Generation of an antibody toolbox to characterize hERG.
The human ether-a-go-go related gene (hERG) potassium channel plays a major role in the repolarization of the cardiac action potential. Inhibition of the hERG function by mutations or a wide variety of pharmaceutical compounds cause long QT syndrome and lead to potentially lethal arrhythmias. For detailed insights into the structural and biochemical background of hERG function and drug binding, the purification of recombinant protein is essential. Because the hERG channel is a challenging protein to purify, fast and easy techniques to evaluate different expression, solubilization and purification conditions are of primary importance. Here, we describe the generation of a set of 12 monoclonal antibodies against hERG. Beside their suitability in western blot, immunoprecipitation and immunostaining, these antibodies were used to establish a sandwich ELISA for the detection and relative quantification of hERG in different expression systems. Furthermore, a Fab fragment was used in fluorescence size exclusion chromatography to determine the oligomeric state of hERG after solubilization. These new tools can be used for a fast and efficient screening of expression, solubilization and purification conditions.


Uveal Melanoma Treatment and Prognostication.
Approximately 90% of uveal melanoma develop in the choroid, with the remainder arising in the ciliary body or the iris. The treatment of uveal melanoma is aimed at conserving the eye and useful vision, and, if possible, preventing metastatic disease. Enucleation is now reserved for tumors that are large and/or involve the optic disc, having largely been replaced by various forms of radiotherapy (plaque brachy-therapy, proton beam or stereotactic radiotherapy) and laser therapy. Whereas iridectomy and iridocyclectomy are widely performed, transscleral exoresection of choroidal tumors is performed only in a few centers because it requires special skills and hypotensive anesthesia. Transretinal endoresection using vitrectomy equipment is easier but controversial because of concerns about tumor seeding. Long-term postoperative surveillance is necessary to identify and treat local tumor recurrence and any other complications, such as radiation-induced morbidity, and to provide counseling to the patient. Factors predicting metastasis include older age, large tumor size, ciliary body involvement, extraocular spread, epithelioid cytomorphology, chromosome 3 loss and chromosome 8q gain, class 2 gene expression profile, loss of BRCA1-associated protein-1 (BAP1), and the presence of inflammation. Prognostication is enhanced by multi-variable analysis combining clinical, histologic, and genetic factors, also taking the patient's age and sex into account. As there is a lack of options for treating metastases, much research is focused on identifying potential therapeutic targets.


Effects of music on work-rate distribution during a cycling time trial.
Previous research work on the ergogenic effects of music has mainly involved constant power tests to exhaustion as dependent variables. Time trials are more externally valid than constant power tests, may be more reliable and allow the distribution of self-selected work-rate to be explored. We examined whether music improved starting, finishing and/or overall power during a 10-km cycling time trial, and whether heart rate and subjective responses to this time trial were altered by music. Sixteen participants performed two 10-km time trials on a Cybex cycle ergometer with, and without, the presence of a form of dance music known as "trance" (tempo = 142 beats x min (-1), volume at ear = 87 dB). Participants also completed the Brunel music rating inventory (BMRI) after each time trial in the music condition. The mean +/- SD time to complete the time trial was 1030 +/- 79 s in the music condition compared to 1052 +/- 77 s without music (95 % CI of difference = 10 to 34 s, p = 0.001). Nevertheless, ratings of perceived exertion were consistently (0.8 units) higher throughout the time trial with music (p < 0.0005). The interaction between distance and condition was significant for cycling speed measured during the time trial (p = 0.007). The largest music-induced increases in cycling speed and heart rate were observed in the first 3 km of the time trial. After completion of the BMRI, participants rated the "tempo" and "rhythm" of the music as more motivating than the "harmony" and "melody" aspects. These results suggest that music improves cycling speed mostly in the first few minutes of a 10-km time trial. In contrast to the findings of previous research, which suggested that music lowers perceived exertion at a constant work-rate, the participants in our time trials selected higher work-rates with music, whilst at the same time perceived these work-rates as being harder than without music.


Diagnosis and management of diastolic dysfunction and heart failure.
Diastolic heart failure occurs when signs and symptoms of heart failure are present but left ventricular systolic function is preserved (i.e., ejection fraction greater than 45 percent). The incidence of diastolic heart failure increases with age; therefore, 50 percent of older patients with heart failure may have isolated diastolic dysfunction. With early diagnosis and proper management the prognosis of diastolic dysfunction is more favorable than that of systolic dysfunction. Distinguishing diastolic from systolic heart failure is essential because the optimal therapy for one may aggravate the other. Although diastolic heart failure is clinically and radiographically indistinguishable from systolic heart failure, normal ejection fraction and abnormal diastolic function in the presence of symptoms and signs of heart failure confirm diastolic heart failure. The pharmacologic therapies of choice for diastolic heart failure are angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, and beta blockers.


Characterization of musclin as a new target for treatment of hypertension.
Musclin is a novel skeletal muscle-derived factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Recently, it has been demonstrated that musclin is involved in the pathogenesis of spontaneously hypertensive rats (SHRs). However, it is known as a genetic hypertension model. In the present study, we aim to investigate the role of musclin in another animal model of hypertension and characterize the direct effect of musclin on vascular contraction. The results show that expression of musclin was increased in arterial tissues isolated from DOCA-salt induced hypertensive rats or the normal rats received repeated vasoconstriction with phenylephrine. Additionally, direct incubation with phenylephrine did not modify the expression of musclin in the in vitro studies. Also, the direct effect of musclin on the increase of intracellular calcium was observed in a concentration-dependent manner. These results provide the evidence to support that musclin is involved in hypertension. Thus, musclin is suitable to be considered as a novel target for treatment of hypertension.


Values and value in simulated participant methodology: A global perspective on contemporary practices.
This article has been written for the 40th year of the publication of Medical Teacher. While we celebrate the contribution of simulated participants (SPs) to health professions education through values and value-based learning, we also offer critical reflection on elements of our practice, commencing with language. We argue for the use of the term simulated rather than standardized and acknowledge the dominant role of the SP as patient and the origins of the methodology. These shifts in terms and their implications in practice reflect changes in the conceptualization of SP-based methodology. Recently published standards for those who work with SPs (SP practitioners) are noted as an important milestone in our community's development. We consider contemporary practices addressing the complex notions of values and value in SP-based learning. We simultaneously refer to the work of SPs and SP practitioners. Phases of educational design including identifying learning objectives, scenario design, implementation, feedback and debriefing are used to illustrate methodological shifts. Within each of these phases, there are relational issues that have to date often gone unchecked and are under reported in literature. Finally, using the metaphor of a murmuration, we celebrate contemporary practices of the global SP practitioner community.


Group-I PAKs-mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination.
The regulation of Rac1 by HACE1-mediated ubiquitination and proteasomal degradation is emerging as an essential element in the maintenance of cell homeostasis. However, how the E3 ubiquitin ligase activity of HACE1 is regulated remains undetermined. Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases downstream Rac1 activation by CNF1 toxin from pathogenic E. coli. Moreover, cell treatment with VEGF also promotes Ser-385 phosphorylation of HACE1. We have established in vitro that HACE1 is a direct target of PAK1 kinase activity. Mechanistically, we found that the phospho-mimetic mutant HACE1(S385E), as opposed to HACE1(S385A), displays a lower capacity to ubiquitinate Rac1 in cells. Concomitantly, phosphorylation of Ser-385 plays a pivotal role in controlling the oligomerization state of HACE1. Finally, Ser-385 phosphorylated form of HACE1 localizes in the cytosol away from its target Rac1. Together, our data point to a feedback inhibition of HACE1 ubiquitination activity on Rac1 by group-I PAK kinases.


Quantitative reagent-free detection of fibrinogen levels in human blood plasma using Raman spectroscopy.
Fibrinogen assays are commonly used as part of clinical screening tests to investigate haemorrhagic states, for detection of disseminated intravascular coagulation and as a predictor of a variety of cardiovascular events. The Clauss assay, which measures thrombin clotting time, is the most commonly used method for measuring fibrinogen levels. Nevertheless, inconsistencies are present in inter-manufacturer reagent sources, calibration standards and methodologies. Automated coagulation analysers, which measure changes in optical density during the prothrombin time (PT-Fg), have found use in many hospitals. However, the PT-Fg method is found to give falsely elevated values due to varying choices of calibrants, reagents and analysers. As an alternative, Raman spectroscopy has previously been applied to the analysis of blood and its various constituents to determine various analyte concentrations such as glucose, urea, triglycerides and cholesterol. In this study, Raman spectroscopy was investigated for its ability to accurately quantify fibrinogen concentration in blood plasma. Samples collected from 34 patients were analysed by Raman spectroscopy and the resultant spectra were fitted with a Partial Least Squares Regression model using target values obtained through a pre-calibrated Clauss fibrinogen assay. Various spectral pre-processing methods were utilised to prepare data to be entered into a calibration model. A root mean square error of prediction of 0.72 ± 0.05 g/L was achieved with as few as 25 spectra. In this pilot study, Raman spectroscopy has been demonstrated to be a robust technique providing rapid and reagent-free quantification of fibrinogen levels in blood plasma and a potential alternative to the Clauss assay.


Role of Nitric Oxide in Glioblastoma Therapy: Another Step to Resolve the Terrible Puzzle ?
Glioblastoma Multiforme, the most common and aggressive primary brain tumor, remains incurable despite of the advent of modern surgical and medical treatments. This poor prognosis depends by the recurrence after surgery and intrinsic or acquired resistance to chemotherapy and radiotherapy. Nitric oxide is a small molecule that plays a key roles in glioma pathophysiology. Many researches showing that NO is involved in induction of apoptosis, radiosensitization and chemosensitization. Therefore, NO role, if clarified, may improve the knowledge about this unsolved puzzle called GBM.


