Does early maternal responsiveness buffer prenatal tobacco exposure effects on young children's behavioral disinhibition?
Children with prenatal tobacco exposure (PTE) exhibit early self-regulatory impairments, reflecting a life-course persistent propensity toward behavioral disinhibition. Previously, we demonstrated the protective role of parental responsiveness for reducing the risk of exposure-related disruptive behavior in adolescence. Here, we expanded this line of inquiry, examining whether responsiveness moderates the relation of PTE to a broader set of behavioral disinhibition features in early childhood and testing alternative diathesis-stress versus differential susceptibility explanatory models. PTE was assessed prospectively using interviews and bioassays in the Midwestern Infant Development Study (MIDS). Mother-child dyads (N = 276) were re-assessed at approximately 5 years of age in a preschool follow-up. We quantified maternal responsiveness and child behavioral disinhibition using a combination of directly observed activities in the lab and developmentally sensitive questionnaires. Results supported a diathesis-stress pattern. Children with PTE and less responsive mothers showed increased disruptive behavior and lower effortful control compared with children without PTE. In contrast, exposed children with more responsive mothers had self-regulatory profiles similar to their non-exposed peers. We did not observe sex differences. Findings provide greater specification of the protective role of maternal responsiveness for self-regulation in children with PTE and help clarify mechanisms that may underscore trajectories of exposure-related behavioral disinhibition.


Integrated Management of Tomato Spotted Wilt on Field-Grown Tomatoes.
Epidemics of spotted wilt caused by Tomato spotted wilt virus (TSWV) vectored by Frankliniella occidentalis and possibly other thrips species occur regularly in tomato in the southeastern United States. Field experiments were conducted to determine the effects of UV-reflective mulch, acibenzolar-S-methyl (plant activator), and insecticides on progress of tomato spotted wilt incidence and population dynamics of flower thrips (including F. occidentalis, F. tritici, and F. bispinosa). Whole plots of tomatoes grown on UV-reflective and black polyethylene mulch were divided into subplots of acibenzolar-S-methyl and no acibenzolar-S-methyl, and sub-subplots of insecticide and no insecticide for thrips control. The UV-reflective mulch was more effective than black polyethylene mulch each year in reducing colonization of thrips in May and the consequent primary infections of tomato spotted wilt. Application of acibenzolar-S-methyl further reduced tomato spotted wilt incidence in 2000 and 2002, when disease pressure was great. Reproduction of thrips on tomato was poor in these experiments, but their control in the insecticide-treated sub-subplots prevented secondary spread in both years. The combination of UV-reflective mulch, acibenzolar-S-methyl, and insecticides was very effective in reducing tomato spotted wilt incidence in tomato.


Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells.
Post-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization. DNA damage promotes mRNA relocation and translation in part due to dissociation of Tia1 from its mRNA targets. Upon DNA damage, p53 mRNA is released from stress granules and associates with polyribosomes to increase protein synthesis in a CAP-independent manner. Global analysis of cellular mRNA abundance and translation indicates that this is an extended ATM-dependent mechanism to increase protein expression of key modulators of the DNA damage response.Sequestering mRNA in cytoplasmic stress granules is a mechanism for translational repression. Here the authors find that p53 mRNA, present in stress granules in activated B lymphocytes, is released upon DNA damage and is translated in a CAP-independent manner.


Surface characterization of zirconia dental implants.
The aim of the study was to characterize the chemical composition, microstructure and roughness of two commercially available zirconia dental implants (WhiteSky and Zit-Z). The chemical composition of the cervical collar and threaded root parts of the implants (n=2) were studied by XPS and HV-EDX. LV-SEM was used for morphological assessment, Raman microanalysis for microstructural characterization and optical profilometry for surface roughness measurements. XRD, HV-EDX and Raman microanalysis of bulk regions (longitudinal sections) were used as reference. XPS showed the presence of C, O, Zr and Y (collar) plus Al (root) at implant surfaces. More C (10-26at%) and a lower Al/Zr ratio were found in WhiteSky (1.05 vs 1.26 in Zit-Z). Zr, Y and Al were detected in single, fully oxidized states. The same elements, plus Hf, were identified by HV-EDX at bulk and surface regions, with a Al/Zr ratio higher in WhiteSky (0.17 vs 0.09 in Zit-Z). Na, K and Cl contaminants were traced at implant root parts by both methods. XRD analysis of cross-sectioned specimens revealed the presence of monoclinic and tetragonal zirconia along with cubic yttria phases. Raman microanalysis showed that the monoclinic zirconia volume fraction was higher at root surfaces than the collar. No monoclinic phase was found at bulk regions. Significantly higher Sa and Sq values were recorded in WhiteSky than Zit-Z, whereas Zit-Z showed higher Rt value. The differences found between the implants in the extent of carbon contamination, residual alumina content, tetragonal to monoclinic ZrO(2) phase transformation and 3D-roughness parameters may contribute to a substantial differentiation in the cellular and tissue response.


The genomic landscape of schwannoma.
Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.


A Systematised Review of the Health Impact of Urban Informal Settlements and Implications for Upgrading Interventions in South Africa, a Rapidly Urbanising Middle-Income Country.
Informal settlements are becoming more entrenched within African cities as the urban population continues to grow. Characterised by poor housing conditions and inadequate services, informal settlements are associated with an increased risk of disease and ill-health. However, little is known about how informal settlement upgrading impacts health over time. A systematised literature review was conducted to explore existing evidence and knowledge gaps on the association between informal settlement characteristics and health and the impact of informal settlement upgrading on health, within South Africa, an upper-middle income African country. Using two databases, Web of Science and PubMed, we identified 46 relevant peer-reviewed articles published since 1998. Findings highlight a growing body of research investigating the ways in which complete physical, mental and social health are influenced by the physical housing structure, the psychosocial home environment and the features of the neighbourhood and community in the context of informal settlements. However, there is a paucity of longitudinal research investigating the temporal impact of informal settlement upgrading or housing improvements on health outcomes of these urban residents. Informal settlements pose health risks particularly to vulnerable populations such as children, the elderly, and people with suppressed immune systems, and are likely to aggravate gender-related inequalities. Due to the complex interaction between health and factors of the built environment, there is a need for further research utilising a systems approach to generate evidence that investigates the interlinked factors that longitudinally influence health in the context of informal settlement upgrading in rapidly growing cities worldwide.


The influence of calcium supplementation on substrate metabolism during exercise in humans: a randomized controlled trial.
High calcium intakes enhance fat loss under restricted energy intake. Mechanisms explaining this may involve reduced dietary fat absorption, enhanced lipid utilization and (or) reductions in appetite. This study aimed to assess the impact of 2 weeks of calcium supplementation on substrate utilization during exercise and appetite sensations at rest. Thirteen physically active males completed two 14-d supplemental periods, in a double-blind, randomized crossover design separated by a ⩾4-week washout period. During supplementation, a test-drink was consumed daily containing 400 and 1400 mg of calcium during control (CON) and high-calcium (CAL) periods, respectively. Cycling-based exercise tests were conducted before and after each supplemental period to determine substrate utilization rates and circulating metabolic markers (non-esterified fatty acid, glycerol, glucose and lactate concentrations) across a range of exercise intensities. Visual analog scales were completed in the fasting, rested state to determine subjective appetite sensations. No significant differences between supplements were observed in lipid or carbohydrate utilization rates, nor in circulating metabolic markers (both P>0.05). Maximum rates of lipid utilization were 0.47±0.05 and 0.44±0.05 g/min for CON and CAL, respectively, prior to supplementation and 0.44±0.05 and 0.42±0.05 g/min, respectively, post-supplementation (main effects of time, supplement and time x supplement interaction effect all P>0.05). Furthermore, no significant differences were detected in any subjective appetite sensations (all P>0.05). Two weeks of calcium supplementation does not influence substrate utilization during exercise in physically active males.


Dependence on Dectin-1 Varies With Multiple Candida Species.
Four Candida spp. (albicans, glabrata, tropicalis, parapsilosis) cause >95% of invasive Candida infections. C. albicans elicits immune responses via pathogen recognition receptors including C-type lectin-like receptors (CLRs). The CLR, Dectin-1 is important for host immunity to C. albicans and C. glabrata, however, whether Dectin-1 is important for host defense against C. tropicalis or C. parapsilosis is unknown. Therefore, we compared the involvement of Dectin-1 in response to these four diverse Candida spp. We found that Dectin-1 mediates innate cytokine responses to these Candida spp. in a species- and cell-dependent manner. Dectin-1 KO mice succumbed to infection with highly virulent C. albicans while they mostly survived infection with less virulent Candida spp. However, Dectin-1 KO mice displayed increased fungal burden following infection with each Candida spp. Additionally, T cells from Dectin-1 KO mice displayed enhanced effector functions likely due to the inability of Dectin-1 KO mice to clear the infections. Together, these data indicate that Dectin-1 is important for host defense to multiple Candida spp., although the specific roles for Dectin-1 varies with different Candida spp.


Toward integrative cancer immunotherapy: targeting the tumor microenvironment.
The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8⁺ T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8⁺ effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of integrative cancer immunotherapies that sculpt the tumor microenvironment to promote definitive tumor rejection.


