Couples coping with nutrition-related problems in advanced cancer: A qualitative study in primary care.
Nutrition-related problems are common in patients with advanced cancer. They can disrupt daily life and routines. This study aimed to explore how couples cope with this source of distress. A qualitative descriptive study design was adopted using semi-structured interviews. Seven couples, each consisting of an advanced cancer patient and his or her co-habiting life partner, participated. The Qualitative Analysis Guide of Leuven (QUAGOL) was used as a guide to facilitate the analysis process. When a patient communicates nutrition-related problems to the partner, individual coping is often complemented by interactive couple-coping pathways, serving two resilient coping strategies: maintaining normality and creating a new normality. These pathways can have either a practical, an emotional or a distant orientation. Different couple-coping pathways can be observed in the same couple when they are dealing with either one or multiple nutrition-related problems. Some couples, however, seem to cope more rigidly, often those with less observed 'we-ness'. Nutrition-related problems are inherent to advanced cancer and are perceived as health-threatening. Couple-coping with nutrition-related problems is a dynamic and interactive process leaning on different coping pathways. There is no evidence that one pathway is superior to another, as they all serve a resilient coping strategy. Our findings can assist homecare nurses and other professional caregivers in providing psychological support and advice to couples confronted with nutrition-related problems in advanced cancer. Future research should shed light on whether an unsuitable match in coping styles within a couple is one of the precursors of non-resilient outcomes.


Maternal smoking impacts key biological pathways in newborns through epigenetic modification in Utero.
Children exposed to maternal smoking during pregnancy exhibit increased risk for many adverse health effects. Maternal smoking influences methylation in newborns at specific CpG sites (CpGs). Here, we extend evaluation of individual CpGs to gene-level and pathway-level analyses among 1062 participants in the Norwegian Mother and Child Cohort Study (MoBa) using the Illumina 450 K platform to measure methylation in newborn DNA and maternal smoking in pregnancy, assessed using the biomarker, plasma cotinine. We used novel implementations of bioinformatics tools to collapse epigenome-wide methylation data into gene- and pathway-level effects to test whether exposure to maternal smoking in utero differentially methylated CpGs in genes enriched in biologic pathways. Unlike most pathway analysis applications, our approach allows replication in an independent cohort. Data on 485,577 CpGs, mapping to a total of 20,199 genes, were used to create gene scores that were tested for association with maternal plasma cotinine levels using Sequence Kernel Association Test (SKAT), and 15 genes were found to be associated (q < 0.25). Six of these 15 genes (GFI1, MYO1G, CYP1A1, RUNX1, LCTL, and AHRR) contained individual CpGs that were differentially methylated with regards to cotinine levels (p < 1.06 × 10-7). Nine of the 15 genes (FCRLA, MIR641, SLC25A24, TRAK1, C1orf180, ITLN2, GLIS1, LRFN1, and MIR451) were associated with cotinine at the gene-level (q < 0.25) but had no genome-wide significant individual CpGs (p > 1.06 × 10-7). Pathway analyses using gene scores resulted in 51 significantly associated pathways, which we tested for replication in an independent cohort (q < 0.05). Of those 32 replicated in an independent cohort, which clustered into six groups. The largest cluster consisted of pathways related to cancer, cell cycle, ERα receptor signaling, and angiogenesis. The second cluster, organized into five smaller pathway groups, related to immune system function, such as T-cell regulation and other white blood cell related pathways. Here we use novel implementations of bioinformatics tools to determine biological pathways impacted through epigenetic changes in utero by maternal smoking in 1062 participants in the MoBa, and successfully replicate these findings in an independent cohort. The results provide new insight into biological mechanisms that may contribute to adverse health effects from exposure to tobacco smoke in utero.


Cellular basis of the proliferative response of human T cells to mouse xenoantigens.
Purified human T cells respond proliferatively to allogenic peripheral blood mononuclear (PBMC) stimulating cells but show no response to murine splenic stimulating cells. Two possible explanations for the lack of xenogeneic response are that human T cells, educated in a human thymus, cannot directly recognize a molecule as disparate as mouse antigen encoded by H-2 and/or that a cytokine(s) produced by the APCs is needed to allow a proliferative response and that the cytokine(s) produced by murine APC do not provide an adequate stimulus to the human T cells under these conditions. We show here that highly purified human T cells can respond directly in an antigen-specific manner to murine stimulating cells if human rIL-1 or rIL-2 or a T cell growth factor (TCGF) preparation are present in the culture. These findings demonstrate that human T cells can recognize murine antigens and that a highly significant response can be obtained if a human cytokine is present to permit that response.


Prevalence and risk factors for extended-spectrum β-lactamase or AmpC-producing Escherichia coli in organic dairy herds in the Netherlands.
Extended-spectrum β-lactamase and AmpC-producing Escherichia coli (ESBL/AmpC) are an emerging problem and are hypothesized to be associated with antimicrobial use (AMU), and more specifically with the use of third- and fourth-generation cephalosporins. Whether ESBL/AmpC also occur in organic dairy herds, which have restricted AMU, is not known. Additionally, it is unknown whether, in addition to restricted AMU, other factors in organic herd management are associated with ESBL/AmpC herd status. The aim of this study was to estimate the prevalence of ESBL/AmpC in organic dairy herds in the Netherlands. Subsequently, the relationships between the ESBL/AmpC herd status and AMU and between ESBL/AmpC herd status and farmers' management were assessed in organic dairy herds. For this study, 90 randomly selected, officially registered organic dairy herds were included. The ESBL/AmpC herd status was determined based on the bacteriological culture result of a slurry sample. The sensitivity of testing slurry samples for ESBL/AmpC herd status is less than 100% for detecting herds with a low ESBL/AmpC prevalence. For that reason, herds that tested positive for ESBL/AmpC in slurry were defined as positive and herds with negative slurry samples were defined as unsuspected. A comprehensive questionnaire on management practices was conducted and records on specified antimicrobials that were provided to these herds by the veterinary service providers were obtained. From the data on antimicrobial supplies by the veterinarian, the animal daily defined dose of antimicrobials per farm per year (DDDAF) was calculated. Descriptive statistics were used to describe the relation between the ESBL/AmpC herd status and DDDAF. Multivariable logistic regression models were used to evaluate management factors associated with the ESBL/AmpC herd status. We found ESBL/AmpC in 12 of the 90 (13%; 95% confidence interval=7-22%) slurry samples from organic dairy herds. The median DDDAF in organic dairy herds was 0.5, which was not significantly different between ESBL/AmpC-positive and unsuspected dairy herds. No association could be found between the use of different types of antimicrobials, such as third- and fourth-generation cephalosporins, and ESBL/AmpC herd status. Factors that were associated with higher odds of being ESBL/AmpC-positive were pig farms located within a 2-km radius of the barn, applying parental treatment for clinical mastitis, and providing milk replacer to the female calves after colostrum intake. The prevalence of ESBL/AmpC in organic dairy herds appeared lower than the prevalence in previous studies conducted in conventional dairy herds. Apparently, ESBL/AmpC are also present in herds with low AMU; this indicates that other factors than AMU are also associated with ESBL/AmpC herd status.


A division in PIN-mediated auxin patterning during organ initiation in grasses.
The hormone auxin plays a crucial role in plant morphogenesis. In the shoot apical meristem, the PIN-FORMED1 (PIN1) efflux carrier concentrates auxin into local maxima in the epidermis, which position incipient leaf or floral primordia. From these maxima, PIN1 transports auxin into internal tissues along emergent paths that pattern leaf and stem vasculature. In Arabidopsis thaliana, these functions are attributed to a single PIN1 protein. Using phylogenetic and gene synteny analysis we identified an angiosperm PIN clade sister to PIN1, here termed Sister-of-PIN1 (SoPIN1), which is present in all sampled angiosperms except for Brassicaceae, including Arabidopsis. Additionally, we identified a conserved duplication of PIN1 in the grasses: PIN1a and PIN1b. In Brachypodium distachyon, SoPIN1 is highly expressed in the epidermis and is consistently polarized toward regions of high expression of the DR5 auxin-signaling reporter, which suggests that SoPIN1 functions in the localization of new primordia. In contrast, PIN1a and PIN1b are highly expressed in internal tissues, suggesting a role in vascular patterning. PIN1b is expressed in broad regions spanning the space between new primordia and previously formed vasculature, suggesting a role in connecting new organs to auxin sinks in the older tissues. Within these regions, PIN1a forms narrow canals that likely pattern future veins. Using a computer model, we reproduced the observed spatio-temporal expression and localization patterns of these proteins by assuming that SoPIN1 is polarized up the auxin gradient, and PIN1a and PIN1b are polarized to different degrees with the auxin flux. Our results suggest that examination and modeling of PIN dynamics in plants outside of Brassicaceae will offer insights into auxin-driven patterning obscured by the loss of the SoPIN1 clade in Brassicaceae.


Global changes in gene expression of Barrett's esophagus compared to normal squamous esophagus and gastric cardia tissues.
Barrett's esophagus (BE) is a metaplastic precursor lesion of esophageal adenocarcinoma (EA), the most rapidly increasing cancer in western societies. While the prevalence of BE is increasing, the vast majority of EA occurs in patients with undiagnosed BE. Thus, we sought to identify genes that are altered in BE compared to the normal mucosa of the esophagus, and which may be potential biomarkers for the development or diagnosis of BE. We performed gene expression analysis using HG-U133A Affymetrix chips on fresh frozen tissue samples of Barrett's metaplasia and matched normal mucosa from squamous esophagus (NE) and gastric cardia (NC) in 40 BE patients. Using a cut off of 2-fold and P<1.12E-06 (0.05 with Bonferroni correction), we identified 1324 differentially-expressed genes comparing BE vs NE and 649 differentially-expressed genes comparing BE vs NC. Except for individual genes such as the SOXs and PROM1 that were dysregulated only in BE vs NE, we found a subset of genes (n = 205) whose expression was significantly altered in both BE vs NE and BE vs NC. These genes were overrepresented in different pathways, including TGF-β and Notch. Our findings provide additional data on the global transcriptome in BE tissues compared to matched NE and NC tissues which should promote further understanding of the functions and regulatory mechanisms of genes involved in BE development, as well as insight into novel genes that may be useful as potential biomarkers for the diagnosis of BE in the future.