N-Acetyl Cysteine Attenuates the Sarcopenia and Muscle Apoptosis Induced by Chronic Liver Disease.
Sarcopenia is characterized by the loss of muscle mass and strength (muscle atrophy) because of aging or chronic diseases, such as chronic liver disease (CLD). Different mechanisms are involved in skeletal muscle atrophy, including decreased muscle fibre diameter and myosin heavy chain levels and increased ubiquitin-proteasome pathway activity, oxidative stress and myonuclear apoptosis. We recently found that all these mechanisms, except myonuclear apoptosis, which was not evaluated in the previous study, were involved in muscle atrophy associated with hepatotoxin 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced CLD. In the present study, we evaluated the involvement of myonuclear apoptosis in CLD-associated sarcopenia and the effect of N-acetyl cysteine (NAC) treatment on muscle strength and apoptosis, using a DDC-supplemented diet-fed mouse model. Four-month-old male C57BL6 mice were fed with a standard or DDCsupplemented diet for six weeks in the absence or presence of NAC treatment. Our results showed that NAC attenuated the decrease in muscle fibre diameter and muscle strength associated with CLD-induced muscle wasting in gastrocnemius (GA) muscle of DDC-supplemented diet-fed mice. In addition, in GA muscle of the mice fed with DDC-supplemented diet-induced CLD showed increased myonuclear apoptosis compared with the GA muscle of the control diet-fed mice, as evidenced by increased apoptotic nuclei number, caspase-8 and caspase-9 expression, enzymatic activity of caspase-3 and BAX/BCL-2 ratio. NAC treatment inhibited all the mechanisms associated with myonuclear apoptosis in the GA muscle. To our knowledge, this is the first study which reports the redox regulation of muscle strength and myonuclear apoptosis in CLD-induced sarcopenia.


Cardiovascular consequences of metabolic syndrome.
The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiological mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review, we highlight current knowledge regarding the pathophysiological consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiological and molecular mechanisms that may contribute to these adverse outcomes.


A phase II trial of topotecan in patients with advanced, persistent, or recurrent endometrial carcinoma: a gynecologic oncology group study.
To estimate the antitumor activity of topotecan in women with advanced, persistent, or recurrent endometrial carcinoma previously treated with chemotherapy, and to determine the nature and degree of toxicity of topotecan in this cohort of patients. Eligible patients were those who had failed one prior chemotherapy regimen. Topotecan 0.5 to 1.5 mg/m(2) was administered iv daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. Of 29 patients entered, 28 were evaluable for toxicity and 22 were evaluable for response. Patient characteristics included a median age of 65, with 41% having prior radiation and 14% having prior hormonal therapy. Nine patients (41%) had a performance status (PS) of 0, 11 (50%) had a PS of 1, and 2 (9%) had a PS of 2. Patients received from 2 to 11 (with a median of 4) courses of treatment. The most frequently observed grade 4 toxicities were neutropenia seen in 17 (61%) patients, leukopenia in 11 (39%), and thrombocytopenia in 7 (25%). Two deaths were considered potentially related to treatment. There was one (4.5%) complete and one (4.5%) partial response; 12 (55%) patients maintained stable disease and eight (36%) experienced increasing tumor. Topotecan at this dose and schedule does not appear to have major activity in patients with advanced or recurrent endometrial carcinoma previously treated with chemotherapy.


Top-down-driven grouping overrules the central attentional bias.
A central bias in spatial selection has been proposed to explain the decreasing search efficiency with increasing target eccentricity that results when distractors can occur closer to fixation than the target (J. M. Wolfe, P. O'Neill, & S. C. Bennett, 1998). The authors found evidence for such a bias using an odd-man-out variant of conjunction search. However, the bias was absent for the same displays when the identity of the odd-man-out target was known in advance. The authors propose that (a) top-down knowledge of a target feature supports grouping on this feature and (b) grouping links a peripheral target to central distractors expressing the same feature, increasing the attentional weighting afforded to the target and, consequently, facilitating its detection. The effects are independent of bottom-up priming effects occurring across trials. Thus, feature-based grouping can be driven top-down and can overrule the central bias in spatial selection.


Caesarean delivery: An experience from a tertiary institution in north western Nigeria.
To assess the overall caesarean section (CS) rate, indications and outcomes in a tertiary hospital in North-western Nigeria. A cross-sectional study carried out over a period of two years. All patients who had caesarean section at any time within the day were noted and followed up till discharge. The socio-demographic data, types of CS, anaesthesia, indications, abdominal wall and uterine incisions, cadre of surgeon and feto-maternal outcomes were documented in a proforma. Statistical analysis was carried out using the EPI INFO 3.5.1 (CDC Atlanta Georgia, USA). The caesarean section rate was 11.3% (504/4462) of total deliveries. The highest rate of 44.6% (225/504) was among the primipara. The most common age group involved was 25 to 29 years. The emergency rate was 57.1% (288/504), while elective CS constituted 42.9% (216/504) of cases. The most common indication for emergency CS was obstructed labour 25.7% (30/288) and previous CS 39.8% (86/216) for elective CS. The complication rate was 13.3% (67/504) and the main complication was haemorrhage 59.7% (40/67). Complications were more with emergency CS compared to elective surgery (χ2 = 6.633, df = 1, P < 0.01) and with junior residents (χ2 = 15.9, df = 1, P < 0.001). There were 10 maternal and 60 perinatal deaths. The rate of caesarean section has been increasing gradually. There is need to improve on facilities and manpower in order to reduce morbidity and mortality.


Evaluation of a culturally-adapted lifestyle intervention to treat elevated cardiometabolic risk of Latino adults in primary care (Vida Sana): A randomized controlled trial.
Latinos bear a disproportionate burden of the dual pandemic of obesity and diabetes. However, successful interventions addressing this disparity through primary care are lacking. To address this gap, the 5-year Vida Sana (Healthy Life) study tests a culturally adapted and technology-enhanced group-based Diabetes Prevention Program intervention in a randomized controlled trial with overweight/obese Latino adults who have metabolic syndrome and/or pre-diabetes. Eligible, consenting patients (n=186) from a large community-based multispecialty group practice in Northern California will be randomly assigned to receive the culturally-adapted intervention or usual care. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework guided the planned evaluations. The primary aim is to determine the effectiveness of the intervention (the "E" in RE-AIM). We hypothesize that the intervention will lead to a greater mean reduction in weight at 24months (primary endpoint) vs. usual care. Secondary outcomes will include measures of cardiometabolic risk factors (e.g., blood pressure), psychosocial well-being (e.g., health-related quality of life), and behavior change (e.g., physical activity). The secondary aim is to evaluate the other RE-AIM dimensions using mixed methods: reach (e.g., participation rate of the target population), adoption (e.g., participating clinic and provider characteristics), implementation (e.g., intervention fidelity), and maintenance (e.g., sustainability in the practice setting). These findings have real word applicability with value to clinicians, patients, and other decision makers considering effective diabetes prevention programs for primary care that would support the millions of Latino adults who experience a disproportionate burden of diabetes. NCT02459691.


Impact of the adenoviral E4 Orf3 protein on the activity and posttranslational modification of p53.
Our previous studies have established that the p53 populations that accumulate in normal human cells exposed to etoposide or infected by an E1B 55-kDa protein-null mutant of human adenovirus type 5 carry a large number of posttranslational modifications at numerous residues (C. J. DeHart, J. S. Chahal, S. J. Flint, and D. H. Perlman, Mol Cell Proteomics 13:1-17, 2014, http://dx.doi.org/10.1074/mcp.M113.030254). In the absence of this E1B protein, the p53 transcriptional program is not induced, and it has been reported that the viral E4 Orf3 protein inactivates p53 (C. Soria, F. E. Estermann, K. C. Espantman, and C. C. O'Shea, Nature 466:1076-1081, 2010, http://dx.doi.org/10.1038/nature09307). As the latter protein disrupts nuclear Pml bodies, sites at which p53 is modified, we used mass spectrometry to catalogue the posttranscriptional modifications of the p53 population that accumulates when neither the E1B 55-kDa nor the E4 Orf3 protein is made in infected cells. Eighty-five residues carrying 163 modifications were identified. The overall patterns of posttranslational modification of this population and p53 present in cells infected by an E1B 55-kDa-null mutant were similar. The efficiencies with which the two forms of p53 bound to a consensus DNA recognition sequence could not be distinguished and were lower than that of transcriptionally active p53. The absence of the E4 Orf3 protein increased expression of several p53-responsive genes when the E1B protein was also absent from infected cells. However, expression of these genes did not attain the levels observed when p53 was activated in response to etoposide treatment and remained lower than those measured in mock-infected cells. The tumor suppressor p53, a master regulator of cellular responses to stress, is inactivated and destroyed in cells infected by species C human adenoviruses, such as type 5. It is targeted for proteasomal degradation by the action of a virus-specific E3 ubiquitin ligase that contains the viral E1B 55-kDa and E4 Orf6 proteins, while the E4 Orf3 protein has been reported to block its ability to stimulate expression of p53-dependent genes. The comparisons reported here of the posttranslational modifications and activities of p53 populations that accumulate in infected normal human cells in the absence of both mechanisms of inactivation or of only the E3 ligase revealed little impact of the E4 Orf3 protein. These observations indicate that E4 Orf3-dependent disruption of Pml bodies does not have a major effect on the pattern of p53 posttranslational modifications in adenovirus-infected cells. Furthermore, they suggest that one or more additional viral proteins contribute to blocking p53 activation and the consequences that are deleterious for viral reproduction, such as apoptosis or cell cycle arrest.