In vitro antileishmanial activity of fisetin flavonoid via inhibition of glutathione biosynthesis and arginase activity in Leishmania infantum.
With the increasing emergence of drug resistant Leishmania sp. in recent years, combination therapy has been considered as a useful way to treat and control of Leishmaniasis. The present study was designed to evaluate the antileishmanial effects of the fisetin alone and combination of fisetin plus Meglumine antimoniate (Fi-MA) against Leishmania infantum. The IC50 values for fisetin were obtained 0.283 and 0.102 μM against promastigotes and amastigote forms, respectively. Meglumine antimoniate (MA, Glucantime) as control drug also revealed IC50 values of 0.247 and 0.105 μM for promastigotes and amastigotes of L. infantum, respectively. In order to determine the mode of action of fisetin and Meglumine antimoniate (MA, Glucantime), the activities of arginase (ARG), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) were measured. Moreover, intracellular glutathione (GSH) and nitric oxide (NO) levels in L. infantum-infected macrophages and L. infantum promastigotes which were treated with IC50 concentrations of fisetin, MA and Fi-MA were investigated. Our results showed that MA decreased CAT and SOD activity and increased NO levels in L. infantum-infected macrophages. In promastigotes, MA inhibited parasite SOD activity and reduced parasite NO production. The decreased levels of most of the antioxidant enzymes, accompanying by the raised level of NO in treated macrophages with MA, were observed to regain their normal profiles due to Fi-MA treatment. Furthermore, fisetin could prevent the growth of promastigotes by inhibition of ARG activity and reduction of GSH levels and NO production. In conclusion, these findings showed that fisetin improves MA side effects.


Tuberculous pericardial disease: a focused update on diagnosis, therapy and prevention of complications.
Tuberculous pericarditis (TBP) is the most important manifestation of tuberculous heart disease and is still associated with a significant morbidity and mortality in TB endemic areas. The high prevalence of the disorder over the last 3 decades has been fueled by the human immunodeficiency virus/AIDS (HIV/AIDS) pandemic in these areas. The objective of this review is to provide a focused update on developments in the diagnosis and therapy of this condition, prevention of its complications, as well as future novel therapies. The definitive diagnosis of a tuberculous etiology in patients with suspected TBP continues to pose a challenge for clinicians. Clinical prediction scores, although never formally validated have been used with some success. However, they may be prone to both over and underdiagnosis due to lack of pericardial fluid analysis. Recent studies evaluating Xpert MTB/RIF, suggest that this advanced polymerase chain reaction (PCR) based technology does not provide increased accuracy compared to earlier iterations. However a combined two test approach starting with Xpert MTB/RIF followed by either adenosine deaminase (ADA) or interferon gamma (IFN-γ) may provide for significantly enhanced specificity and sensitivity cost permitting. Pericardiocentesis remains the gold standard for managing the compressive pericardial fluid and its adverse hemodynamic sequelae. A four drug anti-TB drug regimen at standard doses and duration is recommended. However recent evidence suggests that these drugs penetrate the pericardium very poorly potentially explaining the high mortality observed particularly in those who are culture positive with a high bacillary load. Constrictive pericarditis is the main long-term complication of TBP and is still a significant cause of heart failure in Sub-Saharan Africa. This is important because access to definitive surgical therapy where TBP is prevalent continues to be low, highlighting the need to develop strategies or interventions to prevent fibrosis and constriction. Recent detailed advanced studies of pericardial fluid in TBP have revealed a strong profibrotic transcriptomic profile, with high amounts of pro-inflammatory cytokines and low levels of the anti-fibrotic tetrapeptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP). These new insights may explain in part the high propensity to fibrosis associated with the condition and offer hope for the future use of targeted therapy to interrupt pathways and mediators of tissue damage and subsequent maladaptive healing and fibrosis. The value of effective pericardiocentesis in reducing these pro-inflammatory and pro-fibrotic cytokines and peptides in an attempt to prevent pericardial constriction has yet to be established but has generated hypotheses for ongoing and future research.


Scaling-up the medical workforce in Timor-Leste: challenges of a great leap forward.
The health services system of Timor-Leste (T-L) will, by 2015, add 800 physicians, most of them trained in Cuba, to the 233 employed by the national health system in 2010-2011. The need for more physicians is not in discussion: poor health indicators, low coverage and utilization of services, and poor quality of services are well documented in T-L. However, the choice of this scaling-up, with a relatively narrow focus on the medical workforce, needs to be assessed for its relevance to the health profile of the country, for its comprehensiveness in terms of other complementary measures needed to make it effective. This article discusses the potential effects of the rapid scaling-up of the medical workforce, and the organizational capacity needed to monitor the process and eventually mitigate any deleterious consequences. The analysis is based on a review of documentation collected on site (T-L) and on interviews with key-informants conducted in 2011. We stress that any workforce scaling-up is not simply a matter of increasing numbers of professionals, but should combine improved training, distribution, working conditions, management and motivation, as a means towards better performing health services' systems. This is a major challenge in a context of limited organizational and managerial capacity, underdeveloped information systems, limited training and research capacity, and dependency on foreign aid and technical assistance. Potential risks are associated with funding the additional costs of recruiting more personnel, associated expenditures on infrastructure, equipment and consumables, the impact on current staff mix, and the expected increased demand for services. We conclude that failing to manage effectively the forthcoming "great leap forward" will have long term effects: formal policies and plans for the balanced development of the health workforce, as well as strengthened institutions are urgently needed.


Rewritable digital data storage in live cells via engineered control of recombination directionality.
The use of synthetic biological systems in research, healthcare, and manufacturing often requires autonomous history-dependent behavior and therefore some form of engineered biological memory. For example, the study or reprogramming of aging, cancer, or development would benefit from genetically encoded counters capable of recording up to several hundred cell division or differentiation events. Although genetic material itself provides a natural data storage medium, tools that allow researchers to reliably and reversibly write information to DNA in vivo are lacking. Here, we demonstrate a rewriteable recombinase addressable data (RAD) module that reliably stores digital information within a chromosome. RAD modules use serine integrase and excisionase functions adapted from bacteriophage to invert and restore specific DNA sequences. Our core RAD memory element is capable of passive information storage in the absence of heterologous gene expression for over 100 cell divisions and can be switched repeatedly without performance degradation, as is required to support combinatorial data storage. We also demonstrate how programmed stochasticity in RAD system performance arising from bidirectional recombination can be achieved and tuned by varying the synthesis and degradation rates of recombinase proteins. The serine recombinase functions used here do not require cell-specific cofactors and should be useful in extending computing and control methods to the study and engineering of many biological systems.


Configurable automatic detection and registration of fiducial frames for device-to-image registration in MRI-guided prostate interventions.
We propose a novel automatic fiducial frame detection and registration method for device-to-image registration in MRI-guided prostate interventions. The proposed method does not require any manual selection of markers, and can be applied to a variety of fiducial frames, which consist of multiple cylindrical MR-visible markers placed in different orientations. The key idea is that automatic extraction of linear features using a line filter is more robust than that of bright spots by thresholding; by applying a line set registration algorithm to the detected markers, the frame can be registered to the MRI. The method was capable of registering the fiducial frame to the MRI with an accuracy of 1.00 +/- 0.73 mm and 1.41 +/- 1.06 degrees in a phantom study, and was sufficiently robust to detect the fiducial frame in 98% of images acquired in clinical cases despite the existence of anatomical structures in the field of view.


Is plate clearing a risk factor for obesity? A cross-sectional study of self-reported data in US adults.
Identifying eating behaviors which contribute to excess weight gain will inform obesity prevention strategies. A tendency to clear one's plate when eating may be a risk factor for obesity in an environment where food is plentiful. Whether plate clearing is associated with increased body weight in a cohort of US participants was examined. Nine hundred and ninety-three US adults (60% male, 80% American European, mean age=31 years) completed self-report measures of habitual plate clearing together with behavioral and demographic characteristics known to be associated with obesity. Plate clearing tendencies were positively associated with BMI and remained so after accounting for a large number of other demographic and behavioral predictors of BMI in analyses (β=0.18, 95% CIs=0.07, 0.29, P<0.001); an increased tendency to plate clear was associated with a significantly higher body weight. The tendency to clear one's plate when eating is associated with increased body weight and may constitute a risk factor for weight gain.


Children show hemispheric differences in the basic auditory response properties.
Auditory cortex in each hemisphere shows preference to sounds from the opposite hemifield in the auditory space. Besides this contralateral dominance, the auditory cortex shows functional and structural lateralization, presumably influencing the features of subsequent auditory processing. Children have been shown to differ from adults in the hemispheric balance of activation in higher-order auditory based tasks. We studied, first, whether the contralateral dominance can be detected in 7- to 8-year-old children and, second, whether the response properties of auditory cortex in children differ between hemispheres. Magnetoencephalography (MEG) responses to simple tones revealed adult-like contralateral preference that was, however, extended in time in children. Moreover, we found stronger emphasis towards mature response properties in the right than left hemisphere, pointing to faster maturation of the right-hemisphere auditory cortex. The activation strength of the child-typical prolonged response was significantly decreased with age, within the narrow age-range of the studied child population. Our results demonstrate that although the spatial sensitivity to the opposite hemifield has emerged by 7 years of age, the population-level neurophysiological response shows salient immature features, manifested particularly in the left hemisphere. The observed functional differences between hemispheres may influence higher-level processing stages, for example, in language function.


