High-risk mesothelioma relation to meteorological and geological condition and distance from naturally occurring asbestos.
Very few studies have investigated the incidence and risk of malignant mesothelioma (MM) associated with distinct sources of asbestos exposure, especially exposure to naturally occurring asbestos (NOA). Subjects were MM, lung, and breast cancer patients who were diagnosed and followed in Diyarbakir Province between 2008 and 2013. The birthplaces of patients were displayed on a geologic map. Geological and meteorological effects on MM were analyzed by logistic regression. A total of 180 MM, 368 breast, and 406 lung cancer patients were included. The median distance from birthplace to ophiolites was 6.26 km for MM, 31.06 km for lung, and 34.31 km for breast cancer (p < 0.001). The majority of MM cases were seen within 20 km from NOA areas. The MM incidence inside of NOA was 1059/100.000, and out of NOA was 397/100.000; this difference was significant (p = 0.014). The largest concentration of MM residential areas was within ± 30° (34 residential areas 36.6%) of the dominant wind direction. Most MM patients were found in or near the dominant wind direction, especially in the acute angle defined by the dominant wind direction. MM incidence was directly proportional to {[area of NOA (km(2))] * [cosine α of wind direction angle]} and was inversely proportional to the square of the distance (R = 0.291, p = 0.023). MM was higher near NOA and in the downwind direction. MM incidence and risk were affected by geological and meteorological factors.


Identification of Key Proteins in Human Epithelial Cells Responding to Bystander Signals From Irradiated Trout Skin.
Radiation-induced bystander signaling has been found to occur in live rainbow trout fish (Oncorhynchus mykiss). This article reports identification of key proteomic changes in a bystander reporter cell line (HaCaT) grown in low-dose irradiated tissue-conditioned media (ITCM) from rainbow trout fish. In vitro explant cultures were generated from the skin of fish previously exposed to low doses (0.1 and 0.5 Gy) of X-ray radiation in vivo. The ITCM was harvested from all donor explant cultures and placed on recipient HaCaT cells to observe any change in protein expression caused by the bystander signals. Proteomic methods using 2-dimensional (2D) gel electrophoresis and mass spectroscopy were employed to screen for novel proteins expressed. The proteomic changes measured in HaCaT cells receiving the ITCM revealed that exposure to 0.5 Gy induced an upregulation of annexin A2 and cingulin and a downregulation of Rho-GDI2, F-actin-capping protein subunit beta, microtubule-associated protein RP/EB family member, and 14-3-3 proteins. The 0.1 Gy dose also induced a downregulation of Rho-GDI2, hMMS19, F-actin-capping protein subunit beta, and microtubule-associated protein RP/EB family member proteins. The proteins reported may influence apoptotic signaling, as the results were suggestive of an induction of cell communication, repair mechanisms, and dysregulation of growth signals.


Density functional reactivity theory study of SN2 reactions from the information-theoretic perspective.
As a continuation of our recent efforts to quantify chemical reactivity with quantities from the information-theoretic approach within the framework of density functional reactivity theory, the effectiveness of applying these quantities to quantify electrophilicity for the bimolecular nucleophilic substitution (SN2) reactions in both gas phase and aqueous solvent is presented in this work. We examined a total of 21 self-exchange SN2 reactions for the compound with the general chemical formula of R1R2R3C-F, where R1, R2, and R3 represent substituting alkyl groups such as -H, -CH3, -C2H5, -C3H7, and -C4H9 in both gas and solvent phases. Our findings confirm that scaling properties for information-theoretic quantities found elsewhere are still valid. It has also been verified that the barrier height has the strongest correlation with the electrostatic interaction, but the contributions from the exchange-correlation and steric effects, though less significant, are indispensable. We additionally unveiled that the barrier height of these SN2 reactions can reliably be predicted not only by the Hirshfeld charge and information gain at the regioselective carbon atom, as previously reported by us for other systems, but also by other information-theoretic descriptors such as Shannon entropy, Fisher information, and Ghosh-Berkowitz-Parr entropy on the same atom. These new findings provide further insights for the better understanding of the factors impacting the chemical reactivity of this vastly important category of chemical transformations.


Effects of nonlinear phase modulation on Bragg scattering in the low-conversion regime.
In this paper, we consider the effects of nonlinear phase modulation on frequency conversion by four-wave mixing (Bragg scattering) in the low-conversion regime. We derive the Green functions for this process using the time-domain collision method, for partial collisions, in which the four fields interact at the beginning or the end of the fiber, and complete collisions, in which the four fields interact at the midpoint of the fiber. If the Green function is separable, there is only one output Schmidt mode, which is free from temporal entanglement. We find that nonlinear phase modulation always chirps the input and output Schmidt modes and renders the Green function formally nonseparable. However, by pre-chirping the pumps, one can reduce the chirps of the Schmidt modes and enable approximate separability. Thus, even in the presence of nonlinear phase modulation, frequency conversion with arbitrary pulse reshaping is possible, as predicted previously [Opt. Express 20, 8367-8396 (2012)].


Inversion and computational maturation of drug response using human stem cell derived cardiomyocytes in microphysiological systems.
While cardiomyocytes differentiated from human induced pluripotent stems cells (hiPSCs) hold great promise for drug screening, the electrophysiological properties of these cells can be variable and immature, producing results that are significantly different from their human adult counterparts. Here, we describe a computational framework to address this limitation, and show how in silico methods, applied to measurements on immature cardiomyocytes, can be used to both identify drug action and to predict its effect in mature cells. Our synthetic and experimental results indicate that optically obtained waveforms of voltage and calcium from microphysiological systems can be inverted into information on drug ion channel blockage, and then, through assuming functional invariance of proteins during maturation, this data can be used to predict drug induced changes in mature ventricular cells. Together, this pipeline of measurements and computational analysis could significantly improve the ability of hiPSC derived cardiomycocytes to predict dangerous drug side effects.


How much do tumor stage and treatment explain socioeconomic inequalities in breast cancer survival? Applying causal mediation analysis to population-based data.
Substantial socioeconomic inequalities in breast cancer survival persist in England, possibly due to more advanced cancer at diagnosis and differential access to treatment. We aim to disentangle the contributions of differential stage at diagnosis and differential treatment to the socioeconomic inequalities in cancer survival. Information on 36,793 women diagnosed with breast cancer during 2000-2007 was routinely collected by an English population-based cancer registry. Deprivation was determined for each patient according to her area of residence at the time of diagnosis. A parametric implementation of the mediation formula using Monte Carlo simulation was used to estimate the proportion of the effect of deprivation on survival mediated by stage and by treatment. One-third (35 % [23-48 %]) of the higher mortality experienced by most deprived patients at 6 months after diagnosis, and one tenth (14 % [-3 to 31 %]) at 5 years, was mediated by adverse stage distribution. We initially found no evidence of mediation via differential surgical treatment. However, sensitivity analyses testing some of our study limitations showed in particular that up to thirty per cent of the higher mortality in most deprived patients could be mediated by differential surgical treatment. This study illustrates the importance of using causal inference methods with routine medical data and the need for testing key assumptions through sensitivity analyses. Our results suggest that, although effort for earlier diagnosis is important, this would reduce the cancer survival inequalities only by a third. Because of data limitations, role of differential surgical treatment may have been under-estimated.


Mindfulness-based cognitive therapy for preventing relapse in recurrent depression: a randomized dismantling trial.
We compared mindfulness-based cognitive therapy (MBCT) with both cognitive psychological education (CPE) and treatment as usual (TAU) in preventing relapse to major depressive disorder (MDD) in people currently in remission following at least 3 previous episodes. A randomized controlled trial in which 274 participants were allocated in the ratio 2:2:1 to MBCT plus TAU, CPE plus TAU, and TAU alone, and data were analyzed for the 255 (93%; MBCT = 99, CPE = 103, TAU = 53) retained to follow-up. MBCT was delivered in accordance with its published manual, modified to address suicidal cognitions; CPE was modeled on MBCT, but without training in meditation. Both treatments were delivered through 8 weekly classes. Allocated treatment had no significant effect on risk of relapse to MDD over 12 months follow-up, hazard ratio for MBCT vs. CPE = 0.88, 95% CI [0.58, 1.35]; for MBCT vs. TAU = 0.69, 95% CI [0.42, 1.12]. However, severity of childhood trauma affected relapse, hazard ratio for increase of 1 standard deviation = 1.26 (95% CI [1.05, 1.50]), and significantly interacted with allocated treatment. Among participants above median severity, the hazard ratio was 0.61, 95% CI [0.34, 1.09], for MBCT vs. CPE, and 0.43, 95% CI [0.22, 0.87], for MBCT vs. TAU. For those below median severity, there were no such differences between treatment groups. MBCT provided significant protection against relapse for participants with increased vulnerability due to history of childhood trauma, but showed no significant advantage in comparison to an active control treatment and usual care over the whole group of patients with recurrent depression.


