Echo-guided injection of botulinum toxin versus blind endoscopic injection in patients with achalasia: final report.
Achalasia, also known as Esophageal achalasia, is an esophageal motility disorder involving the smooth muscle layer of the esophagus and the lower esophageal sphincter (LES). It is characterized by incomplete LES relaxation, increased LES tone, and lack of peristalsis of the esophagus (inability of smooth muscle to move food down the esophagus) in the absence of other explanations like cancer or fibrosis. In our experience, the echo-guided injection technique is the first procedure to implement to cure patients. After endoscopic-echo-guided injection technique, in patients presenting with refractory symptoms, the authors believe in surgical technique (extramucosal myotomy) as a good alternative technique to be implemented. From 1999 to 2010, the authors have treated 36 patients (Group A), 24 male and 12 female (age 26-78) with diagnosis of esophageal achalasia. Patients underwent botulinum toxin injection during echo-guided identification of the lower esophageal sphincter. Results were compared with 32 patients (Group B) (age 36-78) who underwent blind treatment. Patients of Group A presented complete relief of obstruction, patients of Group B had an obstruction remission in the 86% of the cases. Results were confirmed by manometric assessments in the early months after endoscopic treatment. The authors emphasize the importance of the injection of botulinum toxin into the thicker area of the muscle layer of the lower esophageal sphincter. Patients undergoing echo-guided injection technique presented complete relief of obstruction, confirmed by manometric assessments in the early months after treatment.


Virtual Reality to Assess and Treat Lower Extremity Disorders in Post-stroke Patients.
This article is part of the Focus Theme of Methods of Information in Medicine on "Methodologies, Models and Algorithms for Patients Rehabilitation". To identify support of a virtual reality system in the kinematic assessment and physiotherapy approach to gait disorders in individuals with stroke. We adapt Virtual Reality Rehabilitation System (VRRS), software widely used in the functional recovery of the upper limb, for its use on the lower limb of hemiplegic patients. Clinical scales have been used to relate them with the kinematic assessment provided by the system. A description of the use of reinforced feedback provided by the system on the recovery of deficits in several real cases in the field of physiotherapy is performed. Specific examples of functional tasks have been detailed, to be considered in creating intelligent health technologies to improve post-stroke gait. Both participants improved scores on the clinical scales, the kinematic parameters in leg stance on plegic lower extremity and walking speed > Minimally Clinically Important Difference (MCID). The use of the VRRS software attached to a motion tracking capture system showed their practical utility and safety in enriching physiotherapeutic assessment and treatment in post-stroke gait disorders.


Boom and bust: ancient and recent diversification in bichirs (Polypteridae: Actinopterygii), a relictual lineage of ray-finned fishes.
Understanding the history that underlies patterns of species richness across the Tree of Life requires an investigation of the mechanisms that not only generate young species-rich clades, but also those that maintain species-poor lineages over long stretches of evolutionary time. However, diversification dynamics that underlie ancient species-poor lineages are often hidden due to a lack of fossil evidence. Using information from the fossil record and time calibrated molecular phylogenies, we investigate the history of lineage diversification in Polypteridae, which is the sister lineage of all other ray-finned fishes (Actinopterygii). Despite originating at least 390 million years (Myr) ago, molecular timetrees support a Neogene origin for the living polypterid species. Our analyses demonstrate polypterids are exceptionally species depauperate with a stem lineage duration that exceeds 380 million years (Ma) and is significantly longer than the stem lineage durations observed in other ray-finned fish lineages. Analyses of the fossil record show an early Late Cretaceous (100.5-83.6 Ma) peak in polypterid genus richness, followed by 60 Ma of low richness. The Neogene species radiation and evidence for high-diversity intervals in the geological past suggest a "boom and bust" pattern of diversification that contrasts with common perceptions of relative evolutionary stasis in so-called "living fossils."


Sequence divergence of heat shock genes within and among 3 Oncorhynchids.
Heat shock proteins (Hsps) are induced in response to high temperatures and other stressors, and sequence variation plays a role in regulation of expression of these genes. In this study, we investigated the sequence variation in the 3 major classes of Hsps (Hsp90, Hsp70, and low-molecular weight Hsp) within and among 3 cold-water fish species of Oncorhynchus (Oncorhynchus clarki, Oncorhynchus mykiss, and Oncorhynchus tshawytscha) with variable life history and thermal tolerance characteristics. Sequences collectively totaled 4556 bp across 9 gene fragments and 198 single nucleotide polymorphisms and 43 indel sites were observed among species. Within species, sequence variation was much lower for O. clarki than the other 2 species. Sequence variation within and among species was high in cis-regulatory regions that are potentially involved in transcription of Hsps under variable stressors. Our results indicate that Hsp genes may be locally adapted in O. clarki, whereas higher Hsp polymorphism is necessary for O. mykiss and O. tshawytscha and variation at the sequence level may have important evolutionary consequences for these species. Further studies are needed to determine the association of observed sequence variation with the regulation of Hsps and performance of fish under stress.


A Novel PANK2 Mutation in a Patient with Atypical Pantothenate-Kinase-Associated Neurodegeneration Presenting with Adult-Onset Parkinsonism.
Pantothenate-kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder that is characterized by progressive extrapyramidal signs, visual loss, and cognitive impairment. PKAN is caused by mutations in the pantothenate kinase gene (PANK2), which is located on chromosome 20p13 and encodes pantothenate kinase, the key regulatory enzyme in coenzyme-A biosynthesis. In this report we describe a case of atypical PKAN with a novel PANK2 mutation, presenting with a 10-year history of postural tremor involving both hands. Upon neurological examination, the patient's face was masked and he spoke in a monotonous voice. The patient presented with mild bradykinesia and rigidity that involved all of the extremities. Horizontal saccadic eye movements were slow and fragmented. Brain MRI revealed a typical "eye-of-the-tiger" sign. A mutation analysis revealed three PANK2 mutations: two in exon 3 (Asp 378Gly and Leu385CysfsX13) and one in exon 4 (Arg440Pro). Parkinsonism is not an unusual presenting symptom in patients with atypical PKAN, and so it is important for physicians to consider PKAN in the differential diagnosis of patients presenting with young-onset parkinsonism.