Influence of laser read and bias power levels on the performance of thermomagnetooptic recording media.
Read and bias power levels are capable of noticeably altering the response of thermomagnetooptic recording materials. The heating caused by the read power can decrease signal levels due to the temperature dependence of the polar Kerr rotation. Preheating caused by bias power levels also influences media sensitivity and responses during the writing process. Increased bias levels reduce the optimum recording power and increase the severity of mark length variations caused by write power fluctuations. Simple predictive expressions were derived to describe the influence of bias and read power levels during the mark formation and readout processes. The predicted results were in good qualitative and quantitative agreement with experimental observations.


Application of long-circulating liposomes to cancer photodynamic therapy.
Photodynamic therapy (PDT) as a cancer treatment is notable for its quite low side effects in comparison with those of chemotherapy and radiotherapy. However, the accumulation of porphyrin derivatives used in PDT into tumor tissues is rather low. Since long-circulating liposomes are known to accumulate passively into tumor tissues, we liposomalized a porphyrin derivative, benzoporphyrin derivative monoacid ring A (BPD-MA), and used these liposomes to investigate the usefulness of PDT for tumor-bearing mice. BPD-MA was liposomalized into glucuronate-modified liposomes, which are known to be long-circulating. These liposomes were injected i.v. into Balb/c mice bearing Meth A sarcoma, and tumor regression and survival time were monitored after irradiation with laser light. Tumor regression and complete curing of tumor (80% cure rate by the treatment with 6 mg/kg BPD-MA) were observed when long circulating liposomalized BPD-MA was injected and laser-irradiated. In contrast, only a 20% cure rate was obtained when the animals were treated with BPD-MA solution or BPD-MA entrapped in conventional liposomes. These results suggest that a long-circulating liposomal formulation of photo-sensitive agents is useful for PDT.


In vitro methods in the prediction of kinetics of drugs: focus on drug metabolism.
The absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of a candidate drug influence its final clinical success. These properties have traditionally been evaluated by using various in vivo animal approaches, but recently, a number of in vitro and in silico methods have been introduced to determine key ADMET features. Basic events, such as absorption through the gut wall, binding to plasma proteins, active and passive transfer through the blood-brain barrier, and various metabolic parameters, can now be screened with rapid in vitro and computer modelling methods. The focus in this short review is on the basic in vitro and in silico methods that are used for studying the metabolism properties of new drug molecules.


Characterizing human perceptual inefficiencies with equivalent internal noise.
A widely used method for characterizing and comparing inefficiencies in perceptual processes is the method of equivalent internal noise--the amount of random internal noise necessary to produce the degree of inefficiency exhibited by the perceptual system in processing [J. Opt. Soc. Am. 46, 634 (1956)]. One normally estimates the amount of equivalent internal noise by systematically increasing the amount of external noise added to the signal stimulus and observing how threshold--signal stimulus energy required for an observer to maintain a given performance level--depends on the amount of external noise. In a variety of perceptual tasks, a simple noisy linear amplifier model [D. Pelli, Ph.D. dissertation (University of Cambridge, Cambridge, UK 1981)] has been utilized to estimate the equivalent internal noise Ninternal by fitting of the relation between threshold contrast c tau and external noise N(ext) at a single (d') performance level: c tau 2 =(d'/beta)2(N(ext)2 + Ninternal2). This model makes a strong prediction: Independent of observer and external noise contrast, the ratio between two thresholds at each external noise level is equal to the ratio of the two corresponding d' values. To our knowledge, this potential test for the internal consistency of the model had never been examined previously. In this study we estimated threshold ratios between multiple performance levels at various external noise contrasts in two different experiments: Gabor orientation identification, and Gabor detection. We found that, in both identification and detection, the observed threshold ratios between different performance levels departed substantially from the d' ratio predicted by the simple noisy linear amplifier model. An elaborated perceptual template model [Vision Res. 38, 1183 (1998)] with nonlinear transducer functions and multiplicative noise in addition to the additive noise in the simple linear amplifier model leads to a substantially better description of the data and suggests a reinterpretation of earlier results that relied on the simple noisy linear amplifier model. The relationship of our model and method to other recent parallel and independent developments [J. Opt. Soc. Am. A 14, 2406 (1997)] is discussed.


A retrospective approach to fractionize variation in body mass of Atlantic cod Gadus morhua.
Eggs of a single spawning batch from wild-caught Norwegian Atlantic cod Gadus morhua were hatched and first fed on either natural zooplankton or enriched rotifers Brachionus plicatilis during the larval period. Juvenile G. morhua (initial mass 14·2 g) from the two first-feeding groups were then reared for 3 months under a variety of temperature (10 and 14° C) and salinity (15 and 32) combinations. All fish were individually tagged and microsatellite markers were used in a multiplex to trace the pedigree of all fish and body mass variation analysed according to different environmental and genetic sources. After the termination of the laboratory trial, the fish were transferred to land-based tanks and later to sea pens and reared at ambient conditions for 26 months until they were harvested in March 2009. Growth gain from the larval and juvenile periods was persistent during the 26 months of sea pen ongrowing. The final mass of the zooplankton group was 12% higher compared to the B. plicatilis group. Similarly, rearing under a temperature of 14° C and salinity of 15 during the initial 3 month period during the early juvenile stage resulted in 7-13% larger size at harvesting compared to the other three temperature and salinity combinations. The study indicates that the first-feeding method and temperature and salinity manipulation explain nearly 90% of the body mass variation explained by the model. The genetic effect (measured as body mass variation within the families studied) only accounted for c. 2% during the initial rearing period, whereas it has a large effect on growth variation (30%) during the long-term rearing at ambient conditions. Sex proportion and final maturation did not differ between family groups, and no interaction between sex and family group was seen.


Deep Learning Electronic Cleansing for Single- and Dual-Energy CT Colonography.
Electronic cleansing (EC) is used for computational removal of residual feces and fluid tagged with an orally administered contrast agent on CT colonographic images to improve the visibility of polyps during virtual endoscopic "fly-through" reading. A recent trend in CT colonography is to perform a low-dose CT scanning protocol with the patient having undergone reduced- or noncathartic bowel preparation. Although several EC schemes exist, they have been developed for use with cathartic bowel preparation and high-radiation-dose CT, and thus, at a low dose with noncathartic bowel preparation, they tend to generate cleansing artifacts that distract and mislead readers. Deep learning can be used for improvement of the image quality with EC at CT colonography. Deep learning EC can produce substantially fewer cleansing artifacts at dual-energy than at single-energy CT colonography, because the dual-energy information can be used to identify relevant material in the colon more precisely than is possible with the single x-ray attenuation value. Because the number of annotated training images is limited at CT colonography, transfer learning can be used for appropriate training of deep learning algorithms. The purposes of this article are to review the causes of cleansing artifacts that distract and mislead readers in conventional EC schemes, to describe the applications of deep learning and dual-energy CT colonography to EC of the colon, and to demonstrate the improvements in image quality with EC and deep learning at single-energy and dual-energy CT colonography with noncathartic bowel preparation. ©RSNA, 2018.


Chemical composition of kale as influenced by dry vermicast, potassium humate and volcanic minerals.
Biofortification using agronomic practices can be used to improve the nutritional quality of food crops. Three natural media amendments (dry vermicast, potassium (K)-humate and volcanic minerals) were assessed under greenhouse conditions to determine the effects on the chemical composition of kale (Brassica oleracea L. var. acephala 'Ripbor'). The results indicated that K-humate had low pH, while the volcanic minerals had high pH. Plants grown in the dry vermicast amended media had the highest levels of macronutrients and micronutrients except for zinc and iron. However, the glycolipid: phospholipid ratio was lower in kale plants cultivated in dry vermicast compared to plants cultivated in the volcanic minerals or K-humate. Conversely, plants cultivated in the dry vermicast had enhanced levels of polyunsaturated fatty acids. The omega-3 fatty acid content was significantly (P < 0.05) higher in plants cultivated in dry vermicast and potassium humate, while the omega-6 fatty acids were unaffected by media amendments. Dry vermicast was the most effective at increasing plant tissue oleic acid content. The total phenolic content and antioxidant capacity were highest in plants treated with K-humate, but lowest in the dry vermicast treated plants. In conclusion, dry vermicast proved to be the most effective in enhancing the phytochemical composition of kale 'Ripbor'. These results suggest dry vermicast could be a potential target natural media amendment for biofortifying kale plants during cultivation.


CD1-restricted microbial lipid antigen-specific recognition found in the CD8+ alpha beta T cell pool.
It is generally accepted that TCR alphabeta+ CD8+ T cells recognize immunogenic peptides bound to MHC-encoded class I molecules. This recognition is a major component of the cellular response mediating immune protection and recovery from viral infections and from certain intracellular bacterial infections. Here, we report two human CD8+ TCR alphabeta+ T cell lines specific for Mycobacterium tuberculosis Ags presented in the context of CD1a or CD1c Ag-presenting molecules. These T cells recognize lipid Ags and display cytotoxicity as well as strong Th cell type I cytokine responses. By extending presentation by the CD1 system to the major TCR alphabeta+ CD8+ T cell pool, this system gains wider applicability beyond the double negative subset of T cells previously shown to have this reactivity. This implies that previous assumptions about the role of CD8+ T cells in microbial immunity may require revision as the relative proportions of CD1-restricted and MHC class I-restricted CD8+ T cells are further defined.