Comparing Machine Learning Methods and Feature Extraction Techniques for the EMG Based Decoding of Human Intention.
With an increasing number of robotic and prosthetic devices, there is a need for intuitive Muscle-Machine Interfaces (MuMIs) that allow the user to have an embodied interaction with the devices they are controlling. Such MuMIs can be developed using machine learning based methods that utilize myoelectric activations from the muscles of the user to decode their intention. However, the choice of the learning method is subjective and depends on the features extracted from the raw Electromyography signals as well as on the intended application. In this work, we compare the performance of five machine learning methods and eight time-domain feature extraction techniques in discriminating between different gestures executed by the user of an EMG based MuMI. From the results, it can be seen that the Willison Amplitude performs consistently better for all the machine learning methods compared in this study, while the Zero Crossings achieves the worst results for the Decision Trees and the Random Forests and the Variance offers the worst performance for all the other learning methods. The Random Forests method is shown to achieve the best results in terms of achieved accuracies (has the lowest variance between subjects). In order to experimentally validate the efficiency of the Random Forest classifier and the Willison Amplitude technique, a series of gestures were decoded in a real-time manner from the myoelectric activations of the operator and they were used to control a robot hand.


Vascular surgical society of great britain and ireland: twenty-three years of experience of carotid endarterectomy
BACKGROUND: Carotid endarterectomy (CEA) has been an evidence-based treatment for symptomatic severe carotid stenosis since 1991. Surgical techniques and patient selection have changed over the years. The results of CEA in a single centre over a 23-year period were reviewed. METHODS: Prospectively gathered preoperative, operative, postoperative and long-term follow-up data were analysed. Routine intraoperative shunting and patch closure has been used since 1988. Data were analysed using the chi2 test or by logistic regression, adjusting for age at operation and date of operation. RESULTS: Five hundred and seventy-three CEAs (37 bilateral and three repeat procedures) were carried out on 533 patients. Trainees performed an increasing proportion of CEAs from 1996 to 1998 (15, 50 and 56 per cent respectively). The perioperative death rate was 0.8 per cent and the rate of any perioperative neurological deficit was 6.9 per cent. Other causes of morbidity included nerve injury (5.1 per cent) of which the commonest was to the hypoglossal nerve (2.7 per cent). During follow-up (median 4 (range 0-22) years) there were 81 neurological events (15.9 per cent) which included 35 ipsilateral (6.6 per cent) and 18 contralateral (3.4 per cent) strokes. There was no significant difference in outcome for grade of surgeon, intraoperative shunting or patch closure. Major causes of death were cardiac death (74; 14.6 per cent) followed by stroke (23; 4.5 per cent) and cancer (20; 3.9 per cent). CONCLUSION: The introduction of routine intraoperative shunting and patch closure, as well as allowing surgical trainees to perform supervised CEAs, has not affected perioperative morbidity and mortality rates or long-term outcome.


Quality initiatives: guidelines for use of medical imaging during pregnancy and lactation.
The use of computed tomography (CT) and magnetic resonance (MR) imaging has increased tremendously in the past 2 decades. Hence, pregnant and breast-feeding women, although generally healthier than the population at large, are also more likely to require contrast material-enhanced imaging. When a contrast-enhanced CT or MR imaging study is being considered for a pregnant or lactating patient, the potential risks to the fetus related to exposure to radiation, high magnetic fields, or contrast agents must be considered and weighed carefully against the risks of potential misdiagnosis due to withholding contrast agents and imaging studies. Fetal radiation doses up to 1 mGy are considered acceptable; with larger doses, the risk of carcinogenesis approximately doubles, although it remains low in absolute terms. No damage to a developing human fetus caused by MR imaging exposure has been documented. However, caution is advised, and risks and benefits must always be considered before evaluating a pregnant patient with MR imaging. The use of iodinated contrast agents is generally safe during pregnancy; nevertheless, these agents should be used with caution due to the risk of fetal hypothyroidism and should be administered only when the clinical situation clearly requires doing so. The use of gadolinium-based contrast agents during pregnancy remains controversial due to lack of human clinical data and potential toxicity. Use of all contrast agents is considered safe during lactation. It is hoped that this knowledge will help radiologists develop a consensus with their clinical colleagues regarding case management of pregnant and lactating patients.


Modelling COVID 19 in the Basque Country from introduction to control measure response.
In March 2020, a multidisciplinary task force (so-called Basque Modelling Task Force, BMTF) was created to assist the Basque health managers and Government during the COVID-19 responses. BMTF is a modelling team, working on different approaches, including stochastic processes, statistical methods and artificial intelligence. Here we describe the efforts and challenges to develop a flexible modeling framework able to describe the dynamics observed for the tested positive cases, including the modelling development steps. The results obtained by a new stochastic SHARUCD model framework are presented. Our models differentiate mild and asymptomatic from severe infections prone to be hospitalized and were able to predict the course of the epidemic, providing important projections on the national health system's necessities during the increased population demand on hospital admissions. Short and longer-term predictions were tested with good results adjusted to the available epidemiological data. We have shown that the partial lockdown measures were effective and enough to slow down disease transmission in the Basque Country. The growth rate [Formula: see text] was calculated from the model and from the data and the implications for the reproduction ratio r are shown. The analysis of the growth rates from the data led to improved model versions describing after the exponential phase also the new information obtained during the phase of response to the control measures. This framework is now being used to monitor disease transmission while the country lockdown was gradually lifted, with insights to specific programs for a general policy of "social distancing" and home quarantining.


Identification of the blood component responsible for increased susceptibility to gut-derived infection.
It has previously been reported that the transfusion of allogeneic whole blood increases sepsis-related mortality and decreases the ability of the host to kill bacteria that have translocated from the intestinal tract. To determine which blood component contributes to this adverse effect, the impact of the transfusion of white cells (WBCs), red cells (RBCs), and plasma on microbial translocation, bacteria killing, and mortality rate was studied. Blood from C3H/HeJ mice was separated into WBCs, RBCs, and plasma, and these fractions were transfused to Balb/c mice. Controls received sterile saline. Five days after transfusion, all Balb/c mice underwent a 20-percent burn and gavage with 1 x 10(10) Escherichia coli labeled with 14C-glucose. Mortality was observed for 10 days. Four additional groups, receiving the same treatment as above, were sacrificed 4 hours after the burn, and mesenteric lymph nodes, liver, kidney, and blood were harvested aseptically. For each tissue, quantitative colony counts, radionuclide counts, and percentage of translocated bacteria that remained alive were calculated. By radionuclide counts, no difference was observed in the degree of 14C E. coli translocation among the groups. In contrast, the percentage of viable bacteria and the mortality rate were significantly higher in the group receiving allogeneic WBCs than in all other groups (p < 0.05). It is concluded that WBCs are the component in transfused blood that has an adverse effect on host resistance to gut-derived infection.


Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice.
Naringenin is a citrus flavonoid that potently inhibits the assembly and secretion of apolipoprotein B100-containing lipoproteins in cultured hepatocytes and improves the dyslipidemia and insulin resistance in a mouse model of the metabolic syndrome. In the present study, we used low-density lipoprotein receptor-null mice fed a high-fat diet (Western, TD96125) to test the hypothesis that naringenin prevents atherosclerosis. Three groups (chow, Western, and Western plus naringenin) were fed ad libitum for 6 months. The Western diet increased fasting plasma triglyceride (TG) (5-fold) and cholesterol (8-fold) levels compared with chow, whereas the addition of naringenin significantly decreased both lipids by 50%. The Western-fed mice developed extensive atherosclerosis in the aortic sinus because plaque area was increased by 10-fold compared with chow-fed animals. Quantitation of fat-soluble dye (Sudan IV)-stained aortas, prepared en face, revealed that Western-fed mice also had a 10-fold increase in plaque deposits throughout the arch and in the abdominal sections of the aorta, compared with chow. Atherosclerosis in both areas was significantly decreased by more than 70% in naringenin-treated mice. Consistent with quantitation of aortic lesions, the Western-fed mice had a significant 6-fold increase in cholesterol and a 4-fold increase in TG deposition in the aorta compared with chow-fed mice. Both were reduced more than 50% by naringenin. The Western diet induced extensive hepatic steatosis, with a 10-fold increase in both TG and cholesteryl ester mass compared with chow. The addition of naringenin decreased both liver TG and cholesteryl ester mass by 80%. The hyperinsulinemia and obesity that developed in Western-fed mice was normalized by naringenin to levels observed in chow-fed mice. These in vivo studies demonstrate that the citrus flavonoid naringenin ameliorates the dyslipidemia in Western-fed low-density lipoprotein receptor-null mice, leading to decreased atherosclerosis; and suggests a potential therapeutic strategy for the hyperlipidemia and increased risk of atherosclerosis associated with insulin resistance.


Encoding of marginal utility across time in the human brain.
Marginal utility theory prescribes the relationship between the objective property of the magnitude of rewards and their subjective value. Despite its pervasive influence, however, there is remarkably little direct empirical evidence for such a theory of value, let alone of its neurobiological basis. We show that human preferences in an intertemporal choice task are best described by a model that integrates marginally diminishing utility with temporal discounting. Using functional magnetic resonance imaging, we show that activity in the dorsal striatum encodes both the marginal utility of rewards, over and above that which can be described by their magnitude alone, and the discounting associated with increasing time. In addition, our data show that dorsal striatum may be involved in integrating subjective valuation systems inherent to time and magnitude, thereby providing an overall metric of value used to guide choice behavior. Furthermore, during choice, we show that anterior cingulate activity correlates with the degree of difficulty associated with dissonance between value and time. Our data support an integrative architecture for decision making, revealing the neural representation of distinct subcomponents of value that may contribute to impulsivity and decisiveness.