[Erythrocyte defects and parasitemia density in patients with Plasmodium falciparum malaria in Buenaventura, Colombia].
To determine the prevalence of some erythrocyte defects and to evaluate the relation that that has with parasitemia density in individuals diagnosed with Plasmodium falciparum malaria in a population in the Pacific coastal region of Colombia. This prevalence study was carried out with 242 persons with P. falciparum malaria who had gone for consultation at the Program of Tropical Diseases diagnostic center in the city of Buenaventura, Colombia. The parasitemia levels were measured, and also determined was the presence of congenital erythrocyte defects (glucose-6-phosphate dehydrogenase (G6PD) deficiency, abnormal hemoglobins, and thalassemias) and of other factors possibly related to parasitemia levels. The prevalence of erythrocyte defects was 26.4% (95% confidence interval, 21.0%-32.5%), which was similar to what had been found in previous studies in the same area of Colombia. In the multiple regression models, individuals with sickle cell anemia or a complete deficiency of G6PD had a lower density of parasitemia than did persons without any erythrocyte defect. After adjusting for other variables of interest, the risk of high parasitemias was lower in persons with sickle cell anemia (odds ratio = 0.30) and individuals with a complete deficiency of G6PD (odds ratio = 0.72). Our results confirm the high prevalence of erythrocyte defects in Colombia's Pacific coastal region, in a population with ethnic characteristics that are similar to those of some populations in West Africa. Our results also lend support for the existence of innate resistance to malaria among carriers of hemoglobin AS and in persons with G6PD deficiency.


Racial differences in the association of CD14 polymorphisms with serum total IgE levels and allergen skin test reactivity.
The CD14 C-159T single nucleotide polymorphism (SNP) has been investigated widely as a candidate genetic locus in patients with allergic disease. There are conflicting results for the association of the CD14 C-159T SNP with total serum immunoglobulin E (IgE) levels and atopy. There are limited data regarding the association of the CD14 C-159T SNP in subjects of African ancestry. The aim of the study was to determine whether the C-159T SNP and other CD14 SNPs (C1188G, C1341T) were associated with total serum IgE levels and with allergy skin test results in nonatopic and atopic subjects; as well as in Caucasian and African American subjects. A total of 291 participants, 18-40 years old, were screened to determine whether they were atopic and/or asthmatic. Analyses were performed to determine the association between CD14 C-159T, C1188G, or C1341T genotypes with serum IgE levels and with the number of positive skin tests among Caucasian or African American subjects. We found no significant association of serum total IgE level with CD14 C-159T, C1188G, or C1341T genotypes within nonatopic or atopic subjects. Subjects with CD14-159 T alleles had significantly more positive allergen skin tests than subjects without CD14-159 T alleles (P = 0.0388). There was a significant association between the CD14 1188 G allele, but not the CD14 1341 T allele, with the number of positive skin-test results in Caucasians, but not in African Americans. These results support a possible association between CD14 polymorphisms and atopy. CD14-159 T or CD14 1188 G alleles were associated with atopic disease. For subjects with CD14 1188 G alleles, the association with atopic disease was stronger in Caucasians compared to African Americans.


Direct effects of metabolic products and sonicated extracts of Porphyromonas gingivalis 2561 on osteogenesis in vitro.
It is well documented that oral microorganisms play a significant role in the initiation and progression of periodontal disease. By using various in vitro models, it has been shown that some bacteria considered periodontal pathogens or their products can stimulate bone resorption and some other parameters of osteoblast-like cell activity. However, the effects of these organisms and their products on osteogenesis itself are not known. This study was undertaken to determine the direct effects of metabolic products and sonicated extracts of Porphyromonas gingivalis on bone formation in the chick periosteal osteogenesis model. Cultures of P. gingivalis 2561 were grown under standard anaerobic culture conditions. The spent medium was collected, and following centrifugation, sonicated bacterial extracts were prepared from the bacterial pellet. These were added in various proportions to the chick periosteal osteogenesis cultures. Sonicated extracts were further fractionated into five molecular-size ranges and similarly tested. Parameters of osteogenesis, including alkaline phosphatase activity, calcium and Pi accumulation, and collagen synthesis, were measured on 6-day-old cultures. Compared with controls devoid of bacterial products, osteogenesis was inhibited significantly in cultures treated with either conditioned medium or extracts obtained from P. gingivalis. Various amounts of inhibitory activity were observed in the different ultrafiltration molecular-size fractions, with very profound inhibitory effects observed in the < 5-kDa range. Histological observations indicated the presence of cells, some bone, and/or new fibrous connective tissue at all concentrations, indicating that toxicity was not a factor. These results suggest that periodontal pathogens such as P. gingivalis might contribute to the bone loss in periodontal diseases not only by stimulating resorption but, possibly, by inhibiting bone formation directly.


Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features.
Little is known about selecting among second-step medications for major depressive disorder after intolerance or lack of remission with an initial selective serotonin reuptake inhibitor. To determine whether sociodemographic, clinical, or first-step treatment features predict remission with or intolerance overall or differentially to any 1 of 3 second-step medications after an unsatisfactory outcome with citalopram hydrobromide. An equipoise stratified randomized study. Participants were recruited from July 17, 2001, through April 20, 2004. Public or private sector primary care (n = 18) and psychiatric care (n = 23) settings across the United States. Representative outpatients aged 18 to 75 years with nonpsychotic major depressive disorder (N = 727). Sustained-release bupropion hydrochloride was started at 150 mg/d and incrementally increased to 400 mg/d. Sertraline hydrochloride was started at 50 mg/d and incrementally increased to 200 mg/d. Extended-release venlafaxine hydrochloride was started at 37.5 mg/d and incrementally increased to 375 mg/d. The 16-item Quick Inventory of Depressive Symptomatology, Self-Rated and the Frequency, Intensity, and Burden of Side Effects Rating. Remission was more likely among participants who were white, employed, cohabiting or married, or privately insured or who had prior intolerance to citalopram or at least a response to citalopram, and no prior suicide attempts. Remission was less likely among participants with concurrent generalized anxiety, obsessive-compulsive, panic, or posttraumatic stress disorders; social phobia; anxious or melancholic features; or more severe depression. Intolerance was less likely for Hispanic participants, but more likely for participants with previous suicide attempts or intolerance to citalopram. Participants with concurrent substance use were less likely to remit (odds ratio, 0.37) and more likely not to tolerate extended-release venlafaxine. Intolerance to citalopram was associated with intolerance to sertraline (P = .04). Clinical, demographic, and treatment history were of little value in recommending 1 medication vs another as a second-step treatment for major depressive disorder. Participants most likely to remit in the second step had less Axis I psychiatric disorder comorbidity, less social disadvantage, and at least a response to citalopram in the first step. clinicaltrials.gov Identifier: NCT00021528.


Calibration of (109)Cd KXRF systems for in vivo bone lead measurements: weighted least-squares regression with different weighting functions.
The use of iteratively reweighted least squares (IRLS) has recently been described as an alternative to ordinary least squares with heteroscedastic data, in the calibration of (109)Cd KXRF systems for in vivo bone lead measurements. This work addresses the use of weighted least squares (WLS) with two different weighting functions and no iteration, with that same data set. The functions are defined as the inverse of the variance of observed ratios of lead to coherent peak amplitudes and the inverse of the square of the error reported by the Marquardt fitting program for these ratios. The results show that if no iteration is implemented when using WLS, then the two weighting functions are highly inefficient in homogenizing the residual variance. Moreover, both methods estimate much more imprecise calibration intercepts and slopes than did the IRLS method. Work is in progress to investigate the implementation of IRLS with these weighting functions, with the focus on the selection of the best function for residuals to be used in each iteration stage.


Is neocortical-hippocampal connectivity a better predictor of subsequent recollection than local increases in hippocampal activity? New insights on the role of priming.
During memory encoding, increased hippocampal activity-thought to reflect the binding of different types of information into unique episodes-has been shown to correlate with subsequent recollection of those episodes. Repetition priming-thought to induce more efficient perceptual processing of stimuli-is normally associated with decreased neocortical activity and is often assumed to reduce encoding into episodic memory. Here, we used fMRI to compare activity to primed and unprimed auditory words in the presence of distracting sounds as a function of whether participants subsequently recollected the word-sound associations or only had a feeling of familiarity with the word in a subsequent surprise recognition task. At the behavioral level, priming increased the incidence of subsequent recollection. At the neuronal level, priming reduced activity in the superior temporal gyrus (STG) but also reversed the traditional increase in encoding-related hippocampal activity associated with subsequent recollection relative to subsequent familiarity. To explain this interaction pattern, further analyses using dynamic causal modeling showed an increase in connectivity from left STG to left hippocampus specific to words that were later recollected. These findings show that successful episodic encoding is not determined solely by local hippocampal activity and emphasize instead the importance of increased functional neocortical-hippocampal coupling. Such coupling might be a better predictor of subsequent recollection than the direction of local hippocampal changes per se. We propose that one consequence of priming is to "free up" attentional resources from processing an item in a noisy context, thereby allowing greater attention to encoding of that context.


Improving Geographic Equity in Kidney Transplantation Using Alternative Kidney Sharing and Optimization Modeling.
The national demand for kidney transplantation far outweighs the supply of kidney organs. Currently, a patient's ability to receive a kidney transplant varies depending on where he or she seeks transplantation. This reality is in direct conflict with a federal mandate from the Department of Health and Human Services. We analyze current kidney allocation and develop an alternative kidney sharing strategy using a multiperiod linear optimization model, KSHARE. KSHARE aims to improve geographic equity in kidney transplantation while also respecting transplant system constraints and priorities. KSHARE is tested against actual 2000-2009 kidney allocation using Organ Procurement and Transplant Network data. Geographic equity is represented by minimizing the range in kidney transplant rates around local areas of the country. In 2009, less than 25% of standard criteria donor kidneys were allocated beyond the local area of procurement, and Donor Service Area kidney transplantation rates varied from 3.0% to 30.0%, for an overall range of 27.0%. Given optimal sharing of kidneys within 600 miles of procurement for 2000-2009, kidney transplant rates vary from 5.0% to 12.5% around the country for an overall kidney transplant range of 7.5%. Nationally sharing kidneys optimally between local areas only further decreases the transplant rate range by 1.7%. Enhancing the practice of sharing kidneys by the KSHARE model may increase geographic equity in kidney transplantation.