[Outpatient female stress urinary incontinence surgery: budget impact study].
The surgical procedures for the insertion of tension free vaginal tapes in the treatment of female stress urinary incontinence (SUI) are simple and can be done as outpatient operations. The aim of this study was to perform a budget study comparing TVT in an outpatient basis with transobturator tape (TOT) with hospital admission. Retrospective analysis of the medical records of 23 patients undergoing surgery for SUI between October 2004 and October 2005. 13 patients were treated by TVT in an outpatient basis (group 1, Department of Urology), 10 patients were treated by TOT with hospital admission (Group 2, Department of Gynaecology). Cost analysis was carried out by the construction of a Marcov model, incorporating the time sequence of the treatment, including adverse events and results. Variables considered for the analysis: number of visits, preoperative tests, operative time, tape cost, hospital stay, unpredicted visits in the first postoperative month at the outpatient clinics or emergency room, and hospital readmissions. Statistical analysis was performed with the G-Stat software. Student's t test was used to compare quantitative variables. 11/13 patients (84.6%) in group 1 completed the day-surgery protocol. Mean surgical time was 61.7 min. (SD 16.2; 35-100) and 61.6 min. (SD 8.3; 50-73) for groups I and 2 respectively. Two cases in group 1 had perioperative complications (15.4%); no patient in group 2 had perioperative complications. Mean hospital stay was 1.3 days for group 1 (SD 0.85; 1-4) and 2.9 days for group 2 (SD 0.31; 2-3). Three patients in group 1 (23%) and 2 in group 2 (20%) presented postoperative complications. Mean cost per process was 4740 EUR for group 1 and 7099 EUR for group 2. SUI correction by tension free tapes as day surgery is a valid option which saves a substantial amount of resources.


Evidence for neuronal interactions by electrical field effects in the CA3 and dentate regions of rat hippocampal slices.
During population spikes in slices of rat hippocampus, transmembrane differential recordings (intracellular minus extracellular) revealed electrical field-effect depolarizations in CA3 pyramidal and dentate granule neurons. The field-effect depolarizations were not seen in single-ended recordings, and were consistently shown to increase neuronal excitability. Therefore, as previously shown for the CA1 area, large population spikes from CA3 pyramidal and dentate granule cells are associated with transmembrane depolarizations that increase neuronal excitability.


The growing importance of PON1 in cardiovascular health: a review.
The wide acceptance of the oxidation theory of atherogenesis has prompted attention to antioxidant mechanisms, particularly the prevention of lipid oxidation by high-density lipoprotein-associated proteins like paraoxonase 1 (PON1) enzyme. PON1 is a calcium-dependent enzyme that has interested toxicologists since its discovery as an organophosphate hydrolase. There is a growing interest in the enzyme's importance in cardiovascular health prompted by evidence that it may have a role in lipid metabolism and the development of atherosclerosis via its antioxidant effects. PON1 is capable of hydrolyzing homocysteine thiolactone, a metabolite of homocysteine that can impair protein function leading to endothelial dysfunction and vascular damage. Although this lactonase activity has been suggested to be PON1's native activity, the enzyme's specific physiological role and substrate remain unclear. In this review, we summarize developments in the field of PON1 research relating to cardiovascular health, and highlight those that perhaps warrant further research.


Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk.
To explore the association of nonmelanoma skin cancer (NMSC) and Alzheimer disease (AD) in the Einstein Aging Study, an epidemiologic study of aging in New York City. Community-residing volunteers aged 70 years or older were assessed annually, followed by multidisciplinary diagnostic consensus. Cancer status and type was obtained by self-report. Cox proportional hazards models were used to test associations between NMSC and subsequent risk of developing a neurocognitive disorder. To deduce a biologically specific association between AD and NMSC, we considered 3 nested outcomes groups: only AD (probable or possible AD as the sole diagnosis), any AD (probable AD or possible AD, as well as mixed AD/vascular dementia), and all-cause dementia. We followed 1,102 adults with a mean age of 79 years at enrollment. Prevalent NMSC was associated with reduced risk of only AD (hazard ratio = 0.21; 95% confidence interval = 0.051-0.87; p = 0.031) among subjects after adjustment for demographics, hypertension, diabetes, and coronary heart disease. APOE ε4 genotypes were available in 769 individuals. The association was similar in magnitude, but nonsignificant, when the number of APOE ε4 alleles was included in the model. No significant association was found between NMSC and subsequent development of any AD or all-cause dementia. This population-based longitudinal study shows that individuals older than 70 years with NMSC have a significantly reduced risk of developing AD compared with individuals without NMSC. We deduce Alzheimer-specific neuroprotection, because the effect is attenuated or eliminated when considering less-specific diagnoses such as AD with another diagnosis (any AD) or all-cause dementia.


A Novel Multilevel-SVD Method to Improve Multistep Ahead Forecasting in Traffic Accidents Domain.
Here is proposed a novel method for decomposing a nonstationary time series in components of low and high frequency. The method is based on Multilevel Singular Value Decomposition (MSVD) of a Hankel matrix. The decomposition is used to improve the forecasting accuracy of Multiple Input Multiple Output (MIMO) linear and nonlinear models. Three time series coming from traffic accidents domain are used. They represent the number of persons with injuries in traffic accidents of Santiago, Chile. The data were continuously collected by the Chilean Police and were weekly sampled from 2000:1 to 2014:12. The performance of MSVD is compared with the decomposition in components of low and high frequency of a commonly accepted method based on Stationary Wavelet Transform (SWT). SWT in conjunction with the Autoregressive model (SWT + MIMO-AR) and SWT in conjunction with an Autoregressive Neural Network (SWT + MIMO-ANN) were evaluated. The empirical results have shown that the best accuracy was achieved by the forecasting model based on the proposed decomposition method MSVD, in comparison with the forecasting models based on SWT.


Effect of chlorphentermine on the pulmonary disposition of norepinephrine in the isolated perfused rabbit lung.
Chlorphentermine (CP) has been noted to cause primary pulmonary hypertension both clinically and experimentally. It was postulated that CP might affect the pulmonary clearance of endogenous vasoactive substances such as norepinephrine (NE). The uptake and metabolism of 14C-NE were followed in artificially ventilated isolated perfused rabbit lung preparations using a constituted perfusate with initial NE concentration of 5 micrograms/100 ml. Perfusate samples were analyzed for total radioactivity, metabolites, and parent compound. Preloading the lungs with 0.25 mM CP significantly increased the concentrations of total radioactivity, deaminated products, and decreased the concentration of normetanephrine in the perfusate. In addition, the accumulation of total radioactivity in the lung tissue after 60 min of perfusion was significantly decreased in CP-treated lungs. The proportion of deaminated metabolites in the lung tissue was slightly decreased while the percent of normetanephrine, and parent compound were significantly increased by the CP treatment. CP (0.1 mM) also inhibited the in vitro metabolism of NE by 79%. These results provide experimental evidence in support of a hindered pulmonary clearance of circulating NE by CP.


Calpain 2 is required for the invasion of glioblastoma cells in the zebrafish brain microenvironment.
Glioblastoma is an aggressive primary brain tumor with a 5-year survival rate of less than 5%. The ability of glioblastoma cells to invade surrounding brain tissue presents the primary challenge for the success of focal therapeutic approaches. We previously reported that the calcium-activated protease calpain 2 is critical for glioblastoma cell invasion in vitro. Here, we show that expression of calpain 2 is required for the dispersal of glioblastoma cells in a living brain microenvironment. Knockdown of calpain 2 resulted in a 2.9-fold decrease in the invasion of human glioblastoma cells in zebrafish brain. Control cells diffusely migrated up to 450 μm from the site of injection, whereas knockdown cells remained confined in clusters. The invasion study was repeated in organotypic mouse brain tissues, and calpain 2 knockdown cells demonstrated a 2.3-fold lower area of dispersal compared with control cells. In zebrafish brain, glioblastoma cells appeared to migrate in part along the blood vessels of the host. Furthermore, angiogenesis was detected in 27% of zebrafish injected with control cells, whereas only 12.5% of fish receiving knockdown cells showed the formation of new vessels, suggesting a role for calpain 2 in tumor cell angiogenesis. Consistent with the progression of glioblastoma in humans, transplanted tumor cells were not observed to metastasize outside the brain of zebrafish. This study demonstrates that calpain 2 expression is required for the dispersal of glioblastoma cells within the dynamic microenvironment of the brain, identifying zebrafish as a valuable orthotopic system for studying glioblastoma cell invasion.


Label-free, single-molecule detection with optical microcavities.
Current single-molecule detection techniques require labeling the target molecule. We report a highly specific and sensitive optical sensor based on an ultrahigh quality (Q) factor (Q > 10(8)) whispering-gallery microcavity. The silica surface is functionalized to bind the target molecule; binding is detected by a resonant wavelength shift. Single-molecule detection is confirmed by observation of single-molecule binding events that shift the resonant frequency, as well as by the statistics for these shifts over many binding events. These shifts result from a thermo-optic mechanism. Additionally, label-free, single-molecule detection of interleukin-2 was demonstrated in serum. These experiments demonstrate a dynamic range of 10(12) in concentration, establishing the microcavity as a sensitive and versatile detector.