Analysis of free online physician advice services.
Online Consumer Health websites are a major source of information for patients worldwide. We focus on another modality, online physician advice. We aim to evaluate and compare the freely available online expert physicians' advice in different countries, its scope and the type of content provided. Using automated methods for information retrieval and analysis, we compared consumer health portals from the US, Canada, the UK and Israel (WebMD,NetDoctor,AskTheDoctor and BeOK). The evaluated content was generated between 2002 and 2011. We analyzed the different sites, looking at the distribution of questions in the various health topics, answer lengths and content type. Answers could be categorized into longer broad-educational answers versus shorter patient-specific ones, with different physicians having personal preferences as to answer type. The Israeli website BeOK, providing 10 times the number of answers than in the other three health portals, supplied answers that are shorter on average than in the other websites. Response times in these sites may be rapid with 32% of the WebMD answers and 64% of the BeOK answers provided in less than 24 hours. The voluntary contribution model used by BeOK and WebMD enables generation of large numbers of physician expert answers at low cost, providing 50,000 and 3,500 answers per year, respectively. Unlike health information in online databases or advice and support in patient-forums, online physician advice provides qualified specialists' responses directly relevant to the questions asked. Our analysis showed that high numbers of expert answers could be generated in a timely fashion using a voluntary model. The length of answers varied significantly between the internet sites. Longer answers were associated with educational content while short answers were associated with patient-specific content. Standard site-specific guidelines for expert answers will allow for more desirable content (educational content) or better throughput (patient-specific content).


Strain dependence of second-harmonic generation in silicon.
Strained silicon is a versatile new type of material, which has found application in microelectronics and integrated optics in the last years. Unlike ordinary silicon, it does not possess a centrosymmetric lattice structure. This allows for stimulation of nonlinear optical processes that involve second-order nonlinear susceptibility. Here, the dependence of the nonlinear susceptibility on the applied strain by means of reflected second-harmonic generation is investigated. This surface-sensitive technique is suitable for the investigation of bulk silicon strained by a layer of thermal oxide. The obtained relation between applied stress and susceptibility enhancement is compared to theoretical prediction based on an analytical model for the deformed silicon orbital. The knowledge of the stress-susceptibility dependence can be used to develop suitable photonic devices that benefit from second-order nonlinear processes in silicon.


Drug-induced acute liver failure and gastrointestinal complications.
The objective of this article is to describe adverse drug events related to the liver and gastrointestinal tract in critically ill patients. PubMed and other resources were used to identify information related to drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis in critically ill patients. This information was reviewed, and data regarding pathophysiology, common drug causes, and guidelines for prevention and management were collected and summarized. In cases in which data in critically ill patients were unavailable, data were extrapolated from other patient populations. Drug-induced acute liver failure can be caused by many drugs routinely used in the intensive care unit and may be associated with significant morbidity and mortality. Drug-related hypomotility and constipation and drug-related diarrhea are reported with many drugs, and these are common adverse drug events in critically ill patients that can substantially complicate the care of these patients. Drug-induced gastrointestinal bleeding and drug-induced pancreatitis occur less frequently, can range in disease severity, and can be associated with morbidity and mortality. Many drugs used in critically ill patients are associated with adverse drug events related to the liver and gastrointestinal tract. Critical care clinicians should be aware of common drug causes of drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis, and should be familiar with the prevention and management of these diverse conditions.


Glutathione-induced amino-activatable micellar photosensitization platform for synergistic redox modulation and photodynamic therapy.
In recent years, photodynamic therapy (PDT) was considered to be a promising cancer treatment modality, however, the therapeutic efficiency was often attenuated by the intrinsic antioxidant defense systems. Herein, a kind of novel glutathione-induced amino-activatable micelle was designed, which was expected to weaken the antioxidant capacity and in the meantime release the photosensitizer by the exhaustion of intracellular glutathione (GSH). The amphiphilic poly(ethylene glycol)-(2-((2,4-dinitro-N-(ethyl) phenyl)sulfonamido) ethyl methacrylate) copolymers were synthesized and assembled into a core-shell nano structure in aqueous media. The nano structure demonstrated high sensitivity and selectivity to bio-thiols in vitro and in vivo. Subsequently, pheophorbide a (PhA) was encapsulated as the model photosensitizer. Upon internalization by HepG2 cells, the strongly electron-withdrawing 2,4-dinitrobenzenesulfonyl groups on the PADEE segments were readily cleaved by GSH, during which time the secondary amino groups (pKb = 11.32) were recovered and completely protonated, leading to disassembly of the micelles and rapid release of PhA. Importantly, the consumption of GSH weakened the intracellular antioxidant capacity, resulting in the synergetic accumulation of reactive oxygen species (ROS) under laser irradiation. As a result, this micellar photosensitization system could overcome the antioxidant capacity of advanced stage tumors through a simultaneous extrinsic and intrinsic strategy, facilitating therapeutic efficiency. These results demonstrate that the as-designed micelles provide a versatile photosensitization platform for on-demand PDT.


Does this patient have a pleural effusion?
Pleural effusion is a common finding among patients presenting with respiratory symptoms. The value of the bedside examination to detect pleural effusion is unclear. To systematically review the evidence regarding the accuracy of the physical examination in assessing the probability of a pleural effusion. We searched MEDLINE (1950-October 2008) and EMBASE (1980-October 2008) using Ovid to identify English-language studies conducted in a clinical setting. Additional studies were identified by searching the bibliographies of retrieved articles and contacting experts in the field. We included prospective studies of diagnostic accuracy that compared at least 1 physical examination maneuver with radiographic confirmation of pleural effusion. Three authors independently appraised study quality and extracted relevant data. Data regarding participant recruitment, reference standard, diagnostic test(s), and test accuracy were extracted. Disagreements were resolved by consensus. We identified 310 unique citations, but only 5 prospectively conducted studies met inclusion criteria (N = 934 patients). A random-effects model was used for quantitative synthesis. Of the 8 physical examination maneuvers evaluated in the included studies (conventional percussion, auscultatory percussion, breath sounds, chest expansion, tactile vocal fremitus, vocal resonance, crackles, and pleural friction rub), dullness to conventional percussion was most accurate for diagnosing pleural effusion (summary positive likelihood ratio, 8.7; 95% confidence interval, 2.2-33.8), while the absence of reduced tactile vocal fremitus made pleural effusion less likely (negative likelihood ratio, 0.21; 95% confidence interval, 0.12-0.37). Based on the limited number of studies, dullness to percussion and tactile fremitus are the most useful findings for pleural effusion. Dull chest percussion makes the probability of a pleural effusion much more likely but requires a chest radiograph to confirm the diagnosis. When the pretest probability of pleural effusion is low, the absence of reduced tactile vocal fremitus makes pleural effusion less likely so that a chest radiograph might not be necessary depending on the overall clinical situation.


Overcoming Abuse: A Phenomenological Investigation of the Journey to Recovery From Past Intimate Partner Violence.
To date, minimal research has focused on the recovery process for survivors of intimate partner violence (IPV). This study utilized a phenomenological methodology to understand the lived experiences of survivors of IPV ( N = 123) who had overcome abusive relationships and created violence-free and meaningful lives. The researchers aimed to understand key factors involved in their recovery processes. Results indicated two main processes in the IPV recovery process: intrapersonal processes and interpersonal processes. Intrapersonal processes included (a) regaining and recreating one's identity, (b) embracing the freedom and power to direct one's own life, (c) healing from the mental and physical health symptoms of the abuse, (d) fostering acceptance and forgiveness with self and abuser, (e) education and examination of abusive relationships, (f) determining whether and how to enter new intimate relationships, and (g) acknowledging the long-term process of overcoming abuse. Interpersonal processes included themes of (a) building positive social support and relationships and (b) using ones' experiences with abuse to help others. Results of the present study are presented, and implications for practitioners are discussed.


Increased activation of protein kinase C with cubic phase lipid compared with liposomes.
Protein kinase C (PKC) activation is measured using liposomes containing phosphatidylserine. Certain lipids display a wide range of polymorphism, depending on conditions. They can give rise to nonlamellar phases, such as hexagonal or cubic phases, as well as to lamellar phases. In this paper, we studied the activity and membrane binding of PKC in lipid bicontinuous cubic phases and hexagonal phases. The cubic phase lipid systems were (1) monoolein with 1-palmitoyl-2-oleoyl-3-phosphatidylserine (MO/PS) and (2) dielaidoylphosphatidylethanolamine/alamethicin (DEPE/alamethicin). Under fully hydrated conditions, both of the above lipid mixtures are bicontinuous cubic phases with a space group of Pn3m within certain concentration ratios and temperature ranges. Dioleoylphosphatidylethanolamine (DOPE) with up to 10 mol % PS exists in the hexagonal phase at room temperature. These cubic and hexagonal phases were able to support the PKC-catalyzed phosphorylation of histone. The amount of PKC bound to the MO/PS cubic phase showed little increase between 5 and 10 mol % PS. For both of the cubic phase systems studied, only a minor fraction of the PKC was bound to the membrane. This indicates that the specific activity of the enzyme bound to cubic phase membranes is much greater than that bound to phospholipid in the lamellar phase. Addition of up to 50 mol % MO to lipid in the lamellar phase had relatively small effects on the activity of PKC. The increase in PKC activity correlated well with an increase in PKC binding, resulting in little change in the specific activity of the membrane-bound form. These findings may be physiologically relevant due to the apparent presence of the cubic phase in certain biological structures. Also, these phases have little or no curvature strain, a property which has been shown to correlate with activation of PKC. Therefore, other factors, such as a curved morphology and/or interfacial polarity, must be responsible for the activation of PKC in these lipid systems.