Tethered-TGF-beta increases extracellular matrix production of vascular smooth muscle cells.
Biomaterials developed for tissue engineering and wound healing applications need to support robust cell adhesion, yet also need to be replaced by new tissue synthesized by those cells. In order to maintain mechanical integrity of the tissue, the cells must generate sufficient extracellular matrix before the scaffold is degraded. We have previously shown that materials containing cell adhesive ligands to promote or improve cell adhesion can decrease extracellular matrix production (Mann et al., Modification of surfaces with cell adhesion peptides alters extracellular matrix deposition. Biomaterials 1999;20:2281-6). Such decreased matrix production by cells in tissue engineering scaffolds may result in tissue failure. However, we have found that TGF-beta1 can be used in scaffolds to dramatically increase matrix production. Matrix production by vascular smooth muscle cells grown on adhesive ligand-modified glass surfaces and in PEG hydrogels containing covalently bound adhesive ligands was increased in the presence of 0.04 pmol/ml (1 ng/ml) TGF-beta1. TGF-beta1 can counteract the effect of these adhesive ligands on matrix production; matrix production could be increased even above that observed in the absence of adhesive peptides. Further, TGF-beta1 covalently immobilized to PEG retained its ability to increase matrix production. Tethering TGF-beta1 to the polymer scaffold resulted in a significant increase in matrix production over the same amount of soluble TGF-beta1.


Schizophrenics show spatial working memory deficits.
The present study demonstrates that schizophrenics are impaired on spatial delayed-response tasks, analogous to those that have been used to assess the working memory function of the dorsolateral prefrontal cortex in rhesus monkeys. Schizophrenic patients and two control groups, normal subjects and bipolar psychiatric patients, were tested on the oculomotor version of the memory task, a haptic version of the same task, and two control tasks: a sensory task that did not require working memory and a digit span test. The schizophrenic patients showed marked deficits relative to the two control groups in both the oculomotor and haptic delayed-response tasks. They were not, however, impaired on the digit span test, which taps verbal working memory as well as voluntary attention, and on the sensory control task, in which their responses were guided by external cues rather than by spatial working memory. These findings provide direct evidence that schizophrenics suffer a loss in representational processing and that this deficit is modality independent. These data on spatial working memory add to the growing evidence for involvement of the dorsolateral prefrontal cortex in schizophrenic disease.


Future directions in the diagnosis and medical treatment of adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.


Long Term Outcomes of a Geriatric Liaison Intervention in Frail Elderly Cancer Patients.
The aim of this study was to evaluate the long term effects after discharge of a hospital-based geriatric liaison intervention to prevent postoperative delirium in frail elderly cancer patients treated with an elective surgical procedure for a solid tumour. In addition, the effect of a postoperative delirium on long term outcomes was examined. A three month follow-up was performed in participants of the Liaison Intervention in Frail Elderly study, a multicentre, prospective, randomized, controlled trial. Patients were randomized to standard treatment or a geriatric liaison intervention. The intervention consisted of a preoperative geriatric consultation, an individual treatment plan targeted at risk factors for delirium and daily visits by a geriatric nurse during the hospital stay. The long term outcomes included: mortality, rehospitalisation, Activities of Daily Living (ADL) functioning, return to the independent pre-operative living situation, use of supportive care, cognitive functioning and health related quality of life. Data of 260 patients (intervention n = 127, Control n = 133) were analysed. There were no differences between the intervention group and usual-care group for any of the outcomes three months after discharge. The presence of postoperative delirium was associated with: an increased risk of decline in ADL functioning (OR: 2.65, 95% CI: 1.02-6.88), an increased use of supportive assistance (OR: 2.45, 95% CI: 1.02-5.87) and a decreased chance to return to the independent preoperative living situation (OR: 0.18, 95% CI: 0.07-0.49). A hospital-based geriatric liaison intervention for the prevention of postoperative delirium in frail elderly cancer patients undergoing elective surgery for a solid tumour did not improve outcomes 3 months after discharge from hospital. The negative effect of a postoperative delirium on late outcome was confirmed. Nederlands Trial Register, Trial ID NTR 823.


Clock genes and diurnal transcriptome dynamics in summer and winter in the gymnosperm Japanese cedar (Cryptomeria japonica (L.f.) D.Don).
The circadian clock and diurnal dynamics of the transcriptome are presumed to play important roles in the regulation of physiological, biological and developmental processes synchronized with diurnal and annual cycles of plant environments. However, little is known about the circadian clock and its regulation in gymnosperms, including conifers. Here we present the diurnal transcriptome dynamics of Japanese cedar (Cryptomeria japonica (L.f.) D.Don) in both active (summer) and dormant (winter) periods. Microarray analysis revealed significant differences in transcripts between summer and winter, and diurnal transcriptome dynamics only in the summer. About 7.7% of unique genes (556 out of 7,254) on the microarray were periodically expressed in summer. Expression patterns of some genes, especially light-related genes, did not show significant oscillation in Japanese cedar, thus differing from those reported in angiosperms. Gene network analysis of the microarray data revealed a network associated with the putative core clock genes (CjLHYa, CjLHYb, CjTOC1, CjGI and CjZTL), which were also isolated, indicating their importance in the diurnal regulation of the transcriptome. This study revealed the existence of core clock genes and diurnal rhythms of the transcriptome in summer in Japanese cedar. Dampening of diurnal rhythms in winter indicated seasonal change in the rhythms according to environmental conditions. The data also revealed genes that showed different expression patterns compared to angiosperms, suggesting a unique gene regulatory network in conifers. This study provides fundamental data to understand transcriptional regulatory mechanisms in conifers.


AST/ALT ratio is not an index of liver fibrosis in chronic hepatitis C when aminotransferase activities are determinate according to the international recommendations.
The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients. ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5'-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard. AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r=0.129, P<0.0035). The ROC curve analyses showed that the AST/ALT ratio does not discriminate significant fibrosis (F≥2) (AUROC=0.531) and had only very poor diagnostic accuracies for severe fibrosis (F≥3) (AUROC=0.584) or cirrhosis (F4) (AUROC=0.626). AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations.


Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta.
Expression of AP-2 transcription factors has been detected previously in embryonic renal tissues. We show here that AP-2beta -/- mice complete embryonic development and die at postnatal days 1 and 2 because of polycystic kidney disease. Analyses of kidney development revealed that induction of epithelial conversion, mesenchyme condensation, and further glomerular and tubular differentiation occur normally in AP-2beta-deficient mice. At the end of embryonic development expression of bcl-X(L), bcl-w, and bcl-2 is down-regulated in parallel to massive apoptotic death of collecting duct and distal tubular epithelia. Addressing the molecular mechanism we show that transfection of AP-2 into cell lines in vitro strongly suppresses c-myc-induced apoptosis pointing to a function of AP-2 in programming cell survival during embryogenesis. The position of the human AP-2beta gene was identified at chromosome 6p12-p21.1, within a region that has been mapped for autosomal recessive polycystic kidney disease (ARPKD). Sequence analyses of ARPKD patients and linkage analyses using intragenic polymorphic markers indicate that the AP-2beta gene is located in close proximity to but distinct from the ARPKD gene.


Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1.
Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an important heme-containing enzyme that is a key drug target for cancer immunotherapy. Several hIDO1 inhibitors have entered clinical trials, among which BMS-986205 (BMS) stands out as the only suicide inhibitor. Despite its "best-in-class" activity, the action mechanism of BMS remains elusive. Here, we report three crystal structures of hIDO1-BMS complexes that define the complete binding trajectory of the inhibitor. BMS first binds in a solvent exposed surface cleft near the active site in an extended conformation. The initial binding partially unfolds the active site, which triggers heme release, thereby exposing a new binding pocket. The inhibitor then undergoes a large scale movement to this new binding pocket, where it binds by adopting a high energy kinked conformation. Finally, the inhibitor relaxes to a bent conformation, via an additional large scale rearrangement, culminating in the energy minimum state. The structural data offer a molecular explanation for the remarkable efficacy and suicide inhibition activity of the inhibitor. They also suggest a novel strategy that can be applied for drug development targeting hIDO1 and related enzymes.


Lactate cross-talk in host-pathogen interactions.
Lactate is the main product generated at the end of anaerobic glycolysis or during the Warburg effect and its role as an active signalling molecule is increasingly recognised. Lactate can be released and used by host cells, by pathogens and commensal organisms, thus being essential for the homeostasis of host-microbe interactions. Infection can alter this intricate balance, and the presence of lactate transporters in most human cells including immune cells, as well as in a variety of pathogens (including bacteria, fungi and complex parasites) demonstrates the importance of this metabolite in regulating host-pathogen interactions. This review will cover lactate secretion and sensing in humans and microbes, and will discuss the existing evidence supporting a role for lactate in pathogen growth and persistence, together with lactate's ability to impact the orchestration of effective immune responses. The ubiquitous presence of lactate in the context of infection and the ability of both host cells and pathogens to sense and respond to it, makes manipulation of lactate a potential novel therapeutic strategy. Here, we will discuss the preliminary research that has been carried out in the context of cancer, autoimmunity and inflammation.