High-content chemical and RNAi screens for suppressors of neurotoxicity in a Huntington's disease model.
To identify Huntington's Disease therapeutics, we conducted high-content small molecule and RNAi suppressor screens using a Drosophila primary neural culture Huntingtin model. Drosophila primary neurons offer a sensitive readout for neurotoxicty, as their neurites develop dysmorphic features in the presence of mutant polyglutamine-expanded Huntingtin compared to nonpathogenic Huntingtin. By tracking the subcellular distribution of mRFP-tagged pathogenic Huntingtin and assaying neurite branch morphology via live-imaging, we identified suppressors that could reduce Huntingtin aggregation and/or prevent the formation of dystrophic neurites. The custom algorithms we used to quantify neurite morphologies in complex cultures provide a useful tool for future high-content screening approaches focused on neurodegenerative disease models. Compounds previously found to be effective aggregation inhibitors in mammalian systems were also effective in Drosophila primary cultures, suggesting translational capacity between these models. However, we did not observe a direct correlation between the ability of a compound or gene knockdown to suppress aggregate formation and its ability to rescue dysmorphic neurites. Only a subset of aggregation inhibitors could revert dysmorphic cellular profiles. We identified lkb1, an upstream kinase in the mTOR/Insulin pathway, and four novel drugs, Camptothecin, OH-Camptothecin, 18β-Glycyrrhetinic acid, and Carbenoxolone, that were strong suppressors of mutant Huntingtin-induced neurotoxicity. Huntingtin neurotoxicity suppressors identified through our screen also restored viability in an in vivo Drosophila Huntington's Disease model, making them attractive candidates for further therapeutic evaluation.


The design of contact lens based ocular drug delivery systems for single-day use: Part (I) Structural factors, surrogate ophthalmic dyes and passive diffusion studies.
The poor retention and efficacy of instilled drops as a means of delivering drugs to the ophthalmic environment is well-recognised. The potential value of contact lenses as a means of ophthalmic drug delivery, and consequent improvement of pre-corneal retention is one obvious route to the development of a more effective ocular delivery system. Furthermore, the increasing availability and clinical use of daily disposable contact lenses provides the platform for the development of viable single-day use drug delivery devices based on existing materials and lenses. In order to provide a basis for the effective design of such devices, a systematic understanding of the factors affecting the interaction of individual drugs with the lens matrix is required. Because a large number of potential structural variables are involved, it is necessary to achieve some rationalisation of the parameters and physicochemical properties (such as molecular weight, charge, partition coefficients) that influence drug interactions. Ophthalmic dyes and structurally related compounds based on the same core structure were used to investigate these various factors and the way in which they can be used in concert to design effective release systems for structurally different drugs. Initial studies of passive diffusional release form a necessary precursor to the investigation of the features of the ocular environment that over-ride this simple behaviour. Commercially available contact lenses of differing structural classifications were used to study factors affecting the uptake of the surrogate actives and their release under 'passive' conditions. The interaction between active and lens material shows considerable and complex structure dependence, which is not simply related to equilibrium water content. The structure of the polymer matrix itself was found to have the dominant controlling influence on active uptake; hydrophobic interaction with the ophthalmic dye playing a major role.


Clinical risk assessment in early pregnancy for preeclampsia in nulliparous women: A population based cohort study.
To evaluate the capacity of multivariable prediction of preeclampsia during pregnancy, based on detailed routinely collected early pregnancy data in nulliparous women. A population-based cohort study of 62 562 pregnancies of nulliparous women with deliveries 2008-13 in the Stockholm-Gotland Counties in Sweden. Maternal social, reproductive and medical history and medical examinations (including mean arterial pressure, proteinuria, hemoglobin and capillary glucose levels) routinely collected at the first visit in antenatal care, constitute the predictive variables. Predictive models for preeclampsia were created by three methods; logistic regression models using 1) pre-specified variables (similar to the Fetal Medicine Foundation model including maternal factors and mean arterial pressure), 2) backward selection starting from the full suite of variables, and 3) a Random forest model using the same candidate variables. The performance of the British National Institute for Health and Care Excellence (NICE) binary risk classification guidelines for preeclampsia was also evaluated. The outcome measures were diagnosis of preeclampsia with delivery <34, <37, and ≥37 weeks' gestation. A total of 2 773 (4.4%) nulliparous women subsequently developed preeclampsia. The pre-specified variables model was superior the other two models, regarding prediction of preeclampsia with delivery <34 and <37 weeks, both with areas under the curve of 0.68, and sensitivity of 30.6% (95% CI 24.5-37.2) and 29.2% (95% CI 25.2-33.4) at a 10% false positive rate, respectively. The performance of these customizable multivariable models at the chosen false positive rate, was significantly better than the binary NICE-guidelines for preeclampsia with delivery <37 and ≥37 weeks' gestation. Multivariable models in early pregnancy had a modest performance, although providing advantages over the NICE-guidelines, in predicting preeclampsia in nulliparous women. Use of a machine learning algorithm (Random forest) did not result in superior prediction.


Design, synthesis and evaluation of (R)-3-(7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor.
Based on (R)-N-methyl-N-(5-azaspiro[2.4]heptan-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a core scaffold, we identified (R)-3-(7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile [(R)-6c] as a JAK1 selective inhibitor. The structural design was based on the combination of tofacitinib's 7-deazapurine and 5-azaspiro[2.4]heptan-7-amine. Compound (R)-6c exhibited an IC50 value of 8.5 nM against JAK1 with a selectivity index of 48 over JAK2. To optimize (R)-6c as a lead compound, we performed in vitro ADME, hERG, kinase profiling, and pharmacokinetic tests. Mouse and rat in vivo studies verified that (R)-6c exhibited desired efficacies in CIA and AIA models.


Transfection of molecular beacons in microchannels for single-cell gene-expression analysis.
Efficient transfection of molecular beacons has to be performed in the microscale in order to fully utilize the potential of molecular beacons and microfluidics for studying the real-time gene-expression dynamics in living cells. Nevertheless, there has been relatively little study on transfection of molecular beacons in microfluidic channels. In this work, the differences between transfection in conventional cell culture systems and in microfluidic cell culture systems were investigated systematically with a combination of computational and experimental methods. Comparison between a no-flow microchannel and a 96-well plate revealed that the scale-dependence of reaction-diffusion kinetics contributes to the reduced transfection efficiency in the no-flow microchannel. Study on transfection in the microfluidic system under flow conditions suggested that the fluid flow enhances mass transfer, while the fluid shear stress can reduce the transfection efficiency. The results of this study will provide useful guidelines in optimizing molecular beacon transfection efficiency in microfluidic systems for studying gene-expression dynamics in living cells.


Implementation and effect of intensified case finding on diagnosis of tuberculosis in a large urban HIV clinic in Uganda: a retrospective cohort study.
Increased detection of tuberculosis (TB) using intensified or active case finding (ICF) is one of the cornerstones of the Stop TB Strategy, and contrasts with passive case finding (PCF) which relies on self-reported symptoms. There is no clear guidance on implementation strategies. We implemented ICF in addition to ongoing PCF in our large urban HIV clinic in July 2010 using a twice-daily announcement screen method by a trained peer educator, asking waiting patients to self-refer to a trained peer supporter for screening of TB symptoms. We sought to determine the associated effect on TB case detection. Suspects were investigated by sputum smear, chest X-ray and ultrasound, if indicated. Routinely collected clinical and laboratory data were merged with the ICF register and TB clinic data for patients attending the clinic in 2010. We compared the yield of TB cases (defined as the prevalence of newly diagnosed TB cases in the screened population), the type of TB diagnosed and the total cost per TB case identified (in United States Dollars [USD]) for the period before and after ICF implementation. Of the 20,456 patients who visited the clinic in 2010, 614 were identified as TB suspects, 220 pre-ICF and 394 post-ICF (229 via PCF and 165 via ICF). The proportion diagnosed with TB dropped from 66% to 48% (60% in suspects identified through PCF and 31% through ICF). During the post-ICF period, TB suspects identified through ICF compared to PCF identification were more likely to be female, older, on ART and to have been enrolled in HIV care for a longer duration. The yield of combined PCF and ICF screening was 1.4% pre-ICF and 1.7% post-ICF with a cost per TB case identified of 12.29 USD and 21.80 USD, respectively. Implementation of ICF in a large HIV clinic yielded more TB suspects and cases, but substantially increased costs and was unable to capture the majority of TB suspects who were referred for diagnosis by clinicians through PCF. The overall yield of TB cases in a mature HIV clinic was low, although targeted screening of those recently enrolled in care may increase the yield.


Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19. We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro-computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression. In patients who died from Covid-19-associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth - predominantly through a mechanism of intussusceptive angiogenesis - was 2.7 times as high as that in the lungs from patients with influenza (P<0.001). In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.).


Understanding the Role of the Immune System in the Development of Cancer: New Opportunities for Population-Based Research.
Understanding the precise role of the immune system in cancer has been hindered by the complexity of the immune response and challenges in measuring immune cell types in health and disease in the context of large epidemiologic studies. In this review, we present the rationale to study immunity in cancer and highlight newly available tools to further elucidate the epidemiologic factors driving individual variation in the immune response in cancer. Here, we summarize key studies that have evaluated the role of immunologic status on risk of cancer, discuss tools that have been used in epidemiologic studies to measure immune status, as well as new evolving methodologies where application to epidemiology is becoming more feasible. We also encourage further development of novel emerging technologies that will continue to enable prospective assessment of the dynamic and complex role played by the immune system in cancer susceptibility. Finally, we summarize characteristics and environmental factors that affect the immune response, as these will need to be considered in epidemiologic settings. Overall, we consider the application of a systems biologic approach and highlight new opportunities to understand the immune response in cancer risk.


Integration of colloids into a semi-flexible network of fibrin.
Typical colloid-polymer composites have particle diameters much larger than the polymer mesh size, but successful integration of smaller colloids into a large-mesh network could allow for the realization of new colloidal states of spatial organization and faster colloid motion which can allow the possibility of switchable re-configuration of colloids or more dramatic stimuli-responsive property changes. Experimental realization of such composites requires solving non-trivial materials selection and fabrication challenges; key questions include composition regime maps of successful composites, the resulting structure and colloidal contact network, and the mechanical properties, in particular the ability to form a network and retain strain stiffening in the presence of colloids. Here, we study these fundamental questions by formulating composites with fluorescent (though not stimuli-responsive) carboxylate modified polystyrene/latex (CML) colloidal particles (diameters 200 nm and 1000 nm) in bovine fibrin networks (a semi-flexible biopolymer network with mesh size 1-5 μm). We describe and characterize two methods of composite preparation: adding colloids before fibrinogen polymerization (Method I), and electrophoretically driving colloids into a network already formed by fibrinogen polymerization (Method II). We directly image the morphology of colloidal and fibrous components with two-color fluorescent confocal microscopy under wet conditions and SEM of fixed dry samples. Mechanical properties are studied with shear and extensional rheology. Both fabrication methods are successful, though with trade-offs. Method I retains the nonlinear strain-stiffening and extensibility of the native fibrin network, but some colloid clustering is observed and fibrin network integrity is lost above a critical colloid concentration that depends on fibrinogen and thrombin concentration. Larger colloids can be included at higher volume fractions before massive aggregation occurs, indicating surface interactions as a limiting factor. Method II results in a loss of measurable strain-stiffening, but colloids are well dispersed and template along the fibrous scaffold. The results here, with insight into both structure and rheology, form a foundational understanding for the integration of other colloids, e.g. with stimuli-responsive functionalities, into semi-flexible networks.


Pharmacologic action of Escherichia coli heat-stable (STa) enterotoxin.
Escherichia coli produces a heat-stable (STa) enterotoxin that belongs to a family of peptides that mediate several diarrheal diseases, including traveler's diarrhea and epidemic diarrhea in infants and newborns. The STa enterotoxin consists of 18 or 19 amino acids and is encoded by genes specified on a transposon. Intestinal secretion is induced by specific binding to high affinity receptors that reside on the brush border cell membrane of the small intestine. Receptor activation by STa enterotoxin induces a sequence of events that culminate in the release of fluid and electrolytes into the intestinal lumen. These events include the stimulation of particulate guanylate cyclae and subsequent increase of intracellular cyclic GMP, involvement of particulate protein kinase, elevation of intracellular calcium, and activation of the phosphatidylinositol pathway. The release of archidonic acid and production of prostaglandins and/or leukotrienes have also been implicated in the action of STa. Evidence indicates that the STa enterotoxin receptor may be a single multifunctional membrane protein.


Impact of NHC ligand conformation and solvent concentration on the ruthenium-catalyzed ring-closing metathesis reaction.
Two saturated N-heterocyclic carbene ligands with substituted naphthyl side chains were used for the preparation of Blechert-type ruthenium metathesis precatalysts. The resulting conformers of the complexes were separated and unambiguously assigned by X-ray diffraction studies. All new complexes were compared in terms of activity to the original, SIMes-derived Blechert catalyst and were shown to be superior. A study on the impact of solvent concentration in RCM reactions using the most active of these new catalysts ultimately led to the ring closing of a variety of substrates at very low catalyst loadings.


Pediatric metabolic syndrome predicts adulthood metabolic syndrome, subclinical atherosclerosis, and type 2 diabetes mellitus but is no better than body mass index alone: the Bogalusa Heart Study and the Cardiovascular Risk in Young Finns Study.
The clinical utility of identifying pediatric metabolic syndrome (MetS) is controversial. This study sought to determine the status of pediatric MetS as a risk factor for adult subclinical atherosclerosis (carotid intima-media thickness [cIMT]) and type 2 diabetes mellitus (T2DM) and compare and contrast this prediction with its individual components. Using data from the population-based, prospective, observational Bogalusa Heart and Cardiovascular Risk in Young Finns studies, we examined the utility of 4 categorical definitions of youth MetS and their components in predicting adult high cIMT and T2DM among 1781 participants aged 9 to 18 years at baseline (1984 to 1988) who were then examined 14 to 27 years later (2001-2007) when aged 24 to 41 years. Youth with MetS were at 2 to 3 times the risk of having high cIMT and T2DM as adults compared with those free of MetS at youth. Risk estimates with the use of high body mass index were similar to those of MetS phenotypes in predicting adult outcomes. Comparisons of area under the receiver operating characteristic curve and net reclassification index suggested that prediction of adult MetS, high cIMT, and T2DM in adulthood with the use of youth MetS was either equivalent or inferior to classification based on high body mass index or overweight and obesity. Youth with MetS are at increased risk of meaningful adult outcomes; however, the simplicity of screening for high BMI or overweight and obesity in the pediatric setting offers a simpler, equally accurate alternative to identifying youth at risk of developing adult MetS, high cIMT, or T2DM.