Efficacy of a web- and text messaging-based intervention to reduce problem drinking in young people: study protocol of a cluster-randomised controlled trial.
Problem drinking, particularly risky single-occasion drinking is widespread among adolescents and young adults in most Western countries. Mobile phone text messaging allows a proactive and cost-effective delivery of short messages at any time and place and allows the delivery of individualised information at times when young people typically drink alcohol. The main objective of the planned study is to test the efficacy of a combined web- and text messaging-based intervention to reduce problem drinking in young people with heterogeneous educational level. A two-arm cluster-randomised controlled trial with one follow-up assessment after 6 months will be conducted to test the efficacy of the intervention in comparison to assessment only. The fully-automated intervention program will provide an online feedback based on the social norms approach as well as individually tailored mobile phone text messages to stimulate (1) positive outcome expectations to drink within low-risk limits, (2) self-efficacy to resist alcohol and (3) planning processes to translate intentions to resist alcohol into action. Program participants will receive up to two weekly text messages over a time period of 3 months. Study participants will be 934 students from approximately 93 upper secondary and vocational schools in Switzerland. Main outcome criterion will be risky single-occasion drinking in the past 30 days preceding the follow-up assessment. This is the first study testing the efficacy of a combined web- and text messaging-based intervention to reduce problem drinking in young people. Given that this intervention approach proves to be effective, it could be easily implemented in various settings, and it could reach large numbers of young people in a cost-effective way. Current Controlled Trials ISRCTN59944705.


Evaluation of an Optimized Injection System for Retinal Gene Therapy in Human Patients.
Many retinal gene therapy clinical trials require subretinal injections of small volumes of adeno-associated viral (AAV) vector solutions in patients with retinal dystrophies, using equipment not specifically designed for this purpose. We therefore evaluated an optimized injection system in order to identify variables that might influence the rate of injection and final dose of vector delivered. An optimized injection system was assembled with a 41G polytetrafluoroethylene tip for retinal gene therapy. Flow rate was recorded at relevant infusion pressures (2-22 psi [14-152 kPa]), different target pressures (0.02-30 mm Hg [0.003-4 kPa]) and temperatures (18°C vs. 36°C) using a semiautomated Accurus(®) Surgical System. Retention of AAV2/8 and AAV2/8(Y733F) vector was quantified after simulating loading/injection with or without 0.001% Pluronic(®) F-68 (PF-68). The optimized injection system provided a linear flow rate (μl/s)-to-infusion pressure (psi) relationship (y = 0.62x; r(2) = 0.99), independent of temperature and pressure changes relevant for intraocular surgery (18-36°C, 0.02-30 mm Hg). Differences in length of 41G polytetrafluoroethylene tips caused significant variation in flow rate (p < 0.001). Use of PF-68 significantly (p < 0.001) reduced loss of vector genomes in the injection system by 55% (AAV2/8) and 52% (AAV2/8(Y733F)). A customized subretinal injection system assembled using equipment currently available in the operating room can deliver a controlled volume of vector at a fixed rate across a range of possible clinical parameters encountered in vitreoretinal surgery. The inclusion of 0.001% PF-68 had a significant effect on the final dose of vector genomes delivered. The described technique is currently used successfully in a clinical trial.


Comparative study of different brands of stavudine capsules for the off-label 'opened capsule' dosing method recommended for HIV-infected infants and children in resource-limited settings.
INTRODUCTION: If a caregiver does not have access to a refrigerator, the South African National Department of Health advises that stavudine adult capsule formulations be employed using the off-label 'opened capsule' dosing method. The accuracy of this dosing method has not previously been validated. AIM: To assess the accuracy of the off-label opened capsule method for stavudine dosing in infants and children. In addition, we assessed the relative ease of dispersion of generic and original capsule preparations in water to determine which preparations, if any, are suitable for the off-label opened capsule dosing method. METHOD: We evaluated 10 Zerit (Bristol-Myers Squibb), 5 Stavudine (Aspen), and 5 Stavir (Cipla) capsules. Each capsule was dispersed in 30 ml water, creating 20 separate solutions. Timed dispersion of each generic was compared with that of the original (Zerit). Each solution was then centrifuged to remove sediment, and the concentration of active drug (mg/ml) was analysed by high-performance liquid chromatography. RESULTS: The ease of dispersion of the contents of Aspen Stavudine capsules was equivalent to that of Zerit, and resulted in a mean recovery of active drug from solution of over 97%, confirming the accuracy of this dosing method. The contents of Stavir capsules, however, were extremely difficult to disperse in water despite prolonged agitation; consequently, the recovery of active drug from the solution was reduced. CONCLUSION: The accuracy of the off-label opened capsule dosing method for stavudine is acceptable. There is no need to instruct caregivers to include sediment in the aliquot given to the infant. However, studies that confirm adequate bioavailability and efficacy are needed. In addition, it is important to avoid supplying generic capsules the contents of which do not disperse easily in water, as this may lead to a significant reduction in the amount of active drug that a child receives.


Non-contact physiological monitoring of preterm infants in the Neonatal Intensive Care Unit.
The implementation of video-based non-contact technologies to monitor the vital signs of preterm infants in the hospital presents several challenges, such as the detection of the presence or the absence of a patient in the video frame, robustness to changes in lighting conditions, automated identification of suitable time periods and regions of interest from which vital signs can be estimated. We carried out a clinical study to evaluate the accuracy and the proportion of time that heart rate and respiratory rate can be estimated from preterm infants using only a video camera in a clinical environment, without interfering with regular patient care. A total of 426.6 h of video and reference vital signs were recorded for 90 sessions from 30 preterm infants in the Neonatal Intensive Care Unit (NICU) of the John Radcliffe Hospital in Oxford. Each preterm infant was recorded under regular ambient light during daytime for up to four consecutive days. We developed multi-task deep learning algorithms to automatically segment skin areas and to estimate vital signs only when the infant was present in the field of view of the video camera and no clinical interventions were undertaken. We propose signal quality assessment algorithms for both heart rate and respiratory rate to discriminate between clinically acceptable and noisy signals. The mean absolute error between the reference and camera-derived heart rates was 2.3 beats/min for over 76% of the time for which the reference and camera data were valid. The mean absolute error between the reference and camera-derived respiratory rate was 3.5 breaths/min for over 82% of the time. Accurate estimates of heart rate and respiratory rate could be derived for at least 90% of the time, if gaps of up to 30 seconds with no estimates were allowed.


[Early primary total hip arthroplasty for acetabular fractures in elderly patients].
The aim of this pilot study was to evaluate the clinical and functional outcomes of total hip arthroplasty (THA) in patients with acetabular fractures due to a low-energy injury. Acute primary THA included an antiprotrusion cage and autologous bone grafting of the acetabulum. This prospective study was carried out between 1998 and 2004. Ten patients, of whom six were men, (average age, 71 years; range, 60 to 83 years) with acetabular fractures were treated by THA. Two patients had type A2, two had type B1, three had type B2 and three had type B3 fractures, as assessed by the AO classification. X-ray showed osteoporosis due to decreased bone mass in all patients, and dislocations of the fragments in the weight-bearing area of the joint exceeded 1 cm. The average follow-up was 36 months. Indications for primary THA included, in addition to higher age, displacement in the fracture line exceeding 1 cm, a fracture line extending to the weight-bearing part of the acetabulum, presence of hip arthritis, cartilage injury, defects of the weight-bearing area of either the femoral head or acetabulum, and Pipkin type IV injury. The interval between accident and surgery ranged from 6 to 12 days (average, 9.5). Three surgical techniques were used, namely, cemented THA with a polyethylene cup cemented into an acetabulum-stabilizing cage; reconstruction with a cementless RSC acetabular component; internal fixation using screws and a cemented cup. Bone grafting of the acetabulum was used in all patients. Evaluated were basic operative parameters, complications, X-ray findings, ability to walk and Merle d'Aubigne scores. The average operative time was 100 min, the average blood loss was 1000 ml. Hip motion showed the following average values: flexion, 110 degrees ; extension, 10 degrees ; rotation, 30 degrees -0 degrees -30 degrees ; adduction, 25 degrees ; abduction, 35 degrees . All patients returned to their preoperative range of motion. X-ray examination showed good reduction, bone graft was completely incorporated in the acetabulum, and no displacement or signs of loosening or graft migration were recorded. Two patients had Brooker type I heterotropic ossification. The final evaluation of function at 36 months on the basis of the Merle d'Aubigne classification showed excellent and good results in four (57 %) and three (43 %) patients, respectively. The remaining three patients had a shorter follow-up, but were fully mobile with no complications observed. It has been reported that bony union of acetabular fracture after open reduction and internal fixation (ORIF) was achieved in 74 % patients younger than 60 years, but in only 44 % of the patients older than 60 years. Secondary THA following ORIF is a demanding technique. Due to adhesions and a frequent malposition of the acetabulum, THA is associated with and increased risk of infection, tendency to develop para-articular ossifications, and a higher risk of early component loosening than in the standard procedure. One of the options is to perform acetabular stabilization and primary THA at one stage. The results of our study are fully in agreement with those reported for THA in hip arthritis or dislocated fracture of the femoral neck. Acute primary THA with the use of a antiprotrusion cage and bone grafting for acetabular fractures in elderly patients allows us to employ only one surgical technique for definitive repair. It provides primary stability and immediate pain relief, permits graded weight-bearing and early pain-free mobilization, and may also treat hip arthritis, if it exists. This technique has also good prospects for a selected group of younger patients in whom the treatment of acetabular fractures has a poor prognosis. Key words: acetabular fracture, elderly patient, primary total hip arthroplasty.


Fat Replacement of Paraspinal Muscles with Aging in Healthy Adults.
The aims of this study were to investigate the age-related changes in fatty replacement and cross-sectional area (CSA) of cervical, thoracic, and lumbar paraspinal muscles versus leg muscles in healthy adults and to test for association between muscle fat fraction and lifestyle factors. Fifty-three healthy adults (24-76 yr) were included. Dixon magnetic resonance imaging technique was used to determine CSA and to quantify the fat fraction of paraspinal and leg muscles. Muscle CSA and fat fractions were tested for association with age and muscle strength. The fat fractions were also tested for association with sex, body mass index (BMI), physical activity, and lower back pain. Both paraspinal and leg fat fractions correlated directly with age (P < 0.0001). At all ages, fat fraction was higher in paraspinal than leg muscles. The age-related increase in fat fraction was higher in paraspinal muscles than leg muscles (P < 0.0001). The CSA of the muscles did not correlate with age. Knee extension strength correlated with fat fraction (P < 0.05), and the muscle strength of hip muscles, thigh muscles, and anterior calf muscles correlated with CSA (P < 0.05). Sex was associated with lumbar paraspinal fat fraction (P < 0.05) and BMI with thigh fat fraction (P < 0.001). There was no association between fat fraction and physical activity or lower back pain. The paraspinal muscles were more susceptible to age-related changes than leg muscles. Further, men had significantly lower fat fractions in lumbar paraspinal muscles, and BMI was positively associated with thigh, but not paraspinal, fat fraction.