Effect of single amino acid substitution on oxidative modifications of the Parkinson's disease-related protein, DJ-1.
Mutations in the gene encoding DJ-1 have been identified in patients with familial Parkinson's disease (PD) and are thought to inactivate a neuroprotective function. Oxidation of the sulfhydryl group to a sulfinic acid on cysteine residue C106 of DJ-1 yields the "2O " form, a variant of the protein with enhanced neuroprotective function. We hypothesized that some familial mutations disrupt DJ-1 activity by interfering with conversion of the protein to the 2O form. To address this hypothesis, we developed a novel quantitative mass spectrometry approach to measure relative changes in oxidation at specific sites in mutant DJ-1 as compared with the wild-type protein. Treatment of recombinant wild-type DJ-1 with a 10-fold molar excess of H(2)O(2) resulted in a robust oxidation of C106 to the sulfinic acid, whereas this modification was not detected in a sample of the familial PD mutant M26I exposed to identical conditions. Methionine oxidized isoforms of wild-type DJ-1 were depleted, presumably as a result of misfolding and aggregation, under conditions that normally promote conversion of the protein to the 2O form. These data suggest that the M26I familial substitution and methionine oxidation characteristic of sporadic PD may disrupt DJ-1 function by disfavoring a site-specific modification required for optimal neuroprotective activity. Our findings indicate that a single amino acid substitution can markedly alter a protein's ability to undergo oxidative modification, and they imply that stimulating the conversion of DJ-1 to the 2O form may be therapeutically beneficial in familial or sporadic PD.


Abstract categories or limited-scope formulae? The case of children's determiners.
ABSTRACTSix tests of the spontaneous speech of twenty-one English-speaking children (1 ; 10 to 2 ; 8; MLUs 1.53 to 4.38) demonstrate the presence of the syntactic category determiner from the start of combinatorial speech, supporting nativist accounts. Children use multiple determiners before a noun to the same extent as their mothers (1) when only a and the or (2) all determiners are analyzed, or (3) when children and mothers are matched on determiner and noun types and determiner+noun tokens. (4) Overlap increases as opportunity for overlap increases: children use multiple determiners with more than 50% of nouns used at least twice with a determiner and with 80% of nouns used at least six times with a determiner. (5) Formulae play a limited role in low-MLU children's determiner usage, increasing with MLU. (6) Less than 1% of determiner uses are errors. Prior results showing no overlap are likely a sampling artifact.


Global and regional drivers of accelerating CO2 emissions.
CO2 emissions from fossil-fuel burning and industrial processes have been accelerating at a global scale, with their growth rate increasing from 1.1% y(-1) for 1990-1999 to >3% y(-1) for 2000-2004. The emissions growth rate since 2000 was greater than for the most fossil-fuel intensive of the Intergovernmental Panel on Climate Change emissions scenarios developed in the late 1990s. Global emissions growth since 2000 was driven by a cessation or reversal of earlier declining trends in the energy intensity of gross domestic product (GDP) (energy/GDP) and the carbon intensity of energy (emissions/energy), coupled with continuing increases in population and per-capita GDP. Nearly constant or slightly increasing trends in the carbon intensity of energy have been recently observed in both developed and developing regions. No region is decarbonizing its energy supply. The growth rate in emissions is strongest in rapidly developing economies, particularly China. Together, the developing and least-developed economies (forming 80% of the world's population) accounted for 73% of global emissions growth in 2004 but only 41% of global emissions and only 23% of global cumulative emissions since the mid-18th century. The results have implications for global equity.


Endovascular Biopsy: In Vivo Cerebral Aneurysm Endothelial Cell Sampling and Gene Expression Analysis.
There is limited data describing endothelial cell (EC) gene expression between aneurysms and arteries partly because of risks associated with surgical tissue collection. Endovascular biopsy (EB) is a lower risk alternative to conventional surgical methods, though no such efforts have been attempted for aneurysms. We sought (1) to establish the feasibility of EB to isolate viable ECs by fluorescence-activated cell sorting (FACS), (2) to characterize the differences in gene expression by anatomic location and rupture status using single-cell qPCR, and (3) to demonstrate the utility of unsupervised clustering algorithms to identify cell subpopulations. EB was performed in 10 patients (5 ruptured, 5 non-ruptured). FACS was used to isolate the ECs and single-cell qPCR was used to quantify the expression of 48 genes. Linear mixed models and exploratory multilevel component analysis (MCA) and self-organizing maps (SOMs) were performed to identify possible subpopulations of cells. ECs were collected from all aneurysms and there were no adverse events. A total of 437 ECs was collected, 94 (22%) of which were aneurysmal cells and 319 (73%) demonstrated EC-specific gene expression. Ruptured aneurysm cells, relative controls, yielded a median p value of 0.40 with five genes (10%) with p values < 0.05. The five genes (TIE1, ENG, VEGFA, MMP2, and VWF) demonstrated uniformly reduced expression relative the remaining ECs. MCA and SOM analyses identified a population of outlying cells characterized by cell marker gene expression profiles different from endothelial cells. After removal of these cells, no cell clustering based on genetic co-expressivity was found to differentiate aneurysm cells from control cells. Endovascular sampling is a reliable method for cell collection for brain aneurysm gene analysis and may serve as a technique to further vascular molecular research. There is utility in combining mixed and clustering methods, despite no specific subpopulation identified in this trial.


Drafting the CLN3 protein interactome in SH-SY5Y human neuroblastoma cells: a label-free quantitative proteomics approach.
Neuronal ceroid lipofuscinoses (NCL) are the most common inherited progressive encephalopathies of childhood. One of the most prevalent forms of NCL, Juvenile neuronal ceroid lipofuscinosis (JNCL) or CLN3 disease (OMIM: 204200), is caused by mutations in the CLN3 gene on chromosome 16p12.1. Despite progress in the NCL field, the primary function of ceroid-lipofuscinosis neuronal protein 3 (CLN3) remains elusive. In this study, we aimed to clarify the role of human CLN3 in the brain by identifying CLN3-associated proteins using a Tandem Affinity Purification coupled to Mass Spectrometry (TAP-MS) strategy combined with Significance Analysis of Interactome (SAINT). Human SH-SY5Y-NTAP-CLN3 stable cells were used to isolate native protein complexes for subsequent TAP-MS. Bioinformatic analyses of isolated complexes yielded 58 CLN3 interacting partners (IP) including 42 novel CLN3 IP, as well as 16 CLN3 high confidence interacting partners (HCIP) previously identified in another high-throughput study by Behrends et al., 2010. Moreover, 31 IP of ceroid-lipofuscinosis neuronal protein 5 (CLN5) were identified (18 of which were in common with the CLN3 bait). Our findings support previously suggested involvement of CLN3 in transmembrane transport, lipid homeostasis and neuronal excitability, as well as link it to G-protein signaling and protein folding/sorting in the ER.


Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer.
Fusion of the 5'-untranslated region of androgen-regulated TMPRSS2 promoter with ETS transcription factor family members is found frequently in prostate cancers, and recent work suggests that the most common TMPRSS2-ERG fusion is associated with an aggressive clinical phenotype compared with fusion-negative prostate cancer. Thus far, analysis of the fusion has been limited to sporadic cases of prostate cancer. In the current study, we explore for an enrichment of TMPRSS2-ERG fusion in familial prostate cancer. TMPRSS2-ERG fusion was identified using a break-apart fluorescence in situ hybridization assay on tissue microarrays. Presence of TMPRSS2-ERG fusion was associated with higher Gleason scores (P = 0.027). Of 75 patients with established history of prostate cancer, we detected the TMPRSS2-ERG fusion in 44 (59%) patients. Almost three quarters (73%) of fusion-positive patients accumulated within 16 specific families whereas only 27% were single fusion-positive cases within one family. Based on reported prevalence rates, we calculated a sibling recurrence risk ratio of up to 18.9. A subset (63%) of families with uniformly TMPRSS2-ERG-positive prostate cancer underwent a genome-wide linkage scan at 500 markers. This revealed several loci located on chromosomes #9, #18, and X that were suggestive of linkage to the TMPRSS2-ERG fusion-positive prostate cancer phenotype with linkage-of-disease scores up to 2.16 and nonparametric linkage scores up to 2.77. This suggests the presence of an inherited susceptibility to developing the TMPRSS2-ERG fusion. Given the association of TMPRSS2-ERG fusion and aggressive prostate cancer, close surveillance of relatives of patients with established fusion-positive prostate cancer or a family history of prostate cancer in general would be warranted.


skNAC, a Smyd1-interacting transcription factor, is involved in cardiac development and skeletal muscle growth and regeneration.
Cardiac and skeletal muscle development and maintenance require complex interactions between DNA-binding proteins and chromatin remodeling factors. We previously reported that Smyd1, a muscle-restricted histone methyltransferase, is essential for cardiogenesis and functions with a network of cardiac regulatory proteins. Here we show that the muscle-specific transcription factor skNAC is the major binding partner for Smyd1 in the developing heart. Targeted deletion of skNAC in mice resulted in partial embryonic lethality by embryonic day 12.5, with ventricular hypoplasia and decreased cardiomyocyte proliferation that were similar but less severe than in Smyd1 mutants. Expression of Irx4, a ventricle-specific transcription factor down-regulated in hearts lacking Smyd1, also depended on the presence of skNAC. Viable skNAC(-/-) adult mice had reduced postnatal skeletal muscle growth and impaired regenerative capacity after cardiotoxin-induced injury. Satellite cells isolated from skNAC(-/-) mice had impaired survival compared with wild-type littermate satellite cells. Our results indicate that skNAC plays a critical role in ventricular cardiomyocyte expansion and regulates postnatal skeletal muscle growth and regeneration in mice.