Language in context: Characterizing the comprehension of referential expressions with MEG.
A critical component of comprehending language in context is identifying the entities that individual linguistic expressions refer to. While previous research has shown that language comprehenders resolve reference quickly and incrementally, little is currently known about the neural basis of successful reference resolution. Using source localized MEG, we provide evidence across 3 experiments and 2 languages that successful reference resolution in simple visual displays is associated with increased activation in the medial parietal lobe. In each trial, participants saw a simple visual display containing three objects which constituted the referential domain. Target referential expressions were embedded in questions about the displays. By varying the displays, we manipulated referential status while keeping the linguistic expressions constant. Follow-up experiments addressed potential interactions of reference resolution with linguistic predictiveness and pragmatic plausibility. Notably, we replicated the effect in Arabic, a language that differs in a structurally informative way from English while keeping referential aspects parallel to our two English studies. Distributed minimum norm estimates of MEG data consistently indicated that reference resolution is associated with increased activity in the medial parietal lobe. With one exception, the timing of the onset of the medial parietal response fell into a mid-latency time-window at 350-500ms after the onset of the resolving word. Through concurrent EEG recordings on a subset of subjects we also describe the EEG topography of the effect of reference resolution, which makes the result available for comparison with a larger existing literature. Our results extend previous reports that medial parietal lobe is involved in referential language processing, indicating that it is relevant for reference resolution to individual referents, and suggests avenues for future research.


The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia.
Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.


3D Hand Tracking in the Presence of Excessive Motion Blur.
We present a sensor-fusion method that exploits a depth camera and a gyroscope to track the articulation of a hand in the presence of excessive motion blur. In case of slow and smooth hand motions, the existing methods estimate the hand pose fairly accurately and robustly, despite challenges due to the high dimensionality of the problem, self-occlusions, uniform appearance of hand parts, etc. However, the accuracy of hand pose estimation drops considerably for fast-moving hands because the depth image is severely distorted due to motion blur. Moreover, when hands move fast, the actual hand pose is far from the one estimated in the previous frame, therefore the assumption of temporal continuity on which tracking methods rely, is not valid. In this paper, we track fast-moving hands with the combination of a gyroscope and a depth camera. As a first step, we calibrate a depth camera and a gyroscope attached to a hand so as to identify their time and pose offsets. Following that, we fuse the rotation information of the calibrated gyroscope with model-based hierarchical particle filter tracking. A series of quantitative and qualitative experiments demonstrate that the proposed method performs more accurately and robustly in the presence of motion blur, when compared to state of the art algorithms, especially in the case of very fast hand rotations.


Switching radical stability by pH-induced orbital conversion.
In most radicals the singly occupied molecular orbital (SOMO) is the highest-energy occupied molecular orbital (HOMO); however, in a small number of reported compounds this is not the case. In the present work we expand significantly the scope of this phenomenon, known as SOMO-HOMO energy-level conversion, by showing that it occurs in virtually any distonic radical anion that contains a sufficiently stabilized radical (aminoxyl, peroxyl, aminyl) non-π-conjugated with a negative charge (carboxylate, phosphate, sulfate). Moreover, regular orbital order is restored on protonation of the anionic fragment, and hence the orbital configuration can be switched by pH. Most importantly, our theoretical and experimental results reveal a dramatically higher radical stability and proton acidity of such distonic radical anions. Changing radical stability by 3-4 orders of magnitude using pH-induced orbital conversion opens a variety of attractive industrial applications, including pH-switchable nitroxide-mediated polymerization, and it might be exploited in nature.


A clinical prediction rule for ambulation outcomes after traumatic spinal cord injury: a longitudinal cohort study.
Traumatic spinal cord injury is a serious disorder in which early prediction of ambulation is important to counsel patients and to plan rehabilitation. We developed a reliable, validated prediction rule to assess a patient's chances of walking independently after such injury. We undertook a longitudinal cohort study of adult patients with traumatic spinal cord injury, with early (within the first 15 days after injury) and late (1-year follow-up) clinical examinations, who were admitted to one of 19 European centres between July, 2001, and June, 2008. A clinical prediction rule based on age and neurological variables was derived from the international standards for neurological classification of spinal cord injury with a multivariate logistic regression model. Primary outcome measure 1 year after injury was independent indoor walking based on the Spinal Cord Independence Measure. Model performances were quantified with respect to discrimination (area under receiver-operating-characteristics curve [AUC]). Temporal validation was done in a second group of patients from July, 2008, to December, 2009. Of 1442 patients with spinal cord injury, 492 had available outcome measures. A combination of age (<65 vs ≥65 years), motor scores of the quadriceps femoris (L3), gastrocsoleus (S1) muscles, and light touch sensation of dermatomes L3 and S1 showed excellent discrimination in distinguishing independent walkers from dependent walkers and non-walkers (AUC 0·956, 95% CI 0·936-0·976, p<0·0001). Temporal validation in 99 patients confirmed excellent discriminating ability of the prediction rule (AUC 0·967, 0·939-0·995, p<0·0001). Our prediction rule, including age and four neurological tests, can give an early prognosis of an individual's ability to walk after traumatic spinal cord injury, which can be used to set rehabilitation goals and might improve the ability to stratify patients in interventional trials. Internationale Stiftung für Forschung in Paraplegie.


In situ cell-by-cell imaging and analysis of small cell populations by mass spectrometry.
Molecular imaging by mass spectrometry (MS) is emerging as a tool to determine the distribution of proteins, lipids, and metabolites in tissues. The existing imaging methods, however, mostly rely on predefined rectangular grids for sampling that ignore the natural cellular organization of the tissue. Here we demonstrate that laser ablation electrospray ionization (LAESI) MS can be utilized for in situ cell-by-cell imaging of plant tissues. The cell-by-cell molecular image of the metabolite cyanidin, the ion responsible for purple pigmentation in onion (Allium cepa) epidermal cells, correlated well with the color of cells in the tissue. Chemical imaging using single-cells as voxels reflects the spatial distribution of biochemical differences within a tissue without the distortion stemming from sampling multiple cells within the laser focal spot. Microsampling by laser ablation also has the benefit of enabling the analysis of very small cell populations for biochemical heterogeneity. For example, with a ∼30 μm ablation spot we were able to analyze 3-4 achlorophyllous cells within an oil gland on a sour orange (Citrus aurantium) leaf. To explore cell-to-cell variations within and between tissues, multivariate statistical analysis on LAESI-MS data from epidermal cells of an A. cepa bulb and a C. aurantium leaf and from human buccal epithelial cell populations was performed using the method of orthogonal projections to latent structures discriminant analysis (OPLS-DA). The OPLS-DA analysis of mass spectra, containing over 300 peaks each, provided guidance in identifying a small number of metabolites most responsible for the variance between the cell populations. These metabolites can be viewed as promising candidates for biomarkers that, however, require further verification.