Comparative analysis of the cold acclimation and freezing tolerance capacities of seven diploid Brachypodium distachyon accessions.
Cold is a major constraint for cereal cultivation under temperate climates. Winter-hardy plants interpret seasonal changes and can acquire the ability to resist sub-zero temperatures. This cold acclimation process is associated with physiological, biochemical and molecular alterations in cereals. Brachypodium distachyon is considered a powerful model system to study the response of temperate cereals to adverse environmental conditions. To date, little is known about the cold acclimation and freezing tolerance capacities of Brachypodium. The main objective of this study was to evaluate the cold hardiness of seven diploid Brachypodium accessions. An integrated approach, involving monitoring of phenological indicators along with expression profiling of the major vernalization regulator VRN1 orthologue, was followed. In parallel, soluble sugars and proline contents were determined along with expression profiles of two COR genes in plants exposed to low temperatures. Finally, whole-plant freezing tests were performed to evaluate the freezing tolerance capacity of Brachypodium. Cold treatment accelerated the transition from the vegetative to the reproductive phase in all diploid Brachypodium accessions tested. In addition, low temperature exposure triggered the gradual accumulation of BradiVRN1 transcripts in all accessions tested. These accessions exhibited a clear cold acclimation response by progressively accumulating proline, sugars and COR gene transcripts. However, whole-plant freezing tests revealed that these seven diploid accessions only have a limited capacity to develop freezing tolerance when compared with winter varieties of temperate cereals such as wheat and barley. Furthermore, little difference in terms of survival was observed among the accessions tested despite their previous classification as either spring or winter genotypes. This study is the first to characterize the freezing tolerance capacities of B. distachyon and provides strong evidence that some diploid accessions such as Bd21 have a facultative growth habit.


Quantifying the statistical impact of GRAPPA in fcMRI data with a real-valued isomorphism.
The interpolation of missing spatial frequencies through the generalized auto-calibrating partially parallel acquisitions (GRAPPA) parallel magnetic resonance imaging (MRI) model implies a correlation is induced between the acquired and reconstructed frequency measurements. As the parallel image reconstruction algorithms in many medical MRI scanners are based on the GRAPPA model, this study aims to quantify the statistical implications that the GRAPPA model has in functional connectivity studies. The linear mathematical framework derived in the work of Rowe , 2007, is adapted to represent the complex-valued GRAPPA image reconstruction operation in terms of a real-valued isomorphism, and a statistical analysis is performed on the effects that the GRAPPA operation has on reconstructed voxel means and correlations. The interpolation of missing spatial frequencies with the GRAPPA model is shown to result in an artificial correlation induced between voxels in the reconstructed images, and these artificial correlations are shown to reside in the low temporal frequency spectrum commonly associated with functional connectivity. Through a real-valued isomorphism, such as the one outlined in this manuscript, the exact artificial correlations induced by the GRAPPA model are not simply estimated, as they would be with simulations, but are precisely quantified. If these correlations are unaccounted for, they can incur an increase in false positives in functional connectivity studies.


Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis.
The influenza A (H1N1) 2009 monovalent vaccination programme was the largest mass vaccination initiative in recent US history. Commensurate with the size and scope of the vaccination programme, a project to monitor vaccine adverse events was undertaken, the most comprehensive safety surveillance agenda in the USA to date. The adverse event monitoring project identified an increased risk of Guillain-Barré syndrome after vaccination; however, some individual variability in results was noted. Guillain-Barré syndrome is a rare but serious health disorder in which a person's own immune system damages their nerve cells, causing muscle weakness, sometimes paralysis, and infrequently death. We did a meta-analysis of data from the adverse event monitoring project to ascertain whether influenza A (H1N1) 2009 monovalent inactivated vaccines used in the USA increased the risk of Guillain-Barré syndrome. Data were obtained from six adverse event monitoring systems. About 23 million vaccinated people were included in the analysis. The primary analysis entailed calculation of incidence rate ratios and attributable risks of excess cases of Guillain-Barré syndrome per million vaccinations. We used a self-controlled risk-interval design. Influenza A (H1N1) 2009 monovalent inactivated vaccines were associated with a small increased risk of Guillain-Barré syndrome (incidence rate ratio 2·35, 95% CI 1·42-4·01, p=0·0003). This finding translated to about 1·6 excess cases of Guillain-Barré syndrome per million people vaccinated. The modest risk of Guillain-Barré syndrome attributed to vaccination is consistent with previous estimates of the disorder after seasonal influenza vaccination. A risk of this small magnitude would be difficult to capture during routine seasonal influenza vaccine programmes, which have extensive, but comparatively less, safety monitoring. In view of the morbidity and mortality caused by 2009 H1N1 influenza and the effectiveness of the vaccine, clinicians, policy makers, and those eligible for vaccination should be assured that the benefits of inactivated pandemic vaccines greatly outweigh the risks. US Federal Government.


General practitioners' attitudes and decision making regarding admission for older adults with infection: a UK qualitative interview study.
The world has an ageing population. Infection is common in older adults; serious infection has a high mortality rate and is associated with unplanned admissions. In the UK, general practitioners (GPs) must identify which older patients require admission to hospital and provide appropriate care and support for those staying at home. To explore attitudes of UK GPs towards referring older patients with suspected infection to hospital, how they weigh up the decision to admit against the alternatives and how alternatives to admission could be made more effective.Methods. Qualitative study using semi-structured interviews. GPs were purposively sampled from across the UK to achieve maximum variation in terms of GP role, experience and practice population. Interview transcripts were coded and analysed using a modified framework approach. GPs' key influences on decision making were grouped into patient, GP and system factors. Patient factors included clinical factors, social factors and shared decision making. GP factors included gut instinct, risk management and acknowledging an associated personal emotional burden. System factors involved weighing up the pressure on secondary care beds against increasing GP workload. GPs described that finding an alternative to admission could be more time consuming, complex to arrange or were restricted by lack of capacity. GPs need to be empowered to make safe decisions about place of care for older adults with suspected infection. This may mean developing strategies to support decision making as well as improving the ease of access to, and capacity of, any alternatives to admission.


Patterns of Sociodemographic and Clinicopathologic Characteristics of Stages II and III Colorectal Cancer Patients by Age: Examining Potential Mechanisms of Young-Onset Disease.
Background and Aims. As a first step toward understanding the increasing incidence of colorectal cancer (CRC) in younger (age < 50) populations, we examined demographic, clinicopathologic, and socioeconomic characteristics and treatment receipt in a population-based sample of patients newly diagnosed with stages II and III CRC. Methods. Patients were sampled from the National Cancer Institute's Patterns of Care studies in 1990/91, 1995, 2000, 2005, and 2010 (n = 6, 862). Tumor characteristics and treatment data were obtained through medical record review and physician verification. We compared sociodemographic and clinicopathologic characteristics and treatment patterns of younger (age < 50) and older (age 50-69, age ≥ 70) CRC patients. Results. Younger patients were more likely to be black (13%) and Hispanic (15%) than patients aged 50-69 years (11% and 10%, resp.) and ≥70 years (7% each). A larger proportion of young white (41%) and Hispanic (33%) patients had rectal tumors, whereas tumors in the right colon were the most common in young black patients (39%). The majority of younger patients received chemotherapy and radiation therapy, although receipt of microsatellite instability testing was suboptimal (27%). Conclusion. Characteristics of patients diagnosed with young-onset CRC differ considerably by race/ethnicity, with a higher proportion of black and Hispanic patients diagnosed at the age of < 50 years.


Usefulness of translatability assessment: results from a retrospective study.
The purpose of the study is to evaluate the extent to which a retrospectively conducted translatability assessment (TA) could identify the items previously singled out during the validation study as having poor content validity or poor measurement performance. This study was performed with the intent of supporting evidence of the usefulness of TA early in the PRO development process. The Weight module of the Youth Quality-of-Life Instrument (YQOL-W) was used for this appraisal of translatability. Two linguists, blinded to the design and results of content validation and psychometric analyses, conducted a TA on the 32-item version of the YQOL-W taken into cross-sectional validation for item reduction. TA results were categorized into (1) issues relating to target culture (cross-cultural issues) and (2) issues relating to the structure of the original questionnaire (structural issues). Items for possible revision or deletion were identified. We compared the results of the TA with the content validity and psychometric results and decisions to eliminate items after cross-sectional validation. Content validation identified seven of the 32 items to be dropped, and psychometric analyses including the 25 remaining items highlighted an additional four to be eliminated, yielding a final instrument with 21 items. Out of these 11 dropped items, TA had identified nine as problematic (82 %) and the developer was advised to drop five of them (45.4 %). In addition, TA results highlighted the need to change the original formulation of eight items for semantic reasons and identified two instances where alternative wording should be used for translation purposes without any change to the original formulation. Our study showed that translatability assessment confirmed problematic issues in items previously identified as having poor content validity or poor measurement performance. In general, a translatability assessment offers the possibility for the identification of alternative formulations for translation purposes, modifications of original formulations to optimize subsequent translations efforts, and the early detection and discussion of irrelevant or inappropriate items.


