Biochemical and histological studies on adverse effects of mobile phone radiation on rat's brain.
With the rapid development of electronic technologies, the public concern about the potential health hazards induced by radiofrequency (RF) radiation has been grown. To investigate the effect of 1800MHz RF radiation emitted from mobile phone on the rat's brain, the present study was performed. Forty male rats were randomly divided into two equal groups; control and exposed group. The later one exposed to 1800MHz emitted from mobile phone with an SAR value of 0.6W/kg for two hours/day for three months. The brain tissues were collected at the end of the experimental period and separated into hippocampus and cerebellum for subsequent biochemical, histological, immunohistochemical and electron microscopic investigations. The rats that were exposed to RF- radiation had a significant elevation in MDA content and a significant reduction in antioxidant parameters (glutathione, super oxide dismutase and glutathione peroxidase) in both regions. Degenerative changes were observed in the hippocampus pyramidal cells, dark cells and cerebellar Purkinje cells with vascular congestion. In addition a significant DNA fragmentation and over expression of cyclooxygenase-2 apoptotic gene was detected. Those results suggested that, direct chronic exposure to mobile phone caused severe biochemical and histopathological changes in the brain.


Overexpression of the aryl hydrocarbon receptor nuclear translocator partially rescues fetoplacental angiogenesis in severe fetal growth restriction.
Pregnancies complicated by severe fetal growth restriction with abnormal umbilical artery Doppler velocimetry (FGRadv) are at substantial risk for adverse perinatal and long-term outcomes. Impaired angiogenesis of the placental vasculature in these pregnancies results in a sparse, poorly branched vascular tree, which structurally contributes to the abnormally elevated fetoplacental vascular resistance that is clinically manifested by absent or reversed umbilical artery Doppler indices. Previous studies have shown that aryl hydrocarbon receptor nuclear translocator (ARNT) is a key mediator of proper placental angiogenesis, and within placental endothelial cells (ECs) from human FGRadv pregnancies, low expression of ARNT leads to decreased vascular endothelial growth factor A (VEGFA) expression and deficient tube formation. Thus, the aim of the present study was to determine the effect of VEGFA administration or ARNT overexpression on angiogenic potential of FGRadv ECs. ECs were isolated and cultured from FGRadv or gestational age-matched control placentas and subjected to either vehicle vs VEGFA treatment or transduction with adenoviral-CMV (ad-CMV) vs adenoviral-ARNT (ad-ARNT) constructs. They were then assessed via wound scratch and tube formation assays. We found that VEGFA administration nominally improved FGRadv EC migration (P<0.01) and tube formation (P<0.05). ARNT overexpression led to significantly enhanced ARNT expression in FGRadv ECs (P<0.01), to a level similar to control ECs. Despite this, FGRadv EC migration (P<0.05) and tube formation (P<0.05) were still only partially rescued. This suggests that although ARNT does play a role in fetoplacental EC migration, other factors in addition to ARNT are likely also important in placental angiogenesis.


Inflammatory breast cancer: The pathologists' perspective.
Inflammatory breast cancer (IBC) is a clinico-pathological entity, which has specific features of inflammation and pathological evidence of cancer, most often involving dermal lymphatics. This review looks at IBC from the pathologists point of view. The diagnostic criteria and differential diagnosis are summarized first. The staging implications are described next. Despite the overall poor prognosis of IBC, it is heterogeneous in terms of most prognostic and predictive factors (such as histological type, grade, receptor status, intrinsic subtype, inflammatory infiltrate). It seems that some molecular features (genes expressed) are unique to IBC, and this may help to identify them as IBC at the molecular level. The key carcinogenetic pathways activated in IBC, the inflammatory pathways present in the disease as well as the relation of IBC to cancer stem cells are also briefly covered. Due to the relative rarity of IBC, preclinical trials are very important in the study of this entity, and models with stromal and microenvironmental elements are expected to outperform the traditional models without these features, as the microenvironment seems to be a key component of IBC.


Retention of health workers in Malawi: perspectives of health workers and district management.
Shortage of human resources is a major problem facing Malawi, where more than 50% of the population lives in rural areas. Most of the district health services are provided by clinical health officers specially trained to provide services that would normally be provided by fully qualified doctors or specialists. As this cadre and the cadre of enrolled nurses are the mainstay of the Malawian health service at the district level, it is important that they are supported and motivated to deliver a good standard of service to the population. This study explores how these cadres are managed and motivated and the impact this has on their performance. A quantitative survey measured health workers' job satisfaction, perceptions of the work environment and sense of justice in the workplace, and was reported elsewhere. It emerged that health workers were particularly dissatisfied with what they perceived as unfair access to continuous education and career advancement opportunities, as well as inadequate supervision. These issues and their contribution to demotivation, from the perspective of both management and health workers, were further explored by means of qualitative techniques.Focus group discussions were held with health workers, and key-informant interviews were conducted with members of district health management teams and human resource officers in the Ministry of Health. The focus groups used convenience sampling that included all the different cadres of health workers available and willing to participate on the day the research team visited the health facility. The interviews targeted district health management teams in three districts and the human resources personnel in the Ministry of Health, also sampling those who were available and agreed to participate. The results showed that health workers consider continuous education and career progression strategies to be inadequate. Standard human resource management practices such as performance appraisal and the provision of job descriptions were not present in many cases. Health workers felt that they were inadequately supervised, with no feedback on performance. In contrast to health workers, managers did not perceive these human resources management deficiencies in the system as having an impact on motivation. A strong human resource management function operating at the district level is likely to improve worker motivation and performance.


The frequency and risk of preclinical coronary artery disease detected using multichannel cardiac computed tomography in patients with ischemic stroke.
Atherosclerosis is a systemic disease. Many ischemic stroke patients may have concomitant coronary artery disease (CAD). Detection and treatment of preclinical CAD in stroke patients may improve long-term outcome and survival because CAD is a major cause of death during follow-up in stroke patients. However, association between coronary and cerebral artery atherosclerosis in stroke patients has not fully been investigated. This study aimed at examining the frequency and high-risk groups of CAD in ischemic stroke patients. Consecutive patients who were admitted due to acute ischemic stroke between July 2006 and June 2010 were prospectively enrolled in this study. A total of 1,304 patients who underwent MSCT coronary angiography and cerebral angiography were included in this study. By using 64-multislice computed tomography coronary angiography, we investigated the frequency of CAD and association between coronary and cerebral artery atherosclerosis in terms of location and burden (severity and extent) in stroke patients. We also sought to identify high-risk groups for CAD among stroke patients. The frequency of significant (≥50%) CAD was 32.3% and the frequency of any degree of CAD was 70.1%. Diabetes mellitus, serum levels of total cholesterol, high-density lipoprotein cholesterol and triglyceride, and significant stenosis of the extracranial carotid, intracranial vertebral and basilar arteries were independently associated with CAD. However, no association was found between CAD and significant stenosis of the anterior, middle and posterior cerebral arteries. The association between CAD and cerebral atherosclerosis was stronger with increased severity and extent of cerebral atherosclerosis. When compared to patients with <2 risk factors and without significant cerebral atherosclerosis, those with multiple (≥2) risk factors and atherosclerosis in both the carotid and the vertebrobasilar arteries had very high risks of CAD [odds ratio (OR) 8.36; 95% confidence interval (CI) 4.15-16.87]. The risk was also high in patients with multiple risk factors and atherosclerosis in either the carotid or the vertebrobasilar artery (OR 4.13; 95% CI 2.62-6.51), and in those with <2 risk factors but atherosclerosis in both the carotid and the vertebrobasilar arteries (OR 3.40; 95% CI 1.22-9.47). A substantial portion of stroke patients had preclinical CAD, and there was a clear relationship between coronary and cerebral artery atherosclerosis in terms of location and burden. The risk of CAD was particularly high in stroke patients with multiple risk factors and atherosclerosis of the carotid and/or vertebrobasilar arteries.


Cell type-specific three-dimensional structure of thalamocortical circuits in a column of rat vibrissal cortex.
Soma location, dendrite morphology, and synaptic innervation may represent key determinants of functional responses of individual neurons, such as sensory-evoked spiking. Here, we reconstruct the 3D circuits formed by thalamocortical afferents from the lemniscal pathway and excitatory neurons of an anatomically defined cortical column in rat vibrissal cortex. We objectively classify 9 cortical cell types and estimate the number and distribution of their somata, dendrites, and thalamocortical synapses. Somata and dendrites of most cell types intermingle, while thalamocortical connectivity depends strongly upon the cell type and the 3D soma location of the postsynaptic neuron. Correlating dendrite morphology and thalamocortical connectivity to functional responses revealed that the lemniscal afferents can account for some of the cell type- and location-specific subthreshold and spiking responses after passive whisker touch (e.g., in layer 4, but not for other cell types, e.g., in layer 5). Our data provides a quantitative 3D prediction of the cell type-specific lemniscal synaptic wiring diagram and elucidates structure-function relationships of this physiologically relevant pathway at single-cell resolution.


Statistical analysis of causes of death (2005-2010) in villages of Simav Plain, Turkey, with high arsenic levels in drinking water supplies.
The purpose of this research was to compare the causes of death in 5 villages situated in Simav Plain, Turkey, during 2005-2010 where different arsenic levels were detected in drinking water supplies. Since groundwater in Simav Plain had arsenic concentrations that ranged between 7.1 and 833.9 ppb, a two-phase research was formulated. In the first phase, public health surveys were conducted with 1,003 villagers to determine the distribution of diseases. In the second phase, verbal autopsy surveys and official death records were used to investigate the causes of death. In total, 402 death cases were found in the study area where cardiovascular system diseases (44%) and cancers (15.2%) were major causes. Cancers of lung (44.3%), prostate (9.8%), colon (9.8%), and stomach (8.2%) were comparably higher in villages with high arsenic levels in drinking water supplies. Furthermore, the majority of cases of liver, bladder, and stomach cancers were observed in villages with high arsenic levels.