Epigenetic regulation of PRAME gene in chronic myeloid leukemia.
Tumor associated antigens (TAA) provide attractive targets for cancer-specific immunotherapy. PRAME is a TAA gene up-regulated in advanced phases of chronic myeloid leukemia (CML). To date, molecular mechanisms for the expression of PRAME have never been studied. We found that some Ph'-positive cell lines did not express PRAME. The expression of PRAME was restored in these cell lines by treatment with 5'-aza-2'-deoxycytidine, suggesting that the expression of PRAME is mainly suppressed by hypermethylation. Bisulfite sequencing analysis of the CpG sites of the PRAME exon 2 in these cancer cell lines revealed a close relationship between the methylation status of the PRAME gene and its expression. A methylation-specific PCR analysis demonstrated that hypomethylation of PRAME was significantly more frequent in CML blast crisis (70%) than in chronic phase (36%) (P=0.01) and was correlated with high expression levels of PRAME transcripts (P<0.0001). These results suggest that hypomethylation of PRAME up-regulates its expression in CML and might play a significant role in the progression of the disease.


White paper defining optimal palliative care in older people with dementia: a Delphi study and recommendations from the European Association for Palliative Care.
Dementia is a life-limiting disease without curative treatments. Patients and families may need palliative care specific to dementia. To define optimal palliative care in dementia. Five-round Delphi study. Based on literature, a core group of 12 experts from 6 countries drafted a set of core domains with salient recommendations for each domain. We invited 89 experts from 27 countries to evaluate these in a two-round online survey with feedback. Consensus was determined according to predefined criteria. The fourth round involved decisions by the core team, and the fifth involved input from the European Association for Palliative Care. A total of 64 (72%) experts from 23 countries evaluated a set of 11 domains and 57 recommendations. There was immediate and full consensus on the following eight domains, including the recommendations: person-centred care, communication and shared decision-making; optimal treatment of symptoms and providing comfort (these two identified as central to care and research); setting care goals and advance planning; continuity of care; psychosocial and spiritual support; family care and involvement; education of the health care team; and societal and ethical issues. After revision, full consensus was additionally reached for prognostication and timely recognition of dying. Recommendations on nutrition and dehydration (avoiding overly aggressive, burdensome or futile treatment) and on dementia stages in relation to care goals (applicability of palliative care) achieved moderate consensus. We have provided the first definition of palliative care in dementia based on evidence and consensus, a framework to provide guidance for clinical practice, policy and research.


Enumeration of the Invasion Efficiency of Plasmodium falciparum In Vitro in Four Different Red Blood Cell Populations Using a Three-Color Flow Cytometry-Based Method.
A novel in vitro culture system using variable concentrations of biotin/streptavidin to label red blood cells (RBCs) that allows for the simultaneous comparison of growth rates in Plasmodium falciparum malaria parasite in four heterogeneous target RBC populations is described. Donor RBCs containing both P. falciparum-infected RBCs and non-infected RBCs at 0.5% parasitemia were first labeled with 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one) succinimidyl ester (DDAO-SE) followed by co-culture with a mixture of equal numbers of four differentially biotin/streptavidin labeled RBC populations. After two to three schizogonic growth cycles, co-cultures were harvested and stained with streptavidin-phycoerythrin (SA-PE) followed by staining of parasite-infected RBCs with nucleic acid fluorochrome SYBR Green I. To demonstrate the application of this method, some target RBC populations that had sialic acid residues removed using neuraminidase treatment were mixed with RBC populations without enzymatic treatment and incubated with donor parasitized RBCs strain W2 (sialic acid-dependent) or 3D7 (sialic acid-independent). Significant less susceptibility to malaria parasite invasion was obtained with enzyme-treated RBC populations when compared with non-treated RBCs in blood samples from the same individual when using malaria parasite strain W2, whereas no difference in percent parasitemias was noted following infection with malaria parasite strain 3D7. This novel malaria culture method is cheap and provides increased sensitivity for direct comparison of parasite growth over time of any of the four RBC populations under identical conditions and eliminates the experimental bias due to contaminated donor RBCs. The application of biotin-labeled RBCs will therefore provide a better understanding of invasion phenotype-specific host-parasite interactions and the extent of complex malaria invasion mechanism. © 2019 International Society for Advancement of Cytometry.


Pest categorisation of Exomala orientalis.
The EFSA Panel on Plant Health performed a pest categorisation of Exomala orientalis (Coleoptera: Rutelidae) (Oriental beetle) for the EU. Larvae feed on the roots of a variety of hosts including most grasses and many vegetable crops. Maize, pineapples, sugarcane are among the main host plants. Larvae are particularly damaging to turfgrass and golf courses. The adults feed on flowers and other soft plant tissues (e.g. Alcea rosea, Dahlia, Iris, Phlox and Rosa). Eggs are laid in the soil. Larvae feed on host roots and overwinter in the soil. Adults emerge from pupae in the soil in May-June and are present for about 2 months. E. orientalis usually completes its life cycle in 1 year although individuals can spend two winters as larvae. Commission Implementing Regulation (EU) 2019/2072 (Annex IIA) regulates E. orientalis. The legislation also regulates the import of soil attached to plants for planting from third countries; therefore, entry of E. orientalis eggs, larvae and pupae is prevented. E. orientalis is native to Japan or the Philippine islands. It is also found in East Asia and India, Hawaii and north-eastern USA. It is assumed to have reached USA via infested nursery stock. Plants for planting (excluding seeds) and cut flowers provide potential pathways for entry into the EU. E. orientalis has been intercepted only once in the EU, on Ilex crenata bonsai. Climatic conditions and the availability of host plants provide conditions to support establishment in the EU. Impacts on maize, grassland and turfgrass would be possible. There is uncertainty on the extent of the impact on host plants which are widely commercially grown (e.g. maize) Phytosanitary measures are available to reduce the likelihood of entry. E. orientalis satisfies the criteria that are within the remit of EFSA to assess for it to be regarded as a potential Union quarantine pest. Of the criteria that are within the remit of EFSA to assess for it to be regarded as a potential Union regulated non-quarantine pest, E. orientalis does not meet the criterion of occurring in the EU.


Use of Intraoperative Computed Tomography for Revisional Procedures in Patients with Complex Maxillofacial Trauma.
In patients with panfacial fractures and distorted anatomic landmarks of zygomatic and orbital complex, there is a risk of zygomaticomaxillary complex (ZMC) malpositioning even with the best efforts for surgical repair. This results in increased number of additional procedures to achieve accurate positioning. We describe the usage of intraoperative C-arm cone-beam computed tomographic (CT) scan for ZMC malpositioning in a representative patient with panfacial fractures. We have successfully used intraoperative CT scan for ZMC malpositioning in 3 patients. The representative patient had ZMC malposition after the initial attempt of surgical repair without any intraoperative imaging. On using intraoperative CT scan during the next attempt, we were able to reposition the ZMC accurately. Intraoperative CT scan might improve the accuracy of ZMC positioning and decrease the chances of potential additional surgeries. In patients with distorted anatomical landmarks and panfacial fractures, it can be especially helpful toward correcting ZMC malposition.


Hip hemiarthroplasty after displaced femoral neck fracture: a survivorship analysis.
The standard of care for displaced femoral neck fractures is not clear. We reviewed all patients 65 years or older with displaced femoral neck fracture who underwent hip hemiarthroplasty at our institution between 1997 and 2006. Women accounted for 70% of the patients. Mean patient age was 78 years, and most of the patients were community ambulators. Complete operative information was available for 226 (79%) of 285 patients. Follow-up was available for 126 patients (mean, 15.8 months; range, 1-97 months). Total mortality rate was 58%. Mean University of California, Los Angeles (UCLA) scores were 8.3 for pain, 6.7 for walking, 5.6 for function, and 3.5 for activity. Two patients had acetabular wear on radiography, but symptoms were not severe enough to warrant revision. Three patients (1.3%) underwent revision, 1 with acetabular wear and 2 for infection. Despite the limited follow-up, the rate of conversion to total hip arthroplasty (THA) was low. Longer, prospective studies are needed to delineate which patients will benefit from THA.


Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations.
Fibrochondrogenesis is documented to be a neonatally lethal rare recessively inherited disorder characterized by short-limbed skeletal dysplasia. Here we report two patients from two unrelated consanguineous Emirati families who have unexpectedly survived till the ages of 3 and 6 years. These patients show additional symptoms which include developmental delay, profound sensory-neural deafness, severe myopia and progressive severe skeletal abnormalities. Linkage of fibrochondrogenesis in the Emirati families to chromosome 1 has been established using homozygosity mapping confirming recent findings by Tompson et al. in 2010. Screening of the COL11A1 gene revealed two null homozygous mutations [c.4084C>T (p.R1362X) and c.3708+437T>G] in the aforementioned two families. The c.4084C>T mutation is predicted to introduce a stop codon at position Arg1362, whereas the c.3708+437T>G mutation causes the activation of an intronic pseudoexon between exons 48 and 49. This resulted in the insertion of 50 nucleotides into the mRNA. The carriers of these mutations display ocular defects with normal hearing. In conclusion, our data shall improve the overall understanding of fibrochondrogenesis especially in surviving homozygous patients and, at least partly, explain the phenotypic variability associated with COL11A1 gene mutations.


RAGE Control: Regulate and Gain Emotional Control.
Advances in neurobiology and computer science make possible interventions designed to strengthen basic processes behind emotional control. We present one such computer-based intervention, RAGE Control (Regulate And Gain Emotional Control). This extends the usual paradigm of biofeedback by requiring relaxation in the midst of engaging executive processes in a quick reaction task. RAGE Control teaches children to simultaneously focus, react, inhibit impulses, and keep their heart rate down in the context of a traditional space battle game. The program is grounded in the theory of Cognitive Behavioral Therapy and is currently in clinical use by psychotherapists at Children's Hospital in Boston. It aims to reduce the need for psychotropic medication to help children gain emotional control. Clinical trials to test the promise of this technology are warranted.