Modulation of nigrostriatal dopaminergic transmission by antisense oligodeoxynucleotide against brain-derived neurotrophic factor.
Brain-derived neurotrophic factor (BDNF) promotes the differentiation and growth of developing dopamine (DA) neurons and supports the survival of mature DA cells in culture. However, the neurotrophic role of endogenous BDNF in the adult DA system in vivo has not been well established. To investigate the hypothesis that blockade of endogenous BDNF expression results in DA dysregulation, we used an 18-mer antisense oligodeoxynucleotide (ODN) targeted to the first ATG codon of the BDNF transcript. The biological activity of the antisense ODN was initially tested in vitro. In cultured dopaminergic MES 23.5 cells, antisense BDNF (20 microM) effectively reduced BDNF protein expression and cell survival. Furthermore, in primary embryonic mesencephalic cultures, antisense BDNF reduced the number of tyrosine hydroxylase positive neurons and inhibited [3H]DA uptake in a time- and dose-dependent manner. The specificity of the antisense molecule was confirmed by comparing its effects with those of a control ODN having the same base composition but in scrambled sequence. In rats, two days following an intranigral or intrastriatal injection of antisense BDNF (0.5 microg), we observed a two-fold and five-fold increase in nigral DA levels, respectively, but no change in striatal DA content. Seven days after an intrastriatal antisense BDNF injection, DA levels were elevated in the striatum apparently due to decreased DA turnover. These observations suggest that inhibition of endogenous BDNF expression tends to augment rather than inhibit nigrostriatal DA transmission. Thus, the biological effects of endogenous BDNF on the nigrostriatal DA system in the adult organism merits further investigation.


The Development of Infants' Sensitivity to Behavioral Intentions when Inferring Others' Social Preferences.
The present study investigated whether infants reason about others' social preferences based on the intentions of others' interactive actions. In Experiment 1, 12-month-old infants were familiarized with an event in which an agent either successfully helped a circle to climb up a hill (successful-helping condition) or failed to help the circle to achieve its goal (failed-helping condition). During the test, the infants saw the circle approach either the helper (approach-helper event) or the hinderer (approach-hinderer event). In the successful-helping condition, the 12-month-old infants looked for longer at the approach-hinderer event than at the approach-helper event, but in the failed-helping condition, looking times were about equal for the two test events. These results suggest that 12-month-old infants could not infer the circle's preference when the helper's action did not lead to its intended outcome. In Experiment 2, 16-month-olds were tested in the failed-helping condition; they looked longer at the approach-hinderer event than at the approach-helper event, which suggests that they could reason about the third party's social preferences based on the exhibited intentions. In Experiment 3, 12-month-olds were familiarized with events in which the final outcomes of helping and hindering actions were ambiguous. The results revealed that 12-month-old infants are also sensitive to intentions when inferring other's social preferences. The results suggest that by 12-months of age, infants expect an agent to prefer and approach another who intends to help the circle to achieve its goal, regardless of the outcome. The current research has implications for moral reasoning and social evaluation in infancy.


Optrodes for combined optogenetics and electrophysiology in live animals.
Optical tissue properties limit visible light depth penetration in tissue. Because of this, the recent development of optogenetic tools was quickly followed by the development of light delivery devices for in vivo optogenetics applications. We summarize the efforts made in the last decade to design neural probes that combine conventional electrophysiological recordings and optical channel(s) for optogenetic activation, often referred to as optodes or optrodes. Several aspects including challenges for light delivery in living brain tissue, the combination of light delivery with electrophysiological recordings, probe designs, multimodality, wireless implantable system, and practical considerations guiding the choice of configuration depending on the questions one seeks to address are presented.


A genetically linked pair of NLR immune receptors shows contrasting patterns of evolution.
Throughout their evolution, plant nucleotide-binding leucine-rich-repeat receptors (NLRs) have acquired widely divergent unconventional integrated domains that enhance their ability to detect pathogen effectors. However, the functional dynamics that drive the evolution of NLRs with integrated domains (NLR-IDs) remain poorly understood. Here, we reconstructed the evolutionary history of an NLR locus prone to unconventional domain integration and experimentally tested hypotheses about the evolution of NLR-IDs. We show that the rice (Oryza sativa) NLR Pias recognizes the effector AVR-Pias of the blast fungal pathogen Magnaporthe oryzae. Pias consists of a functionally specialized NLR pair, the helper Pias-1 and the sensor Pias-2, that is allelic to the previously characterized Pia pair of NLRs: the helper RGA4 and the sensor RGA5. Remarkably, Pias-2 carries a C-terminal DUF761 domain at a similar position to the heavy metal-associated (HMA) domain of RGA5. Phylogenomic analysis showed that Pias-2/RGA5 sensor NLRs have undergone recurrent genomic recombination within the genus Oryza, resulting in up to six sequence-divergent domain integrations. Allelic NLRs with divergent functions have been maintained transspecies in different Oryza lineages to detect sequence-divergent pathogen effectors. By contrast, Pias-1 has retained its NLR helper activity throughout evolution and is capable of functioning together with the divergent sensor-NLR RGA5 to respond to AVR-Pia. These results suggest that opposite selective forces have driven the evolution of paired NLRs: highly dynamic domain integration events maintained by balancing selection for sensor NLRs, in sharp contrast to purifying selection and functional conservation of immune signaling for helper NLRs.


Discriminant function analysis: a case study of some socioeconomic constraints on child nutrition.
Discriminant function analysis was used to understand the combination of socioeconomic variables in various forms of malnutrition in preschool children. Data available (1976) from two sets viz., 4000 children of rural and urban areas of Hyderabad (in south India) and 215 children of urban and rural areas of Jaipur (in north India) were used for the study. The prevalence rates of various forms of malnutrition in children were different by variations in socioeconomic status and sex (P less than 0.05). Discriminant function analysis of all socioeconomic indicators showed that educational levels and occupational status of parents and percaput income were most important for differentiation of children who were normals and undernourished. Occupational status of the father and the child's calorie intake or duration of lactation improved the differentiation of normals from those who were under-nourished. Higher prevalence of malnutrition in female children than in the male children was found due to variations in per capita income and levels of maternal education. Closely associated best set of factors could be traced using the discriminant function analysis.


Cardiovascular changes in the exercising emu.
Cardiovascular variables were studied as a function of oxygen consumption in the emu, a large, flightless ratite bird well suited to treadmill exercise. At the highest level of exercise, the birds' rate of oxygen consumption (VO2) was approximately 11.4 times the resting level (4.2 ml kg-1 min-1). Cardiac output was linearly related to VO2, increasing 9.5 ml for each 1 ml increase in oxygen consumption. The increase in cardiac output is similar to that in other birds, but appears to be larger than in mammals. The venous oxygen content dropped during exercise, thus increasing the arteriovenous oxygen content difference. At the highest levels of exercise, heart rate showed a 3.9-fold increase over the resting rate (45.8 beats min-1). The mean resting specific stroke volume was 1.5 ml per kg body mass, which is larger than shown by most mammals. However, birds have larger hearts relative to body mass than do mammals, and stroke volume expressed per gram of heart (0.18 ml g-1) is similar to that for mammals. Stroke volume showed a 1.8-fold increase as a result of exercise in the emus, but a change in heart rate plays a greater role in increasing cardiac output during exercise.


Modeling Study of a Proposed Field Calibration Source Using K-40 and High-Z Targets for Sodium Iodide Detectors.
Calibration sources based on the primordial isotope potassium-40 (K) have reduced controls on the source's activity due to its terrestrial ubiquity and very low specific activity. Potassium-40's beta emissions and 1,460.8 keV gamma ray can be used to induce K-shell fluorescence x rays in high-Z metals between 60 and 80 keV. A gamma ray calibration source that uses potassium chloride salt and a high-Z metal to create a two-point calibration for a sodium iodide field gamma spectroscopy instrument is thus proposed. The calibration source was designed in collaboration with the Sandia National Laboratory using the Monte Carlo N-Particle eXtended (MCNPX) transport code. Two methods of x-ray production were explored. First, a thin high-Z layer (HZL) was interposed between the detector and the potassium chloride-urethane source matrix. Second, bismuth metal powder was homogeneously mixed with a urethane binding agent to form a potassium chloride-bismuth matrix (KBM). The bismuth-based source was selected as the development model because it is inexpensive, nontoxic, and outperforms the high-Z layer method in simulation. Based on the MCNPX studies, sealing a mixture of bismuth powder and potassium chloride into a thin plastic case could provide a light, inexpensive field calibration source.


Evaluation of haplotypes associated with copper toxicosis in Bedlington Terriers in Australia.
To evaluate the haplotype distribution associated with the copper toxicosis gene and the segregation of the mutated allele in a Bedlington Terrier population in Australia. 131 Bedlington Terriers. Samples of DNA and RNA were obtained from each dog. Genetic status of each dog was evaluated by use of the DNA markers C04107; single nucleotide polymorphism (SNP), which was adjacent to exon 2 of Murr1; and a deletion marker for exon 2. A subgroup of the study population was evaluated by use of biochemical and histologic techniques to elucidate the correlation between genotype and phenotype. We identified a recombination between the C04107 marker and Murr1 and a variation in a nucleotide in the splice site of exon 2 in our Bedlington Terrier cohort. Furthermore, we identified a novel haplotype associated with copper toxicosis in this cohort. Our findings indicate that the deletion of exon 2 was not the sole cause of copper toxicosis, although only exon 2 deletion of Murr1 has been responsible for copper toxicosis in Bedlington Terriers. Although we failed to find a novel mutation in our cohort, we identified an affected dog family with an intact exon 2. Furthermore, we found that an SNP in the 5' splicing site of exon 2 may or may not be associated with a novel mutation of the Murr1 gene or other genes. Loss of linkage between the C04107 marker and the Murr1 gene was also identified in a certain family of dogs.


Spectroscopic studies of kinetically trapped conformations in the gas phase: the case of triply protonated bradykinin.
Understanding the relation between the gas-phase structure of biological molecules and their solution-phase structure is important when attempting to use gas-phase techniques to address biologically relevant questions. Directly after electrospray ionization, molecules can be kinetically trapped in a state that retains some "memory" of its conformation in solution and is separated from the lowest-energy gas-phase structure by barriers on the potential energy surface. In order to identify and characterize kinetically trapped structures, we have explored the conformational space of triply protonated bradykinin in the gas phase by combining field-asymmetric ion mobility spectrometry (FAIMS) with cold ion spectroscopy. We isolate three distinct conformational families and characterize them by recording their UV-photofragment spectra and vibrational spectra. Annealing of the initial conformational distribution produced by electrospray reveals that one of the conformational families is kinetically trapped, while two others are stable, gas-phase structures. We compare our results to previously published results obtained using drift-tube ion mobility spectrometry (IMS) and propose a correspondence between the conformational families separated by FAIMS and those by IMS.