A New Application of CBCT Image Fusion in Temporal Bone Studies.
Temporal bone (TB) studies are essential during the development of new arrays. Postoperative cochlear histology is still regarded as golden standard for the assessment of electrode localization and trauma though it is time consuming, expensive and technically very demanding. The aim of this study is to investigate whether pre-operative evacuation of perilymph improve the assessment of electrode localization and insertion trauma in TBs applying fusion imaging. The results were compared to a prior validated image fusion technique based on the quantification of the electrode placement. 12 prototype electrodes were implanted in fresh frozen TBs. The perilymph was evacuated from the scale prior to pre-operative cone-beam computer tomography (CBCT). The TB were then immersed in Ringer solution to rehydrated both scalae. After electrode insertion post-operative CBCT were obtained. 3D fusions of the pre- and postoperative registration were reconstructed. The electrode localization with respect to the basilar membrane was visually assessed. The visualization of the BM on the pre-operative scans was achieved beyond the second turn in all TBs. The visual assessment was found to be as accurate as the previously validated fusion technique. There was no statistically significant difference between the methods (p=0.564). The image reconstructions and evaluations, however, were faster to perform and the insertion results are immediately available. CBCT in combination with pre- and postoperative image fusion is an accurate method for the post-operative assessment of insertion trauma in TBs. This new application facilitates the identification of the BM and allows for a visual assessment of insertion trauma.


Arterial pressure control at the onset of type I diabetes: the role of nitric oxide and the renin-angiotensin system.
Little is known about how hyperglycemia in diabetes directly affects renal and cardiovascular function. Therefore, we modified the streptozotocin-model of Type I diabetes in rats to enable chronic cardiovascular study at the earliest stages of diabetes, before there was time for development of vascular structural changes. We showed that the onset of diabetic hyperglycemia increased total peripheral resistance, decreased skeletal muscle blood flow, increased thromboxane production, and caused a transient increase in plasma renin activity (PRA). Mean arterial pressure (MAP) also increased, but the amplitude was modest. Moreover, we measured significant increases in glomerular filtration rate (GFR) and renal plasma flow, and also showed that endothelially mediated vasodilation in skeletal muscle was not impaired. We then tested the hypothesis that nitric oxide (NO) was playing an important role in counteracting a pressor response to the onset of diabetes. Our results showed that induction of diabetes in rats with chronic NO synthase inhibition caused a marked and progressive increase in MAP. In addition, PRA increased progressively under those conditions and the increase in GFR was prevented. This suggests that NO may work to keep arterial pressure in control at the onset of hyperglycemia very early in the development of diabetes, possibly by facilitating renal vasodilation and by suppressing activity of the renin-angiotensin system. However, the mechanisms for these interactions and the role of renal vascular resistance and other factors in mediating the hypertensive response remain unknown.


Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection.
Pathogenic human coronaviruses (CoVs), such as the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome-CoV, cause acute respiratory illness. Epidemiological data from the 2002-2003 SARS epidemic and recent Middle East respiratory syndrome outbreak indicate that there may be sex-dependent differences in disease outcomes. To investigate these differences, we infected male and female mice of different age groups with SARS-CoV and analyzed their susceptibility to the infection. Our results showed that male mice were more susceptible to SARS-CoV infection compared with age-matched females. The degree of sex bias to SARS-CoV infection increased with advancing age, such that middle-aged mice showed much more pronounced differences compared with young mice. Enhanced susceptibility of male mice to SARS-CoV was associated with elevated virus titers, enhanced vascular leakage, and alveolar edema. These changes were accompanied by increased accumulation of inflammatory monocyte macrophages and neutrophils in the lungs of male mice, and depletion of inflammatory monocyte macrophages partially protected these mice from lethal SARS. Moreover, the sex-specific differences were independent of T and B cell responses. Furthermore, ovariectomy or treating female mice with an estrogen receptor antagonist increased mortality, indicating a protective effect for estrogen receptor signaling in mice infected with SARS-CoV. Together, these data suggest that sex differences in the susceptibility to SARS-CoV in mice parallel those observed in patients and also identify estrogen receptor signaling as critical for protection in females.


Central hypothyroidism or subclinical hyperthyroidism: can they be confused with each other?
Isolated, adult-onset central hypothyroidism is very rare, and its diagnosis can be challenging. A 42-year-old patient was referred for evaluation of a 2.8 cm thyroid nodule. She referred symptoms that could be attributed to hypothyroidism and thyroid tests showed low TSH and normal-low levels of free T4. However, evaluation of the remaining pituitary hormones and pituitary MRI were normal, yet a radionuclide scanning revealed that the thyroid nodule was 'hot' and the tracer uptake in the remaining thyroid tissue was suppressed. Interpretation of these studies led to a misdiagnosis of subclinical hyperthyroidism and the patient was treated with radioiodine. Soon after treatment, she developed a frank hypothyroidism without appropriate elevation of TSH and the diagnosis of central hypothyroidism was made a posteriori. Long term follow-up revealed a progressive pituitary failure, with subsequent deficiency of ACTH and GH. This case should alert to the possibility of overlooking central hypothyroidism in patients simultaneously bearing primary thyroid diseases able to cause subclinical hyperthyroidism. Although rarely, acquired central hypothyroidism can occur in the absence of other pituitary hormone deficiencies. In these cases, diagnosis is challenging, as symptoms are unspecific and usually mild, and laboratory findings are variable, including low, normal or even slightly elevated TSH levels, along with low or low-normal concentrations of free T4. In cases with low TSH levels, the coexistence of otherwise common disorders able to cause primary thyroid hyperfunction, such as autonomous nodular disease, may lead to a misdiagnosis of subclinical hyperthyroidism.