High-content profiling of cell responsiveness to graded substrates based on combinyatorially variant polymers.
We have developed a novel approach combining high information and high throughput analysis to characterize cell adhesive responses to biomaterial substrates possessing gradients in surface topography. These gradients were fabricated by subjecting thin film blends of tyrosine-derived polycarbonates, i.e. poly(DTE carbonate) and poly(DTO carbonate) to a gradient temperature annealing protocol. Saos-2 cells engineered with a green fluorescent protein (GFP) reporter for farnesylation (GFP-f) were cultured on the gradient substrates to assess the effects of nanoscale surface topology and roughness that arise during the phase separation process on cell attachment and adhesion strength. The high throughput imaging approach allowed us to rapidly identify the "global" and "high content" structure-property relationships between cell adhesion and biomaterial properties such as polymer chemistry and topography. This study found that cell attachment and spreading increased monotonically with DTE content and were significantly elevated at the position with intermediate regions corresponding to the highest "gradient" of surface roughness, while GFP-f farnesylation intensity descriptors were sensitively altered by surface roughness, even in cells with comparable levels of spreading.


Individual unmet needs for care: are they sensitive as outcome criterion for the effectiveness of mental health services interventions?
Mental health interventions should demonstrate an effect on patients' functioning as well as his/her needs, in particular on unmet needs whose assessment depends on the perspective of either the patient or the clinician. However, individual met and unmet needs appear to change over time, qualitatively and quantitatively, raising questions about their sensitivity to change and about the association between level of needs and treatment. Data on baseline and follow-up need assessment in community mental health services in four European countries in the context of a cluster randomised trial on a novel mental health service intervention were used, which involved 102 clinicians with key worker roles and 320 patients with schizophrenia or related psychotic disorders. Need assessment was performed with the Camberwell assessment of needs short appraisal schedule (CANSAS) among patients as well as clinicians. Focus is the sensitivity to change in unmet needs over time as well as the concordance between patient and clinician ratings and their relationship with treatment condition. At follow-up 294 patients (92%) had a full need assessment, while clinician rated needs were available for 302 patients (94%). Generally, the total number of met needs remained quite stable, but unmet needs decreased significantly over time, according to patients as well as to clinicians. Sensitivity to change of unmet needs is quite high: about two third of all unmet needs made a transition to no or met need, and more than half of all unmet needs at follow-up were new. Agreement between patient and clinician on unmet needs at baseline as well as follow-up was rather low, without any indication of a specific treatment effect. Individual unmet needs appear to be quite sensitive to change over time but as yet less suitable as outcome criterion of treatment or specific interventions.


Cardiac rehabilitation availability and delivery in Europe: How does it differ by region and compare with other high-income countries?: Endorsed by the European Association of Preventive Cardiology.
The aims of this study were to establish cardiac rehabilitation availability and density, as well as the nature of programmes, and to compare these by European region (geoscheme) and with other high-income countries. A survey was administered to cardiac rehabilitation programmes globally. Cardiac associations were engaged to facilitate programme identification. Density was computed using global burden of disease study ischaemic heart disease incidence estimates. Four high-income countries were selected for comparison (N = 790 programmes) to European data, and multilevel analyses were performed. Cardiac rehabilitation was available in 40/44 (90.9%) European countries. Data were collected in 37 (94.8% country response rate). A total of 455/1538 (29.6% response rate) programme respondents initiated the survey. Programme volumes (median 300) were greatest in western European countries, but overall were higher than in other high-income countries (P < 0.001). Across all Europe, there was on average only 1 CR spot per 7 IHD patients, with an unmet regional need of 3,449,460 spots annually. Most programmes were funded by social security (n = 25, 59.5%; with significant regional variation, P < 0.001), but in 72 (16.0%) patients paid some or all of the programme costs (or ∼18.5% of the ∼€150.0/programme) out of pocket. Guideline-indicated conditions were accepted in 70% or more of programmes (lower for stable coronary disease), with no regional variation. Programmes had a multidisciplinary team of 6.5 ± 3.0 staff (number and type varied regionally; and European programmes had more staff than other high-income countries), offering 8.5 ± 1.5/10 core components (consistent with other high-income countries) over 24.8 ± 26.0 hours (regional differences, P < 0.05). European cardiac rehabilitation capacity must be augmented. Where available, services were consistent with guidelines, but varied regionally.


The effectiveness of body age-based intervention in workplace health promotion: Results of a cohort study on 9851 Danish employees.
The aging population emphasize the need for effective health promotion interventions. The workplace is a prioritized setting for health promotion to reach widely within a population. Body age can be used as a health-risk estimate and as a motivational tool to change health behavior. In this study we investigate body age-based intervention including motivational interview and its effect on health, when applied to real life workplace health promotion. Body age-based intervention was performed in 90 companies on 9851 Danish employees from 2011-2017. Metabolic risk factors were assessed, body age score was determined and an individualized motivational interview was conducted at baseline and follow-up. Change in body age score, single risk factors, smoking habits and metabolic syndrome were analyzed. The body age score is a composite score comprising 11 weighted variables. A body age score ≤ 0 is preferred, as this elicit a younger/healthier or equal body age compared to chronological age. At 1.3 year follow-up the unhealthiest employees were less likely to participate. Within follow-up participants (39%, n = 3843) body age had improved by a decline in mean body age score of -0.6 and -0.7 years for men and women, respectively (p<0.001). Number of employees with metabolic syndrome had decreased from 646 at baseline to 557 at follow-up (p = 0.005) and 42% of smokers had quit smoking (p<0.001). On the basis of this study, we suggest that body age assessment motivates to participate in workplace health promotion, affect high risk behavior such as smoking thus have potential in public health promotion.


Production of calves from G1 fibroblasts.
Since the landmark study of Wilmut et al. describing the birth of a cloned lamb derived from a somatic cell nucleus, there has been debate about the donor nucleus cell cycle stage required for somatic cell nuclear transfer (NT). Wilmut et al. suggested that induction of quiescence by serum starvation was critical in allowing donor somatic cells to support development of cloned embryos. In a subsequent report, Cibelli et al. proposed that G0 was unnecessary and that calves could be produced from actively dividing fibroblasts. Neither study conclusively documented the importance of donor cell cycle stage for development to term. Other laboratories have had success with NT in several species, and most have used a serum starvation treatment. Here we evaluate methods for producing G0 and G1 cell populations and compare development following NT. High confluence was more effective than serum starvation for arresting cells in G0. Pure G1 cell populations could be obtained using a "shake-off" procedure. No differences in in vitro development were observed between cells derived from the high-confluence treatment and from the "shake-off" treatment. However, when embryos from each treatment were transferred to 50 recipients, five calves were obtained from embryos derived from "shake-off" cells, whereas no embryos from confluent cells survived beyond 180 days of gestation. These results indicate that donor cell cycle stage is important for NT, particularly during late fetal development, and that actively dividing G1 cells support higher development rates than cells in G0.


Fractional statistics: quantum possibilities in two dimensions.
A standard notion of quantum mechanics is that all particles, elementary or composite, must fall into one of two fundamental categories: fermions or bosons. However, it has recently been discovered that there can be quantum particles which are neither fermions nor bosons. Such particles (anyons) can only occur in two spatial dimensions-yet this does not rule out their existence, for they are found as elementary excitations in confined, quasi-two-dimensional condensed-matter systems and may occur in other systems as well. An overview of the argument for the existence of anyons is presented, along with a discussion of their role in condensed-matter physics.


Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.


Visual grading system for vasospasm based on perfusion CT imaging: comparisons with conventional angiography and quantitative perfusion CT.
The purpose of this study was to compare simple visual grading of perfusion CT (PCT) maps to a more quantitative, threshold-based interpretation of PCT parameters in the characterization of presence and severity of vasospasm. Thirty-three patients with acute subarachnoid hemorrhage were enrolled in a prospective study and underwent a total of 40 paired PCT and digital subtraction angiography (DSA) examinations. A neuroradiologist and a neurologist reviewed the PCT mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume maps independently; they evaluated five anatomical regions (frontal, temporal, parietal, occipital/thalami, and basal ganglia/insula) and graded them for abnormality (0 if normal, 1 if abnormal in <50% of the region, and 2 if abnormal in >or=50% of the region). A third neuroradiologist blinded to the PCT results reviewed the DSA examinations and assessed 19 segments for the presence or absence of vasospasm. Correlation between PCT and DSA scores was assessed, as well as the sensitivity and specificity of PCT compared to DSA used as a gold standard. MTT (R(2) = 0.939) and CBF (R(2) = 0.907) scores correlated best with DSA scores (p < 0.001). MTT scoring had a sensitivity of 92% and a specificity of 86% compared to DSA; CBF scoring had a sensitivity of 75% and a specificity of 95%. The interobserver agreement between neuroradiologist and neurologist was found to have kappa = 0.789 for MTT and 0.658 for CBF. We propose a user-friendly visual grading system for PCT maps in patients with suspected vasospasm. This visual approach compares favorably to the results of DSA. Sensitive MTT maps should be used for screening, and specific CBF maps for confirmation of vasospasm.