Positive argument for debate in J Neural Transmission: Alzheimer's disease: are we intervening too late? Yes, by years if not decades.
The ongoing debate as to whether we are or are not early enough in treatment for Alzheimer's disease presents distinct vantage points. Points expressed range from stressing the need for early preventive measures to highlighting the failure of "alternative" therapies, and concluding that we are unfortunately doing all that we can at present. Herein, we stress the worth of nutritional intervention, and review why such studies are often inherently compromised. We conclude that considerable education is needed to advance lifestyle modifications early enough to obtain their optimal effect, and instead of positioning "classical" interventions against "alternative" interventions, the combinations of both may impart maximal benefit. The introduction of novel detection methods at the earliest indications of cognitive impairment may provide a window of opportunity for initiation of preventative approaches.


Collection and motif-based prediction of phosphorylation sites in human viruses.
Although various databases have been established that are designed to compile an ever-growing list of protein phosphorylation sites in plants and animals, no such repository exists for viruses. Here, we developed the viral posttranslational modification (virPTM) database, which contains a comprehensive list of 329 accurately localized phosphorylation sites in proteins from 52 human viruses published between 1986 and the present. Additionally, to aid in the detection of new viral phosphorylation sites, we used the scan-x tool to make thousands of high-specificity serine, threonine, and tyrosine phosphorylation predictions in 229 viruses that replicate in human cells. By cross-validating our prediction results with the literature-based entries in the virPTM database, we highlight the effectiveness of the scan-x tool with viral data and extrapolate the existence of at least 4000 as yet unidentified phosphorylation sites on hundreds of viral proteins. Together, these results imply a substantial role for human kinases in mediating viral protein functions and suggest, more generally, that viral primary structure may provide important clues to aid in the rational design of therapeutic agents.


Plant production of volatile semiochemicals in response to insect-derived elicitors.
An increase in the release of volatile compounds by plants in response to insect feeding is triggered by interaction of elicitors in the oral secretions of insect herbivores with damaged plant tissues. This herbivore damage triggers de novo biosynthesis of volatile plant metabolites derived from several different biochemical pathways. Natural enemies of herbivores use these volatile semiochemicals to locate their hosts. Although some volatile compounds are released from storage in plants immediately whenever damage to cells or glands occurs, the induced compounds are only synthesized and released during the light period. This often results in a delay between feeding damage and release of volatiles. Plants release the induced compounds from undamaged as well as damaged leaves. Thus, damage to only a few leaves results in a systemic response and release of volatiles by the entire plant. We propose that plants respond differently to individual herbivore species at least in part due to the composition of insect elicitors that come in contact with the plant. Specialist parasitoids can differentiate the volatile blends released due to damage by hosts from those resulting from non-host damage as well as from mechanical damage, thereby facilitating host location for the parasitoid. Elicitors in the oral secretions of beet armyworm caterpillars have been identified and synthesized.


[A WHO concept- patient blood management].
Blood transfusions are in general considered as lifesaving. Current data and evidence show, that blood transfusions are associated with increased morbidity and mortality, and this apparently dose-dependent. Basic research and results from randomized controlled trials show a causal relationship between blood transfusion and adverse outcome. Based on the current state of knowledge it has to be questioned that blood transfusions are "life-saving" as patients are exposed to an increased risk of disease or death. Furthermore, blood transfusions are more costly than previously assumed. For these reasons novel approaches in the treatment of anemia and bleeding are needed. Patient Blood Management (PBM) allows reduction of transfusion rates by correcting anemia by stimulating erythropoiesis, minimizing perioperative blood loss and optimizing the physiological tolerance of anemia. In 2010 the World Health Organization has claimed PBM to be considered as golden standard. PBM reduces morbidity and mortality by lowering the excessive use of blood transfusions. This concept has partially and successfully been implemented in the University Hospital Balgrist in Zurich.


What response properties do individual neurons need to underlie position and clutter "invariant" object recognition?
Primates can easily identify visual objects over large changes in retinal position--a property commonly referred to as position "invariance." This ability is widely assumed to depend on neurons in inferior temporal cortex (IT) that can respond selectively to isolated visual objects over similarly large ranges of retinal position. However, in the real world, objects rarely appear in isolation, and the interplay between position invariance and the representation of multiple objects (i.e., clutter) remains unresolved. At the heart of this issue is the intuition that the representations of nearby objects can interfere with one another and that the large receptive fields needed for position invariance can exacerbate this problem by increasing the range over which interference acts. Indeed, most IT neurons' responses are strongly affected by the presence of clutter. While external mechanisms (such as attention) are often invoked as a way out of the problem, we show (using recorded neuronal data and simulations) that the intrinsic properties of IT population responses, by themselves, can support object recognition in the face of limited clutter. Furthermore, we carried out extensive simulations of hypothetical neuronal populations to identify the essential individual-neuron ingredients of a good population representation. These simulations show that the crucial neuronal property to support recognition in clutter is not preservation of response magnitude, but preservation of each neuron's rank-order object preference under identity-preserving image transformations (e.g., clutter). Because IT neuronal responses often exhibit that response property, while neurons in earlier visual areas (e.g., V1) do not, we suggest that preserving the rank-order object preference regardless of clutter, rather than the response magnitude, more precisely describes the goal of individual neurons at the top of the ventral visual stream.


The relationship between neurological disease and bullous pemphigoid: a population-based case-control study.
Previous small studies and case reports have suggested that neurological disorders may be associated with bullous pemphigoid (BP). The objective of this study was to assess BP risk in patients with neurological diseases. Computerized medical records from the Health Improvement Network, a large population-based UK general practice database, were used to conduct a matched case-control analysis. Conditional logistic regression was used to calculate odds ratios for specified neurological disorders. Comparing cases (n=868) to controls (n=3,453), stroke was seen in 8 vs. 5%, odds ratio (OR) 1.8 (1.3-2.5); dementia in 7 vs. 2%, OR 3.4 (2.4-4.8); Parkinson's disease in 3 vs. 1%, OR 3.0 (1.8-5.0); epilepsy in 2 vs. 1%, OR 1.7 (1.0-3.0); and multiple sclerosis in 1 vs 0.1% (OR 10.7 (2.8-40.2). Estimates were not altered greatly when diagnoses up to 3 years before BP were excluded, except the association with epilepsy was no longer significant. Significant associations were only observed where neurological disease was diagnosed before the onset of pemphigoid. Study findings, except the association with epilepsy, were robust to sensitivity analysis. Strong associations were observed between specific neurological diseases and the later development of BP, supporting possible causal associations. Mechanisms for disease occurrence based on these findings include immobility or age-related autoimmunity.


Accidental blood exposures among medical residents in Paris, France.
Accidental blood exposure (ABE) exposes healthcare workers, including medical residents, to the risk of occupational infection. We aimed to determine the characteristics of ABEs in residents with an anonymous self-reporting electronic questionnaire. A total of 350 residents (33% from surgical disciplines) entered this survey. One hundred and eighty-five residents (52%) reported at least one ABE during their residency (median, 2; range, 1-25), 53% of which occurred in operating theatres. Sixty-nine per cent of residents followed the current procedures for local disinfection. ABEs were notified to the hospital administration by 62% of residents, but only 51% of residents were referred to the occupational medicine department. The most frequently reported concerns following ABEs were human immunodeficiency virus (52%) and hepatitis C virus infection (39%). In 74% of cases, the serological status of the index patient was investigated. Only 54% of residents were aware of their hepatitis B surface antibody titres. Medical residents behaved inappropriately in 33% of cases in this survey. Further educational programmes should include residents, and not only senior healthcare workers, in order to improve individual behaviours.


Detection of hypoxia in human brain tumor xenografts using a modified comet assay.
We used the standard comet assay successfully to generate in vitro dose-response curves under oxic and hypoxic conditions. We then made mixtures of cells that had been irradiated with 3 and 9 Gy of X-rays to simulate two subpopulations in a tumor, but efforts to accurately detect and quantify the subpopulations using the standard comet assay were unsuccessful. Therefore, we investigated a modified comet assay to determine whether it could be used for measuring hypoxia in our model systems. U251 MG cells were grown as subcutaneous tumors in athymic mice; U251 MG and U87 MG cells were grown as intracerebral (i.c.) tumors in athymic rats. Animals were injected with RSU 1069, irradiated, and euthanized. Tumors and normal brains were removed, and the cells were analyzed using a modified comet assay. Differences in comet tail moment distributions between tumor and contralateral normal brain, using tail moments at either the 25th or 50th percentile in each distribution, were taken as measures of the degree of tumor hypoxia. For U251 MG tumors, there was a positive relationship between tumor size and the degree of hypoxia, whereas preliminary data from U87 MG i.c. tumors showed less hypoxia and no apparent relationship between tumor size and hypoxia.


In vitro exposure of human fibroblasts to local anaesthetics impairs cell growth.
Lidocaine, bupivacaine or ropivacaine are used routinely to manage perioperative pain. Sparse data exist evaluating the effects of local anaesthetics (LA) on fibroblasts, which are involved actively in wound healing. Therefore, we investigated the effects of the three LA to assess the survival, viability and proliferation rate of fibroblasts. Human fibroblasts were exposed to 0·3 mg/ml and 0·6 mg/ml of each LA for 2 days, followed by incubation with normal medium for another 1, 4 or 7 days (group 1). Alternatively, cells were incubated permanently with LA for 3, 6 or 9 days (group 2). Live cell count was assessed using trypan blue staining. Viability was measured by the tetrazolium bromide assay. Proliferation tests were performed with the help of the colorimetric bromodeoxyuridine assay. Production of reactive oxygen species (ROS) was determined, measuring the oxidation of non-fluorescent-2,7'-dichlorofluorescin. Treatment of cells with the three LA showed a concentration-dependent decrease of live cells, mitochondrial activity and proliferation rate. Group arrangement played a significant role for cell count and proliferation, while exposure time influenced viability. Among the analysed LA, bupivacaine showed the most severe cytotoxic effects. Increased production of ROS correlated with decreased viability of fibroblasts in lidocaine- and bupivacaine-exposed cells, but not upon stimulation with ropivacaine. This study shows a concentration-dependent cytotoxic effect of lidocaine, bupivacaine and ropivacaine on fibroblasts in vitro, with more pronounced effects after continuous incubation. A possible mechanism of cell impairment could be triggered by production of ROS upon stimulation with lidocaine and bupivacaine.