Dietary Patterns Are Associated with Predicted 10-Year Risk of Cardiovascular Disease Among Ghanaian Populations: the Research on Obesity and Diabetes in African Migrants (RODAM) Study.
Sub-Saharan African populations are disproportionately affected by cardiovascular disease (CVD). Although diet is an important lifestyle factor associated with CVD, evidence on the relation between dietary patterns (DPs) and CVD risk among sub-Saharan African populations is limited. We assessed the associations of DPs with estimated 10-y atherosclerotic cardiovascular disease (ASCVD) risk in Ghanaian adults in Ghana and Europe. Three DPs ('mixed'; 'rice, pasta, meat, and fish'; and 'roots, tubers, and plantain') were derived by principal component analysis (PCA) based on intake frequencies obtained by a self-administered Food Propensity Questionnaire in the multi-center, cross-sectional RODAM (Research on Obesity and Diabetes among African Migrants) study. The 10-y ASCVD risk was estimated using the Pooled Cohort Equations (PCE) for 2976 subjects, aged 40-70 y; a risk score ≥7.5% was defined as 'elevated' ASCVD risk. The associations of DPs with 10-y ASCVD risk were determined using Poisson regression with robust variance. Stronger adherence to a 'mixed' DP was associated with a lower predicted 10-y ASCVD in urban and rural Ghana and a higher 10-y ASCVD in Europe. The observed associations were attenuated after adjustment for possible confounders with the exception of urban Ghana (prevalence ratio [PR] for Quintile 5 compared with 1: 0.70; 95% CI: 0.53, 0.93, P-trend = 0.013). The 'rice, pasta, meat, and fish' DP was inversely associated with 10-y ASCVD across all study sites, with the adjusted effect being significant only in urban Ghana. A 'roots, tubers, and plantain' DP was directly associated with increased 10-y ASCVD risk. Adherence to 'mixed' and 'rice, pasta, meat, and fish' DPs appears to reduce predicted 10-y ASCVD risk in adults in urban Ghana. Further investigations are needed to understand the underlying contextual-level mechanisms that influence dietary habits and to support context-specific dietary recommendations for CVD prevention among sub-Saharan African populations.


Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis.
Because a role for nuclear factor-kappaB (NF-kappaB) has been implicated in the pathogenesis of pancreatic carcinoma, this transcription factor is a potential target for the treatment of this devastating disease. Curcumin (diferuloylmethane) is a phytochemical with potent NF-kappaB-inhibitory activity. It is pharmacologically safe, but its bioavailability is poor after oral administration. The authors encapsulated curcumin in a liposomal delivery system that would allow intravenous administration. They studied the in vitro and in vivo effects of this compound on proliferation, apoptosis, signaling, and angiogenesis using human pancreatic carcinoma cells. NF-kappaB was constitutively active in all human pancreatic carcinoma cell lines evaluated and liposomal curcumin consistently suppressed NF-kappaB binding (electrophoretic mobility gel shift assay) and decreased the expression of NF-kappaB-regulated gene products, including cyclooxygenase-2 (immunoblots) and interleukin-8 (enzyme-linked immunoassay), both of which have been implicated in tumor growth/invasiveness. These in vitro changes were associated with concentration and time-dependent antiproliferative activity (3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay [MTT assay]) and proapoptotic effects (annexin V/propidium iodide staining [fluorescence-activated cell sorting] and polyadenosine-5'-diphosphate-ribose-polymerase cleavage). The activity of liposomal curcumin was equal to or better than that of free curcumin at equimolar concentrations. In vivo, curcumin suppressed pancreatic carcinoma growth in murine xenograft models and inhibited tumor angiogenesis. Liposomal curcumin down-regulated the NF-kappaB machinery, suppressed growth, and induced apoptosis of human pancreatic cells in vitro. Antitumor and antiangiogenesis effects were observed in vivo. The experiments in the current study provide a biologic rationale for treatment of patients suffering from pancreatic carcinoma with this nontoxic phytochemical encapsulated in liposomes for systemic delivery.


Natriuretic Peptides in Post-mortem Brain Tissue and Cerebrospinal Fluid of Non-demented Humans and Alzheimer's Disease Patients.
Animal studies suggest the involvement of natriuretic peptides (NP) in several brain functions that are known to be disturbed during Alzheimer's disease (AD). However, it remains unclear whether such findings extend to humans. In this study, we aimed to: (1) map the gene expression and localization of NP and their receptors (NPR) in human post-mortem brain tissue; (2) compare the relative amounts of NP and NPR between the brain tissue of AD patients and non-demented controls, and (3) compare the relative amounts of NP between the cerebrospinal fluid (CSF) of AD patients and non-demented controls. Using the publicly available Allen Human Brain Atlas dataset, we mapped the gene expression of NP and NPR in healthy humans. Using immunohistochemistry, we visualized the localization of NP and NPR in the frontal cortex of AD patients (n = 10, mean age 85.8 ± 6.2 years) and non-demented controls (mean age = 80.2 ± 9.1 years). Using Western blotting and ELISA, we quantified the relative amounts of NP and NPR in the brain tissue and CSF of these AD patients and non-demented controls. Our results showed that NP and NPR genes were ubiquitously expressed throughout the brain in healthy humans. NP and NPR were present in various cellular structures including in neurons, astrocyte-like structures, and cerebral vessels in both AD patients and non-demented controls. Furthermore, we found higher amounts of NPR type-A in the brain of AD patients (p = 0.045) and lower amounts of NP type-B in the CSF of AD patients (p = 0.029). In conclusion, this study shows the abundance of NP and NPR in the brain of humans suggesting involvement of NP in various brain functions. In addition, our findings suggest alterations of NP levels in the brain of AD patients. The role of NP in the development and progression of AD remains to be elucidated.


Phenanthriplatin(iv) conjugated multifunctional up-converting nanoparticles for drug delivery and biomedical imaging.
Platinum-based drugs cisplatin, carboplatin, and oxaliplatin are widely used in the clinical treatment of cancer. However, the clinical applications of platinum-based drugs are greatly limited by the side-effects, lack of selectivity, fast blood clearance, and intrinsic or acquired drug resistance. In this study, we report an anticancer drug delivery system based on phenanthriplatin(iv) (Phen-Pt(iv))-conjugated NaGdF4:Yb3+/Er3+ nanoparticles. The upconversion luminescent NaGdF4:Yb3+/Er3+ nanoparticles (UCNPs) were further modified with polyethyleneimine (PEI), poly(ethylene glycol) (PEG) and the cancer targeting ligand arginine-glycine-aspartic peptide (RGD), resulting in the formation of water-dispersible and biologically functionalized UCNP@PEI-Phen-Pt-PEG-RGD nanoparticles. The Phen-Pt-conjugated UCNP@PEI-Phen-Pt-PEG-RGD nanoparticles exhibited an obvious cytotoxic effect on Hep-2 cells (Human Laryngeal Carcinoma cell line) via MTT assay. Meanwhile, the endocytosis process of Phen-Pt-conjugated NaGdF4:Yb3+/Er3+ nanoparticles by Hep-2 cells was demonstrated through flow cytometry and ICP-MS. In addition, the upconversion luminescence image of UCNP@PEI-Phen-Pt-PEG-RGD taken up by cells shows green emission under 980 nm infrared laser excitation, making the UCNP@PEI-Phen-Pt-PEG-RGD nanocomposites promising candidates as bioimaging agents. Moreover, these UCNPs were further explored for in vitro and in vivo T1-weighted magnetic resonance (MR) imaging. The in vivo experiments on mice also confirmed that the Phen-Pt(iv)-conjugated nanoparticles have a relatively high tumor inhibition rate. These results indicate that the multifunctional nanoparticles can be expected to be a platform for simultaneous imaging and cancer therapeutic applications.