Ultimate Limit for Optical Losses in Gold, Revealed by Quantitative Near-Field Microscopy.
We report thorough measurements of surface plasmon polaritons (SPPs) running along nearly perfect air-gold interfaces formed by atomically flat surfaces of chemically synthesized gold monocrystals. By means of amplitude- and phase-resolved near-field microscopy, we obtain their propagation length and effective mode index at visible wavelengths (532, 594, 632.8, 729, and 800 nm). The measured values are compared with the values obtained from the dielectric functions of gold that are reported in literature. Importantly, a reported dielectric function of monocrystalline gold implies ∼1.5 times shorter propagation lengths than those observed in our experiments, whereas a dielectric function reported for properly fabricated polycrystalline gold leads to SPP propagation lengths matching our results. We argue that the SPP propagation lengths measured in our experiments signify the ultimate limit of optical losses in gold, encouraging further comprehensive characterization of optical material properties of pure gold as well as other plasmonic materials.


A multiple-choice task with changes of mind.
The role of changes of mind and multiple choices has recently received increased attention in the study of perceptual decision-making. Previously, these extensions to standard two-alternative tasks have been studied separately. Here we explored how changes of mind depend on the number of choice-alternatives. To this end, we tested 14 human subjects on a 2- and 4-alternative direction-discrimination task. Changes of mind in the participants' movement trajectories could be observed for two and for four choice alternatives. With fewer alternatives, participants responded faster and more accurately. The frequency of changes of mind, however, did not significantly differ for the different numbers of choice alternatives. Nevertheless, mind-changing improved the participants' final performance, particularly for intermediate difficulty levels, in both experimental conditions. Moreover, the mean reaction times of individual participants were negatively correlated with their overall tendency to make changes of mind. We further reproduced these findings with a multi-alternative attractor model for decision-making, while a simple race model could not account for the experimental data. Our experiment, combined with the theoretical models allowed us to shed light on: (1) the differences in choice behavior between two and four alternatives, (2) the differences between the data of our human subjects and previous monkey data, (3) individual differences between participants, and (4) the inhibitory interaction between neural representations of choice alternatives.


The impact of weather on summer and winter exercise behaviors.
Outdoor exercise is an enjoyable way for individuals to improve fitness, but it is dependent on weather conditions. This study examines the association between weather conditions and outdoor exercise after adjustment for age, sex, race, and socioeconomic status. We used data representative of American adults from the University of Michigan/Thomson Reuters June 2013 surveys of consumers (core and supplement) to investigate self-reported exercise behavior in summer and winter. Multivariate multinomial logistic regression models estimated the odds of delayed or indoor exercise compared with outdoor exercise. Of the 502 respondents, 16.3% did not regularly exercise outdoors (i.e., at least once a week), and many would delay exercise both in summer (51.8%) and winter (43.9%). Individuals listing rain as the predominant adverse weather condition had 3.33 times higher odds of exercising indoors (95% confidence interval (CI): 1.34-8.28) and 3.49 times higher odds of delaying exercise (95%CI: 1.69-7.21) compared with those mentioning heat as the predominant adverse condition. Individuals for whom ice or snow was an adverse winter weather condition were more likely to delay exercise (odds ratio (OR) = 3.34; 95%CI: 1.19-9.36), compared with those concerned with cold. This study found that race, age, and education exacerbate the negative effects of adverse weather conditions on the decision to exercise outdoors. Accordingly, any recommendation for an individual to exercise outdoors should be combined with an evaluation of the individual's outdoor environment along with strategies for the individual to continue exercising, indoors or outdoors, when adverse weather is present.


Foetal hypothalamic and pituitary expression of gonadotrophin-releasing hormone and galanin systems is disturbed by exposure to sewage sludge chemicals via maternal ingestion.
Animals and humans are chronically exposed to endocrine disrupting chemicals (EDCs) that are ubiquitous in the environment. There are strong circumstantial links between environmental EDC exposure and both declining human/wildlife reproductive health and the increasing incidence of reproductive system abnormalities. The verification of such links, however, is difficult and requires animal models exposed to 'real life', environmentally relevant concentrations/mixtures of environmental contaminants (ECs), particularly in utero, when sensitivity to EC exposure is high. The present study aimed to determine whether the foetal sheep reproductive neuroendocrine axis, particularly gondotrophin-releasing hormone (GnRH) and galaninergic systems, were affected by maternal exposure to a complex mixture of chemicals, applied to pasture, in the form of sewage sludge. Sewage sludge contains high concentrations of a spectrum of EDCs and other pollutants, relative to environmental concentrations, but is frequently recycled to land as a fertiliser. We found that foetuses exposed to the EDC mixture in utero through their mothers had lower GnRH mRNA expression in the hypothalamus and lower GnRH receptor (GnRHR) and galanin receptor (GALR) mRNA expression in the hypothalamus and pituitary gland. Strikingly, this, treatment had no significant effect on maternal GnRH or GnRHR mRNA expression, although GALR mRNA expression within the maternal hypothalamus and pituitary gland was reduced. The present study clearly demonstrates that the developing foetal neuroendocrine axis is sensitive to real-world mixtures of environmental chemicals. Given the important role of GnRH and GnRHR in the regulation of reproductive function, its known role programming role in utero, and the role of galanin in the regulation of many physiological/neuroendocrine systems, in utero changes in the activity of these systems are likely to have long-term consequences in adulthood and represent a novel pathway through which EC mixtures could perturb normal reproductive function.


[Supply and demand of the medium-complexity/SUS: relation with primary health care].
This work aims at investigating the supply and demand of the medium-complexity services from the Federal District and surrounding municipalities from the state of Goiás. Our hypothesis is that the services organization offer of primary care (PC) from the Federal District (DF) and its surroundings overloads the medium-complexity services (MC), contributing to less equity in terms of communities access. Our objective is to analyze the demand for MC (medium-complexity) services in DF (Federal District) and its relation with PC (Primary Care); to quantify the origin, health problem, reason, transportation time and performed procedures of the ones who go to the Federal District hospitals; to set up priorities of managerial changes in the Brazilian Health System (SUS) in order to have more access to users. The evaluation was triangulation of methods, and complementing qualitative and quantitative approaches. The study of the offer via the analysis of SUS information systems, and the demand through a survey with 1,585 users of seven hospitals of the Federal District. There is a sub utilization of services offer at the Federal District, with duplicity of basic actions among hospitals and other health centers. It is recommended a revision in the health services regionalization and hierarchy of the Federal District and Goiás, as well as more investments on implementation of technology to primary care.


Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells.
The effect of VP-16-213 on cellular DNA was studied by following the sedimentation profiles of radioactive DNA in HeLa cells on alkaline sucrose gradients. In VP-16-213 treated cells, high-molecular-weight DNA is converted to a lower molecular-weight form in a dose-dependent, temperature-dependent reaction. The effect of VP-16-213 on cellular DNA is reversed after the drug has been removed from the growth medium for 150 min. These results suggest that VP-16-213 induces single-stranded breaks in DNA in HeLa cells and that HeLa cells can repair these breaks within 150 min. The nonglucoside derivative of VP-16-213, 4'-demethylepipodophyllotoxin, also induces the cleavage of cellular DNA but podophyllotoxin has no effect on DNA. A structure-activity relationship study, in which the effects of various VP-16-213 and podophyllotoxin congeners were tested for their ability to cleave cellular DNA,revealed that an hydroxyl group at the C-4' position is required for activity and that the configuration of the C-4 carbon influences the activity of a congener. These results may offer insights into the mechanism of action of VP-16-213 as an antitumor agent.


Microparticles Impair Hypotensive Cerebrovasodilation and Cause Hippocampal Neuronal Cell Injury after Traumatic Brain Injury.
Endothelin-1 (ET-1), tissue plasminogen activator (tPA), and extracellular signal-regulated kinases-mitogen activated protein kinase (ERK-MAPK) are mediators of impaired cerebral hemodynamics after fluid percussion brain injury (FPI) in piglets. Microparticles (MPs) are released into the circulation from a variety of cells during stress, are pro-thrombotic and pro-inflammatory, and may be lysed with polyethylene glycol telomere B (PEG-TB). We hypothesized that MPs released after traumatic brain injury impair hypotensive cerebrovasodilation and that PEG-TB protects the vascular response via MP lysis, and we investigated the relationship between MPs, tPA, ET-1, and ERK-MAPK in that process. FPI was induced in piglets equipped with a closed cranial window. Animals received PEG-TB or saline (vehicle) 30-minutes post-injury. Serum and cerebrospinal fluid (CSF) were sampled and pial arteries were measured pre- and post-injury. MPs were quantified by flow cytometry. CSF samples were analyzed with enzyme-linked immunosorbent assay. MP levels, vasodilatory responses, and CSF signaling assays were similar in all animals prior to injury and treatment. After injury, MP levels were elevated in the serum of vehicle but not in PEG-TB-treated animals. Pial artery dilation in response to hypotension was impaired after injury but protected in PEG-TB-treated animals. After injury, CSF levels of tPA, ET-1, and ERK-MAPK were all elevated, but not in PEG-TB-treated animals. PEG-TB-treated animals also showed reduction in neuronal injury in CA1 and CA3 hippocampus, compared with control animals. These results show that serum MP levels are elevated after FPI and lead to impaired hypotensive cerebrovasodilation via over-expression of tPA, ET-1, and ERK-MAPK. Treatment with PEG-TB after injury reduces MP levels and protects hypotensive cerebrovasodilation and limits hippocampal neuronal cell injury.