A link between benzyl isothiocyanate-induced cell cycle arrest and apoptosis: involvement of mitogen-activated protein kinases in the Bcl-2 phosphorylation.
In the present study, we clarified the molecular mechanism underlying the relationship between benzyl isothiocyanate (BITC)-induced cell cycle arrest and apoptosis and the involvement of mitogen-activated protein kinases (MAPKs). The exposure of Jurkat human T-cell leukemia cells to BITC resulted in the inhibition of the G(2)-M progression that coincided with the apoptosis induction. The experiment using the phase-specific synchronized cells demonstrated that the G(2)-M phase-arrested cells are more sensitive to undergoing apoptotic stimulation by BITC than the cells in other phases. We also confirmed that BITC activated c-Jun N-terminal kinase (JNK) and p38 MAPK, but not extracellular signal-regulated kinase, at the concentration required for apoptosis induction. An experiment using a JNK-specific inhibitor SP600125 or a p38 MAPK inhibitor SB202190 indicated that BITC-induced apoptosis might be regulated by the activation of these two kinases. Conversely, BITC is likely to confine the Jurkat cells in the G(2)-M phase mainly through the p38 MAPK pathway because only the p38 MAPK inhibitor significantly attenuated the accumulation of inactive phosphorylated Cdc2 protein and the G(2)-M-arrested cell numbers. We reported here for the first time that the antiapoptotic Bcl-2 protein was phosphorylated by the BITC treatment without significant alteration of the Bcl-2 total protein amount. This was abrogated by a JNK specific inhibitor SP600125 at the concentration required for specific inhibition of the c-Jun phosphorylation. Moreover, the spontaneous phosphorylation of antiapoptotic Bcl-2 in the G(2)-M synchronized cells was enhanced synergistically by the BITC treatment. Involvement of the MAPK activation in the Bcl-2 phosphorylation and apoptosis induction also was observed in HL-60 and HeLa cells. Thus, we identified the phosphorylated Bcl-2 as a key molecule linking the p38 MAPK-dependent cell cycle arrest with the JNK activation by BITC.


The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm.
The frequency of melanoma and nonmelanoma skin cancer is increasing rapidly in the United States. However, the linkage of these cancers to sun exposure has been questioned because of differences in anatomic site distribution. To obtain insights into the development of these skin cancers, we examined reports of 132 patients with xeroderma pigmentosum (XP), an inherited cancer-prone, DNA repair-deficient disorder with marked clinical and laboratory UV hypersensitivity. Malignant skin neoplasms were present in 70% of the patients with XP at a median age of 8 years, which is 50 years earlier than in the US white population. Fifty-seven percent of the patients had basal cell or squamous cell carcinoma, and 22% had melanoma. The frequency of melanomas, like the frequency of nonmelanoma skin cancers (basal cell and squamous cell carcinomas), anterior eye cancers, and tongue cancers, but unlike that of internal neoplasms, was increased 1000-fold or more in patients with XP who were younger than 20 years. As in the general population, the anatomic distribution of melanomas was different from that of nonmelanomas in the patients with XP. These data suggest that (1) DNA repair plays a major role in the prevention of cutaneous cancers in the general population and (2) sunlight exposure is responsible for the induction of melanoma as well as nonmelanoma skin cancer in patients with XP, although acting by different mechanisms for the two types of skin cancer.


Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome.
Lennox-Gastaut syndrome is a catastrophic pediatric epilepsy syndrome characterized by multiple types of treatment-resistant seizures and high rates of seizure-related injury. Current available treatments are inadequate, leaving patients with few treatment options and opportunities. We conducted a double-blind, randomized, placebo-controlled trial of the antiepileptic drug rufinamide in patients with Lennox-Gastaut syndrome. Eligible patients between 4 and 30 years of age had multiple types of seizures (including tonic-atonic and atypical absence seizures) with a minimum of 90 seizures in the month before baseline and a recent history of a slow spike-and-wave pattern on EEG. After a 28-day baseline period, 139 eligible patients were randomized; 138 patients received either rufinamide (n = 74) or placebo (n = 64) in addition to their other antiepileptic drugs. The median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7% vs 11.7%, p = 0.0015). There was a difference (p < 0.0001) in tonic-atonic ("drop attack") seizure frequency with rufinamide (42.5% median percentage reduction) vs placebo (1.4% increase). The rufinamide group had a greater improvement in seizure severity (p = 0.0041) and a higher 50% responder rate compared with placebo for total seizures (p = 0.0045) and tonic-atonic seizures (p = 0.002). The common adverse events (reported by >or=10% of patients receiving rufinamide) were somnolence (24.3% with rufinamide vs 12.5% with placebo) and vomiting (21.6% vs 6.3%). Rufinamide was an effective and well-tolerated treatment for seizures associated with Lennox-Gastaut syndrome.


Risk factors for delirium among older adults in the emergency department: a systematic review protocol.
Delirium is commonly missed in older adults presenting to the emergency department (ED). Although current recommendations for active screening of delirium in the ED, this might not be feasible or practical. Identifying patients at high risk for prevalent and incident delirium in the ED will help to improve the screening process and to build interventions. There is currently scattered synthesis of evidence on risk factors associated with delirium in the ED. To address this gap, we are conducting a systematic review to describe the risk factors (patient vulnerability factors and precipitating factors) for delirium in the ED. A literature search was performed from inception to March 2020 in Ovid EBM Reviews, Ovid EMBASE, Ovid MEDLINE, Scopus and Web of Science. We will include original research studies that report a quantitative relationship between at least one risk factor and delirium in the ED setting. Two investigators will use eligibility criteria from this protocol to independently screen titles and abstracts, and select studies based on full-text review of potentially eligible studies. After arriving at a final set of included studies, two investigators will extract data using a standardised data collection form. If appropriate, data regarding each risk factor will be pooled through a random-effect meta-analysis. The Grading of Recommendations Assessment, Development and Evaluation approach will be used to evaluate the overall quality of evidence. To our knowledge, this will be the first systematic review evaluating risk factors for prevalent and incident delirium specifically related to the ED setting. Results of this study will aid in the identification of older adults at risk for delirium in the ED. We aim to publish the results of this systematic review in a peer-reviewed journal with good visibility for the fields of emergency medicine and geriatrics.PROSPERO registration numberCDR42020175261.


Separate mechanisms for perception of numerosity and density.
Despite the existence of much evidence for a number sense in humans, several researchers have questioned whether number is sensed directly or derived indirectly from texture density. Here, we provide clear evidence that numerosity and density judgments are subserved by distinct mechanisms with different psychophysical characteristics. We measured sensitivity for numerosity discrimination over a wide range of numerosities: For low densities (less than 0.25 dots/deg(2)), thresholds increased directly with numerosity, following Weber's law; for higher densities, thresholds increased with the square root of texture density, a steady decrease in the Weber fraction. The existence of two different psychophysical systems is inconsistent with a model in which number is derived indirectly from noisy estimates of density and area; rather, it points to the existence of separate mechanisms for estimating density and number. These results provide strong confirmation for the existence of neural mechanisms that sense number directly, rather than indirectly from texture density.


Effects of Tai Chi versus Proprioception Exercise Program on Neuromuscular Function of the Ankle in Elderly People: A Randomized Controlled Trial.
Background. Tai Chi is a traditional Chinese medicine exercise used for improving neuromuscular function. This study aimed to investigate the effects of Tai Chi versus proprioception exercise program on neuromuscular function of the ankle in elderly people. Methods. Sixty elderly subjects were randomly allocated into three groups of 20 subjects per group. For 16 consecutive weeks, subjects participated in Tai Chi, proprioception exercise, or no structured exercise. Primary outcome measures included joint position sense and muscle strength of ankle. Subjects completed a satisfaction questionnaire upon study completion in Tai Chi and proprioception groups. Results. (1) Both Tai Chi group and proprioception exercise group were significantly better than control group in joint position sense of ankle, and there were no significant differences in joint position sense of ankle between TC group and PE group. (2) There were no significant differences in muscle strength of ankle among groups. (3) Subjects expressed more satisfaction with Tai Chi than with proprioception exercise program. Conclusions. None of the outcome measures on neuromuscular function at the ankle showed significant change posttraining in the two structured exercise groups. However, the subjects expressed more interest in and satisfaction with Tai Chi than proprioception exercise.


Predictors of Early Mortality After Surgical Resection of Pancreatic Adenocarcinoma in the Era of Neoadjuvant Treatment.
Neoadjuvant treatments are increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), yet some experience early mortality after resection. We sought to identify predictors of early mortality after PDAC resection and determine their interaction with neoadjuvant therapy. We performed a retrospective study of patients with PDAC resection from March 2011 to March 2014. We compared those who died within one year after surgery to those living beyond 1 year, and those who received neoadjuvant therapy to those taken directly to surgery. We used logistic regression to identify predictors of early mortality and determine their interaction with neoadjuvant therapy. Of 191 patients who underwent resection, 59 (30.9%) died within 1 year and 79 (41.4%) received neoadjuvant therapy. Early mortality patients were older, with higher comorbidity, and more likely to have lymph node positivity. Patients receiving neoadjuvant therapy were younger, with lower comorbidity, and more likely to have upfront unresectable disease. Predictors of early mortality included: higher comorbidity, poorly differentiated tumor grade, and lymph node positivity. We found that neoadjuvant therapy moderated the effects of comorbidity and lymph node positivity on early mortality risk. We identified predictors of early mortality after PDAC resection and determined their interaction with neoadjuvant therapy.