Expression of functional protease and subviral particles by vaccinia virus containing equine infectious anaemia virus gag and 5' pol genes.
Cells infected with vaccinia viruses expressing the equine infectious anaemia virus (EIAV) gag gene (VGag) or gag plus the 5' pol encoding protease (VGag/PR) were evaluated with monoclonal antibody to a p26 capsid protein linear epitope (QEISKFLTD). Both recombinant viruses expressed Gag precursor protein (55K) whereas only VGag/PR expressed a detectable Gag-Pol fusion protein (82K) with a functional protease, shown by subviral particles containing processed p26. Horses inoculated with VGag/PR produced antibodies reactive with EIAV Gag proteins.


Chronic dietary n-3 PUFA intervention improves dyslipidaemia and subsequent cardiovascular complications in the JCR:LA- cp rat model of the metabolic syndrome.
There is increasing interest in the potential chronic beneficial effects of dietary n-3 PUFA on the metabolic syndrome (MetS) and associated cardiovascular complications. We have recently established that increased dietary n-3 PUFA has a profound acute benefit on fasting lipids and the postprandial pro-inflammatory response in the JCR:LA-cp rat, a model of the MetS. However, it is unclear to what extent chronic dietary n-3 PUFA intervention can modulate the progression of end-stage metabolic and vascular complications. The present study aimed to determine the chronic effects of dietary n-3 PUFA supplementation on fasting and non-fasting dyslipidaemia, insulin resistance and vascular complications in the JCR:LA-cp rodent model. JCR:LA-cp rats were fed an isoenergetic lipid-balanced diet supplemented with 5 % n-3 PUFA (w/w) of the total fat (fish oil-derived EPA/DHA) for 16 weeks. Fasting and non-fasting (postprandial) plasma lipid profile was assessed. Hepatic and adipose tissue was probed for the expression of lipogenic proteins (acyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and sterol regulatory element-binding protein-1 (SREBP-1)), while the activity of Jun N-terminal kinase (JNK) was assessed via Western blot to target phosphorylated JNK protein in primary enterocytes. The frequency of myocardial lesions was assessed by haematoxylin and eosin staining. Increased dietary n-3 PUFA improved both the fasting and postprandial lipid profiles (TAG, cholesterol and apoB48) in the JCR:LA-cp rat, potentially via the down-regulation of the hepatic or adipose tissue expression of lipogenic enzymes (ACC, FAS and SREBP-1). Rats fed the 5 % n-3 PUFA diet had lower (58·2 %; P < 0·01) enterocytic phosphorylated JNK protein and secreted less cholesterol (30 %; P < 0·05) into mesenteric lymph compared with the control. The chronic metabolic benefits of dietary n-3 PUFA may underlie the potential to reduce vascular complications during the MetS, including the observed reduction in the frequency (approximately 80 %) of late-stage 3 myocardial lesions.


Long-term cost-effectiveness of screening strategies for hearing loss.
Routine hearing screening can identify patients who are motivated to seek out and adhere to treatment, but little information exists on the cost-effectiveness of hearing screening in a general population of older veterans. We compared the cost-effectiveness of three screening strategies (tone-emitting otoscope, hearing handicap questionnaire, and both together) against no screening (control group) in 2,251 older veterans. The effectiveness measure for each group was the proportion of hearing aid use 1 year after screening. The audiology cost measure included costs of hearing loss screening and audiology care for 1 year after screening. Incremental cost-effectiveness was the audiology cost of additional hearing aid use for each screening group compared with the control group. The mean total audiology cost per patient was $77.04, $122.70, $121.37, and $157.08 for the control, otoscope, questionnaire, and dual screening groups, respectively. The tone-emitting otoscope appears to be the most cost-effective approach for hearing loss screening, with a significant increase in hearing aid use 1 year after screening (2.8%) and an insignificant incremental cost-effectiveness of $1,439.00 per additional hearing aid user compared with the control group. For this population of older veterans, screening for hearing loss with the tone-emitting otoscope is cost-effective.


To know or not to know: ethical issues related to early diagnosis of Alzheimer's disease.
In Alzheimer's disease (AD), pathological processes start in the brain long before clinical dementia. Biomarkers reflecting brain alterations may therefore indicate disease at an early stage, enabling early diagnosis. This raises several ethical questions and the potential benefits of early diagnosis must be weighted against possible disadvantages. Currently, there are few strong arguments favouring early diagnosis, due to the lack of disease modifying therapy. Also, available diagnostic methods risk erroneous classifications, with potentially grave consequences. However, a possible benefit of early diagnosis even without disease modifying therapy is that it may enable early decision making when patients still have full decision competence, avoiding problems of hypothetical consents. It may also help identifying patients with cognitive dysfunction secondary to other diseases that may be responsive to treatment already today.


Mechanisms of sharp wave initiation and ripple generation.
Replay of neuronal activity during hippocampal sharp wave-ripples (SWRs) is essential in memory formation. To understand the mechanisms underlying the initiation of irregularly occurring SWRs and the generation of periodic ripples, we selectively manipulated different components of the CA3 network in mouse hippocampal slices. We recorded EPSCs and IPSCs to examine the buildup of neuronal activity preceding SWRs and analyzed the distribution of time intervals between subsequent SWR events. Our results suggest that SWRs are initiated through a combined refractory and stochastic mechanism. SWRs initiate when firing in a set of spontaneously active pyramidal cells triggers a gradual, exponential buildup of activity in the recurrent CA3 network. We showed that this tonic excitatory envelope drives reciprocally connected parvalbumin-positive basket cells, which start ripple-frequency spiking that is phase-locked through reciprocal inhibition. The synchronized GABA(A) receptor-mediated currents give rise to a major component of the ripple-frequency oscillation in the local field potential and organize the phase-locked spiking of pyramidal cells. Optogenetic stimulation of parvalbumin-positive cells evoked full SWRs and EPSC sequences in pyramidal cells. Even with excitation blocked, tonic driving of parvalbumin-positive cells evoked ripple oscillations. Conversely, optogenetic silencing of parvalbumin-positive cells interrupted the SWRs or inhibited their occurrence. Local drug applications and modeling experiments confirmed that the activity of parvalbumin-positive perisomatic inhibitory neurons is both necessary and sufficient for ripple-frequency current and rhythm generation. These interneurons are thus essential in organizing pyramidal cell activity not only during gamma oscillation, but, in a different configuration, during SWRs.


Highways and outposts: economic development and health threats in the central Brazilian Amazon region.
Economic development is often evoked as a driving force that has the capacity to improve the social and health conditions of remote areas. However, development projects produce uneven impacts on local communities, according to their different positions within society. This study examines the spatial distribution of three major health threats in the Brazilian Amazon region that may undergo changes through highway construction. Homicide mortality, AIDS incidence and malaria prevalence rates were calculated for 70 municipalities located within the areas of influence of the Cuiabá-Santarém highway (BR-163), i.e. in the western part of the state of Pará state and the northern part of Mato Grosso. The municipalities were characterized using social and economic indicators such as gross domestic product (GDP), urban and indigenous populations, and recent migration. The municipalities' connections to the region's main transportation routes (BR-163 and Trans-Amazonian highways, along with the Amazon and Tapajós rivers) were identified by tagging the municipalities that have boundaries crossing these routes, using GIS overlay operations. Multiple regression was used to identify the major driving forces and constraints relating to the distribution of health threats. The main explanatory variables for higher malaria prevalence were: proximity to the Trans-Amazonian highway, high proportion of indigenous population and low proportion of migrants. High homicide rates were associated with high proportions of migrants, while connection to the Amazon River played a protective role. AIDS incidence was higher in municipalities with recent increases in GDP and high proportions of urban population. Highways induce social and environmental changes and play different roles in spreading and maintaining diseases and health threats. The most remote areas are still protected against violence but are vulnerable to malaria. Rapid economic and demographic growth increases the risk of AIDS transmission and violence. Highways connect secluded localities and may threaten local populations. This region has been undergoing rapid localized development booms, thus creating outposts of rapid and temporary migration, which may introduce health risks to remote areas.


The death domain of kidney ankyrin interacts with Fas and promotes Fas-mediated cell death in renal epithelia.
Ankyrins are a ubiquitously expressed family of conserved proteins that mediate the linkage of integral membrane proteins such as transporters and channels with the underlying cytoskeleton. Ankyrins possess a conserved death domain, the functional significance of which has remained puzzling. In this study, the death domain of AnkG190, the isoform of ankyrin expressed in kidney tubules, was used as bait in a yeast two-hybrid screen to identify interacting partners. One of these interactions was with the proapoptotic molecule Fas. This was confirmed by coimmunoprecipitation, colocalization, and glutathione S-transferase pull-down assays in cultured renal epithelial (MDCK) cells. Site-directed mutagenesis of a conserved arginine (R1496 in AnkG190), previously shown to be critical for the binding of Fas (R234 in Fas) to FADD, abolished the interaction of ankyrin's death domain with Fas. Overexpression of constructs containing ankyrin's death domain promoted Fas-mediated apoptosis in MDCK cells. The linkage between ankyrin and Fas was confirmed in vivo in mouse kidney tubule cells by coimmunoprecipitation and colocalization. In an established mouse model of renal ischemia-reperfusion injury characterized by apoptotic tubule cell death, the expression of both ankyrin and Fas was markedly induced, and the interaction between these molecules remained intact. The results identify a novel tethering interaction between ankyrin and Fas in kidney epithelia and suggest that AnkG190 may play a role as an adapter molecule in renal tubule cell death.