Evaluation of the effective dose during BNCT at TRR thermal column epithermal facility.
An epithermal neutron beam has been designed for Boron neutron Capture Therapy (BNCT) at the thermal column of Tehran Research Reactor (TRR) recently. In this paper the whole body effective dose, as well as the equivalent doses of several organs have been calculated in this facility using MCNP4C Monte Carlo code. The effective dose has been calculated by using the absorbed doses determined for each individual organ, taking into account the radiation and tissue weighting factors. The ICRP 110 whole body male phantom has been used as a patient model. It was found that the effective dose during BNCT of a brain tumor is equal to 0.90Sv. This effective dose may induce a 4% secondary cancer risk.


Nanocarriers for optimizing the balance between interfollicular permeation and follicular uptake of topically applied clobetasol to minimize adverse effects.
The treatment of various hair disorders has become a central focus of good dermatologic patient care as it affects men and women all over the world. For many inflammatory-based scalp diseases, glucocorticoids are an essential part of treatment, even though they are known to cause systemic as well as local adverse effects when applied topically. Therefore, efficient targeting and avoidance of these side effects are of utmost importance. Optimizing the balance between drug release, interfollicular permeation, and follicular uptake may allow minimizing these adverse events and simultaneously improve drug delivery, given that one succeeds in targeting a sustained release formulation to the hair follicle. To test this hypothesis, three types of polymeric nanocarriers (nanospheres, nanocapsules, lipid-core nanocapsules) for the potent glucocorticoid clobetasol propionate (CP) were prepared. They all exhibited a sustained release of drug, as was desired. The particles were formulated as a dispersion and hydrogel and (partially) labeled with Rhodamin B for quantification purposes. Follicular uptake was investigated using the Differential Stripping method and was found highest for nanocapsules in dispersion after application of massage. Moreover, the active ingredient (CP) as well as the nanocarrier (Rhodamin B labeled polymer) recovered in the hair follicle were measured simultaneously, revealing an equivalent uptake of both. In contrast, only negligible amounts of CP could be detected in the hair follicle when applied as free drug in solution or hydrogel, regardless of any massage. Skin permeation experiments using heat-separated human epidermis mounted in Franz Diffusion cells revealed equivalent reduced transdermal permeability for all nanocarriers in comparison to application of the free drug. Combining these results, nanocapsules formulated as an aqueous dispersion and applied by massage appeare to be a good candidate to maximize follicular targeting and minimize drug penetration into the interfollicular epidermis. We conclude that such nanotechnology-based formulations provide a viable strategy for more efficient drug delivery to the hair follicle. Moreover, they present a way to minimize adverse effects of potent glucocorticoids by releasing the drug in a controlled manner and simultaneously decreasing interfollicular permeation, offering an advantage over conventional formulations for inflammatory-based skin/scalp diseases.


Exposure to Rabies in Small Indian Mongooses (Herpestes auropunctatus) from Two Regions in Puerto Rico.
The small Indian mongoose (Herpestes auropunctatus) was introduced to several Caribbean Islands to control rat (Rattus spp.) damage to sugarcane plantations. Mongooses failed at suppressing rat populations and are now considered pests throughout most of their introduced range. Importantly, mongooses are rabies reservoirs on several Caribbean Islands. In Puerto Rico, mongooses have been implicated in up to 70% of reported animal rabies cases. There is no rabies vaccination program for wildlife in Puerto Rico, and data on rabies in mongooses are limited. We conducted a serosurvey of mongooses in two different ecologic environments in Puerto Rico: El Yunque National Forest and Cabo Rojo National Wildlife Refuge. We collected 119 serum samples from 112 mongooses, 44 (39.3%) of which were positive for rabies virus-neutralizing antibodies. We also collected oral swabs from 147 mongooses, including 88 from which we also collected serum. No oral swabs were positive for rabies virus RNA. Our data support previous research suggesting rabies virus is circulating within the mongoose population on Puerto Rico.


Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling.
Receptor activator of NF-kappaB ligand (RANKL) activates signaling pathways that regulate osteoclast differentiation, function, and survival. The microphthalmia transcription factor (MITF) is required for terminal differentiation of osteoclasts. To determine whether MITF could be a target of RANKL signaling, a phosphospecific MITF antibody directed against conserved residue Ser(307), a potential mitogen-activated protein kinase (MAPK) site, was produced. Using this antibody, we could demonstrate that MITF was rapidly and persistently phosphorylated upon stimulation of primary osteoclasts with RANKL and that phosphorylation of Ser(307) correlated with expression of the target gene tartrate-resistant acid phosphatase. MITF phosphorylation at Ser(307) also correlated with persistent activation of p38 MAPK, and p38 MAPK could utilize MITF Ser(307) as a substrate in vitro. The phosphorylation of MITF and activation of target gene expression in osteoclasts were blocked by p38 MAPK inhibitor SB203580. In transient transfections, a constitutively active Rac1 or MKK6 gene could collaborate with MITF to activate the tartrate-resistant acid phosphatase gene promoter dependent on Ser(307). Dominant negative p38 alpha and beta could inhibit the collaboration between upstream signaling components and MITF in the transient assays. These results indicate that MITF is a target for the RANKL signaling pathway in osteoclasts and that phosphorylation of MITF leads to an increase in osteoclast-specific gene expression.


On-chip, planar integration of Er doped silicon-rich silicon nitride microdisk with SU-8 waveguide with sub-micron gap control.
On-chip, planar integration of Er-doped Silicon-rich silicon nitride microdisks with SU-8 waveguide and polymer cladding is achieved. The lack of high temperature or etching processes allows back-end integration without any optical damage to the microcavity resonator. The maximum measured Q-factor at 1475.5 nm was 13,000, corresponding to calculated intrinsic resonator Q-factor of 25,000 that is limited by process-related roughness.


Prevention of type 1 diabetes by immature dendritic cells treated with an ethanol extract of Paecilomyces hepiali Chen mycelium.
Dendritic cells (DCs) classically promote immune responses but can be manipulated to induce antigen-specific hyporesponsiveness. It has been shown that phenotypically "immature" DCs, defined by low levels of costimulatory molecules at the cell surface, are involved in the induction of peripheral immune tolerance in autoimmunity. Paecilomyces hepiali Chen (PHC) mycelium, as a substitute for Cordyceps, has been used extensively as an immunomodulator to treat numerous diseases. In this study, the effects of an ethanol extract of PHC (EEPHC) on the phenotypic and functional maturation of bone marrow-derived DCs (BM-DCs) from NOD mice were evaluated. EEPHC significantly suppressed the expression of major histocompatibility complex (MHC) class II molecules and the costimulatory molecules CD40 and CD86 in NOD BM-DCs. These DCs also exhibited impaired production of the proinflammatory cytokine interleukin-12 (IL-12) and poor stimulatory capacity in the presence of EEPHC. Moreover, inhibition of the activation and differentiation of cultured DCs was associated with reduced DNA binding activity of nuclear factor kappa B (NF- kappaB), a transcription factor recently shown to be responsible for DC maturation. Administration of 3x10(5) EEPHC-treated DCs into NOD mice aged 3-4 weeks effectively prevented the onset of diabetes. Furthermore, splenocytes from the protected mice produced high amounts of IL-4 and IL-10 and low levels of IL-2 and interferon gamma, suggesting that these DCs deficient in NF- kappaB activity are responsible for the apparent shift in type 2 helper T cells. These novel results showed that EEPHC could specifically inhibit NF- kappaB activity and maintain DCs in a potentially tolerogenic state, permitting their use in strategies to induce immune tolerance in type 1 diabetes.


Maternal upward socioeconomic mobility and black-white disparities in infant birthweight.
We estimate the extent to which upward socioeconomic mobility limits the probability that Black and White women who spent their childhoods in or near poverty will give birth to a low-birthweight baby. Data from the National Longitudinal Survey of Youth 1979 and the 1970 US Census were used to complete a series of logistic regression models. We restricted multivariate analyses to female survey respondents who, at 14 years of age, were living in households in which the income-to-needs ratio did not exceed 200% of poverty. For White women, the probability of giving birth to a low-birthweight baby decreases by 48% for every 1 unit increase in the natural logarithm of adult family income, once the effects of all other covariates are taken into account. For Black women, the relation between adult family income and the probability of low birthweight is also negative; however, this association fails to reach statistical significance. Upward socioeconomic mobility contributes to improved birth outcomes among infants born to White women who were poor as children, but the same does not hold true for their Black counterparts.


Maca (Lepidium meyenii) for treatment of menopausal symptoms: A systematic review.
Maca (Lepidium meyenii), an Andean plant of the brassica (mustard) family has been used for centuries in the Andes as an adaptogenic plant to manage anemia, infertility and female hormone balance. The aim of this review was to assess the evidence for and against the effectiveness of the maca plant as a treatment for menopausal symptoms. We searched 17 databases from their inception up to June 2011 and included all randomized clinical trials (RCTs) that compared any type of maca-based intervention to a placebo for the treatment of menopausal symptoms. All studies were assessed for methodological quality using the Cochrane 'risk of bias' assessment tool. Four RCTs met all inclusion criteria. These RCTs tested the effects of maca on menopausal symptoms in healthy perimenopausal, early postmenopausal, and late postmenopausal women. Using the Kupperman Menopausal Index and the Greene Climacteric Score, all RCTs demonstrated favorable effects of maca. There have been very few rigorous trials of maca for menopausal symptoms. The results of our systematic review provide limited evidence for the effectiveness of maca as a treatment for menopausal symptoms. However, the total number of trials, the total sample size, and the average methodological quality of the primary studies, were too limited to draw firm conclusions. Furthermore, the safety has not been proved yet. Therefore, the efficacy and safety should be tested in larger studies.


