhance synchronization when the oscillators are coupled. Strikingly, our analysis also shows that uncorrelated noise can be more effective than common noise in enhancing synchronization. We first establish these results theoretically for phase and phase-amplitude oscillators subject to either or both additive and multiplicative noise. We then confirm the predictions through experiments on coupled electrochemical oscillators. Our findings suggest that uncorrelated noise can promote rather than inhibit coherence in natural systems and that the same effect can be harnessed in engineered systems.


Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation.
Purpose: Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. Methods: RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Results: Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 (r = 0.4, p < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8+ T cell abundance and proliferation scores (r = 0.52, 0.56, and 0.6, respectively with p < 0.001). Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, p < 0.05) and T-cell infiltration (CD8+T-cells: HR = 2.2, p < 0.05; CD8+T-cells/Treg: HR = 2.6, p < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Conclusion: Tumor acute and chronic hypoxia, stem cell-ness, and CD8+ T-cell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC.


Selenium concentrations in water and plant tissues of a newly formed arid wetland in Las Vegas, Nevada.
There is concern that elevated levels of selenium found in the source water of a newly formed wetland park in Las Vegas, Nevada, may have detrimental effects on local wildlife. In this study, we collected and analyzed water samples monthly for a three year period from the inflow and outflow of the system. We also gathered dominant aquatic plants and selected terrestrial plants and analyzed the water and plant tissues (root, shoot, leaf and flower) for selenium by high resolution Inductively Coupled Plasma Mass Spectrometer. Except for storm events and the introduction of an alternative low selenium content source water during summer low-flow conditions, selenium in the water was relatively stable. The concentration in the outflow tended to be slightly lower than the inflow. Concentrations of selenium in the dominant plant taxa in this wetlands were typical of ecosystems in the western United States and varied by taxa, tissue type, localized conditions (e.g., contact with selenium-laden water), and to a lesser extent, seasons. Selenium in the aquatic plant spiny naiad (Najas marina) was relatively high and may pose an ecological risk to wildlife during the late spring and summer. Additional work is underway investigating aquatic food chain accumulations of selenium as well as mass balance of selenium in the system.


The quasi-unchanged gas-phase molecular structures of the atmospheric aerosol precursor β-pinene and its oxidation product nopinone.
The rotational spectra of the two bicyclic molecules β-pinene and its oxidation product nopinone were investigated in the gas phase, using Fourier transform microwave spectroscopy coupled to a supersonic jet, in the 2-20 GHz range. The parent species and all heavy atom isotopologues have been observed in their natural abundance. The spectroscopic parameters of the ground states were determined from a Watson's Hamiltonian in the A reduction. The rotational constants were used together with geometrical parameters obtained from ab initio calculations to determine the r0 and r structures of the skeletons, without any structural assumption in the fit concerning the heavy atoms. Comparison with solid phase and other bicyclic monoterpenes unveiled an unprecedented complete set of geometrical parameters for the rigid cages. The structures of β-pinene and nopinone are very close, except for the substituents at C2. In the gas phase C2 is a centre of planarity in both molecules.


Differential Expression of Genes that Control Respiration Contribute to Thermal Adaptation in Redband Trout (Oncorhynchus mykiss gairdneri).
Organisms can adapt to local environmental conditions as a plastic response or become adapted through natural selection on genetic variation. The ability to adapt to increased water temperatures will be of paramount importance for many fish species as the climate continues to warm and water resources become limited. Because increased water temperatures will reduce the dissolved oxygen available for fish, we hypothesized that adaptation to low oxygen environments would involve improved respiration through oxidative phosphorylation (OXPHOS). To test this hypothesis, we subjected individuals from two ecologically divergent populations of inland (redband) rainbow trout (Oncorhynchus mykiss gairdneri) with historically different temperature regimes (desert and montane) and their F1 progeny to diel cycles of temperature stress and then examined gene expression data for 80 nuclear- and mitochondrial-encoded OXPHOS subunits that participate in respiration. Of the 80 transcripts, 7 showed ≥ 2-fold difference in expression levels in gill tissue from desert fish under heat stress whereas the montane fish had none and the F1 only had one differentially expressed gene. A structural analysis of the proteins encoded by those genes suggests that the response could coordinate the formation of supercomplexes and oligomers. Supercomplexes may increase the efficiency of respiration because complexes I, III, and IV are brought into close proximity and oligomerization of complex V alters the macrostructure of mitochondria to improve respiration. Significant differences in gene expression patterns in response to heat stress in a common environment indicate that the response was not due to plasticity but had a genetic basis.