Variation in predictive ability of common genetic variants by established strata: the example of breast cancer and age.
Recent studies of breast cancer and common genetic markers have failed to identify pervasive gene-gene and gene-environment interactions. Theoretical considerations also suggest that the contribution of modest interactions to risk discrimination in the general population is likely small. However, the clinical utility of common breast cancer risk markers may nonetheless differ across strata defined by known risk factors, such as age. We examined the age-specific per-allele odds ratios of 15 common single nucleotide polymorphisms (SNPs) found to be associated with breast cancer in 1142 breast cancer cases and 1145 controls from the Nurses' Health Study. We calculated the age-specific discriminatory ability of risk models incorporating these SNPs. We then conducted simulation studies to explore how hypothetical underlying genetic models may fit the observed results. Although all individual SNP-by-age interactions were modest, we found a negative interaction effect between age and a genetic risk score defined by the sum of risk alleles (P = 0.04). We also observed a decrease in discriminatory ability, as measured by the area under the curve (AUC), of the SNPs with age (P = 0.04). Simulation studies revealed models where the AUC can differ by strata defined by a risk factor without the presence of interactions; however, our study suggests that the observed differences in AUC are explained by the age-specific effect of the SNPs. The identification of risk factors that alter the effect of multiple genetic variants can help to explain the genetic architecture of multifactorial diseases and identify subgroups of persons who may benefit from genetic screening.


Time to initial antibiotic administration, and short-term mortality among patients admitted with community-acquired severe infections with and without the presence of systemic inflammatory response syndrome: a follow-up study.
The prognosis for patients with severe infection is related to early treatment, including early administration of antibiotics. The study aim was to compare the short-term mortality among patients admitted with severe infection with and without systemic inflammatory response syndrome (SIRS) at arrival, and to ascertain whether the presence of SIRS might affect the timing of antibiotic administration. In this retrospective follow-up study, we included all adult patients (≥15 years) presenting to a medical emergency department in the period between September 2010 and August 2011 with a first-time admission of community-acquired severe infection (infection with evidence of organ dysfunction), with and without SIRS at arrival. The presence of SIRS was defined as two or more of the criteria according to the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) definitions. Cases were identified by manual chart review using predefined criteria of infection. Data on vital signs, laboratory values and antibiotic treatment were obtained electronically. We included 1169 patients with infection and organ dysfunction, treated with antibiotics within 24 h after arrival (median age 76.1 years (IQR 63.1-83.5), 567 (48.5%) men). In all, 886 (75.8%) presented with SIRS, and 283 (24.2%) presented without SIRS. Median time to antibiotics was 4.6 h (IQR 2.9-7.0) in patients with SIRS and 6.7 h (IQR 4.5-10.3) in patients without SIRS (p<0.0001). Thirty-day mortality in patients with and without SIRS was 18.4% (95% CI 15.9% to 21.1%) and 16.6% (95% CI 12.5% to 21.5%), respectively. SIRS was absent in one-quarter of patients admitted with severe infection. The 'door-to-antibiotics' time was significantly shorter for patients with SIRS compared with patients without SIRS, but no difference was found in 30-day mortality.


Extrafloral nectar production of the ant-associated plant, Macaranga tanarius, is an induced, indirect, defensive response elicited by jasmonic acid.
Plant species in at least 66 families produce extrafloral nectar (EFN) on their leaves or shoots and therewith attract predators and parasitoids, such as ants and wasps, which in turn defend them against herbivores. We investigated whether EFN secretion is induced by herbivory and/or artificial damage, and thus can be regarded as an induced defensive response. In addition, we studied the underlying signaling pathway. EFN secretion by field-grown Macaranga tanarius increased after herbivory, artificial leaf damage, and exogenous jasmonic acid (JA) application. Artificial damage strongly enhanced endogenous JA concentrations. The response in EFN production to artificial damage was much less pronounced in those leaves that were treated with phenidone to inhibit endogenous JA synthesis. Quantitative dose-response relations were found between the increase in nectar production and both the intensity of leaf damage and the amounts of exogenously applied JA. The amount of endogenously produced JA was positively correlated with the intensity of leaf damage. Increased numbers of defending insects and decreased numbers of herbivores were observed on leaves after inducing EFN production by exogenous JA treatment. Over 6 weeks, repeatedly applied JA or artificial damage resulted in a ten-fold reduction in herbivory. These results demonstrate that EFN production represents an alternative mechanism for induced, indirect defensive plant responses that are mediated via the octadecanoid signal transduction cascade.


Healthcare utilization and costs in persons with insomnia in a managed care population.
To better understand the direct costs of insomnia. Our study aimed to compare healthcare costs and utilization of patients diagnosed with insomnia who received care in a managed care organization with a set of matched controls. Our observational, retrospective cohort study compared 7647 adults with an insomnia diagnosis with an equally sized matched cohort of health plan members without an insomnia diagnosis between 2003 and 2006. We also compared a subset of patients diagnosed with and treated for insomnia with those diagnosed with insomnia but not treated. A large Midwestern health plan with more than 600,000 members. Multivariate analysis was used to estimate the association between insomnia diagnosis and costs, controlling for covariates, in the baseline and follow-up periods. Although we cannot conclude a causal relationship between insomnia and healthcare costs, our analysis found that insomnia diagnosis was associated with 26% higher costs in the baseline and 46% in the 12 months after diagnosis. When comorbidities were recognized, the insomnia cohort had 80% higher costs, on average, than the matched control cohort. These outcomes suggest the need to look beyond the direct cost of insomnia to how its interaction with comorbid conditions drives healthcare cost and utilization.


Breathing pattern and respiratory mechanics in patients with amyotrophic lateral sclerosis.
The aim of this study was to evaluate the time course of breathing pattern and respiratory mechanics in patients with amyotrophic lateral sclerosis (ALS). A study was conducted on 25 out of 38 eligible ALS patients. Neurological status, arterial blood gases (ABGs), spirometry, breathing pattern (minute ventilation (V'E), tidal volume (VT), respiratory frequency (fR), duty cycle (duration of inspiration/duration of total breathing cycle (tI/ttot)), respiratory drive (P0.1)), respiratory mechanics (oesophageal pressure (Ppl), dynamic compliance (CL,dyn), pressure time product (PTP) and index (PTI), work of breathing (WOB)), and respiratory muscle (RM) strength as assessed by maximal oesophageal pressure (Ppl,max) were evaluated at presentation (to) in all patients and after 6 months (t6) in 11 patients. At to, the mean values of the degree of neurological impairment were 60+/-20 and 103+/-30 as assessed by the Norris scale and Medical Research Council (MRC) score, respectively. From the time of the first neurological symptom, survival time ranged 7-50 months. Diurnal ABGs were normal. A mild restrictive pattern was observed, a forced vital capacity (FVC) <70% of predicted being present in 45% of patients, only FVC % pred (r=0.59; p<0.05), forced expiratory volume in one second (FEV1) % pred (r=0.53; p<0.05) and survival (r=0.64; p<0.05) showing a significant correlation with the Norris scale. A Ppl,max <30 cmH2O was associated with a significantly greater mortality, Ppl,max being correlated with survival (r=0.79, p<0.05). At t6, fR, fR/VT, P0.1/Ppl,max, were significantly increased in comparison to to, while FVC % pred, vital capacity (VC) % pred, FEV1 % pred, VT and Ppl,max were significantly reduced. These results suggest a progressive deterioration in breathing pattern and in respiratory muscle strength with progression of disease.


Acceptance by private patients of resident involvement in their outpatient care.
The attitudes of private patients toward resident participation in their ambulatory care were evaluated. Of 195 patients (29 percent) responding to 667 mailed prospective questionnaires, 143 (73 percent) stated that they would allow resident participation in their care. Satisfactory prior experiences with trainees was the most important factor predicting acceptance (p less than .0001) of resident participation. A majority of "accepting" respondents would allow the following limited delegation of responsibility to residents: history-taking, physical examination, and visit scheduling. The majority (71 percent) desired faculty consultation at every visit. A small, retrospective survey of resident-treated private patients revealed that 70 percent were fully satisfied, 20 percent partially satisfied, and 10 percent dissatisfied. Dissatisfaction by the patients was associated with not knowing beforehand that a trainee would participate in the health care delivery. The private patients usually accepted trainees for outpatient care if: (a) they had been informed in advance, (b) they had not had a prior unsatisfactory resident experience, and (c) the responsibility of the residents had been carefully delegated and the residents closely supervised.


Fabrication of an optical fiber reflective notch coupler.
A method of fabricating a reflective notch coupler in an optical fiber has been developed. The coupler consists of a 45° microprism that penetrates into the core of a multimode optical fiber. One face, at 90° to the fiber axis, is nonreflective, and one face, at 45° to the fiber axis, is reflective. Our method of fabricating a notch and selectively mirroring only the 45° face is low-cost, precise, and easily scalable. The coupler allows near-100% coupling of light into an optical fiber from the side, while allowing coupling of any desired fraction of light out from the core at a 90° angle on the opposite side of the fiber.


A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families.
Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.


Neural correlates of the rejection of unfair offers in the impunity game.
This study examined the roles of the insula and the anterior cingulate activations in the rejection of unfair offers in the impunity game. Fifteen participants played the impunity game in ten trials as responders during neuroimaging. About 45% of the unfair offers were rejected by the responders even when responders could not restore a fair outcome, which cannot be accounted for by social preference of inequity aversion. Imaging data showed that the right anterior insula was activated when participants faced and rejected unfair offers. The insula activation during a rejection of the unfair offers is the reflection of an emotional response, rather than social preference of inequity aversion. The role of emotion in the neuroeconomics of fairness was demonstrated.