Lack of chemokine receptor CCR5 promotes murine fulminant liver failure by preventing the apoptosis of activated CD1d-restricted NKT cells.
Fulminant liver failure (FLF) consists of a cascade of events beginning with a presumed uncontrolled systemic activation of the immune system. The etiology of FLF remains undefined. In this study, we demonstrate that CCR5 deficiency promotes the development of acute FLF in mice following Con A administration by preventing activated hepatic CD1d-restricted NKT cells (but not conventional T cells) from dying from activation-induced apoptosis. The resistance of CCR5-deficient NKT cells from activation-induced apoptosis following Con A administration is not due to a defective Fas-driven death pathway. Moreover, FLF in CCR5-deficient mice also correlated with hepatic CCR5-deficient NKT cells, producing more IL-4, but not IFN-gamma, relative to wild-type NKT cells. Furthermore, FLF in these mice was abolished by IL-4 mAb or NK1.1 mAb treatment. We propose that CCR5 deficiency may predispose individuals to the development of FLF by preventing hepatic NKT cell apoptosis and by regulating NKT cell function, establishing a novel role for CCR5 in the development of this catastrophic liver disease that is independent of leukocyte recruitment.


Early thermal experience has different effects on growth and muscle fibre recruitment in spring- and autumn-running Atlantic salmon populations.
The consequence of early thermal experience for subsequent growth patterns was investigated in Atlantic salmon (Salmo salar L.). Spring- and autumn-running salmon were caught in upland (Baddoch) and lowland (Sheeoch) tributaries of the River Dee, Aberdeenshire, Scotland, respectively, on the final stages of their spawning migrations. The eggs were incubated at the simulated natural temperature regime of each stream, which was on average 2.8 degrees C lower for the Baddoch. The offspring, representing 11 families per population, were transferred at first feeding to constant environmental conditions (12-14 degrees C; 16h:8h light:dark photoperiod) and reared in replicate tanks. Salmon of both populations were longer and heavier at 6 and 12 weeks in fish initially reared under the cooler Baddoch regime. Length frequency distributions became bimodal after 18 weeks, and only the upper growth mode was studied. Modelling of length distributions at 40 weeks revealed significantly different patterns of muscle growth according to initial temperature regime, but only for the Sheeoch salmon. In fish of Sheeoch origin, significantly more white muscle fibres were recruited per mm(2) increase in myotomal cross-sectional area at Sheeoch than at Baddoch temperatures (P<0.01). After 40 weeks, the density of white fibres was 10.4 % higher in fish initially reared at the Sheeoch (533+/-6 mm(-2)) than at the Baddoch (483+/-5 mm(-2)) thermal regimes (means +/- s.e.m., 16 fish per group; P<0.001). Muscle satellite cells were identified using an antibody to c-met. At 24 weeks, the density of muscle satellite cells was 29 % higher in Sheeoch salmon reared to first feeding at the temperature of their natal stream than at cooler Baddoch temperatures (P<0.01). In contrast, the number and size distributions of white muscle fibres in the myotomes of Baddoch salmon were independent of early thermal experience.


Randomised feasibility study of a novel experience-based internet intervention to support self-management in chronic asthma.
To determine the feasibility of a randomised controlled trial (RCT) assessing the effects of an experience-based website as a resource for the self-management of chronic asthma. Feasibility, single-blind RCT in 2 regions of England. Randomisation used computer-generated random number sequence in a 1:1 ratio, after baseline data collection, to website access for 2 weeks. Adults (age ≥18 years), with clinically diagnosed asthma as coded in their primary care electronic record, prescribed inhaled corticosteroids for at least 3 months in the previous year, were recruited from 9 general practices. The EXPERT asthma intervention is an interactive PC/laptop/tablet/smartphone compatible website designed with extensive input from adults with asthma. It provides experience-based information and aims to support subjective perception of self-efficacy, self-management and improve health status. Primary outcomes were consent/recruitment, website usage and completion of outcome measures. Secondary outcomes included Partners in Health (PIH) questionnaire, the Chronic Disease Self-Efficacy Scale, the SF36 and the E-Health Impact Questionnaire. Participant blinding postrandomisation was not possible. The analysis was blind to allocation. Recruitment target exceeded. 148 participants randomised (73 intervention group). Age range 19-84 years; 59% female. 121 of 148 (84%; 62 intervention group) followed up. The median number of logins was 2 (IQR 2-3, range 1-48). Minimal differences of change from baseline between groups; both showed improvement in health state or management of their condition with no significant differences between arms. No adverse events. Recruitment and retention confirmed feasibility. The trends towards improved outcomes suggest that further research on digital interventions based on exposure to others' personal experiences may be of value in the self-management of chronic asthma. ISRCTN29549695; Results.


Quantitative Analysis of Candidate Endodontic Pathogens and Their Association with Cause and Symptoms of Apical Periodontitis in a Sudanese Population.
To investigate the prevalence of key endodontic pathogens and their association with the clinical features and the cause of apical periodontitis. The study population included patients referred to Khartoum Dental teaching Hospital, Sudan for endodontic treatment. Samples were collected from single-rooted teeth carious or traumatised teeth with clinical and radiographic evidence of apical periodontitis. The endodontic pathogens Porphyromonas endodontalis, Fusobacterium nucleatum and Treponema denticola were quantified by real time polymerase chain reaction (qPCR). The prevalence of each species was identified at both a low detection threshold (>50 bacteria) and a high detection threshold (>1000 bacteria). 75 patients (mean age 30.1 yrs SD 10.1) were included in the analysis. The most prevalent bacterium at both the low and high threshold was F. nucleatum followed by T. denticola at the low threshold and P. endodontalis at the high threshold. There was no association with symptoms at the low detection threshold, but at high threshold P. endodontalis was associated with swelling, adjusted odds ratio (OR), 9.32 95%CI 1.11- 78.66, P=0.04. All species were more prevalent in apical periodontitis due to caries only at the low detection threshold, OR=5.01 (P=0.006) for T. denticola; 4.84 (P=0.01) for F. nucleatum; and 3.62 (P=0.03) for P. endodontalis. There was a high prevalence of the F. nucleatum, T. denticola and P. endodontalis in apical periodontitis associated with caries. None of these bacterial were associated with pain but the presence of P. endodontalis at high levels was associated with swelling.


A novel method for estimating distributions of body mass index.
Understanding trends in the distribution of body mass index (BMI) is a critical aspect of monitoring the global overweight and obesity epidemic. Conventional population health metrics often only focus on estimating and reporting the mean BMI and the prevalence of overweight and obesity, which do not fully characterize the distribution of BMI. In this study, we propose a novel method which allows for the estimation of the entire distribution. The proposed method utilizes the optimization algorithm, L-BFGS-B, to derive the distribution of BMI from three commonly available population health statistics: mean BMI, prevalence of overweight, and prevalence of obesity. We conducted a series of simulations to examine the properties, accuracy, and robustness of the method. We then illustrated the practical application of the method by applying it to the 2011-2012 US National Health and Nutrition Examination Survey (NHANES). Our method performed satisfactorily across various simulation scenarios yielding empirical (estimated) distributions which aligned closely with the true distributions. Application of the method to the NHANES data also showed a high level of consistency between the empirical and true distributions. In situations where there were considerable outliers, the method was less satisfactory at capturing the extreme values. Nevertheless, it remained accurate at estimating the central tendency and quintiles. The proposed method offers a tool that can efficiently estimate the entire distribution of BMI. The ability to track the distributions of BMI will improve our capacity to capture changes in the severity of overweight and obesity and enable us to better monitor the epidemic.


Beginning community engagement at a busy biomedical research programme: experiences from the KEMRI CGMRC-Wellcome Trust Research Programme, Kilifi, Kenya.
There is wide acknowledgement of the need for community engagement in biomedical research, particularly in international settings. Recent debates have described theoretical approaches to identifying situations where this is most critical and potential mechanisms to achieve it. However, there is relatively little published experience of community engagement in practice. A major component of the Kenya Medical Research Institute (KEMRI) Wellcome Trust Research Programme is centred on Kilifi District General Hospital and surrounding community of 240,000 local residents. Documented community perceptions of the research centre are generally positive, but many indicate a low understanding of research and therapeutic misconceptions of its activities. As in other settings, these misunderstandings have contributed to concerns and rumours, and potentially undermine ethical aspects of research and local trust in the institution. Through a series of consultative activities, a community engagement strategy has been developed in Kilifi to strengthen mutual understanding between community members and the Centre. One important component is the establishment of a representative local resident network in different geographic locations commonly involved in research, to supplement existing communication channels. Early implementation of the strategy has provided new and diverse opportunities for dialogue, interaction and partnership building. Through the complex social interactions inherent in the community engagement strategy, the centre aims to build context specific ethical relations with local residents and to strengthen understanding of how ethical principles can be applied in practice. Evaluations over time will assess the effectiveness and sustainability of these strategies, provide generalisable information for similar research settings, and contribute to debates on the universality of ethical principles for research. This paper aims to summarise the rationale for community engagement in research, drawing on published literature and local findings, to outline the process of community engagement in Kilifi and to describe issues emerging from its development and early implementation.


The effect of improved periodontal health on metabolic control in type 2 diabetes mellitus.
The aim of the present study was to investigate the effect of improved periodontal health on metabolic control in type 2 diabetes mellitus (DM) patients. Fourty-four patients with type 2 DM were selected. Subjects were randomly assigned into two groups. Plaque index (PI), gingival index (GI), probing pocket depth (PPD), clinical attachment levels (CALs), gingival recession (GR) and bleeding on probing (BOP) were recorded at baseline at 1st and 3rd months. Fasting plasma glucose (FPG), 2-h post-prandial glucose (PPG), glycated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), HDL-cholesterol, LDL-cholesterol and microalbuminure were analysed at baseline, 3 months following the periodontal therapy. The treatment group received full-mouth scaling and root planing whereas the control group received no periodontal treatment. A statistically significant effect could be demonstrated for PI, GI, PPD, CAL and BOP for the treatment group. HbA1c levels in the treatment group decreased significantly whereas the control group showed a slight but insignificant increase for this parameter. The results of our study showed that non-surgical periodontal treatment is associated with improved glycaemic control in type 2 patients and could be undertaken along with the standard measures for the diabetic patient care.