[Chest pain unit: first experience in Chile].
In large series, nearly 60% of admissions for suspected acute coronary syndrome (ACS) had a non-coronary etiology of the pain. However, short term mortality of non recognized ACS patients, mistakenly discharged from the emergency room is at least twice greater than the expected if they would had been admitted. The concept of a chest pain unit (CPU) is a methodological approach developed to address these issues. To evaluate the efficacy of a CPU in the emergency room of a general hospital for evaluation of acute chest pain. Prospective study of patients with chest pain admitted in the CPU. After a clinical, electrocardiographic and laboratory evaluation with cardiac injury serum markers, patients were stratified in three risk groups, based on the likelihood of ACS of the American Heart Association. High probability patients were admitted to the Coronary Unit (CU) for treatment. Moderate probability patients remained in the CPU for further evaluation and low probability patients were discharged with telephonic follow-up. Of 407 patients, 35, 30 and 35% were stratified as high, intermediate and low probability ACS, respectively. Among patients admitted with high probability, 73% had a confirmed ACS diagnosis. Among intermediate probability patients, 86% were discharged after an evaluation in the CPU without adverse events in the follow-up. Structured risk evaluation approach in a CPU improves the management of acute chest pain, identifying high probability patients for fast admission and start of treatment in a CU and allowing safe discharge of low probability ones.


Single molecule analysis of a red fluorescent RecA protein reveals a defect in nucleoprotein filament nucleation that relates to its reduced biological functions.
Fluorescent fusion proteins are exceedingly useful for monitoring protein localization in situ or visualizing protein behavior at the single molecule level. Unfortunately, some proteins are rendered inactive by the fusion. To circumvent this problem, we fused a hyperactive RecA protein (RecA803 protein) to monomeric red fluorescent protein (mRFP1) to produce a functional protein (RecA-RFP) that is suitable for in vivo and in vitro analysis. In vivo, the RecA-RFP partially restores UV resistance, conjugational recombination, and SOS induction to recA(-) cells. In vitro, the purified RecA-RFP protein forms a nucleoprotein filament whose k(cat) for single-stranded DNA-dependent ATPase activity is reduced approximately 3-fold relative to wild-type protein, and which is largely inhibited by single-stranded DNA-binding protein. However, RecA protein is also a dATPase; dATP supports RecA-RFP nucleoprotein filament formation in the presence of single-stranded DNA-binding protein. Furthermore, as for the wild-type protein, the activities of RecA-RFP are further enhanced by shifting the pH to 6.2. As a consequence, RecA-RFP is proficient for DNA strand exchange with dATP or at lower pH. Finally, using single molecule visualization, RecA-RFP was seen to assemble into a continuous filament on duplex DNA, and to extend the DNA approximately 1.7-fold. Consistent with its attenuated activities, RecA-RFP nucleates onto double-stranded DNA approximately 3-fold more slowly than the wild-type protein, but still requires approximately 3 monomers to form the rate-limited nucleus needed for filament assembly. Thus, RecA-RFP reveals that its attenuated biological functions correlate with a reduced frequency of nucleoprotein filament nucleation at the single molecule level.


The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine.
Clonidine (Catapres, Catapresan), guanfacine (Estulic), and methyldopa (Aldomet) are the prototypes of centrally acting antihypertensive drugs. Clonidine and guanfacine are lipophilic drugs that readily penetrate into the brain, where they stimulate alpha-adrenergic receptors in the pontomedullary region. The stimulation of these central alpha-adrenergic receptors has been shown to activate an inhibiting neuron, which causes a reduction of peripheral sympathetic tone and a subsequent fall in arterial blood pressure and heart rate. Both a centrally initiated reduction of vagus reflex activity and the activation of presynaptic alpha 2-adrenergic blocking agents in the heart may contribute to the bradycardia. Studies indicate that methyldopa also penetrates into the brain, where it is converted into alpha-methylnorepinephrine. This amine may stimulate the same central alpha-adrenergic receptors as those activated by clonidine, which will result in a hypotensive effect. Possibly, alpha-methyldopamine might also play a role. Accordingly, the modes of action of clonidine and alpha-methyldopa probably are very similar at a basic level. The central adrenergic receptors probably are located postsynaptically. Their receptor demand corresponds more closely to that of the alpha 2-subtype. Central alpha 1-adrenergic receptors might possibly play a part in the modulation of vagally induced baroreflex bradycardia. A discussion on the pharmacological basis of the side effects of the centrally acting antihypertensives has been limited to those adverse reactions that are somehow related to alpha-adrenergic receptors. Sedation, a common side effect, appears to be mediated by central alpha 2-adrenergic receptors, at least in animal models.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of p16 and p14ARF in radio- and chemosensitivity of malignant gliomas.
In addition to cytoreductive surgery, most patients with malignant gliomas also undergo radio- and chemotherapy. An improved understanding of the molecular genetic mechanisms underlying the radio- and chemosensitivity of gliomas may help to identify glioma patients who will benefit from aggressive and, therefore, potentially toxic adjuvant treatment. It may also allow for the development of new therapies aimed at improving the response of these tumors towards chemo- and radiotherapy. The INK4a gene products, p16 and p14ARF, have been suggested as potential regulators of glioma chemo- and radiosensitivity. We have used tetracycline controlled expression of p16 and plasmid-based p14ARF expression to study the chemo- and radiosensitivity of glioma cell lines. Ectopic p16 sensitized U-87MG cells towards treatment with vincristine and possibly also BCNU by approximately 1.5 to 2-fold, and towards ionizing radiation by a factor of 1.5. p14ARF expression was found to render U-87MG cells 2-fold more radioresistant than controls. These findings support a role for p16 and p14ARF as modulators of the radio-and chemosensitivity of gliomas. Further studies of the role of cell cycle regulators in glioma chemo- and radio-sensitivity seem warranted. We would like to point out that such candidate genes which may code for potent growth suppressors (like p16) or even toxic gene products can be successfully investigated using the approach detailed in this manuscript.


A novel family of P-loop NTPases with an unusual phyletic distribution and transmembrane segments inserted within the NTPase domain.
Recent sequence-structure studies on P-loop-fold NTPases have substantially advanced the existing understanding of their evolution and functional diversity. These studies provide a framework for characterization of novel lineages within this fold and prediction of their functional properties. Using sequence profile searches and homology-based structure prediction, we have identified a previously uncharacterized family of P-loop NTPases, which includes the neuronal membrane protein and receptor tyrosine kinase substrate Kidins220/ARMS, which is conserved in animals, the F-plasmid PifA protein involved in phage T7 exclusion, and several uncharacterized bacterial proteins. We refer to these (predicted) NTPases as the KAP family, after Kidins220/ARMS and PifA. The KAP family NTPases are sporadically distributed across a wide phylogenetic range in bacteria but among the eukaryotes are represented only in animals. Many of the prokaryotic KAP NTPases are encoded in plasmids and tend to undergo disruption to form pseudogenes. A unique feature of all eukaryotic and certain bacterial KAP NTPases is the presence of two or four transmembrane helices inserted into the P-loop NTPase domain. These transmembrane helices anchor KAP NTPases in the membrane such that the P-loop domain is located on the intracellular side. We show that the KAP family belongs to the same major division of the P-loop NTPase fold with the AAA+, ABC, RecA-like, VirD4-like, PilT-like, and AP/NACHT-like NTPase classes. In addition to the KAP family, we identified another small family of predicted bacterial NTPases, with two transmembrane helices inserted into the P-loop domain. This family is not specifically related to the KAP NTPases, suggesting independent acquisition of the transmembrane helices. We predict that KAP family NTPases function principally in the NTP-dependent dynamics of protein complexes, especially those associated with the intracellular surface of cell membranes. Animal KAP NTPases, including Kidins220/ARMS, are likely to function as NTP-dependent regulators of the assembly of membrane-associated signaling complexes involved in neurite growth and development. One possible function of the prokaryotic KAP NTPases might be in the exclusion of selfish replicons, such as viruses, from the host cells. Phylogenetic analysis and phyletic patterns suggest that the common ancestor of the animals acquired a KAP NTPase via lateral transfer from bacteria. However, an earlier transfer into eukaryotes followed by multiple losses in several eukaryotic lineages cannot be ruled out.


Knowledge-based methods to help clinicians find answers in MEDLINE.
Large databases of published medical research can support clinical decision making by providing physicians with the best available evidence. The time required to obtain optimal results from these databases using traditional systems often makes accessing the databases impractical for clinicians. This article explores whether a hybrid approach of augmenting traditional information retrieval with knowledge-based methods facilitates finding practical clinical advice in the research literature. Three experimental systems were evaluated for their ability to find MEDLINE citations providing answers to clinical questions of different complexity. The systems (SemRep, Essie, and CQA-1.0), which rely on domain knowledge and semantic processing to varying extents, were evaluated separately and in combination. Fifteen therapy and prevention questions in three categories (general, intermediate, and specific questions) were searched. The first 10 citations retrieved by each system were randomized, anonymized, and evaluated on a three-point scale. The reasons for ratings were documented. Metrics evaluating the overall performance of a system (mean average precision, binary preference) and metrics evaluating the number of relevant documents in the first several presented to a physician were used. Scores (mean average precision = 0.57, binary preference = 0.71) for fusion of the retrieval results of the three systems are significantly (p < 0.01) better than those for any individual system. All three systems present three to four relevant citations in the first five for any question type. The improvements in finding relevant MEDLINE citations due to knowledge-based processing show promise in assisting physicians to answer questions in clinical practice.