Outcome of unstable fractures of metacarpal and phalangeal bones treated by bone tie.
Unstable fractures of the metacarpal and phalangeal bones of the hand need surgical stabilization which should be rigid enough for early active mobilization. Conventional methods of open reduction and stabilization in the form of composite fixation or screws with or without plates have served the purpose but can be definitely improvised addressing both biological and mechanical principles of fixation. 34 patients (29 males and 5 females) with an average age of 32 years (range 10-64 years) with unstable fractures of the metacarpal and phalangeal bones of hand who were treated with the modified bone tie between June 2009 and June 2013 were included in this study. 42 fractures, involving the 31 metacarpals and 11 phalanges were included. We have not used this technique in fractures involving the terminal phalanges. Thirty nine of the fractures were treated with K-wires along with the modified bone tie, whereas the other two cases were treated with modified bone tie alone and in one case the bone tie has been used along with the external fixator. The nature of injuries were Road Traffic Accident (n = 24), domestic/industrial injuries (n = 8) and blast (n = 2) injuries. Etiology was crush (n = 24), blunt (n = 7) and incised (n = 3) injuries, respectively. Twenty seven patients were involved with single fractures (either metacarpal or the phalanges), 6 patients had two fractures (both metacarpals or phalanges or one each of metacarpal and phalanx), and 1 patient had three fractures in this study. Dominant hand was involved in 14 patients (40%). We achieved excellent to good results in 83% of 42 fractures within an average period of 10 weeks. Postoperative grip strength of 85% was achieved with in an average period of 12 weeks. Twenty six (20 metacarpals and 6 phalanges) of the 42 fractures regained >85% of the total active movements (TAMs) compared to the contralateral side were considered excellent results. All patients were followed up for a minimum of 1 year. This method of composite fixation allowed the surgeon to remove the concomitantly used axial K-wire at or <3 weeks clearly explaining the biomechanical basis for better results with minimum complication rates.


A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels.
Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K2P) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca2+)-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design.


Screening athletes for cardiovascular disease in Africa: a challenging experience.
Preparticipation cardiovascular (CV) screening has been advocated as an efficient strategy to reduce sudden cardiac death in Caucasian athletes. At present, uncertainty remains if such strategy is feasible and efficient in native African athletes. To this scope, we performed a CV screening in an African setting. 210 male Gabonian football players were examined with history, physical examination, ECG and echocardiography. On history, 19 players (9%) referred atypical chest discomfort/oppression. Familial sudden death was referred by 36 (17%). No anomalies were detected at physical examination. ECG showed large proportions of 'training-related' abnormalities, that is, ST-segment elevation in precordial leads in 150 (71.4%), and isolated increase in R/S-wave voltage in 116 (55.2%). A substantial subset (12.4%) showed 'training-unrelated' abnormalities, that is, inverted T-waves in 10 (4.8%), left atrial enlargement in 8 (4%), deep Q-waves in 3 (1.4%). On echocardiography, one athlete meet criteria for hypertrophic cardiomyopathy (HCM); none showed evidence for arrhythmogenic right ventricular cardiomyopathy (ARVC) or dilated cardiomyopathy (DCM). Other abnormalities included mitral valve prolapse in three, atrial septal defect in two and pulmonary hypertension in one. About 12% of native African athletes showed ECG abnormalities unrelated to training and requiring additional testing and periodical follow-up. Structural abnormalities were found, however, in a minority (5%), including HCM in one, but no ARVC or DCM. In conclusion, this study demonstrates that preparticipation CV screening is efficient to identify (or raise suspicion) for CV abnormalities in native African athletes, but challenging for conclusive identification of cardiac diseases in the difficult scenario of a developing African country.


Acute kidney injury due to anti-tuberculosis drugs: a five-year experience in an aging population.
Patients on anti-tuberculosis treatment may develop acute kidney injury (AKI), but little is known about the renal outcome and prognostic factors, especially in an aging population. This study aimed to calculate the incidence of AKI due to anti-TB drugs and analyze the outcomes and predictors of renal recovery. From 2006 to 2010, patients on anti-TB treatment were identified and their medical records reviewed. Acute kidney injury was defined according to the criteria established by the AKI Network, while renal recovery was defined as a return of serum creatinine to baseline. Predictors of renal recovery were identified by Cox regression analysis. Ninety-nine out of 1394 (7.1%) patients on anti-TB treatment had AKI. Their median age was 68 years and there was male predominance. Sixty (61%) developed AKI within two months of anti-TB treatment, including 11 (11%) with a prior history of rifampin exposure. Thirty (30%) had co-morbid chronic kidney disease or end-stage renal disease. The median time of renal recovery was 39.6 days (range, 1-180 days). Factors predicting renal recovery were the presence of fever, rash, and gastro-intestinal disturbance at the onset of AKI. Sixty-two of the 71 (87%) patients who recovered from AKI had successful re-introduction or continuation of rifampin. Renal function impairment is not a rare complication during anti-TB treatment in an elderly population. The presence of fever and rash may be associated with renal recovery. Rifampin can still be used in most patients who recover from AKI.


Brown propolis-metabolomic innovative approach to determine compounds capable of killing Staphylococcus aureus biofilm and Trichomonas vaginalis.
Propolis, a resin produced by bees, is widely used in industrial products, including food, cosmetics, supplements, and pharmaceuticals. Extracts (ethanolic and hydroethanolic) and fractions, yielded by accelerated solvent extraction methodology, were obtained from different samples of Brazilian brown propolis (BBP). They were evaluated for antioxidant capacity, antibacterial, antibiofilm, and anti-Trichomonas vaginalis activities. The metabolomics profiling was determined by LC-DAD-MS and an innovative application of statistical analyses (univariate and chemometrics) was applied to correlate chemical compounds with biological activities. Eighty-six compounds were identified, including phenylpropanoic acids, flavonoids, chlorogenic acids, and prenylated phenylpropanoic acids. Propolis-fractions killed about 93% of Staphylococcus aureus in biofilm (at concentration of 125 μg/mL), showed activity against T. vaginalis with MIC at 400 μg/mL and significative antioxidant capacity (IC50 2.32-3.80 μg/mL). Propolis extracts and fractions did not show antibacterial and antibiofilm activities against Pseudomonas aeruginosa. The prenylated phenylpropanoic acids positively correlated with both the antibiofilm (S. aureus) and anti-T. vaginalis activities, such as the metabolites artepillin C, drupanin, and baccharin.


Competition from newborn granule cells does not drive axonal retraction of silenced old granule cells in the adult hippocampus.
In the developing nervous system synaptic refinement, typified by the neuromuscular junction where supernumerary connections are eliminated by axon retraction leaving the postsynaptic target innervated by a single dominant input, critically regulates neuronal circuit formation. Whether such competition-based pruning continues in established circuits of mature animals remains unknown. This question is particularly relevant in the context of adult neurogenesis where newborn cells must integrate into preexisting circuits, and thus, potentially compete with functionally mature synapses to gain access to their postsynaptic targets. The hippocampus plays an important role in memory formation/retrieval and the dentate gyrus (DG) subfield exhibits continued neurogenesis into adulthood. Therefore, this region contains both mature granule cells (old GCs) and immature recently born GCs that are generated throughout adult life (young GCs), providing a neurogenic niche model to examine the role of competition in synaptic refinement. Recent work from an independent group in developing animals indicated that embryonically/early postnatal generated GCs placed at a competitive disadvantage by selective expression of tetanus toxin (TeTX) to prevent synaptic release rapidly retracted their axons, and that this retraction was driven by competition from newborn GCs lacking TeTX. In contrast, following 3-6 months of selective TeTX expression in old GCs of adult mice we did not observe any evidence of axon retraction. Indeed ultrastructural analyses indicated that the terminals of silenced GCs even maintained synaptic contact with their postsynaptic targets. Furthermore, we did not detect any significant differences in the electrophysiological properties between old GCs in control and TeTX conditions. Thus, our data demonstrate a remarkable stability in the face of a relatively prolonged period of altered synaptic competition between two populations of neurons within the adult brain.


Bayesian bivariate meta-analysis of diagnostic test studies using integrated nested Laplace approximations.
For bivariate meta-analysis of diagnostic studies, likelihood approaches are very popular. However, they often run into numerical problems with possible non-convergence. In addition, the construction of confidence intervals is controversial. Bayesian methods based on Markov chain Monte Carlo (MCMC) sampling could be used, but are often difficult to implement, and require long running times and diagnostic convergence checks. Recently, a new Bayesian deterministic inference approach for latent Gaussian models using integrated nested Laplace approximations (INLA) has been proposed. With this approach MCMC sampling becomes redundant as the posterior marginal distributions are directly and accurately approximated. By means of a real data set we investigate the influence of the prior information provided and compare the results obtained by INLA, MCMC, and the maximum likelihood procedure SAS PROC NLMIXED. Using a simulation study we further extend the comparison of INLA and SAS PROC NLMIXED by assessing their performance in terms of bias, mean-squared error, coverage probability, and convergence rate. The results indicate that INLA is more stable and gives generally better coverage probabilities for the pooled estimates and less biased estimates of variance parameters. The user-friendliness of INLA is demonstrated by documented R-code.