Dynamic reconfiguration of human brain networks during learning.
Human learning is a complex phenomenon requiring flexibility to adapt existing brain function and precision in selecting new neurophysiological activities to drive desired behavior. These two attributes--flexibility and selection--must operate over multiple temporal scales as performance of a skill changes from being slow and challenging to being fast and automatic. Such selective adaptability is naturally provided by modular structure, which plays a critical role in evolution, development, and optimal network function. Using functional connectivity measurements of brain activity acquired from initial training through mastery of a simple motor skill, we investigate the role of modularity in human learning by identifying dynamic changes of modular organization spanning multiple temporal scales. Our results indicate that flexibility, which we measure by the allegiance of nodes to modules, in one experimental session predicts the relative amount of learning in a future session. We also develop a general statistical framework for the identification of modular architectures in evolving systems, which is broadly applicable to disciplines where network adaptability is crucial to the understanding of system performance.


Follow-up care for survivors of lymphoma who have received curative-intent treatment.
This evidence summary set out to assess the available evidence about the follow-up of asymptomatic survivors of lymphoma who have received curative-intent treatment. The medline and embase databases and the Cochrane Database of Systematic Reviews were searched for evidence published between 2000 and August 2015 relating to lymphoma survivorship follow-up. The evidence summary was developed by a Working Group at the request of the Cancer Care Ontario Survivorship and Cancer Imaging programs because of the absence of evidence-based practice documents in Ontario for the follow-up and surveillance of asymptomatic patients with lymphoma in complete remission. Eleven retrospective studies met the inclusion criteria. The proportion of relapses initially detected by clinical manifestations ranged from 13% to 78%; for relapses initially detected by imaging, the proportion ranged from 8% to 46%. Median time for relapse detection ranged from 8.6 to 19 months for patients initially suspected because of imaging and from 8.6 to 33 months for those initially suspected because of clinical manifestations. Only one study reported significantly earlier relapse detection for patients initially suspected because of clinical manifestations (mean: 4.5 months vs. 6.0 months, p = 0.042). No benefit in terms of overall survival was observed for patients depending on whether their relapse was initially detected because of clinical manifestations or surveillance imaging. Findings in the present study support the importance of improving awareness on the part of survivors and clinicians about the symptoms that might be associated with recurrence. The evidence does not support routine imaging for improving outcomes in this patient population.


Immune thrombocytopenic purpura.
Immune thrombocytopenic purpura (ITP) is an autoantibody-mediated thrombocytopenic disorder in which accelerated destruction of platelets occurs; platelet production may also be impaired by these antibodies. ITP is characterized by mucocutaneous bleeding. Rarely, more severe hemorrhages, such as intracranial hemorrhage, may occur. Traditional therapies, such as steroids, immunoglobulin therapy, and splenectomy, generally reduce peripheral destruction of platelets. More recently, with a better understanding of the immunopathologic mechanisms underlying thrombocytopenia, several new treatments have been developed, including thrombopoietic agents, specific inhibitors of Fcgamma receptor (FcgammaR) signaling, and B-cell depletion therapies. This article outlines current understanding of the epidemiology, etiology, diagnosis, and treatment of ITP. The focus is on recent pathophysiologic insights and areas of potential controversy in which studies are ongoing.


Trefoil peptide gene expression in small intestinal Crohn's disease and dietary adaptation.
We examined the patterns of trefoil peptide gene expression in the ulcer-associated cell lineage (UACL) and mucosa adjacent to Crohn's disease in humans and during gastrointestinal adaptation to enteral feeding in rats. In the UACL, human spasmolytic polypeptide (hSP) mRNA and peptide are present in the acinar and proximal duct cells, whereas pS2 mRNA and peptide are found in the distal duct cells and in the surface cells. In mucosa adjacent to UACL, pS2 mRNA and peptide are expressed ectopically by goblet cells and neuroendocrine cells. Intestinal crypts associated with the UACL showed marked neuroendocrine cell hyperplasia. Ultrastructural immunolocalization showed pS2 to be copackaged in the mucous cell and neuroendocrine granules. The copackaging of a secretory protein in both mucous and neuroendocrine granules, which have different functions, is unusual and indicates an important role for pS2 in the secretory process itself or as a ligand delivered to its receptor via multiple routes. We also cloned the newest trefoil peptide, intestinal trefoil factor (ITF), from human and rat intestinal mucosa. Using in situ hybridization we demonstrated its synthesis by normal rat intestinal goblet cells. RNAse protection analysis revealed that the level of mRNA for rat ITF in small and large intestine was affected by the process of enteral feeding. We conclude that trefoil peptides are widely distributed in the intestine in human inflammatory bowel disease and are of considerable potential functional importance.


Reproductive health in young male adults with chronic diseases in childhood.
The Centres for Disease Control and Prevention have defined a chronic diseases as an "illnesses that are prolonged, do not resolve spontaneously, and are rarely cured completely". Approximately 20% of all children have a chronic illness and 65% of them the illness is severe enough to interfere with daily activities. Failure of pubertal growth, delay or absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are well recognized disturbances among adolescents and young male adult patients with chronic diseases. The causes are multifactorial and can be due to disease itself, associated complications or drugs. Haemoglobinopathies, endocrine disorders, gastrointestinal and renal diseases are some examples that frequently cause some degree of disability. Infertility affects the future quality of life of these patients and is a predictor of stress in current and future relationships. Health care providers often neglect the reproductive health of chronically ill adolescents and young adults, although many studies indicate that they are sexually active and interested in knowing about their future fertility. This review article provides an overview of the literature concerning the impact of some chronic diseases in adolescents and young adults on reproductive health but will not address patients with cancer because it has been tackled adequately in the literature.MEDLINE database search of English-language medical journal articles published between 1975 and 2012 for papers related to reproductive health in adolescents and young adults with chronic diseases since childhood was done. Several Authors, recommend that all young adult patients with severe/prolonged chronic disease in childhood should be offered reproductive health care in a specialized center with appropriate expertise, involving a multidisciplinary team, including endocrinologists, andrologists, geneticists, psychologists, urologists and specialist nurses. Adequate information must be provided to these patients about adolescent reproductive health, including types of contraception, pregnancy, sexually transmitted infections and fertility. The importance of transitional care between pediatric and adult medical care should not be ignored. In the development of this process the adolescent must be involved in decision-making regarding treatment or referral. Reproductive health medicine should take a wider view to create a physical, psychological and genetic wellbeing of these patients.


Improved electroporation and cloning vector system for gram-positive bacteria.
A protocol for transformation of intact Enterococcus faecalis cells by electroporation was developed through a systematic examination of the effects of changes in various parameters, including (i) growth conditions; (ii) composition of the electroporation solution; (iii) electroporation conditions, such as field strength and resistance; (iv) size, concentration, and purity of DNA used for transformation; and (v) conditions used to select for transformants. Key features of this protocol include the use of exponential-phase cells grown in inhibitory concentrations of glycine and the use of an acidic sucrose electroporation solution. Frequencies of greater than 2 x 10(5) transformants per microgram of plasmid DNA were obtained for E. faecalis cells, whereas various strains of streptococci and Bacillus anthracis were transformed at frequencies of 10(3) to 10(4) transformants per microgram of plasmid DNA with the same protocol. A novel Escherichia coli-Streptococcus and Enterococcus shuttle cloning vector, pDL276, was constructed for use in conjunction with the electroporation system. This vector features a multiple cloning site region flanked by E. coli transcription termination sequences, a relatively small size (less than 7 kb), and a kanamycin resistance determinant expressed in both gram-positive and gram-negative hosts. Various enterococcal and streptococcal DNA sequences were cloned in E. coli (including sequences that could not be cloned on other vectors) and were returned to the original host by electroporation. The vector and electroporation system was also used to clone directly into E. faecalis.


Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918.
The H1N1 subtype of influenza A virus has caused substantial morbidity and mortality in humans, first documented in the global pandemic of 1918 and continuing to the present day. Despite this disease burden, the evolutionary history of the A/H1N1 virus is not well understood, particularly whether there is a virological basis for several notable epidemics of unusual severity in the 1940s and 1950s. Using a data set of 71 representative complete genome sequences sampled between 1918 and 2006, we show that segmental reassortment has played an important role in the genomic evolution of A/H1N1 since 1918. Specifically, we demonstrate that an A/H1N1 isolate from the 1947 epidemic acquired novel PB2 and HA genes through intra-subtype reassortment, which may explain the abrupt antigenic evolution of this virus. Similarly, the 1951 influenza epidemic may also have been associated with reassortant A/H1N1 viruses. Intra-subtype reassortment therefore appears to be a more important process in the evolution and epidemiology of H1N1 influenza A virus than previously realized.