Nonoperative fracture treatment in the modern era.
Nonoperative fracture treatment has been used for millennia, but there has been no demographic study of its use for half a century. In the last 50 to 60 years, there has been an increased interest in operative fracture fixation and in many specialized Trauma hospitals nonoperative management is less frequently used. However, these specialized hospitals do not reflect fracture treatment in the whole community, and we have undertaken a study to investigate the current prevalence of nonoperative fracture treatment. A retrospective analysis of 7,863 consecutive fractures in a defined population was undertaken. The use of nonoperative management in different fractures was assessed as was the influence of fracture severity, mode of injury, multiple fractures and social deprivation in the choice of treatment. A comparison of current treatment with that of the 1940s and 1950s was undertaken. The prevalence of nonoperative treatment was 74.6% with 91.6% of children and 67.6% of adults being treated nonoperatively. There were significant differences in upper and lower limb fractures in both children and adults. The major determinant of nonoperative management was age, although the severity of fracture, mode of injury, and presence of multiple fractures were also important. Social deprivation was not a significant factor except in adult metacarpal fractures. Nonoperative treatment remains the most widely used method of fracture management. Its prevalence decreases with age, particularly in lower limb fractures. In children, there is a bimodal operative treatment distribution and an increasing prevalence of operative treatment. In some adult fractures, the prevalence of surgery is increasing, but in others, we operate no more frequently than in the 1950s, despite improved operative techniques.


Use of dynamic soil-vegetation models to assess impacts of nitrogen deposition on plant species composition: an overview.
Field observations and experimental data of effects of nitrogen (N) deposition on plant species diversity have been used to derive empirical critical N loads for various ecosystems. The great advantage of such an approach is the inclusion of field evidence, but there are also restrictions, such as the absence of explicit criteria regarding significant effects on the vegetation, and the impossibility to predict future impacts when N deposition changes. Model approaches can account for this. In this paper, we review the possibilities of static and dynamic multispecies models in combination with dynamic soil-vegetation models to (1) predict plant species composition as a function of atmospheric N deposition and (2) calculate critical N loads in relation to a prescribed protection level of the species composition. The similarities between the models are presented, but also several important differences, including the use of different indicators for N and acidity and the prediction of individual plant species vs. plant communities. A summary of the strengths and weaknesses of the various models, including their validation status, is given. Furthermore, examples are given of critical load calculations with the model chains and their comparison with empirical critical N loads. We show that linked biogeochemistry-biodiversity models for N have potential for applications to support European policy to reduce N input, but the definition of damage thresholds for terrestrial biodiversity represents a major challenge. There is also a clear need for further testing and validation of the models against long-term monitoring or long-term experimental data sets and against large-scale survey data. This requires a focused data collection in Europe, combing vegetation descriptions with variables affecting the species diversity, such as soil acidity, nutrient status and water availability. Finally, there is a need for adaptation and upscaling of the models beyond the regions for which dose-response relationships have been parameterized, to make them generally applicable.


The Natural History of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children: A Systematic Review.
The clinical manifestations and natural history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related multisystem inflammatory syndrome in children (MIS-C) are poorly defined. Using a systematic review of individual cases and case series and collating elements of the clinical course, the objective of this study was to provide a detailed clinical description and natural history of MIS-C. Case reports and series of MIS-C were recovered from repeated MEDLINE searches, a single EMBASE search, and table of contents reviews of major general medicine and pediatric journals performed between June 3 and July 23, 2020. Fever, evidence of inflammation, and evidence of organ dysfunction were required for inclusion. MEDLINE and EMBASE searches produced 129 articles, and 10 articles were identified from journal contents or article bibliographies; 16 reports describing 505 children with MIS-C comprise this review. Thirty-two children (14.7%) had negative results for SARS-CoV-2 by nucleic acid and/or antibody testing. The weighted median age was 9 years (6 months to 20 years). Clinical findings included fever (100%), gastrointestinal symptoms (88.0%), rash (59.2%), conjunctivitis (50.0%), cheilitis/ "strawberry tongue" (55.7%), or extremity edema/erythema (47.5%). Median serum C-reactive protein, ferritin, fibrinogen, and D-dimer concentrations were above the normal range. Intravenous gammaglobulin (78.1%) and methylprednisolone/prednisone (57.6%) were the most common therapeutic interventions; immunomodulation was used in 24.3% of cases. Myocardial dysfunction requiring ionotropic support (57.4%) plus extracorporeal membrane oxygenation (5.3%), respiratory distress requiring mechanical ventilation (26.1%), and acute kidney injury (11.9%) were the major complications; anticoagulation was used commonly (54.4%), but thrombotic events occurred rarely (3.5%). Seven (1.4%) children died. MIS-C following SARS-CoV-2 infection frequently presents with gastrointestinal complaints and/or rash; conjunctivitis, cheilitis, and/or extremity changes also occur frequently. Serious complications occur frequently and respond to aggressive supportive therapy.


Defining the burden of febrile illness in rural South and Southeast Asia: an open letter to announce the launch of the Rural Febrile Illness project.
In rural areas of South and Southeast Asia malaria is declining but febrile illnesses still account for substantial morbidity and mortality. Village health workers (VHWs) are often the first point of contact with the formal health system, and for patients with febrile illnesses they can provide early diagnosis and treatment of malaria. However, for the majority of febrile patients, VHWs lack the training, support and resources to provide further care. Consequently, treatable bacterial illnesses are missed, antibiotics are overused and poorly targeted, and patient attendance wanes along with declining malaria. This Open Letter announces the start of a new initiative, the Rural Febrile Illness (RFI) project, the first in a series of projects to be implemented as part of the South and Southeast Asian Community-based Trials Network (SEACTN) research programme. This multi-country, multi-site project will run in Bangladesh, Cambodia, Lao PDR, Thailand, and Myanmar. It will define the epidemiological baseline of febrile illness in nine remote and underserved areas of Asia where malaria endemicity is declining and access to health services is limited. The RFI project aims to determine the incidence, causes and outcomes of febrile illness; understand the opportunities, barriers and appetite for adjustment of the role of VHWs to include management of non-malarial febrile illnesses; and establish a network of community healthcare providers and facilities capable of implementing interventions designed to triage, diagnose and treat patients presenting with febrile illnesses within these communities in the future.


The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost.
Membrane-associated guanylate kinase (Maguk) proteins are scaffold proteins that contain PSD-95-Discs Large-zona occludens-1 (PDZ), Src homology 3, and guanylate kinase domains. A subset of Maguk proteins, such as mLin-2 and protein associated with Lin-7 (Pals)1, also contain two L27 domains: an L27C domain that binds mLin-7 and an L27N domain of unknown function. Here, we demonstrate that the L27N domain targets Pals1 to tight junctions by binding to a PDZ domain protein, Pals1-associated tight junction (PATJ) protein, via a unique Maguk recruitment domain. PATJ is a homologue of Drosophila Discs Lost, a protein that is crucial for epithelial polarity and that exists in a complex with the apical polarity determinant, Crumbs. PATJ and a human Crumbs homologue, CRB1, colocalize with Pals1 to tight junctions, and CRB1 interacts with PATJ albeit indirectly via binding the Pals1 PDZ domain. In agreement, we find that a Drosophila homologue of Pals1 participates in identical interactions with Drosophila Crumbs and Discs Lost. This Drosophila Pals1 homologue has been demonstrated recently to represent Stardust, a crucial polarity gene in Drosophila. Thus, our data identifies a new multiprotein complex that appears to be evolutionarily conserved and likely plays an important role in protein targeting and cell polarity.


Training new community health, food service, and environmental protection workers could boost health, jobs, and growth.
General job training programs, and separate disease prevention or health promotion programs, are usually viewed as two different strategies for reducing poverty and promoting community development. We propose that with better alignment of the strategies, new jobs with the potential to simultaneously improve population health, lower the cost of health care, and reduce unemployment could be created and filled. Initiatives for three types of entry-level positions-in the fields of community health, environmental remediation and protection, and food preparation-show particular promise as vehicles for health and economic improvement at the individual and community levels. Building on current federal programs, new pilot projects financed by federal funding should be created to test and refine such initiatives and their impact and assemble an evidence base for future policy action.


Mechanisms for eliminating monoterpenes of sagebrush by specialist and generalist rabbits.
Pygmy rabbits (Brachylagus idahoensis) are one of only three vertebrates that subsist virtually exclusively on sagebrush (Artemisia spp.), which contains high levels of monoterpenes that can be toxic. We examined the mechanisms used by specialist pygmy rabbits to eliminate 1,8-cineole, a monoterpene of sagebrush, and compared them with those of cottontail rabbits (Sylvilagus nuttalli), a generalist herbivore. Rabbits were offered food pellets with increasing concentrations of cineole, and we measured voluntary intake and excretion of cineole metabolites in feces and urine. We expected pygmy rabbits to consume more, but excrete cineole more rapidly by using less-energetically expensive methods of detoxification than cottontails. Pygmy rabbits consumed 3-5 times more cineole than cottontails relative to their metabolic body mass, and excreted up to 2 times more cineole metabolites in their urine than did cottontails. Urinary metabolites excreted by pygmy rabbits were 20 % more highly-oxidized and 6 times less-conjugated than those of cottontails. Twenty percent of all cineole metabolites recovered from pygmy rabbits were in feces, whereas cottontails did not excrete fecal metabolites. When compared to other mammals that consume cineole, pygmy rabbits voluntarily consumed more, and excreted more cineole metabolites in feces, but they excreted less oxidized and more conjugated cineole metabolites in urine. Pygmy rabbits seem to have a greater capacity to minimize systemic exposure to cineole than do cottontails, and other cineole-consumers, by minimizing absorption and maximizing detoxification of ingested cineole. However, mechanisms that lower systemic exposure to cineole may come with a higher energetic cost in pygmy rabbits than in other mammalian herbivores.