Novel laser datum system for nanometric profilometry for large optical surfaces.
We report a new laser datum system for precision point-by-point profilometry of large curved optical surfaces. The laser datum is sensed by a nulling quadrant photodiode mounted in a flexural system with hybrid actuators, which also carries interferometer reference optics for vertical and horizontal displacement measurement. The flexure characteristics such as cross-talk and hysteresis were investigated. The optimum environmental conditions for the active position-control were studied, and closed-loop control was modeled. The experimental results for compensation accuracy showed a repeatability of +/- 4 nm rms, the compensation accuracy of 10 nm (vertical channel) and 20 nm (horizontal channel).


ER stress in adipocytes inhibits insulin signaling, represses lipolysis, and alters the secretion of adipokines without inhibiting glucose transport.
The endoplasmic reticulum (ER) is the intra-cellular site, where secreted and membrane proteins are synthesized. ER stress and activation of the unfolded protein response (UPR) contribute to insulin resistance and the development of diabetes in obesity. It was shown previously in hepatocytes that the UPR activates c-jun N-terminal kinase (JNK), which phosphorylates insulin receptor substrate (IRS) proteins on serine residues thereby inhibiting insulin signal transduction. Here we describe how ER stress affects insulin signaling and the biological function of adipocytes. In addition to inhibition of IRS we found that ER stress downregulates the expression of the insulin receptor. Concomitantly, insulin-induced activation of Akt/PKB and of ERK1/2 was strongly inhibited. Ectopic expression of IRS1 or IRS2 strongly counteracted the inhibitory effect of ER stress on insulin signaling while pharmacological inhibition of JNK with SP600125 resulted only in a mild improvement. ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. ER stress inhibited expression and insulin-induced phosphorylation of AS160, reduced lipolysis but did not inhibit glucose transport. Finally, supernatants collected from 3T3-L1 adipocytes undergoing ER stress improved or impaired proliferation when used to condition the culture medium of INS-1E beta-cells dependent on the degree of ER stress. It appears that ER stress in adipocytes might initially lead to changes resembling early prediabetic stages, which at least in part support the regulation of systemic energy homeostasis.


Long-term clinical outcomes of endoscopic submucosal dissection for colorectal neoplasms in 423 cases: a retrospective study.
Background and study aim Endoscopic submucosal dissection (ESD) is known as a curative treatment for colorectal superficial neoplasms. There is however a need for more long-term clinical data to establish the full advantages of colorectal ESD regarding very low recurrence rates. The aim of this retrospective study was to determine long-term clinical outcomes of colorectal ESD. Methods A total of 423 lesions treated by ESD for colorectal adenoma/dysplasia or adenocarcinoma between 1998 and 2008 at a single high volume referral center were included. We conducted a retrospective survey on patients with follow-up and obtained complete 1-, 3-, and 5-year outcome data for 358 (85 %), 292 (69 %), and 209 (49 %) lesions, respectively. Curative resection was defined when the pathological specimen had carcinoma-free resection margins, irrespective of piecemeal or en bloc resection, without submucosal deep invasion (≥ 1000 µm), lymphovascular involvement, or a poorly differentiated adenocarcinoma component. Results After a median 4.9 years of follow-up, the 3-year overall cumulative endoscopic recurrence rate and cancerous recurrence rate were 2.9 % (95 % confidence interval [95 %CI] 1.2 - 4.7) and 1.1 % (0 - 2.1), respectively. The 5-year overall cumulative endoscopic recurrence and cancerous recurrence rates were 3.8 % (1.7 - 5.9) and 1.6 % (0.1 - 3.0), respectively. In 361 lesions eligible for endoscopic follow-up, the 3-year endoscopic recurrence and cancerous recurrence rates were 2.4 % (0.8 - 4.1) and 0.4 % (0 - 1.4), respectively. Multivariate analysis revealed that piecemeal resection and submucosal deep tumor invasion were associated with recurrence. Conclusions The current study demonstrated favorable long-term clinical outcomes of colorectal ESD when en bloc curative resection is achieved.


The Proteome of Primary Prostate Cancer.
Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries. To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness. Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker. Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p<0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score ≤ 7 tumors. This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors. The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers.


Measles outbreak in Greater Manchester, England, October 2012 to September 2013: epidemiology and control.
This paper describes the epidemiology and management of a prolonged outbreak of measles across the 2.7 million conurbation of Greater Manchester in the United Kingdom. Over a period of one year (from October 2012 to September 2013), over a thousand suspected measles cases (n = 1,073) were notified across Greater Manchester; of these, 395 (37%) were laboratory-confirmed, 91 (8%) were classed as probable, 312 (29%) were classed as possible and 275 (26%) excluded. Most confirmed and probable cases occurred in children within two age groups—infants (too young to be eligible for measles-mumps-rubella (MMR) vaccination according to the national immunisation programme) and children aged 10-19 years (low vaccine uptake in this cohort because of unfounded alleged links between the MMR vaccine and autism). During this one year period, there were a series of local outbreaks and many of these occurred within the secondary school setting. A series of public health measures were taken to control this prolonged outbreak: setting up incident management teams to control local outbreaks, a concerted immunisation catch-up campaign (initially local then national) to reduce the pool of children partially or totally unprotected against measles, and the exclusion of close contacts from nurseries and school settings for a period of 10 days following the last exposure to a case of measles.


Risk-sensitivity in sensorimotor control.
Recent advances in theoretical neuroscience suggest that motor control can be considered as a continuous decision-making process in which uncertainty plays a key role. Decision-makers can be risk-sensitive with respect to this uncertainty in that they may not only consider the average payoff of an outcome, but also consider the variability of the payoffs. Although such risk-sensitivity is a well-established phenomenon in psychology and economics, it has been much less studied in motor control. In fact, leading theories of motor control, such as optimal feedback control, assume that motor behaviors can be explained as the optimization of a given expected payoff or cost. Here we review evidence that humans exhibit risk-sensitivity in their motor behaviors, thereby demonstrating sensitivity to the variability of "motor costs." Furthermore, we discuss how risk-sensitivity can be incorporated into optimal feedback control models of motor control. We conclude that risk-sensitivity is an important concept in understanding individual motor behavior under uncertainty.


A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects.
Numerous unclassified variants (UVs) have been found in the mismatch repair genes MLH1 and MSH2 involved in hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Some of these variants may have an effect on pre-mRNA splicing, either by altering degenerate positions of splice site sequences or by affecting intronic or exonic splicing regulatory sequences such as exonic splicing enhancers (ESEs). In order to determine the consequences of UVs on splicing, we used a functional assay of exon inclusion. For each variant, mutant and wild-type exons to be tested were PCR-amplified from patient genomic DNA together with approximately 150 bp of flanking sequences and were inserted into a splicing reporter minigene. After transfection into HeLa cells, the effects on splicing were evaluated by RT-PCR analysis and systematic sequencing. A total of 22 UVs out of 85 different variant alleles examined in 82 families affected splicing, including four exonic variants that affected putative splicing regulatory elements. We analyzed short stretches spanning the latter variants by cloning them into the ESE-dependent central exon of a three-exon splicing minigene and we showed in cell transfection experiments that the wild-type sequences indeed contain functional ESEs. We then used this construct to query for ESE elements in the MLH1 or MSH2 regions affected by 14 previously reported exonic splicing mutations and showed that they also contain functional ESEs. These splicing assays represent a valuable tool for the interpretation of UVs and should contribute to the optimization of the molecular diagnosis of the Lynch syndrome and of other genetic diseases.


Computed tomographic coronary angiography in risk stratification prior to non-cardiac surgery: a systematic review and meta-analysis.
Utility of CT coronary angiography (CTA) and coronary artery calcium (CAC) scoring in risk stratification prior to non-cardiac surgery is unclear. Although current guidelines recommend stress testing in intermediate-high risk individuals, over one-third of perioperative major adverse cardiovascular events (MACE) occur in patients with a negative study. This systematic review and meta-analysis evaluates the value of CTA and CAC score in preoperative risk prognostication prior to non-cardiac surgery. MEDLINE, PubMed and EMBASE databases were searched for articles published up to June 2018. Summary ORs for degree of coronary artery disease (CAD) and perioperative MACE were pooled using a random-effects model. Eleven studies were included. Two hundred and fifty-two (7.2%) MACE occurred in 3480 patients. Risk of perioperative MACE rose with the severity and extent of CAD on CTA (no CAD 2.0%; non-obstructive 4.1%; obstructive single-vessel 7.1%; obstructive multivessel 23.1%, p<0.001). Multivessel disease (MVD) demonstrated the greatest risk (OR 8.9, 95% CI 5.1 to 15.3, p<0.001). Increasing CAC score was associated with higher perioperative MACE (CAC score: ≥100 OR 5.1, ≥1000 OR 10.4, both p<0.01). In a cohort deemed high risk by established clinical indices, absence of MVD on CTA demonstrated a negative predictive value of 96% (95% CI 92.8 to 98.4) for predicting freedom from MACE. Severity and extent of CAD on CTA conferred incremental risk for perioperative MACE in patients undergoing non-cardiac surgery. The 'rule-out' capability of CTA is comparable to other non-invasive imaging modalities and offers a viable alternative for risk stratification of patients undergoing non-cardiac surgery. CRD42018100883.