Introductory lecture: when the density of the noninteracting reference system is not the density of the physical system in density functional theory.
A major challenge in density functional theory (DFT) is the development of density functional approximations (DFAs) to overcome errors in existing DFAs, leading to more complex functionals. For such functionals, we consider roles of the noninteracting reference systems. The electron density of the Kohn-Sham (KS) reference with a local potential has been traditionally defined as being equal to the electron density of the physical system. This key idea has been applied in two ways: the inverse calculation of such a local KS potential for the reference from a given density and the direct calculation of density and energy based on given DFAs. By construction, the inverse calculation can yield a KS reference with the density equal to the input density of the physical system. In application of DFT, however, it is the direct calculation of density and energy from a DFA that plays a central role. For direct calculations, we find that the self-consistent density of the KS reference defined by the optimized effective potential (OEP), is not the density of the physical system, when the DFA is dependent on the external potential. This inequality holds also for the density of generalized KS (GKS) or generalized OEP reference, which allows a nonlocal potential, when the DFA is dependent on the external potential. Instead, the density of the physical system, consistent with a given DFA, is given by the linear response of the total energy with respect to the variation of the external potential. This is a paradigm shift in DFT on the use of noninteracting references: the noninteracting KS or GKS references represent the explicit computational variables for energy minimization, but not the density of the physical system for external potential-dependent DFAs. We develop the expressions for the electron density so defined through the linear response for general DFAs, demonstrate the results for orbital functionals and for many-body perturbation theory within the second-order and the random-phase approximation, and explore the connections to developments in DFT.


High resolution fiber optic surface plasmon resonance sensors with single-sided gold coatings.
The surface plasmon resonance (SPR) performance of gold coated tilted fiber Bragg gratings (TFBG) at near infrared wavelengths is evaluated as a function of the angle between the tilt plane orientation and the direction of single- and double-sided, nominally 50 nm-thick gold metal depositions. Scanning electron microscope images show that the coating are highly non-uniform around the fiber circumference, varying between near zero and 50 nm. In spite of these variations, the experimental results show that the spectral signature of the TFBG-SPR sensors is similar to that of simulations based on perfectly uniform coatings, provided that the depositions are suitably oriented along the tilt plane direction. Furthermore, it is shown that even a (properly oriented) single-sided coating (over only half of the fiber circumference) is sufficient to provide a theoretically perfect SPR response with a bandwidth under 5 nm, and 90% attenuation. Finally, using a pair of adjacent TFBG resonances within the SPR response envelope, a power detection scheme is used to demonstrate a limit of detection of 3 × 10-6 refractive index units.


Real-time respiratory triggered SPECT myocardial perfusion imaging using CZT technology: impact of respiratory phase matching between SPECT and low-dose CT for attenuation correction.
To assess the impact of respiratory phase matching between single-photon-emission computed tomography myocardial perfusion imaging (SPECT-MPI) and low-dose computed tomography (CT) for attenuation correction (AC). Forty patients underwent 1-day 99mTc-tetrofosmin pharmacological stress/rest SPECT-MPI using a cadmium-zinc-telluride gamma camera. Low-dose CT for AC was performed at deep-inspiration breath-hold. SPECT-MPI was acquired once with free-breathing (FB) and repeated at deep-inspiration breath-hold (BH) to match the respiratory phase of AC. From these acquisitions we reconstructed four data sets: free-breathing SPECT-MPI without AC (non-corrected; FB-NC), breath-hold SPECT-MPI without AC (non-corrected; BH-NC), free-breathing SPECT-MPI with AC (FB-AC), and breath-hold SPECT-MPI with AC (BH-AC), the latter representing respiratory-phase-matched AC SPECT-MPI. We compared semi-quantitative segmental tracer uptake, visual diagnosis, inter-observer agreement, and image quality. Compared with FB-NC, deep-inspiration BH-NC increases inferior and lateral uptake, but decreases septal uptake. Addition of AC to FB increases inferior and septal uptake, but decreases anterolateral uptake. Combining breath-hold MPI with breath-hold CT AC (BH-AC) increases inferior, inferolateral, and septal uptake, but reduces apical uptake, without affecting anterolateral uptake, with significant differences to all other protocols. Frequency of normal scans increases across protocols: 10% with FB-NC, 21% with BH-NC, 38% with FB-AC, and 51% with BH-AC. Image quality and inter-observer agreement were highest for BH-AC among all protocols. Compared with non-corrected breath-hold SPECT-MPI and with free-breathing AC SPECT-MPI, respiratory-phase-matched AC SPECT-MPI significantly affects segmental semi-quantitative uptake, increases the frequency of normal scans, yields the best inter-observer agreement, and significantly improves image quality. These findings suggest a potential role of respiratory triggered SPECT-MPI in clinical routine.


Ingestion of egg raises plasma low density lipoproteins in free-living subjects.
In addition to their usual diet, 17 lactovegetarian college students consumed 400 kcal of test foods per day containing one extra-large egg for three weeks and similar isocaloric eggless foods for an additional three weeks in a randomised double-blind crossover trial. Ingestion of the egg increased dietary cholesterol from 97 to 418 mg per day. Mean plasma low density lipoprotein (LDL) cholesterol was 12% higher (p = 0.005) and mean plasma apolipoprotein B was 9% higher (p = 0.007) when eggs were being consumed than during the eggless period. Mean plasma high density lipoprotein cholesterol, apolipoproteins A-I and A-II, very low density lipoprotein cholesterol, and total triglycerides did not change significantly. Thus, ingestion of egg seems selectively to raise cholesterol and protein in LDL particles in the plasma of free-living normal people. Plasma LDL may be more sensitive to cholesterol at low intakes than at moderate to high intakes.


Unit testing, model validation, and biological simulation.
The growth of the software industry has gone hand in hand with the development of tools and cultural practices for ensuring the reliability of complex pieces of software. These tools and practices are now acknowledged to be essential to the management of modern software. As computational models and methods have become increasingly common in the biological sciences, it is important to examine how these practices can accelerate biological software development and improve research quality. In this article, we give a focused case study of our experience with the practices of unit testing and test-driven development in OpenWorm, an open-science project aimed at modeling Caenorhabditis elegans. We identify and discuss the challenges of incorporating test-driven development into a heterogeneous, data-driven project, as well as the role of model validation tests, a category of tests unique to software which expresses scientific models.


Effects of stride length and running mileage on a probabilistic stress fracture model.
The fatigue life of bone is inversely related to strain magnitude. Decreasing stride length is a potential mechanism of strain reduction during running. If stride length is decreased, the number of loading cycles will increase for a given mileage. It is unclear if increased loading cycles are detrimental to skeletal health despite reductions in strain. To determine the effects of stride length and running mileage on the probability of tibial stress fracture. Ten male subjects ran overground at their preferred running velocity during two conditions: preferred stride length and 10% reduction in preferred stride length. Force platform and kinematic data were collected concurrently. A combination of experimental and musculoskeletal modeling techniques was used to determine joint contact forces acting on the distal tibia. Peak instantaneous joint contact forces served as inputs to a finite element model to estimate tibial strains during stance. Stress fracture probability for stride length conditions and three running mileages (3, 5, and 7 miles x d(-1)) were determined using a probabilistic model of bone damage, repair, and adaptation. Differences in stress fracture probability were compared between conditions using a 2 x 3 repeated-measures ANOVA. The main effects of stride length (P = 0.017) and running mileage (P = 0.001) were significant. Reducing stride length decreased the probability of stress fracture by 3% to 6%. Increasing running mileage increased the probability of stress fracture by 4% to 10%. Results suggest that strain magnitude plays a more important role in stress fracture development than the total number of loading cycles. Runners wishing to decrease their probability for tibial stress fracture may benefit from a 10% reduction in stride length.


Counting the cost of meningococcal disease : scenarios of severe meningitis and septicemia.
Meningococcal disease can result in severe disabling sequelae, but there is no published information about the lifelong rehabilitation costs of patients with severe outcome in the UK. As cost-effectiveness studies play a crucial role in determining whether immunization programmes will be implemented, it is important to identify these costs. The aim of the study was to estimate lifelong rehabilitation costs associated with severe cases of meningococcal disease and to present these costs in a format appropriate for use in a cost-effectiveness analysis. Two severe scenarios of meningococcal disease with major sequelae were developed; one that presented acutely as meningitis and the other as septicemia. Scenarios were based on systematic reviews of the literature describing the sequelae of meningococcal disease, dialogue with Meningitis Research Foundation members who have experience of the disease, and discussions with pediatricians who have been responsible for managing children with this disease over many years. The two scenarios were devised to represent cases typical of the severe end of the spectrum. To obtain a comprehensive list of the health, educational and other resources used by survivors during and since their acute illness, families of individuals with sequelae similar to those in each of our scenarios were interviewed. Relevant academics and professionals in health, social care and education were consulted in order to ensure that our scenarios accurately represented the treatment and support that individuals with such sequelae might realistically receive from the National Health Service (NHS), the local authority and Personal Social Services (PSS). The majority of costs were derived from English Department of Health reference costs and unit costs of health and social care reflecting values for the financial year 2008-2009 indexed to 2010-2011. Costs were based on a life expectancy of 70 years in each scenario and are presented at a discount rate of 3.5 % for the first 30 years and 3 % thereafter, as recommended by the UK treasury (non-discounted costs are also presented for comparison). Costs are presented from both an NHS/PSS perspective and a government perspective. This study has revealed that severe cases of disease that result in long-term sequelae can result in costs to the NHS/PSS of around £160,000-£200,000 in the first year alone. Over a lifetime of 70 years, discounted costs from an NHS/PSS perspective ranged from approximately £590,000 to £1,090,000 (£1,250,000-£3,320,000 undiscounted) and discounted costs from a government perspective ranged from £1,360,000 to £1,720,000 (£3,030,000-£4,470,000 undiscounted). This study fills a gap in the UK literature and produces estimates that can be used in cost-effectiveness analysis to better represent the cost of illness at the severe end of the spectrum. Costs from a government perspective highlight the wider impacts of this disease, which is important for clinical decision makers, and budgetary and service planners to be aware of when making decisions about the benefits of implementing public health interventions such as immunization programmes.