Cell surface major histocompatibility complex class II proteins are regulated by the products of the gamma(1)34.5 and U(L)41 genes of herpes simplex virus 1.
Modulation of host immune responses has emerged as a common strategy employed by herpesviruses both to establish life-long infections and to affect recovery from infection. Herpes simplex virus 1 (HSV-1) blocks the major histocompatibility complex (MHC) class I antigen presentation pathway by inhibiting peptide transport into the endoplasmic reticulum. The interaction of viral gene products with the MHC class II pathway, however, has not been thoroughly investigated, although CD4(+) T cells play an important role in human recovery from infection. We have investigated the stability, distribution, and state of MHC class II proteins in glioblastoma cells infected with wild-type HSV-1 or mutants lacking specific genes. We report the following findings. (i) Wild-type virus infection caused a decrease in the accumulation of class II protein on the surface of cells and a decrease in the endocytosis of lucifer yellow or dextran conjugated to fluorescein isothiocyanate but no decrease in the total amount of MHC class II proteins relative to the levels seen in mock-infected cells. (ii) Although the total amount of MHC class II protein remained unchanged, the amounts of cell surface MHC class II proteins were higher in cells infected with the U(L)41-negative mutant, which lacks the virion host shutoff protein, and especially high in cells infected with the gamma(1)34.5-negative mutant. We conclude that infected cells attempt to respond to infection by increased acquisition of antigens and transport of MHC class II proteins to the cell surface and that these responses are blocked in part by the virion host shutoff protein encoded by the U(L)41 gene and in large measure by the direct or indirect action of the infected cell protein 34.5, the product of the gamma(1)34.5 gene.


Dynamics of soft nanomaterials captured by transmission electron microscopy in liquid water.
In this paper we present in situ transmission electron microscopy of synthetic polymeric nanoparticles with emphasis on capturing motion in a solvated, aqueous state. The nanoparticles studied were obtained from the direct polymerization of a Pt(II)-containing monomer. The resulting structures provided sufficient contrast for facile imaging in situ. We contend that this technique will quickly become essential in the characterization of analogous systems, especially where dynamics are of interest in the solvated state. We describe the preparation of the synthetic micellar nanoparticles together with their characterization and motion in liquid water with comparison to conventional electron microscopy analyses.


An epidemiological reconsideration of the Geschwind-Galaburda theory of cerebral lateralization.
To contribute to the Geschwind-Galaburda theory of cerebral lateralization, we examined the relationship of left-handedness to allergic disorders and stuttering, using epidemiological data of two French samples, one of which (N = 9591) is representative of the French male population between 17 and 24 years of age. Results showed a higher frequency of stuttering but not of allergic disorders in left-handers. Extreme right-handedness was observed to be significantly associated with a lower frequency of allergic disorders; response bias might explain such a relationship. Findings were confirmed after allowing for potential confounding factors, such as age and education. In both samples, stuttering and allergic disorders were significantly related.


Fecal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae in swine and cattle at slaughter in Switzerland.
During the past decade, extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae have become a matter of great concern in human medicine. ESBL-producing strains are found in the community, not just in hospital-associated patients, which raises a question about possible reservoirs. Recent studies describe the occurrence of ESBL-producing Enterobacteriaceae in meat, fish, and raw milk; therefore, the impact of food animals as reservoirs for and disseminators of such strains into the food production chain must be assessed. In this pilot study, fecal samples of 59 pigs and 64 cattle were investigated to determine the occurrence of ESBL-producing Enterobacteriaceae in farm animals at slaughter in Switzerland. Presumptive-positive colonies on Brilliance ESBL agar were subjected to identification and antibiotic susceptibility testing including the disc diffusion method and E-test ESBL strips. As many as 15.2% of the porcine and 17.1% of the bovine samples, predominantly from calves, yielded ESBL producers. Of the 21 isolated strains, 20 were Escherichia coli, and one was Citrobacter youngae. PCR analysis revealed that 18 strains including C. youngae produced CTX-M group 1 ESBLs, and three strains carried genes encoding for CTX-M group 9 enzymes. In addition, eight isolates were PCR positive for TEM β-lactamase, but no bla(SHV) genes were detected. Pulsed-field gel electrophoresis showed a high genetic diversity within the strains. The relatively high rates of occurrence of ESBLproducing strains in food animals and the high genetic diversity among these strains indicate that there is an established reservoir of these organisms in farm animals. Further studies are necessary to assess future trends.


Antimycobacterial terpenoids from Juniperus communis L. (Cuppressaceae).
Juniperus communis is a plant which has been reported as a traditional cure for tuberculosis (TB) and other respiratory diseases. The aim of this study was to isolate and identify the constituents responsible for the activity of the n-hexane extract of Juniperus communis roots against Mycobacterium tuberculosis H(37)Rv and Juniperus communis aerial parts against Mycobacterium aurum. Subsequently, it was to evaluate the activity of the pure isolated compounds against (i) drug-resistant Mycobacterium tuberculosis variants, (ii) non-replicating Mycobacterium tuberculosis and (iii) a range of non-tuberculous mycobacteria (NTM). The antimycobacterial activity of Juniperus communis extracts, fractions and constituents was determined against Mycobacterium tuberculosis H(37)Rv, and against rifampicin-, isoniazid-, streptomycin- and moxifloxacin-resistant variants, using the microplate broth Alamar Blue assay (MABA) method. Isolated constituents were tested against non-replicating Mycobacterium tuberculosis H(37)Rv, using the low oxygen recovery assay (LORA), and against NTM (Mycobacterium aurum, Mycobacterium phlei, Mycobacterium fortuitum and Mycobacterium smegmatis), using a broth microdilution method. Cytotoxicity studies were performed using mammalian Vero cells. The antimycobacterial activity of Juniperus communis was attributed to a sesquiterpene identified as longifolene (1) and two diterpenes, characterised as totarol (2) and trans-communic acid (3). All compounds were identified following analysis of their spectroscopic data (1D- and 2D-NMR, MS) and by comparison with the literature and commercial authentic standards when available. Revised assignments for 3 are reported. Totarol showed the best activity against Mycobacterium tuberculosis H(37)Rv (MIC of 73.7 microM). It was also most active against the isoniazid-, streptomycin-, and moxifloxacin-resistant variants (MIC of 38.4, 83.4 and 60 microM, respectively). Longifolene and totarol were most active against the rifampicin-resistant variant (MICs of 24 and 20.2 microM, respectively). Totarol showed the best activity in the LORA assay (MIC of 81.3 microM) and against all NTM species (MICs in the range of 7-14 microM). Trans-communic acid showed good activity against Mycobacterium aurum (MIC of 13.2 microM). The low selectivity indices (SI) obtained following cytotoxicity studies indicated that the isolated terpenoids were relatively toxic towards mammalian cells. This is the first report of the isolation of (1) and (2) from Juniperus communis roots, and of (3) from the aerial parts. The antimycobacterial activity of (1) and (3), and the activity of (2) against Mycobacterium aurum, Mycobacterium fortuitum and Mycobacterium phlei, is reported for the first time. The effect of totarol on drug-resistant variants and non-replicating Mycobacterium tuberculosis has never been published. The presence of antimycobacterial terpenoids in Juniperus communis aerial parts and roots justifies, to some extent, the ethnomedicinal use of this species as a traditional anti-TB remedy.


Impaired Sensory Processing During Low-Oxygen Exposure: A Noninvasive Approach to Detecting Changes in Cognitive States.
The ability to detect novelty in our environment is a critical sensory function. A reliable set of event-related potentials (ERP), known as the auditory deviance response (ADR), are elicited in the absence of directed attention and indexes functionally relevant networks. The ADR consists of three peaks: mismatch negativity (MMN), P3a, and reorienting negativity (RON) that are sequentially evoked in response to unattended changes in repetitive background stimulation. While previous studies have established the ADR's sensitivity to a range of pharmacologic and nonpharmacologic interventions and are leading candidate biomarkers of perturbations of the central nervous system (CNS), here we sought to determine if ADR peaks are sensitive to decreases in breathable oxygen. Participants performed a visuomotor tracking task while EEG was recorded during two 27-min sessions. The two sessions differed in the amount of environmental oxygen available: 10.6% O2 (hypoxia) versus 20.4% O2 (normoxia). ERPs were measured while a series of identical, or "standard," tones combined with occasional "oddball," tones, were presented. MMN, P3a, and RON were assessed in response to the oddball compared to the standard stimuli. Behavioral impairment during hypoxia was demonstrated by a deficit in tracking performance compared to the normoxia condition. Whereas no changes were detected in the MMN or RON, the amplitude of the P3a component was significantly reduced during hypoxia compared to normoxia, within the first 9 min of exposure. To our knowledge, this is the first study to demonstrate the effect of low oxygen exposure on passively elicited neural measures of early sensory processing. This study demonstrates that passively elicited EEG measures, reflecting preattentive auditory processing, are disrupted by acute hypoxia. Results have implications for the development of biomarkers for the noninvasive assessment of CNS perturbations.


Crystal structure of the ATP-gated P2X(4) ion channel in the closed state.
P2X receptors are cation-selective ion channels gated by extracellular ATP, and are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is at present no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X(4) receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in beta-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the 'gate' is defined by an approximately 8 A slab of protein. We define the location of three non-canonical, intersubunit ATP-binding sites, and suggest that ATP binding promotes subunit rearrangement and ion channel opening.


Tumor necrosis factor-alpha inhibitor associated ulcerative colitis.
Flares or onset of inflammatory bowel disease in association with immunosuppression has been reported in the literature. We studied 4 cases of patients with rheumatic disease who developed or had a flare of ulcerative colitis either after initiation of or while taking a tumor necrosis factor-alpha inhibitor. We identified 4 patients, three male and one female. Two of the male patients had a seronegative spondyloarthropathy and one had rheumatoid arthritis. The female patient had amyopathic dermatomyositis. Two of the 4 patients had ulcerative colitis prior to tumor necrosis factor-alpha treatment. Both of these patients had quiescent ulcerative colitis that flared after they began taking etanercept. Two patients developed de novo ulcerative colitis while taking a tumor necrosis factor-alpha inhibitor. The data presented in these 4 cases supports a temporal relationship between initiating a tumor necrosis factor-alpha inhibitor and onset or flare of ulcerative colitis. These observations raise the possibility that tumor necrosis factor-alpha inhibitor therapy, which has been used as treatment for inflammatory bowel disease, may rarely be a factor in the development of disease.