Bimodal electric tissue ablation (BETA): a study on ablation size when the anode is placed on the peritoneum and the liver.
In bimodal electric tissue ablation (BETA), the cathode of the DC circuit is attached to the radiofrequency (RF) electrode to increase the surrounding tissue hydration. This will delay tissue desiccation and allowing the ablation process to continue for a longer period of time before "roll-off" occurs, resulting in larger ablations compared with standard radiofrequency ablation (RFA). Previous research showed that attaching the anode to the skin using electrosurgical grounding pads would reduce the efficacy of BETA because of the high electrical resistivity of the skin. This study investigated the ablation size produced when the anode was attached to the peritoneum (BETA-peritoneum) and the liver (BETA-liver) respectively. The anode of the DC circuit in BETA was attached to the peritoneum and the liver in a pig model using ECG dots. In BETA, 9 V of DC was provided for 10 min, after which the radiofrequency generator were switched on and both electrical circuits allowed to run concurrently until "roll-off." The size of ablations produced was compared to when the anode attached to the skin (BETA-skin) and standard RFA, respectively. The sites of anode placement were examined for local tissue injury. The transverse diameters in BETA-peritoneum and BETA-liver were significantly larger compared with BETA-skin and standard RFA, respectively (P < 0.001). The axial diameter in the BETA-peritoneum and BETA-liver groups were also larger compared with the BETA-skin and RFA groups, although the differences did not reach statistical significance (P = 0.09). Hematoxylin and eosin (H and E) examination of the peritoneum and the liver where the anode was attached showed coagulation necrosis involving the superficial epithelium and the liver capsule, respectively. BETA can be used to treat larger liver tumors more effectively and may reduce the tumor recurrence rates compared with standard RFA. The efficacy of BETA depends on ensuring good electrical conductivity between the cathode and the anode of the DC circuit. Research so far has shown that BETA works best when the anode is placed deep to the skin as the stratum corneum consisted of a layer of a-nucleated cells, which have high electrical resistivity. The liver could be the ideal location to place the anode as it has excellent electrical conductivity, therefore ensuring maximum tissue hydration around the cathode to produce the largest ablations possible.


A review of the validity of malnutrition screening tools used in older adults in community and healthcare settings - A MaNuEL study.
Older adults are at increased risk of malnutrition compared to their younger counterparts. Malnutrition screening should be conducted using a valid malnutrition screening tool. An aim of the Healthy Diet for a Healthy Life (HDHL) Joint Programming Initiative (JPI) 'Malnutrition in the Elderly Knowledge Hub' (MaNuEL) was to review the reported validity of existing malnutrition screening tools used in older adults. A literature search was conducted to identify validation studies of malnutrition screening tools in older populations in community, rehabilitation, residential care and hospital settings. A database of screening tools was created containing information on how each tool was validated. Seventy-four articles containing 119 validation studies of 34 malnutrition screening tools used in older adults were identified across the settings. Twenty-three of these tools were designed for older adults. Sensitivity and specificity ranged from 6 to 100% and 12-100% respectively. Seventeen different reference standards were used in criterion validation studies. Acceptable reference standards were used in 68 studies; 38 compared the tool against the Mini Nutritional Assessment-Full Form (MNA-FF), 16 used clinical assessment by a nutrition-trained professional and 14 used the Subjective Global Assessment (SGA). Twenty-five studies used inappropriate reference standards. Predictive validity was measured in 14 studies and was weak across all settings. Validation results differed significantly between tools, and also between studies using the same tool in different settings. Many studies have not been appropriately conducted, leaving the true validity of some tools unclear. Certain tools appear to be more valid for use in specific settings.


Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing.
The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery-an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.


CLAVATA signaling pathway receptors of Arabidopsis regulate cell proliferation in fruit organ formation as well as in meristems.
The CLAVATA1 (CLV1), CLV2, and CORYNE (CRN) receptors in Arabidopsis thaliana maintain cell proliferation in shoot apical meristems by restricting expression of the transcription factor WUSCHEL (WUS). Previously characterized receptor mutants generate extra fruit and floral organs that are proposed to arise from enlarged floral meristems (FMs). We identified new alleles in clv1, clv2, and crn and found that most mutants produce only extra fruit organs and generate FMs of similar dimensions as wild type. Characterization of gynoecium development in receptor mutants revealed increased cell proliferation and ectopic fruit organ initiation after FM termination. These regions of increased cell division also display expanded expression of the cell proliferation-promoting transcription factor SHOOTMERISTEMLESS (STM), similar to the expansion of WUS expression in the shoot apical meristems of strong clv1 mutants. We also examined genetic interactions between the ERECTA (ER) and BARELY ANY MERISTEM 1 (BAM1) receptor-like kinases and CLV pathway receptors. Our results suggest a model in which CLV1/BAM1 and CLV2/CRN complexes act in separate, parallel pathways in shoot meristems, while the CLV1, CLV2, and CRN receptors function together in a linear pathway during fruit development. These results demonstrate the importance of regulating cell proliferation in plants that undergo organogenesis throughout their life cycle.


Metabolite profiles correlate closely with neurobehavioral function in experimental spinal cord injury in rats.
Traumatic spinal cord injury (SCI) results in direct physical damage and the generation of local factors contributing to secondary pathogenesis. Untargeted metabolomic profiling was used to uncover metabolic changes and to identify relationships between metabolites and neurobehavioral functions in the spinal cord after injury in rats. In the early metabolic phase, neuronal signaling, stress, and inflammation-associated metabolites were strongly altered. A dynamic inflammatory response consisting of elevated levels of prostaglandin E2 and palmitoyl ethanolamide as well as pro- and anti-inflammatory polyunsaturated fatty acids was observed. N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) were significantly decreased possibly reflecting neuronal cell death. A second metabolic phase was also seen, consistent with membrane remodeling and antioxidant defense response. These metabolomic changes were consistent with the pathology and progression of SCI. Several metabolites, including NAA, NAAG, and the ω-3 fatty acids docosapentaenoate and docosahexaenoate correlated greatly with the established Basso, Beattie and Bresnahan locomotive score (BBB score). Our findings suggest the possibility of a biochemical basis for BBB score and illustrate that metabolites may correlate with neurobehavior. In particular the NAA level in the spinal cord might provide a meaningful biomarker that could help to determine the degree of injury severity and prognosticate neurologic recovery.