Multiplexing of polarization-maintaining photonic crystal fiber based Sagnac interferometric sensors.
Three multiplexing schemes are presented for polarization-maintaining photonic crystal fiber based Sagnac interferometric sensors. The first technique is wavelength division multiplexing using coarse wavelength division multiplexers (CWDMs) to distinguish signals from each multiplexed sensor in different wavelength channels. The other two schemes are to multiplex sensors in series along a single fiber link and in parallel by using fiber-optic couplers. While for the CWDM scheme, the multiplexed sensing signal can be obtained by direct measurement; for the other two multiplexing techniques, the sensing signal is more complex and cannot be easily demultiplexed. Thus, some signal processing methods are required. In this regard, two mathematical transformations, namely the discrete wavelet transform and Fourier transform, have been independently and successfully implemented into these two schemes. The operating principles, experimental setup, and overall performance are discussed.


Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with 3,5,3'-triiodothyronine-predominant Graves' disease.
3,5,3'-triiodothyronine-predominant Graves' disease (T(3)-P-GD) is characterized by a persistently high serum T(3) level and normal or even lower serum thyroxine (T(4)) level during antithyroid drug therapy. The source of this high serum T(3) level has not been clarified. Our objective was to evaluate the contribution of type 1 and type 2 iodothyronine deiodinase (D1 (or DIO1) and D2 (or DIO2) respectively) in the thyroid gland to the high serum T(3) level in T(3)-P-GD. We measured the activity and mRNA level of both D1 and D2 in the thyroid tissues of patients with T(3)-P-GD (n=13) and common-type GD (CT-GD) (n=18) who had been treated with methimazole up until thyroidectomy. Thyroidal D1 activity in patients with T(3)-P-GD (492.7±201.3 pmol/mg prot per h) was significantly higher (P<0.05) than that in patients with CT-GD (320.7±151.9 pmol/mg prot per h). On the other hand, thyroidal D2 activity in patients with T(3)-P-GD (823.9±596.4 fmol/mg prot per h) was markedly higher (P<0.005) than that in patients with CT-GD (194.8±131.6 fmol/mg prot per h). There was a significant correlation between the thyroidal D1 activity in patients with T(3)-P-GD and CT-GD and the serum FT(3)-to-FT(4) ratio (r=0.370, P<0.05). Moreover, there was a strong correlation between the thyroidal D2 activity in those patients and the serum FT(3)-to-FT(4) ratio (r=0.676, P<0.001). Our results suggest that the increment of thyroidal deiodinase activity, namely D1 and especially D2 activities, may be responsible for the higher serum FT(3)-to-FT(4) ratio in T(3)-P-GD.


Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice.
Mutation and loss of function in p53 are common features among human breast cancers. Here we use BALB/c-Trp53+/- mice as a model to examine the sequence of events leading to mammary tumors. Mammary gland proliferation rates were similar in both BALB/c-Trp53+/- mice and wild-type controls. In addition, sporadic mammary hyperplasias were rare in BALB/c-Trp53+/- mice and not detectably different from those of wild-type controls. Among the 28 mammary tumors collected from BALB/c-Trp53+/- mice, loss of heterozygosity for Trp53 was detected in more than 90% of invasive mammary tumors. Transplantation of Trp53+/- ductal hyperplasias also indicated an association between loss of the wild-type allele of Trp53 and progression to invasive carcinomas. Therefore, loss of p53 function seems to be a rate-limiting step in progression. Moreover, expression of biomarkers such as estrogen receptor alpha, progesterone receptor, Her2/Neu, and activated Notch1 varied among mammary tumors, suggesting that multiple oncogenic lesions collaborate with loss of p53 function. Expression of biomarkers was retained when tumor fragments were transplanted to syngeneic hosts. Tumors expressing solely luminal or basal keratins were also observed (27 and 11%, respectively), but the largest class of tumors expressed both luminal and basal keratins (62%). Overall, this panel of transplantable tumors provides a resource for detailed evaluation of the cell lineages undergoing transformation and preclinical testing of therapeutic agents targeting a variety of oncogenic pathways including cancer stem cells.


Early Life Factors and Inter-Country Heterogeneity in BMI Growth Trajectories of European Children: The IDEFICS Study.
Starting from birth, this explorative study aimed to investigate between-country differences in body mass index (BMI) trajectories and whether early life factors explain these differences. The sample included 7,644 children from seven European countries (Belgium, Cyprus, Germany, Hungary, Italy, Spain, Sweden) participating in the multi-centre IDEFICS study. Information on early life factors and in total 53,409 repeated measurements of height and weight from 0 to <12 years of age were collected during the baseline (2007/2008) and follow-up examination (2009/2010) supplemented by records of routine child health visits. Country-specific BMI growth curves were estimated using fractional polynomial mixed effects models. Several covariates focussing on early life factors were added to the models to investigate their role in the between-countries differences. Large between-country differences were observed with Italian children showing significantly higher mean BMI values at all ages ≥ 3 years compared to the other countries. For instance, at age 11 years mean BMI values in Italian boys and girls were 22.3 [21.9;22.8; 99% confidence interval] and 22.0 [21.5;22.4], respectively, compared to a range of 18.4 [18.1;18.8] to 20.3 [19.8;20.7] in boys and 18.2 [17.8;18.6] to 20.3 [19.8;20.7] in girls in the other countries. After adjustment for early life factors, differences between country-specific BMI curves became smaller. Maternal BMI was the factor being most strongly associated with BMI growth (p<0.01 in all countries) with associations increasing during childhood. Gestational weight gain (GWG) was weakly associated with BMI at birth in all countries. In some countries, positive associations between BMI growth and children not being breastfed, mothers' smoking during pregnancy and low educational level of parents were found. Early life factors seem to explain only some of the inter-country variation in growth. Maternal BMI showed the strongest association with children's BMI growth.


[Diabetes mellitus mortality among elderly as an underlying or secondary cause of death].
To analyze diabetes mellitus-related mortality among elderly and the rate of undereporting of diabetes mellitus as a cause of death when statistical data on diabetes exclusively on the underlying cause of death are considered. A total of 2.974 death certificates of elderly people living in a housing project in the city of Rio de Janeiro were revised. The study period was 1994. Of them, 291 deaths were due to diabetes mellitus, 150 as the underlying and 141 as the secondary cause of death. The proportion of deaths where diabetes was stated as the underlying cause in relation to the total of diabetes deaths was calculated globally and categorized by sex and age groups. Of the 291 deaths studied, 138 (47.4%) were men and 153 (52.6%) were women. Mortality rates showed a continuous age increase and were higher among men, though sex difference was smaller when only the underlying cause was considered. It was found a higher proportion of deaths (22%) occurring at home. Overall rate of diabetes deaths as the underlying cause was 51.5%, with higher rates seen in women. The analysis of mortality statistics based exclusively on the underlying cause of death can yield misleading profiles due to unrandomized underreporting. There is a need of further studies with diabetic elderly cohorts for a more accurate mortality analysis in this population group.