Modeling the solvation of nonpolar amino acids in guanidinium chloride solutions.
It is common to denature proteins by using high temperatures or by adding guanidinium chloride (GdmCl). However, the physical mechanism of denaturation is not well understood. Based on extensive experimental data, we developed a thermodynamic binding-polynomial model for the process of transferring nonpolar amino acids from water into GdmCl solutions, as a function of temperature and GdmCl concentration. To mimic nonpolar amino acids, we utilized the model compound, N-acetyl-tryptophanamide (NATA). We find that all nonpolar amino acids behave like NATA, with a scale factor linearly dependent on the surface area. Our model with three thermodynamic parameters fully captures the nonlinear dependencies on both the temperature and GdmCl concentration: binding the first guanidinium ion (Gdm(+)) to NATA has favorable entropy and unfavorable enthalpy of desolvation (ΔS = +11.7 cal/mol, ΔH = +3.9 kcal/mol), while cooperativity of binding a second Gdm(+) has a small contribution (K = 0.032 ± 0.003). This model may be useful for a better understanding of protein denaturation by temperature and GdmCl.


The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier.
Stabilization of the blood-brain barrier during and after stroke can lead to less adverse outcome. For elucidation of underlying mechanisms and development of novel therapeutic strategies validated in vitro disease models of the blood-brain barrier could be very helpful. To mimic in vitro stroke conditions we have established a blood-brain barrier in vitro model based on mouse cell line cerebEND and applied oxygen/glucose deprivation (OGD). The role of astrocytes in this disease model was investigated by using cell line C6. Transwell studies pointed out that addition of astrocytes during OGD increased the barrier damage significantly in comparison to the endothelial monoculture shown by changes of transendothelial electrical resistance as well as fluorescein permeability data. Analysis on mRNA and protein levels by qPCR, western blotting and immunofluorescence microscopy of tight junction molecules claudin-3,-5,-12, occludin and ZO-1 revealed that their regulation and localisation is associated with the functional barrier breakdown. Furthermore, soluble factors of astrocytes, OGD and their combination were able to induce changes of functionality and expression of ABC-transporters Abcb1a (P-gp), Abcg2 (bcrp), and Abcc4 (mrp4). Moreover, the expression of proteases (matrixmetalloproteinases MMP-2, MMP-3, MMP-9, and t-PA) as well as of their endogenous inhibitors (TIMP-1, TIMP-3, PAI-1) was altered by astrocyte factors and OGD which resulted in significant changes of total MMP and t-PA activity. Morphological rearrangements induced by OGD and treatment with astrocyte factors were confirmed at a nanometer scale using atomic force microscopy. In conclusion, astrocytes play a major role in blood-brain barrier breakdown during OGD in vitro.


Multiple-strain colonization in nasal carriers of Staphylococcus aureus.
Staphylococcus aureus is a commensal that can also cause invasive infection. Reports suggest that nasal cocolonization occurs rarely, but the resources required to sequence multiple colonies have precluded its large-scale investigation. A staged protocol was developed to maximize detection of mixed-spa-type colonization while minimizing laboratory resources using 3,197 S. aureus-positive samples from a longitudinal study of healthy individuals in Oxfordshire, United Kingdom. Initial typing of pooled material from each sample identified a single unambiguous strain in 89.6% of samples. Twelve single-colony isolates were typed from samples producing ambiguous initial results. All samples could be resolved into one or more spa types using the protocol. Cocolonization point prevalence was 3.4 to 5.8% over 24 months of follow-up in 360 recruitment-positives. However, 18% were cocolonized at least once, most only transiently. Cocolonizing spa types were completely unrelated in 56% of samples. Of 272 recruitment-positives returning ≥12 swabs, 166 (61%) carried S. aureus continuously but only 106 (39%) carried the same single spa type without any cocolonization; 31 (11%) switched spa type and 29 (11%) had transient cocarriage. S. aureus colonization is dynamic even in long-term carriers. New unrelated cocolonizing strains could increase invasive disease risk, and ongoing within-host evolution could increase invasive potential, possibilities that future studies should explore.


Robust Object Tracking with Online Multiple Instance Learning.
In this paper, we address the problem of tracking an object in a video given its location in the first frame and no other information. Recently, a class of tracking techniques called "tracking by detection" has been shown to give promising results at real-time speeds. These methods train a discriminative classifier in an online manner to separate the object from the background. This classifier bootstraps itself by using the current tracker state to extract positive and negative examples from the current frame. Slight inaccuracies in the tracker can therefore lead to incorrectly labeled training examples, which degrade the classifier and can cause drift. In this paper, we show that using Multiple Instance Learning (MIL) instead of traditional supervised learning avoids these problems and can therefore lead to a more robust tracker with fewer parameter tweaks. We propose a novel online MIL algorithm for object tracking that achieves superior results with real-time performance. We present thorough experimental results (both qualitative and quantitative) on a number of challenging video clips.


Mode shaping in multicore fibers.
We propose a novel multicore fiber design strategy for obtaining a flat in-phase supermode that optimizes utilization of the active medium inversion in the multiple cores. The spatially flat supermode is achieved by engineering the fiber so that the total mutual coupling between neighboring active cores is equal. Different designs suitable for different fabrication processes, such as stack-and-draw and drilling, are proposed. An important improvement over previous methods is the design simplicity and better tolerance to perturbations.


Absorption kinetics of 5-aminosalicylic acid in rat: influence of indomethacin-induced gastrointestinal lesions and Escherichia Coli Nissle 1917 medication.
The therapeutic effect of probiotics has been studied in many clinical and experimental studies but no data exist concerning the influence of probiotics on pharmacokinetics of contemporary administered drugs. In this paper, we describe the influence of indomethacin-induced gastrointestinal lesions and Escherichia Coli Nissle 1917 medication on absorption of 5-aminosalicylic acid and its metabolite N-acetyl-5-aminosalicylic acid in rat. 5-aminosalicylic acid (5-ASA) was given orally to rat using gastric probe as a suspension (25 mg/kg). The plasma time profiles of 5-ASA and its metabolite were compared between Group A (animals medicated with a suspension of Escherichia coli Nissle 1917 [EcN] in dose of 5 × 108 CFUs/day for 14 consecutive days), Group B (animals with indomethacin [IND]-induced gastrointestinal lesions; single dose of 25 mg/kg of IND), Group C (simultaneous administration of EcN and IND), and Group D (control animals without any medication). The blood samples for HPLC analysis has been taken from incannulated vena jugularis in time 30, 60, 90, 120, 180, 240, 360 min after 5-ASA administration to rat. The pharmacokinetics of 5-ASA was not significantly changed by EcN medication (Group A) in comparison to control animals (Group D). The significantly elevated absorption (AUC and cmax) of 5-ASA was found in animals with induced gastro-enteropathy with concurrently medicated with EcN (Group C) when compred to controls. In the case of metabolite N-acetyl-5-ASA, statistically no-significant differences were found between groups. Simultaneous probiotics (EcN) medication did not affect absorption 5-ASA from intestinal tract (the main site of ASAs action).


Isolation and characterization of Streptococcus cremoris Wg2-specific promoters.
By cloning MboI fragments in the promoter selection vector pGKV210, which replicates in Streptococcus lactis, Bacillus subtilis, and Escherichia coli and carries a promoterless chloramphenicol acetyltransferase gene, we obtained a number of fragments endowed with promoter activity, partly by direct selection for chloramphenicol resistance in S. lactis IL1403 and partly by selection in B. subtilis. Five fragments were sequenced, and the promoters were mapped with S1 nuclease. The promoters agreed with the E. coli promoter consensus and the B. subtilis vegetative sigma 43 promoter consensus. The promoters were preceded by an A + T-rich region (ranging from 64 to 78% A + T). S1 nuclease mapping data showed that the transcriptional start point in three of the fragments was at a TAG sequence 5 to 9 nucleotides downstream from the promoter. Three fragments carried an open reading frame preceded by a ribosome-binding site which can be recognized by E. coli, B. subtilis, and S. lactis ribosomes.


The prevalence of harmful content on outdoor advertising in Los Angeles: land use, community characteristics, and the spatial inequality of a public health nuisance.
Our study sought to examine associations between the content of outdoor advertising and neighborhood ethnic/racial and socioeconomic composition to see whether particular communities disproportionately host harmful content. We constructed a spatial database of photographs taken from June 2012 until December 2012 in 7 identically zoned communities in Los Angeles, California, to compare outdoor advertising area and content. We selected communities to contrast by ethnicity/race, income, education, and youth population. At-risk communities and communities of color hosted more outdoor advertising depicting harmful content than other communities. Among included neighborhoods, harmful content and the proportion of outdoor advertising overall were most prevalent in communities of Asian Americans and Latino Americans. In all communities, harmful content represented at least 24% of outdoor advertising space. This study provides evidence of the potential for land-use decisions to result in spatially inequitable health impacts. Although dictating the placement of outdoor advertising through zoning may seem sensible, such a decision might have the unintended consequence of disadvantaging the well-being of local communities. Neighborhood factors require more contextually nuanced public health and land-use policy.