Intrachromosomal Rearrangements in Rodents from the Perspective of Comparative Region-Specific Painting.
It has long been hypothesized that chromosomal rearrangements play a central role in different evolutionary processes, particularly in speciation and adaptation. Interchromosomal rearrangements have been extensively mapped using chromosome painting. However, intrachromosomal rearrangements have only been described using molecular cytogenetics in a limited number of mammals, including a few rodent species. This situation is unfortunate because intrachromosomal rearrangements are more abundant than interchromosomal rearrangements and probably contain essential phylogenomic information. Significant progress in the detection of intrachromosomal rearrangement is now possible, due to recent advances in molecular biology and bioinformatics. We investigated the level of intrachromosomal rearrangement in the Arvicolinae subfamily, a species-rich taxon characterized by very high rate of karyotype evolution. We made a set of region specific probes by microdissection for a single syntenic region represented by the p-arm of chromosome 1 of Alexandromys oeconomus, and hybridized the probes onto the chromosomes of four arvicolines (Microtus agrestis, Microtus arvalis, Myodes rutilus, and Dicrostonyx torquatus). These experiments allowed us to show the intrachromosomal rearrangements in the subfamily at a significantly higher level of resolution than previously described. We found a number of paracentric inversions in the karyotypes of M. agrestis and M. rutilus, as well as multiple inversions and a centromere shift in the karyotype of M. arvalis. We propose that during karyotype evolution, arvicolines underwent a significant number of complex intrachromosomal rearrangements that were not previously detected.


Coronal Plane Deformity Correction in Distal Radius Fracture Fixation With the Volar Locking Plate.
The goal of treatment for distal radius fractures is anatomic articular reduction and restoration of coronal and sagittal plane alignment, rotation, and angulation of the metadiaphyseal component of these fractures. This article presents a reproducible technique for restoring coronal plane alignment of the metadiaphyseal component of the fracture using an indirect reduction maneuver leveraging the volar locking plate as an indirect reduction aid. After applying an appropriately sized volar locking plate, the first screw is placed in the center of the shaft of the plate. Next, the distal row of subarticular locking screws is placed to neutralize a reduced articular surface. The shaft screw is subsequently loosened, and two Freer elevators are used to rotate the plate, indirectly translating the distal articular block and achieving improved coronal plane alignment. Last, the remaining diaphyseal screws are applied to appropriately neutralize the fracture. (Journal of Surgical Orthopaedic Advances 27(2):160-163, 2018).


Mycosis fungoides progression could be regulated by microRNAs.
Differentiating early mycosis fungoides (MF) from inflammatory dermatitis is a challenge. We compare the differential expression profile of early-stage MF samples and benign inflammatory dermatoses using microRNA (miRNA) arrays. 114 miRNAs were found to be dysregulated between these entities. The seven most differentially expressed miRNAs between these two conditions were further analyzed using RT-PCR in two series comprising 38 samples of early MFs and 18 samples of inflammatory dermatitis. A series of 51 paraffin-embedded samples belonging to paired stages of 16 MF patients was also analyzed. MiRNAs 26a, 222, 181a and 146a were differentially expressed between tumoral and inflammatory conditions. Two of these miRNAs (miRNA-181a and miRNA-146a) were significantly deregulated between early and advanced MF stages. Bioinformatic analysis showed FOXP3 expression to be regulated by these miRNAs. Immunohistochemistry revealed the level of FOXP3 expression to be lower in tumoral MFs than in plaque lesions in paraffin-embedded tissue. A functional study confirmed that both miRNAs diminished FOXP3 expression when overexpressed in CTCL cells. The data presented here suggest that the analysis of a restricted number of miRNAs (26a, 222, 181a and 146a) could be sufficient to differentiate tumoral from reactive conditions. Moreover, these miRNAs seem to be involved in MF progression.


The analgesic NSAID lornoxicam inhibits cyclooxygenase (COX)-1/-2, inducible nitric oxide synthase (iNOS), and the formation of interleukin (IL)-6 in vitro.
To investigate anti-inflammatory effects of lornoxicam in vitro on COX-1/COX-2, on NO formation from iNOS and on the formation of the pro-inflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IL-8. COX-1 inhibition in intact cells was assessed employing two systems: measurement of aggregation in human washed platelets and assessment of TXB2 formation in HEL cells. COX-2 inhibition was assessed by measuring 6-keto-PGF1alpha in supernatants of intact cells of LPS-stimulated J774.2 cells (murine) and of Mono Mac 6 cells (human). In whole blood inhibition of COX-1 was performed by measuring TXB2 formation after clotting, and COX-2 inhibition was examined in LPS-stimulated whole blood cultures. The reduction of NO levels as a measure of the inhibition of cellular NO formation was assayed in supernatants of LPS-stimulated RAW 264.7 cells using the Griess reaction. Compound influence on the formation ofTNF-alpha, IL-1beta, IL-6, and IL-8 was examined using LPS-stimulated monocytic cells (THP-1) and measurement of cytokine concentrations by specific ELISAs. In intact human cells, lornoxicam showed a balanced inhibition of COX-1/-2 exhibiting the lowest IC50 (0.005 microM/0.008 microM) of the large panel of NSAIDs tested. Similar results were obtained in the whole blood for COX-1/-2. NO formation was dose-dependently inhibited by lornoxicam (IC50 of 65 microM) whereas piroxicam, diclofenac, ibuprofen, ketorolac and naproxen inhibited the NO formation markedly less. Indomethacin was approximately equipotent with lornoxicam. In stimulated monocytic cells (THP-1), lornoxicam showed a marked inhibition of IL-6 formation (IC50 54 microM) while the formation ofTNF-alpha, IL-1beta and IL-8 was only moderately affected. Of the panel of NSAIDs tested, lornoxicam was found to be the most potent balanced inhibitor of human COX-1/-2. The equipotent COX-isoenzyme inhibition by lornoxicam is complemented by a marked inhibition of IL-6 production and of iNOS-derived NO formation. The in vitro activities described support the marked anti-inflammatory and analgesic activities of lornoxicam found in animal models as well as in clinical studies.


Utilizing heartbeat evoked potentials to identify cardiac regulation of vagal afferents during emotion and resonant breathing.
The importance of the bi-directional communication between the heart and brain has been known for over 100 years (Lane et al. in NeuroImage 44:213-222, 2009a, Psychosom Med 2:117-134, 2009b) and plays an important role in many of the prominent theories of psychophysiology today. Utilizing heartbeat evoked potentials (HEPs), we sought to determine whether heart rate variability (HRV) was related to the strength of the connection between the heart and brain. We also hypothesized that differing emotion states would result in differing amplitudes of HEPs. Participants were induced into emotional states with an autobiographical script of their happiest and saddest memory. HEPs were also recorded during diaphragmatic breathing at six breaths per minute. The evoked potentials during the emotional conditions, especially negative emotion were most attenuated. We believe that the signal from the heart to the brain may be filtered by central limbic structures affecting the level of the signal at the cortex. It also appears that HRV affects the strength of HEPs, especially during resonant breathing. Significant neurocardiac gender differences were also present across all conditions. The results of this study support the theory and speculation of many authors who believe vagal afferents play a role in brain function.


Efficacy of Adjuvant Chemotherapy in Colon Cancer With Microsatellite Instability: A Large Multicenter AGEO Study.
Deficient mismatch repair (dMMR) colon cancer (CC) is reportedly resistant to 5-fluorouracil (5FU) adjuvant chemotherapy while preliminary data suggest chemosensitivity to oxaliplatin. We assessed the efficacy of fluoropyrimidine with and without oxaliplatin in a large cohort of dMMR CC patients. This retrospective multicenter study included all consecutive patients who underwent curative surgical resection for stage II or III dMMR CC between 2000 and 2011. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided. A total of 433 dMMR CC patients were included (56.8% stage II, 43.2% stage III). Mean follow-up was 47.0 months. The patients received surgery alone (n = 263) or surgery plus adjuvant chemotherapy consisting of fluoropyrimidine with (n = 119) or without (n = 51) oxaliplatin. Adjuvant chemotherapy was administered to 16.7% of stage II and 69.0% of stage III CC patients. As compared with surgery alone, adjuvant oxaliplatin-based chemotherapy improved disease-free survival (DFS) in multivariable analysis (HR = 0.35, 95% CI = 0.19 to 0.65, P < .001), contrary to adjuvant fluoropyrimidine alone (HR = 0.73, 95% CI = 0.36 to 1.49, P = .38). In the subgroup analysis, the DFS benefit of oxaliplatin-based chemotherapy was statistically significant in multivariable analysis only in stage III (HR = 0.41, 95% CI = 0.19 to 0.87, P = .02). This study supports the use of adjuvant chemotherapy with fluoropyrimidine plus oxaliplatin in stage III dMMR CC.


[Data and the process of formulating health policies].
To evaluate the use of the available information systems in decision-making process involving municipalities' health services, since technical scientific information is becoming an important tool for managers' decision-making both in the private and public sectors. Four case studies were undertaken in the state of Sao Paulo between 1998 and 2000. The municipalities included in this study varied in size and in terms of the of complexity of their health systems. Research involved the use of both quantitative (survey of epidemic, demographic, economic-financial and social indicators) and qualitative methods (interviews with key actors and focus group). "Triangulation" was adopted in the analysis in order to establish an articulation among the diverse sources of data and methodological procedures utilized. The strategy of implementation of the Unified Health System (SUS) in itself implies in a pattern of consumption of information already available in large data banks within public institutions and local production of information concerning, primarily, the financial dimension of the city or district, whatever its size, the complexity of the local health system and the type of health administration. The information available on the data banks are, in general, considered outdated with respect to the immediate needs of local health managers. The equipment infrastructure and training of human resources in health data management were considered precarious for use in the decision-making process.