Causes of death of patients with methamphetamine dependence: a record-linkage study.
Methamphetamine use leads to increased likelihood of premature death. The authors investigated the causes of death and risk of mortality in a large cohort of patients with methamphetamine dependence. A cohort of 1254 subjects with methamphetamine dependence, admitted to a psychiatric centre in Taiwan from January 1990 to December 2007, was retrospectively studied. Diagnostic and sociodemographic data for each subject were extracted from the medical records based on a chart review process. Mortality data were obtained by linking to the National Death Certification System and standardised mortality ratios (SMRs) were estimated. The risk and protective factors for all-cause deaths were explored by means of survival analyses. During the study period, 130 patients died. Of them, 63.1% died unnatural deaths, while the remaining 36.9% died natural deaths. The 1 year cumulative rates for unnatural and natural deaths were 0.018 and 0.006, respectively, and the 5 year rates were 0.046 and 0.023, respectively. The cohort had excessive mortality (SMR = 6.02), and women had a higher SMR for unnatural deaths than men (26.19 vs. 9.82, P = 0.001). For all-cause deaths, comorbidity with other substance use disorders was associated with increased risk of death, despite that being married was associated with a reduced risk. A substantial proportion of the deceased died natural deaths, but most died unnatural deaths. The findings show significant evidence to provide valuable insight into premature deaths among methamphetamine-dependent users. This information is valuable for development of prevention and intervention programs.


Probing individual molecules with confocal fluorescence microscopy.
Confocal fluorescence microscopy coupled with a diffraction-limited laser beam and a high-efficiency detection system has been used to study the diffusive movement and emission process of individual fluorescent molecules in the liquid phase at room temperature. The high detection sensitivity achieved at fast data acquisition speeds (greater than 1 kilohertz) allows real-time observation of single-molecule fluorescence without statistical analysis. The results show fluorescence-cycle saturation at the single-molecule level and multiple recrossings of a single molecule into and out of the probe volume as well as the triplet state.


The process of problem-based learning: what works and why.
In this review, we portray the process of problem-based learning (PBL) as a cognitive endeavour whereby the learner constructs mental models relevant to problems. Two hypotheses are proposed to explain how learning is driven in PBL; an activation-elaboration hypothesis and a situational interest hypothesis. Research relevant to these hypotheses is discussed. In addition, research studying the effects of various support strategies used in PBL is reviewed. Finally, we summarise a number of recent studies in which a new 'micro-analytical' methodology was used to trace the process of PBL in the natural classroom setting. We conclude that there is considerable support for the idea that PBL works because it encourages the activation of prior knowledge in the small-group setting and provides opportunities for elaboration on that knowledge. These activities facilitate the comprehension of new information related to the problem and enhance its long-term memorability. In addition, there is evidence that problems arouse situational interest that drives learning. Flexible scaffolding provided by cognitively and socially congruent tutors also seems to be reasonably effective, as opposed to 'hard' scaffolding represented by, for instance, worksheets or questions added to problems. Small-group work protects against dropout and encourages students to study regularly. Initially, students do not study much beyond the learning issues generated; the development of personal agency in self-study needs time to develop. The extent of learning in PBL results from neither group collaboration only (the social constructivist point of view) nor individual knowledge acquisition only; both activities contribute equally to learning in PBL.


Syntheses, structure, and photoluminescence properties of the 1-dimensional chain compounds [(TPA)(2)Au][Au(CN)(2)] and (TPA)AuCl (TPA = 1,3,5-triaza-7-phosphaadamantane).
The structures and temperature-dependent photoluminescence properties of the one-dimensional compounds [(TPA)(2)Au][Au(CN)(2)], 1, and (TPA)AuCl, 2, are reported. An extended linear chain with weak Au.Au interactions along the c-axis is evident in the structure of 1, and a helical chain with a pitch of 3.271 A is seen for 2. The intrachain Au...Au separation is 3.457(1) and 3.396(2) A in 1 and 2, respectively. As a result of this weak Au...Au interaction, the physical properties of these compounds are anisotropic. Scanning electron microscopy (SEM) studies indicate that single crystals of both compounds are noninsulating. Single crystals of 1 do not luminesce visibly, but grinding the crystals finely initiates a strong green emission under UV irradiation at room temperature. Further interesting optical properties include the dependence of the emission profile of the powder on the exciting wavelength and luminescence thermochromism. When excited at wavelengths < 360 nm, the powder exhibits a blue emission at 425 nm while excitation with longer wavelengths leads to a green emission near 500 nm. While the green emission dominates at ambient temperature, cooling to cryogenic temperatures leads to the dominance of the blue emission. Fibers of 2 are luminescent at 78 K with an emission band centered at 580 nm. Compound 1 crystallizes in the orthorhombic space group Cccm (No. 66), with Z = 2, a = 6.011(1) A, b = 23.877(6) A, c = 6.914(1) A, V = 992.3(3) A(3), and R = 0.0337. Compound 2 crystallizes in the trigonal space group R3 (No. 148), with Z = 18, a = 22.587(2) A, b = 22.587(2) A, c = 9.814(2) A, V = 4336 A(3), and R = 0.0283.


Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers.
Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598-608. ©2017 AACR.


A Generative Probabilistic Model and Discriminative Extensions for Brain Lesion Segmentation--With Application to Tumor and Stroke.
We introduce a generative probabilistic model for segmentation of brain lesions in multi-dimensional images that generalizes the EM segmenter, a common approach for modelling brain images using Gaussian mixtures and a probabilistic tissue atlas that employs expectation-maximization (EM), to estimate the label map for a new image. Our model augments the probabilistic atlas of the healthy tissues with a latent atlas of the lesion. We derive an estimation algorithm with closed-form EM update equations. The method extracts a latent atlas prior distribution and the lesion posterior distributions jointly from the image data. It delineates lesion areas individually in each channel, allowing for differences in lesion appearance across modalities, an important feature of many brain tumor imaging sequences. We also propose discriminative model extensions to map the output of the generative model to arbitrary labels with semantic and biological meaning, such as "tumor core" or "fluid-filled structure", but without a one-to-one correspondence to the hypo- or hyper-intense lesion areas identified by the generative model. We test the approach in two image sets: the publicly available BRATS set of glioma patient scans, and multimodal brain images of patients with acute and subacute ischemic stroke. We find the generative model that has been designed for tumor lesions to generalize well to stroke images, and the extended discriminative -discriminative model to be one of the top ranking methods in the BRATS evaluation.


Differential diagnosis generators: an evaluation of currently available computer programs.
Differential diagnosis (DDX) generators are computer programs that generate a DDX based on various clinical data. We identified evaluation criteria through consensus, applied these criteria to describe the features of DDX generators, and tested performance using cases from the New England Journal of Medicine (NEJM©) and the Medical Knowledge Self Assessment Program (MKSAP©). We first identified evaluation criteria by consensus. Then we performed Google® and Pubmed searches to identify DDX generators. To be included, DDX generators had to do the following: generate a list of potential diagnoses rather than text or article references; rank or indicate critical diagnoses that need to be considered or eliminated; accept at least two signs, symptoms or disease characteristics; provide the ability to compare the clinical presentations of diagnoses; and provide diagnoses in general medicine. The evaluation criteria were then applied to the included DDX generators. Lastly, the performance of the DDX generators was tested with findings from 20 test cases. Each case performance was scored one through five, with a score of five indicating presence of the exact diagnosis. Mean scores and confidence intervals were calculated. Twenty three programs were initially identified and four met the inclusion criteria. These four programs were evaluated using the consensus criteria, which included the following: input method; mobile access; filtering and refinement; lab values, medications, and geography as diagnostic factors; evidence based medicine (EBM) content; references; and drug information content source. The mean scores (95% Confidence Interval) from performance testing on a five-point scale were Isabel© 3.45 (2.53, 4.37), DxPlain® 3.45 (2.63-4.27), Diagnosis Pro® 2.65 (1.75-3.55) and PEPID™ 1.70 (0.71-2.69). The number of exact matches paralleled the mean score finding. Consensus criteria for DDX generator evaluation were developed. Application of these criteria as well as performance testing supports the use of DxPlain® and Isabel© over the other currently available DDX generators.


Transient intercellular adhesion: the importance of weak protein-protein interactions.
Intercellular adhesion is a complex phenomenon central to the development, structure and functioning of all multicellular organisms. Adhesion is mediated by distinct families of cell-adhesion molecules (CAMs), and recent studies have identified key characteristics of CAMs that influence their function. Affinity and kinetic analyses using a novel technique based on surface plasmon resonance have shown that CAM interactions that mediate transient cell adhesion may have surprisingly low affinities and extremely fast dissociation rate constants.


Drinking water from private wells and risks to children.
Drinking water for approximately one sixth of US households is obtained from private wells. These wells can become contaminated by pollutant chemicals or pathogenic organisms and cause illness. Although the US Environmental Protection Agency and all states offer guidance for construction, maintenance, and testing of private wells, there is little regulation. With few exceptions, well owners are responsible for their own wells. Children may also drink well water at child care or when traveling. Illness resulting from children's ingestion of contaminated water can be severe. This policy statement provides recommendations for inspection, testing, and remediation for wells providing drinking water for children.