Odyssean malaria outbreaks in Gauteng Province, South Africa, 2007 - 2013.
Odyssean malaria refers to malaria transmitted by translocated mosquitoes and is a diagnosis of exclusion, as the probability of finding the responsible vector is miniscule. We believe that road traffic from endemic areas in and around South Africa is the source of most of the infected mosquitoes. Because of the unexpected nature of the disease, diagnosis is often delayed and severe and complicated malaria is common. To describe outbreaks of odyssean malaria during the period 2007 through 2013 in Gauteng Province, South Africa, and to educate healthcare workers about this form of malaria. Site visits, environmental hygiene inspections, patient interviews, and entomological investigations for adult mosquitoes and larvae in potential breeding sites were done in each identified outbreak. Over the period, 14 laboratory-proven and 7 probable cases of odyssean malaria were investigated. There were 2 deaths (9.5% case fatality rate, approximately 10 times higher than the national fatality rate for malaria). We describe two recent clusters of cases in detail, and emphasise the importance of clinician awareness of this rare but frequently severe form of malaria. Odyssean malaria cases are inevitable in South Africa, given the volume of road, rail and air traffic from malaria risk areas into Gauteng and other non-endemic provinces. It is likely that many cases are missed, owing to the rare and sporadic nature of the condition. Malaria should always be kept in mind as a cause of unexplained fever and thrombocytopenia, even in the absence of a travel history.


Autoantibodies to ribonucleoproteins.
Presently we recognize at least 12 different autoantibodies that involve ribonucleoproteins as antigens in patients with SLE and other rheumatic diseases. Such autoantibodies have a number of clinically useful diagnostic associations. Moreover, they have proved to be powerful tools for understanding the structure and function of a variety of cellular components that involve RNA molecules. In SLE, autoantibodies that recognize the U1 snRNP (i.e. anti-(U1)RNP and anti-Sm antibodies) and the Ro scRNPs (i.e. anti-Ro and anti-La antibodies) are especially prominent in terms of their high frequency and titre. These particles, along with the nucleosome (which is the principal focus of autoantibodies to chromatin) appear to have active roles in eliciting autoimmune responses in such patients. Future studies aimed at understanding how and when these particular structures interact with the immune system could provide important insights into the aetiology and pathogenesis of this disorder.


Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.
Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).


Characterization of integrons and tetracycline resistance determinants in Aeromonas spp. isolated from South African aquaculture systems.
An increasing incidence of multidrug resistance amongst Aeromonas spp. isolates, which are both fish pathogens and emerging opportunistic human pathogens, has been observed worldwide. This can be attributed to the horizontal transfer of mobile genetic elements, viz.: plasmids and class 1 integrons. The antimicrobial susceptibilities of 37 Aeromonas spp. isolates, from tilapia, trout and koi aquaculture systems, were determined by disc-diffusion testing. The plasmid content of each isolate was examined using the alkaline lysis protocol. Tet determinant type was determined by amplification using two degenerate primer sets and subsequent HaeIII restriction. The presence of integrons was determined by PCR amplification of three integrase genes, as well as gene cassettes, and the qacEDelta1-sulI region. Thirty-seven Aeromonas spp. isolates were differentiated into six species by aroA PCR-RFLP, i.e., A. veronii biovar sobria, A. hydrophila, A. encheleia, A. ichtiosoma, A. salmonicida, and A. media. High levels of resistance to tetracycline (78.3%), amoxicillin (89.2%), and augmentin (86.5%) were observed. Decreased susceptibility to erythromycin was observed for 67.6% of isolates. Although 45.9% of isolates displayed nalidixic acid resistance, majority of isolates were susceptible to the fluoroquinolones. The MAR index ranged from 0.12 to 0.59, with majority of isolates indicating high-risk contamination originating from humans or animals where antibiotics are often used. Plasmids were detected in 21 isolates, with 14 of the isolates displaying multiple plasmid profiles. Single and multiple class A family Tet determinants were observed in 27% and 48.7% of isolates, respectively, with Tet A being the most prevalent Tet determinant type. Class 1 integron and related structures were amplified and carried different combinations of the antibiotic resistance gene cassettes ant(3'')Ia, aac(6')Ia, dhfr1, oxa2a and/or pse1. Class 2 integrons were also amplified, but the associated resistance cassettes could not be identified. Integrons and Tet determinants were carried by 68.4% of isolates bearing plasmids, although it was not a strict association. These plasmids could potentially mobilize the integrons and Tet determinants, thus transferring antimicrobial resistance to other water-borne bacteria or possible human pathogens. The identification of a diversity of resistance genes in the absence of antibiotic selective pressure in Aeromonas spp. from aquaculture systems highlights the risk of these bacteria serving as a reservoir of resistance genes, which may be transferred to other bacteria in the aquaculture environment.


Global mapping of H3K4me3 and H3K27me3 reveals chromatin state-based regulation of human monocyte-derived dendritic cells in different environments.
Depending on the environment, dendritic cells (DCs) may become active or tolerogenic, but little is known about whether heritable epigenetic modifications are involved in these processes. Here, we have found that epigenetic histone modifications can regulate the differentiation of human monocyte-derived DCs (moDCs) into either activated or tolerized DCs. The inhibition or silencing of methyltransferases or methylation-associated factors affects the expression of multiple genes. Genome mapping of transforming growth factor (TGF-β)- or lipopolysaccharide (LPS)-associated H3K4 trimethylation (H3K4me3) and H3K27 trimethylation (H3K27me3) demonstrated the presence of histone modification of gene expression in human TGF-β- or LPS-conditioned moDCs. Although the upregulated or downregulated genes were not always associated with H3K4me3 and/or H3K27me3 modifications in TGF-β-conditioned (tolerized) or LPS-conditioned (activated) moDCs, some of these genes may be regulated by the increased and/or decreased H3K4me3 or H3K27me3 levels or by the alteration of these epigenetic marks, especially in TGF-β-conditioned moDCs. Thus, our results suggested that the differentiation and function of moDCs in tumor and inflammation environments are associated with the modification of the H3K4me3 and K3K27me3 epigenetic marks.


Anaemia in low-income and middle-income countries.
Anaemia affects a quarter of the global population, including 293 million (47%) children younger than 5 years and 468 million (30%) non-pregnant women. In addition to anaemia's adverse health consequences, the economic effect of anaemia on human capital results in the loss of billions of dollars annually. In this paper, we review the epidemiology, clinical assessment, pathophysiology, and consequences of anaemia in low-income and middle-income countries. Our analysis shows that anaemia is disproportionately concentrated in low socioeconomic groups, and that maternal anaemia is strongly associated with child anaemia. Anaemia has multifactorial causes involving complex interaction between nutrition, infectious diseases, and other factors, and this complexity presents a challenge to effectively address the population determinants of anaemia. Reduction of knowledge gaps in research and policy and improvement of the implementation of effective population-level strategies will help to alleviate the anaemia burden in low-resource settings.


Arbitrarily thin metamaterial structure for perfect absorption and giant magnification.
In our common understanding, for strong absorption or amplification in a slab structure, the desire of reducing the slab thickness seems contradictory to the condition of small loss or gain. In this paper, this common understanding is challenged. It is shown that an arbitrarily thin metamaterial layer can perfectly absorb or giantly amplify an incident plane wave at a critical angle when the real parts of the permittivity and permeability of the metamaterial are zero while the absolute imaginary parts can be arbitrarily small. The metamaterial layer needs a totally reflective substrate for perfect absorption, while this is not required for giant magnification. Detailed analysis for the existence of the critical angle and physical explanation for these abnormal phenomena are given.


Strength of Structural and Functional Frontostriatal Connectivity Predicts Self-Control in the Healthy Elderly.
Self-regulation refers to the successful use of executive functions and initiation of top-down processes to control one's thoughts, behavior, and emotions, and it is crucial to perform self-control. Self-control is needed to overcome impulses and can be assessed by delay of gratification (DoG) and delay discounting (DD) paradigms. In children/adolescents, good DoG/DD ability depends on the maturity of frontostriatal connectivity, and its decline in strength with advancing age might adversely affect self-control because prefrontal brain regions are more prone to normal age-related atrophy than other regions. Here, we aimed at highlighting the relationship between frontostriatal connectivity strength and DoG performance in advanced age. We recruited 40 healthy elderly individuals (mean age 74.0 ± 7.7 years) and assessed the DoG ability using the German version of the DoG test for adults in addition to the delay discounting (DD) paradigm. Based on diffusion-weighted and resting-state functional magnetic resonance imaging data, respectively, the structural and functional whole-brain connectome were reconstructed based on 90 different brain regions of interest in addition to a 12-node frontostriatal DoG-specific network and the resulting connectivity matrices were subjected to network-based statistics. The 90-nodes whole-brain connectome analyses revealed subnetworks significantly associated with DoG and DD with a preponderance of frontostriatal nodes involved suggesting a high specificity of the findings. Structural and functional connectivity strengths between the putamen, caudate nucleus, and nucleus accumbens on the one hand and orbitofrontal, dorsal, and ventral lateral prefrontal cortices on the other hand showed strong positive correlations with DoG and negative correlations with DD corrected for age, sex, intracranial volume, and head motion parameters. These associations cannot be explained by differences in impulsivity and executive functioning. This pattern of correlations between structural or functional frontostriatal connectivity strength and self-control suggests that, in addition to the importance of the frontostriatal nodes itself, the structural and functional properties of different connections within the frontostriatal network are crucial for self-controlled behaviors in the healthy elderly. Because high DoG/low DD is a significant predictor of willpower and wellbeing in the elderly population, interventions aiming at strengthening frontostriatal connectivity to strengthen self-controlled behavior are needed in the future.


Functional Ultrasound (fUS) During Awake Brain Surgery: The Clinical Potential of Intra-Operative Functional and Vascular Brain Mapping.
Oncological neurosurgery relies heavily on making continuous, intra-operative tumor-brain delineations based on image-guidance. Limitations of currently available imaging techniques call for the development of real-time image-guided resection tools, which allow for reliable functional and anatomical information in an intra-operative setting. Functional ultrasound (fUS), is a new mobile neuro-imaging tool with unprecedented spatiotemporal resolution, which allows for the detection of small changes in blood dynamics that reflect changes in metabolic activity of activated neurons through neurovascular coupling. We have applied fUS during conventional awake brain surgery to determine its clinical potential for both intra-operative functional and vascular brain mapping, with the ultimate aim of achieving maximum safe tumor resection. During awake brain surgery, fUS was used to image tumor vasculature and task-evoked brain activation with electrocortical stimulation mapping (ESM) as a gold standard. For functional imaging, patients were presented with motor, language or visual tasks, while the probe was placed over (ESM-defined) functional brain areas. For tumor vascular imaging, tumor tissue (pre-resection) and tumor resection cavity (post-resection) were imaged by moving the hand-held probe along a continuous trajectory over the regions of interest. A total of 10 patients were included, with predominantly intra-parenchymal frontal and temporal lobe tumors of both low and higher histopathological grades. fUS was able to detect (ESM-defined) functional areas deep inside the brain for a range of functional tasks including language processing. Brain tissue could be imaged at a spatial and temporal resolution of 300 μm and 1.5-2.0 ms respectively, revealing real-time tumor-specific, and healthy vascular characteristics. The current study presents the potential of applying fUS during awake brain surgery. We illustrate the relevance of fUS for awake brain surgery based on its ability to capture both task-evoked functional cortical responses as well as differences in vascular characteristics between tumor and healthy tissue. As current neurosurgical practice is still pre-dominantly leaning on inherently limited pre-operative imaging techniques for tumor resection-guidance, fUS enters the scene as a promising alternative that is both anatomically and physiologically informative.


A rare case of epilepsy and acute pancreatitis induced by severe paraquat poisoning.
Paraquat can lead to injury of multiple organs. As there is no specific treatment for paraquat poisoning, it represents a serious clinical problem. Antioxidants are required to treat oxidative stress in paraquat poisoning and paraquat-induced injury. In this study, we report on successful treatment of a rare case of epilepsy and acute pancreatitis caused by paraquat poisoning. A 29-year-old woman at our hospital presented with a 13-day history of nausea and vomiting after ingesting 20 mL of paraquat (20% W/V). After therapies, the symptoms were controlled. The patient remained asymptomatic during 1 year of follow-up.


Provocative chelation with DMSA and EDTA: evidence for differential access to lead storage sites.
OBJECTIVES--To validate a provocative chelation test with 2,3-dimercaptosuccinic acid (DMSA) by direct comparison with the standard ethylene diamine tetraacetic acid (EDTA) test in the same subjects; and to compare and contrast the predictors of lead excretion after DMSA with those after EDTA. A metal chelating agent given orally, DMSA may mobilise and enhance the excretion of lead from the storage sites in the body that are most directly relevant to the health effects of lead. A provocative chelation test with DMSA could thus have wide potential application in clinical care and epidemiological studies. METHODS--34 male lead workers in the Republic of Korea were given a single oral dose of 10 mg/kg DMSA, urine was collected over the next eight to 24 hours, and urine volume and urinary lead concentration determined at 0, 2, 4, 6, 8, and 24 hours. Either two weeks before or two weeks after the dose of DMSA 17 of these workers also received 1 g intravenous EDTA followed by an eight hour urine collection with fractionation at 0, 2, 4, 6, and 8 hours. RESULTS--Urinary lead concentration peaked at two hours after DMSA and four hours after EDTA. Lead excretion after DMSA was less than after EDTA, and cumulative excretion after DMSA plateaued at six to eight hours. The two hour and four hour cumulative lead excretions after DMSA were highly correlated with the eight hour total (r = 0.76 and 0.95). In multiple linear regression analyses, blood lead was found to be an important predictor of EDTA-chelatable lead, whereas urinary aminolevulinic acid (ALAU) was associated with DMSA-chelatable lead. Notably, lead excretion after DMSA was greatly increased if EDTA was given first. An earlier dose of EDTA also modified the relation between ALAU and DMSA-chelatable lead in that workers who received EDTA before DMSA showed a much steeper dose-response relation between these two measures. CONCLUSIONS--The predictors of lead excretion after DMSA and EDTA are different and an earlier dose of EDTA may increase lead excretion after a subsequent dose of DMSA. The results suggest that two hour or four hour cumulative lead excretion after DMSA may provide an estimate of lead in storage sites that are most directly relevant to the health effects of lead.


Engineered 3D hydrogels with full-length fibronectin that sequester and present growth factors.
Extracellular matrix (ECM)-derived matrices such as Matrigel are used to culture numerous cell types in vitro as they recapitulate ECM properties that support cell growth, organisation, migration and differentiation. These ECM-derived matrices contain various growth factors which make them highly bioactive. However, they suffer lot-to-lot variability, undefined composition and lack of controlled physical properties. There is a need to develop rationally designed biomaterials that can also recapitulate ECM roles. Here, we report the development of fibronectin (FN)-based 3D hydrogels of controlled stiffness and degradability that incorporate full-length FN to enable solid-phase presentation of growth factors in a physiological manner. We demonstrate, in vitro and in vivo, the effect of incorporating vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) in these hydrogels to enhance angiogenesis and bone regeneration, respectively. These hydrogels represent a step-change in the design of well-defined, reproducible, synthetic microenvironments for 3D cell culture that incorporate growth factors to achieve functional effects.


Cryptococcus neoformans mediator protein Ssn8 negatively regulates diverse physiological processes and is required for virulence.
Cryptococcus neoformans is a ubiquitously distributed human pathogen. It is also a model system for studying fungal virulence, physiology and differentiation. Light is known to inhibit sexual development via the evolutionarily conserved white collar proteins in C. neoformans. To dissect molecular mechanisms regulating this process, we have identified the SSN8 gene whose mutation suppresses the light-dependent CWC1 overexpression phenotype. Characterization of sex-related phenotypes revealed that Ssn8 functions as a negative regulator in both heterothallic a-α mating and same-sex mating processes. In addition, Ssn8 is involved in the suppression of other physiological processes including invasive growth, and production of capsule and melanin. Interestingly, Ssn8 is also required for the maintenance of cell wall integrity and virulence. Our gene expression studies confirmed that deletion of SSN8 results in de-repression of genes involved in sexual development and melanization. Epistatic and yeast two hybrid studies suggest that C. neoformans Ssn8 plays critical roles downstream of the Cpk1 MAPK cascade and Ste12 and possibly resides at one of the major branches downstream of the Cwc complex in the light-mediated sexual development pathway. Taken together, our studies demonstrate that the conserved Mediator protein Ssn8 functions as a global regulator which negatively regulates diverse physiological and developmental processes and is required for virulence in C. neoformans.


Time-dependent infectivity and flexible latent and infectious periods in compartmental models of plant disease.
Compartmental models have become the dominant theoretical paradigm in mechanistic modeling of plant disease and offer well-known advantages in terms of analytic tractability, ease of simulation, and extensibility. However, underlying assumptions of constant rates of infection and of exponentially distributed latent and infectious periods are difficult to justify. Although alternative approaches, including van der Plank's seminal discrete time model and models based on the integro-differential formulation of Kermack and McKendrick's model, have been suggested for plant disease and relax these unrealistic assumptions, they are challenging to implement and to analyze. Here, we propose an extension to the susceptible, exposed, infected, and removed (SEIR) compartmental model, splitting the latent and infection compartments and thereby allowing time-varying infection rates and more realistic distributions of latent and infectious periods to be represented. Although the model is, in fact, more general, we specifically target plant disease by demonstrating how it can represent both the van der Plank model and the most commonly used variant of the Kermack and McKendrick (K & M) model (in which the infectivity response is delay Gamma distributed). We show how our reformulation retains the numeric and analytic tractability of SEIR models, and how it can be used to replicate earlier analyses of the van der Plank and K & M models. Our reformulation has the advantage of using elementary mathematical techniques, making implementation easier for the nonspecialist. We show a practical implication of these results for disease control. By taking advantage of the easy extensibility characteristic of compartmental models, we also investigate the effects of including additional biological realism. As an example, we show how the more realistic infection responses we consider interact with host demography and lead to divergent invasion thresholds when compared with the "standard" SEIR model. An ever-increasing number of analyses purportedly extract more biologically realistic invasion thresholds by adding additional biological detail to the SEIR model framework; we contend that our results demonstrate that extending a model that has such a simplistic representation of the infection dynamics may not, in fact, lead to more accurate results. Therefore, we suggest that modelers should carefully consider the underlying assumptions of the simplest compartmental models in their future work.


Residential traffic noise exposure and headaches: Results from the population-based heinz nixdorf recall study.
The link between headaches and exposure to loud noise in occupational settings has been established. However, the effect of less intense but chronic residential traffic noise exposure on headache occurrence is less clear. We included 3,025 participants from the Heinz Nixdorf Recall study in Germany for this cross-sectional analysis. Residential road traffic noise exposure at the 2006-2008 address was modelled in A-weighted decibels (dB(A)) according to the European Noise Directive (2002/49/EC) for 24-hour (Lden) and night-time noise (22-6 h, Lnight). Indoor traffic noise exposure was obtained by modifying Lden and Lnight based on residence orientation, window type, and personal window opening habits. Traffic noise exposure below 55, 45 dB(A), 35 and 25 dB(A) were set as the reference for Lden, Lnight, Lden,indoor and Lnight,indoor, respectively. Average number of days with headache per month over the past three months was ascertained during the follow-up (2011-2015) medical interview. Prevalence Odds Ratios (POR) of having eight or more headaches per month per 5 dB(A) increase in traffic noise exposure were calculated using logistic regression, adjusting for age, sex, sport, number of chronic conditions, years of education and smoking status. The mean age of participants was 58.3. Mean Lden was 54 dB(A). Median monthly headache days was one. No association was seen between traffic noise exposure and having ≥8 headaches/month for all the examined traffic noise indicators. However, traffic noise was positively associated with traffic noise-annoyance and insomnia; and night-time traffic noise-annoyance and insomnia were positively associated with headache. In conclusion, our data did not provide any evidence for an association between chronic traffic noise exposure and prevalence of headaches at this population's exposure levels. This should be explored in different populations given that this is the first study of its type and that noise exposure was generally low in our population.