U.S. Primary Care Clinics' Experiences During Introduction of the 9-Valent HPV Vaccine.
Changes in the routine immunization schedule are common and may pose challenges to primary care clinics. We sought to assess the experiences of U.S. providers and clinic staff during the introduction of 9-valent HPV vaccine. In 2015-2016, we conducted a survey in a probability sample of 127 pediatric (40%) and family medicine (60%) clinics in three U.S. states. The 211 respondents included clinicians (63%) and staff (37%). Overall, 83% of clinics stocked 9-valent HPV vaccine, with adoption ranging from 60% among early respondents to 100% among later respondents. Almost all respondents believed that providers in their clinics would recommend the 9-valent vaccine as strongly as (66%) or more strongly than (33%) the quadrivalent vaccine. Over half (61%) had no concerns about the 9-valent vaccine, while others reported concerns about increased parental hesitancy (29%), private insurance coverage (17%), or other issues (10%). Respondents from pediatric versus family medicine clinics more often reported a concern (OR = 2.06, 95% CI 1.02-4.15). Among the 169 respondents who stocked 9-valent vaccine, about half (56%, n = 94) anticipated that providers in their clinics would recommend a "booster" dose of 9-valent HPV vaccine for adolescents who had completed the 3-dose series with prior versions. Among the 42 respondents who did not stock 9-valent vaccine, few (17%, n = 7) believed providers would recommend adolescents delay vaccination until it was available. In conclusion, providers and staff generally had positive views of 9-valent HPV vaccine and many had no concerns. For others, responses regarding parental hesitancy, insurance coverage, and the use of booster doses suggests opportunities for enhancing future educational support.


NMDA receptor gene variations as modifiers in Huntington disease: a replication study.
Several candidate modifier genes which, in addition to the pathogenic CAG repeat expansion, influence the age at onset (AO) in Huntington disease (HD) have already been described. The aim of this study was to replicate association of variations in the N-methyl D-aspartate receptor subtype genes GRIN2A and GRIN2B in the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). The analyses did replicate the association reported between the GRIN2A rs2650427 variation and AO in the entire cohort. Yet, when subjects were stratified by AO subtypes, we found nominally significant evidence for an association of the GRIN2A rs1969060 variation and the GRIN2B rs1806201 variation. These findings further implicate the N-methyl D-aspartate receptor subtype genes as loci containing variation associated with AO in HD.


Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder.
We conducted a genome-wide association study of symptom response in an open-label study of a methylphenidate transdermal system (MTS). All DNA extraction and genotyping was conducted at SUNY Upstate Medical University using the Affymetrix Genome-Wide Human SNP Array 6.0. All quality control and association analyses were conducted using the software package PLINK. After data cleaning and quality control, there were 187 subjects (72% (N = 135) male) with mean age 9.2 +/- 2.0 years and 319,722 SNPs available for analysis. The most statistically significant association (rs9627183 and rs11134178; P = 3 x 10(-6)) fell short of the threshold for a genome-wide significant association. The most intriguing association among suggestive findings (rs3792452; P = 2.6 x 10(-5)) was with the metabotropic glutamate receptor 7 gene (GRM7) as it is expressed in brain structures also previously associated with ADHD. Among the 102 available SNPs covering previously studied candidate genes, two SNPs within the norepinephrine transporter gene (NET, SLC6A2) were significant at P < or = 1 x 10(-2). These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate.


Are We Underestimating Benthic Cyanotoxins? Extensive Sampling Results from Spain.
Microcystins (MCs) are potent hepatotoxins, and their presence in water bodies poses a threat to wildlife and human populations. Most of the available information refers to plankton, and much less is known about microcystins in other habitats. To broaden our understanding of the presence and environmental distribution of this group of toxins, we conducted extensive sampling throughout Spain, under a range of conditions and in distinct aquatic and terrestrial habitats. More than half of the tested strains were toxic; concentrations of the hepatotoxin were low compared with planktic communities, and the number of toxic variants identified in each sample of the Spanish strains ranged from 1-3. The presence of microcystins LF and LY (MC-LF and MC-LY) in the tested samples was significant, and ranged from 21.4% to 100% of the total microcystins per strain. These strains were only detected in cyanobacteria Oscillatoriales and Nostocales. We can report, for the first time, seven new species of microcystin producers in high mountain rivers and chasmoendolithic communities. This is the first report of these species in Geitlerinema and the confirmation of Anatoxin-a in Phormidium uncinatum. Our findings show that microcystins are widespread in all habitat types, including both aerophytic and endolithic peat bogs and that it is necessary to identify all the variants of microcystins in aquatic bodies as the commonest toxins sometimes represent a very low proportion of the total.


Causes and Characteristics of Death in Intensive Care Units: A Prospective Multicenter Study.
Different modes of death are described in selected populations, but few data report the characteristics of death in a general intensive care unit population. This study analyzed the causes and characteristics of death of critically ill patients and compared anticipated death patients to unexpected death counterparts. An observational multicenter cohort study was performed in 96 intensive care units. During 1 yr, each intensive care unit was randomized to participate during a 1-month period. Demographic data, characteristics of organ failures (Sequential Organ Failure Assessment subscore greater than or equal to 3), and organ supports were collected on all patients who died in the intensive care unit. Modes of death were defined as anticipated (after withdrawal or withholding of treatment or brain death) or unexpected (despite engagement of full-level care or sudden refractory cardiac arrest). A total of 698 patients were included during the study period. At the time of death, 84% had one or more organ failures (mainly hemodynamic) and 89% required at least one organ support (mainly mechanical ventilation). Deaths were considered unexpected and anticipated in 225 and 473 cases, respectively. Compared to its anticipated counterpart, unexpected death occurred earlier (1 day vs. 5 days; P< 0.001) and had fewer organ failures (1 [1 to 2] vs. 1 [1 to 3]; P< 0.01) and more organ supports (2 [2 to 3] vs. 1 [1 to 2]; P< 0.01). Withdrawal or withholding of treatments accounted for half of the deaths. In a general intensive care unit population, the majority of patients present with at least one organ failure at the time of death. Anticipated and unexpected deaths represent two different modes of dying and exhibit profiles reflecting the different pathophysiologic underlying mechanisms.


Site-specific associations of muscle thickness with bone mineral density in middle-aged and older men and women.
It is unknown whether age-related site-specific muscle loss is associated with areal bone mineral density (aBMD) in older adults. To examine the relationships between aBMD and whole-body muscle thickness distribution, 97 healthy adults (46 women and 51 men) aged 50-78 years volunteered. Total and appendicular lean soft tissue mass, aBMD of the lumbar spine (LS-aBMD) and femoral neck (FN-aBMD) were determined using dual-energy X-ray absorptiometry. Muscle thickness (MT) was measured by ultrasound at nine sites of the body (forearm, upper arm, trunk, upper leg, and lower leg). Relationships of each co-variate with aBMD were tested partialling out the effect of age. aBMD was not correlated with either MT of the trunk or anterior lower leg in either sex. In men, significant and relatively strong correlations were observed between anterior and posterior upper arms, posterior lower leg, and anterior upper leg MT and LS-aBMD or FN-aBMD. In women, significant correlations were observed between anterior and posterior upper legs, posterior lower leg, and anterior upper arm MT and FN-aBMD. LS-aBMD was only correlated with forearm and posterior upper leg MT in women. In conclusion, the site-specific association of MT and aBMD differs between sexes and may be associated with the participants' daily physical activity profile.


mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia.
Signaling by the mammalian target of rapamycin (mTOR) plays an important role in the modulation of both innate and adaptive immune responses. However, the role and underlying mechanism of mTOR signaling in poststroke neuroinflammation are largely unexplored. In this study, we injected rapamycin, a mTOR inhibitor, by the intracerebroventricular route 6 h after focal ischemic stroke in rats. We found that rapamycin significantly reduced lesion volume and improved behavioral deficits. Notably, infiltration of γδ T cells and granulocytes, which are detrimental to the ischemic brain, was profoundly reduced after rapamycin treatment, as was the production of proinflammatory cytokines and chemokines by macrophages and microglia. Rapamycin treatment prevented brain macrophage polarization toward the M1 type. In addition, we also found that rapamycin significantly enhanced anti-inflammation activity of regulatory T cells (Tregs), which decreased production of proinflammatory cytokines and chemokines by macrophages and microglia. Depletion of Tregs partially elevated macrophage/microglia-induced neuroinflammation after stroke. Our data suggest that rapamycin can attenuate secondary injury and motor deficits after focal ischemia by enhancing the anti-inflammation activity of Tregs to restrain poststroke neuroinflammation.


Task-specific codes for face recognition: how they shape the neural representation of features for detection and individuation.
The variety of ways in which faces are categorized makes face recognition challenging for both synthetic and biological vision systems. Here we focus on two face processing tasks, detection and individuation, and explore whether differences in task demands lead to differences both in the features most effective for automatic recognition and in the featural codes recruited by neural processing. Our study appeals to a computational framework characterizing the features representing object categories as sets of overlapping image fragments. Within this framework, we assess the extent to which task-relevant information differs across image fragments. Based on objective differences we find among task-specific representations, we test the sensitivity of the human visual system to these different face descriptions independently of one another. Both behavior and functional magnetic resonance imaging reveal effects elicited by objective task-specific levels of information. Behaviorally, recognition performance with image fragments improves with increasing task-specific information carried by different face fragments. Neurally, this sensitivity to the two tasks manifests as differential localization of neural responses across the ventral visual pathway. Fragments diagnostic for detection evoke larger neural responses than non-diagnostic ones in the right posterior fusiform gyrus and bilaterally in the inferior occipital gyrus. In contrast, fragments diagnostic for individuation evoke larger responses than non-diagnostic ones in the anterior inferior temporal gyrus. Finally, for individuation only, pattern analysis reveals sensitivity to task-specific information within the right "fusiform face area". OUR RESULTS DEMONSTRATE: 1) information diagnostic for face detection and individuation is roughly separable; 2) the human visual system is independently sensitive to both types of information; 3) neural responses differ according to the type of task-relevant information considered. More generally, these findings provide evidence for the computational utility and the neural validity of fragment-based visual representation and recognition.