Medical image processing on the GPU - past, present and future.
Graphics processing units (GPUs) are used today in a wide range of applications, mainly because they can dramatically accelerate parallel computing, are affordable and energy efficient. In the field of medical imaging, GPUs are in some cases crucial for enabling practical use of computationally demanding algorithms. This review presents the past and present work on GPU accelerated medical image processing, and is meant to serve as an overview and introduction to existing GPU implementations. The review covers GPU acceleration of basic image processing operations (filtering, interpolation, histogram estimation and distance transforms), the most commonly used algorithms in medical imaging (image registration, image segmentation and image denoising) and algorithms that are specific to individual modalities (CT, PET, SPECT, MRI, fMRI, DTI, ultrasound, optical imaging and microscopy). The review ends by highlighting some future possibilities and challenges.


Impact of Vital Dyes on Cell Viability and Transduction Efficiency of AAV Vectors Used in Retinal Gene Therapy Surgery: An In Vitro and In Vivo Analysis.
Treatment of inherited retinal degenerations using adeno-associated viral (AAV) vectors involves delivery by subretinal injection. In the latter stages, alteration of normal anatomy may cause difficulty in visualizing the retinotomy, retinal detachment extension, and vector diffusion. Vital dyes may be useful surgical adjuncts, but their safety and impact on AAV transduction are largely unknown. The effects of Sodium Fluorescein (SF), Membrane Blue (MB), and Membrane Blue Dual (DB) at a range of dilutions were assessed on human embryonic kidney cells in vitro using an AAV2-green fluorescent protein (GFP) reporter at different multiplicities of infection. Flow cytometry analysis was performed to assess both cell viability and transduction efficiency. The effect on quantitative (q)PCR titer was determined. Balanced salt solution (BSS) or dilute DB (1:5 in BSS) were delivered subretinally into left/right eyes of C57BL/6J mice (n = 12). Retinal structure and function were analyzed by optical coherence tomography, autofluorescence, dark-and light-adapted full-field electroretinography. DB and MB were not toxic at any concentration tested, SF only when undiluted. The presence of dyes did not adversely affect the genomic titer. DB even increased the values, due to presence of surfactant in the formulation. AAV2-GFP transduction efficiency was not reduced by the dyes. No structural and functional toxic effects were observed following subretinal delivery of DB. Only undiluted SF affected cell viability. No effects on qPCR titer and transduction efficiency were observed. DB does not appear toxic when delivered subretinally and improves titer accuracy. DB may therefore be a safe and helpful adjunct during gene therapy surgery. This paper might be of interest to the retinal gene therapy community: it is a "bench to bedside" research paper about the potential use of dyes as a surgical adjunct during the gene therapy surgery. We have tested the potential toxicity and impact on transduction efficiency in an in vitro and in vivo model.


Temperature-compensated fiber-optic 3D shape sensor based on femtosecond laser direct-written Bragg grating waveguides.
Temperature-compensated 3D fiber shape sensing is demonstrated with femtosecond laser direct-written optical and Bragg grating waveguides that were distributed axially and radially inside a single coreless optical fiber. Efficient light coupling between the laser-written optical circuit elements and a standard single-mode fiber (SMF) was obtained for the first time by 3D laser writing of a 1 × 3 directional coupler to meet with the core waveguide in the fusion-spliced SMF. Simultaneous interrogation of nine Bragg gratings, distributed along three laterally offset waveguides, is presented through a single waveguide port at 1 kHz sampling rate to follow the Bragg wavelength shifts in real-time and thereby infer shape and temperature profile unambiguously along the fiber length. This distributed 3D strain and thermal sensor is freestanding, flexible, compact, lightweight and opens new directions for creating fiber cladding photonic devices for a wide range of applications from shape and thermal sensing to guidance of biomedical catheters and tools in minimally invasive surgery.


ABPC 48 cross-reactive idiotopes in BALB/c mice. Natural and levan-induced expression.
Using monoclonal antiidiotypic antibodies, we developed a sensitive binding assay that detects molecules with one or with two idiotopes of the ABPC48 idiotype. ABPC48 cross-reactive idiotypes were thus shown to be present in substantial amounts in sera of nonimmunized mice. Levan binding sites are found on these idiotypes. During the life time of the mice, the natural anti-levan titer increases while ABPC48 idiotypic expression remains constant, suggesting different controls for these two activities. On the other hand, ABPC48 cross-reactive idiotypes participate--as minor components--in the response that follows a deliberate immunization with bacterial levan. This induction process is likely to reflect the selection of idiotopes expressed by the B cell clones preactivated in sera of nonimmunized mice rather than the activation of silent clones. We suggest that a similar situation might explain the reported emergence of ABPC48 idiotypes in animals primed with antiidiotypic antibodies and subsequently stimulated with levan.


Expression of fusion proteins of Aspergillus terreus reveals a novel allene oxide synthase.
Aspergilli oxidize C18 unsaturated fatty acids by dioxygenase-cytochrome P450 fusion proteins to signal molecules involved in reproduction and host-pathogen interactions. Aspergillus terreus expresses linoleate 9R-dioxygenase (9R-DOX) and allene oxide synthase (AOS) activities in membrane fractions. The genome contains five genes (ATEG), which may code for a 9R-DOX-AOS fusion protein. The genes were cloned and expressed, but none of them oxidized 18:2n-6 to 9R-hydroperoxy-10(E),12(Z)-octadecadienoic acid (9R-HPODE). ATEG_02036 transformed 9R-HPODE to an unstable allene oxide, 9(R),10-epoxy-10,12(Z)-octadecadienoic acid. A substitution in the P450 domain (C1073S) abolished AOS activity. The N964V and N964D mutants both showed markedly reduced AOS activity, suggesting that Asn(964) may facilitate homolytic cleavage of the dioxygen bond of 9R-HPODE with formation of compound II in analogy with plant AOS (CYP74) and prostacyclin synthase (CYP8A1). ATEG_03992 was identified as 5,8-linoleate diol synthase (5,8-LDS). Replacement of Asn(878) in 5,8-LDS with leucine (N878L) mainly shifted ferryl oxygen insertion from C-5 toward C-6, but replacements of Gln(881) markedly affected catalysis. The Q881L mutant virtually abolished the diol synthase activity. Replacement of Gln(881) with Asn, Glu, Asp, or Lys residues augmented the homolytic cleavage of 8R-HPODE with formation of 10-hydroxy-8(9)-epoxy-12(Z)-octadecenoic acid (erythro/threo, 1-4:1) and/or shifted ferryl oxygen insertion from C-5 toward C-11. We conclude that homolysis and heterolysis of the dioxygen bond with formation of compound II in AOS and compound I in 5,8-LDS are influenced by Asn and Gln residues, respectively, of the I-helices. AOS of A. terreus appears to have evolved independently of CYP74 but with an analogous reaction mechanism.


Recent changes of invasive meningococcal disease in France: arguments to revise the vaccination strategy in view of those of other countries.
In France, the incidence of invasive meningococcal disease (IMD) is around 1/100,000, with the following trends over the 2011-2018 period: a leading role of group B in subjects <15 years, a decrease of group C among <1 year since 2017, an increase of group W in all age groups including subjects <1 year since 2014 and a positive correlation between group Y and age group. In Europe, vaccination progressed with conjugate ACWY vaccines and proteins-based B vaccines. Their benefit-risk-cost balance is however not so obvious for area at low incidence (<2/100,000), explaining tremendous variations between countries, from no recommendation to recommend all available vaccines. In France, the calendar still includes only C with a good adhesion in infants but a fiasco of the catch-up campaign in adolescents and young adults. In Europe, it is time to consider not only national epidemiology but also trends in the neighborhood. The increase of group W cases encourages switching C to ACWY vaccine both in infants and adolescents. It is also time to protect infants with B vaccine. Large pedagogy on the disease is required to increase the adhesion to the vaccination and to recognize and treat earlier the residual cases.


On the challenge of fitting tree size distributions in ecology.
Patterns that resemble strongly skewed size distributions are frequently observed in ecology. A typical example represents tree size distributions of stem diameters. Empirical tests of ecological theories predicting their parameters have been conducted, but the results are difficult to interpret because the statistical methods that are applied to fit such decaying size distributions vary. In addition, binning of field data as well as measurement errors might potentially bias parameter estimates. Here, we compare three different methods for parameter estimation--the common maximum likelihood estimation (MLE) and two modified types of MLE correcting for binning of observations or random measurement errors. We test whether three typical frequency distributions, namely the power-law, negative exponential and Weibull distribution can be precisely identified, and how parameter estimates are biased when observations are additionally either binned or contain measurement error. We show that uncorrected MLE already loses the ability to discern functional form and parameters at relatively small levels of uncertainties. The modified MLE methods that consider such uncertainties (either binning or measurement error) are comparatively much more robust. We conclude that it is important to reduce binning of observations, if possible, and to quantify observation accuracy in empirical studies for fitting strongly skewed size distributions. In general, modified MLE methods that correct binning or measurement errors can be applied to ensure reliable results.


Acculturative Stress, Perceived Social Support, and Mental Health: The Mediating Effect of Negative Emotions Associated with Discrimination.
The role of perceived social support in the acculturation process of immigrants remains unclear. In this study, we jointly evaluated the associations between acculturative stress and negative emotions associated with discrimination as antecedents of anxiety, depression, and stress symptoms in 283 immigrants living in Chile. Three competing models were tested via structural equation modelling to assess (1) the association among these variables and mental health symptoms and (2) to clarify the role of perceived social support. The third model was theoretically more adequate, showed a better fit, and explained 42.7% of the variance of mental health symptoms. In this model, perceived social support was associated with acculturative stress by reducing mental health symptomatology. Moreover, a direct relationship and an indirect relationship were found between acculturative stress (through negative emotions associated with discrimination) and mental health symptomatology. These results contribute to the understanding of the acculturation process experienced by immigrants in Chile and provide empirical evidence to be used to improve migration policies.