Digital chemsex support and care: The potential of just-in-time adaptive interventions.
Chemsex among gay, bisexual and other men who have sex with men (GBMSM) has received increasing attention as a public health concern in recent years. Chemsex can affect a variety of aspects of the lives of GBMSM and contribute to physical, social and emotional health burden. Starting from a continuum perspective of chemsex, rather than a binary view of problematic vs. non-problematic use, we argue that men engaging in chemsex at different points in their chemsex journey may benefit from tailored and personalized support to cope with the various and evolving challenges and concerns that may be related to their chemsex behavior. To date, interactive digital communication technologies are not much used to provide support and care for GBMSM engaging in chemsex, neither for community-based support and care nor by health services. This suggests potential for missed opportunities, as GBMSM are generally avid users of these technologies for social connections and hookups, including in relation to chemsex. Recent research has provided emerging evidence of the potential effects of so-called just in time adaptive interventions (JITAI) to provide effective support and care for a variety of health issues. JITAI hold much promise for the provision of appropriate, tailored support and care for GBMSM at different points in the chemsex journey. Co-designing JITAI with potential users and other stakeholders (co-design) is key to success. At the Institute for Tropical Medicine, in Antwerp (Belgium), we initiated the Chemified project to develop an innovative digital chemsex support and care tool for GBMSM. This project illustrates how current understanding of chemsex as a journey can be integrated with a JITAI approach and make use of co-design principles to advance the available support and care for GBMSM engaging in chemsex.


Exploring the impact of analysis software on task fMRI results.
A wealth of analysis tools are available to fMRI researchers in order to extract patterns of task variation and, ultimately, understand cognitive function. However, this "methodological plurality" comes with a drawback. While conceptually similar, two different analysis pipelines applied on the same dataset may not produce the same scientific results. Differences in methods, implementations across software, and even operating systems or software versions all contribute to this variability. Consequently, attention in the field has recently been directed to reproducibility and data sharing. In this work, our goal is to understand how choice of software package impacts on analysis results. We use publicly shared data from three published task fMRI neuroimaging studies, reanalyzing each study using the three main neuroimaging software packages, AFNI, FSL, and SPM, using parametric and nonparametric inference. We obtain all information on how to process, analyse, and model each dataset from the publications. We make quantitative and qualitative comparisons between our replications to gauge the scale of variability in our results and assess the fundamental differences between each software package. Qualitatively we find similarities between packages, backed up by Neurosynth association analyses that correlate similar words and phrases to all three software package's unthresholded results for each of the studies we reanalyse. However, we also discover marked differences, such as Dice similarity coefficients ranging from 0.000 to 0.684 in comparisons of thresholded statistic maps between software. We discuss the challenges involved in trying to reanalyse the published studies, and highlight our efforts to make this research reproducible.


Taking the Universe's Temperature with Spectral Distortions of the Cosmic Microwave Background.
The cosmic microwave background (CMB) energy spectrum is a near-perfect blackbody. The standard model of cosmology predicts small spectral distortions to this form, but no such distortion of the sky-averaged CMB spectrum has yet been measured. We calculate the largest expected distortion, which arises from the inverse Compton scattering of CMB photons off hot, free electrons, known as the thermal Sunyaev-Zel'dovich (TSZ) effect. We show that the predicted signal is roughly one order of magnitude below the current bound from the COBE-FIRAS experiment, but it can be detected at enormous significance (≳1000σ) by the proposed Primordial Inflation Explorer (PIXIE). Although cosmic variance reduces the effective signal-to-noise ratio to 230σ, this measurement will still yield a subpercent constraint on the total thermal energy of electrons in the observable Universe. Furthermore, we show that PIXIE can detect subtle relativistic effects in the sky-averaged TSZ signal at 30σ, which directly probe moments of the optical depth-weighted intracluster medium electron temperature distribution. These effects break the degeneracy between the electron density and the temperature in the mean TSZ signal, allowing a direct inference of the mean baryon density at low redshift. Future spectral distortion probes will thus determine the global thermodynamic properties of ionized gas in the Universe with unprecedented precision. These measurements will impose a fundamental "integral constraint" on models of galaxy formation and the injection of feedback energy over cosmic time.


Sequence and peptide map of guinea pig aquaporin 0.
Hyperbaric oxygen-treated guinea pigs serve as a useful animal model of nuclear cataract. To understand the structure and function of major intrinsic proteins in this model, the primary sequence and major posttranslational modifications to guinea pig aquaporin 0 (AQP0) were determined. The cDNA encoding guinea pig AQP0 was amplified by PCR, cloned and sequenced. After protein enrichment from guinea pig lens tissue, the protein sequence and the posttranslational modifications to AQP0 were determined by using combined chemical cleavage, trypsin and pepsin digestion with matrix assisted laser desorption/ionization mass spectrometry or capillary liquid chromatography tandem mass spectrometry. The primary structure of AQP0 was determined from the DNA sequence and the translated sequence confirmed by mass spectrometry. Serine 235 was identified to be the major phosphorylation site. Significant sequence homology was observed between species including putative regulatory sites of phosphorylation and pH regulation. These data form a foundation of information from which to begin assessing posttranslational modifications in cataract models.


Evidence for abnormalities of cortical development in adolescent-onset schizophrenia.
Voxel-Based Morphometry (VBM) identifies differences in grey matter brain structure in patients with schizophrenia relative to healthy controls, with particularly prominent differences found in patients with the more severe, adolescent-onset form of the disease. However, as VBM is sensitive to a combination of changes in grey matter thickness, intensity and folding, specific neuropathological interpretations are not possible. Here, we attempt to more precisely define cortical changes in 25 adolescent-onset schizophrenic patients and 25 age- and sex-matched healthy volunteers using Surface-Based Morphometry (SBM) to disambiguate the relative contributions of cortical thickness and surface area differences to changes in regional grey matter (GM) density measured with VBM. Cortical changes in schizophrenia were widespread, including particularly the prefrontal cortex and superior temporal gyrus. Nine regions of apparent reduction in GM density in patients relative to healthy matched controls were found using VBM that were not found with SBM-derived cortical thickness measures. In Regions of Interest (ROIs) derived from the VBM group results, we confirmed that local surface area differences accounted for these VBM changes. Our results emphasize widespread, but focally distinct cortical pathology in adolescent-onset schizophrenia. Evidence for changes in local surface area (as opposed to simply cortical thinning) is consistent with a neurodevelopmental contribution to the underlying neuropathology of the disease.


OMIT: dynamic, semi-automated ontology development for the microRNA domain.
As a special class of short non-coding RNAs, microRNAs (a.k.a. miRNAs or miRs) have been reported to perform important roles in various biological processes by regulating respective target genes. However, significant barriers exist during biologists' conventional miR knowledge discovery. Emerging semantic technologies, which are based upon domain ontologies, can render critical assistance to this problem. Our previous research has investigated the construction of a miR ontology, named Ontology for MIcroRNA Target Prediction (OMIT), the very first of its kind that formally encodes miR domain knowledge. Although it is unavoidable to have a manual component contributed by domain experts when building ontologies, many challenges have been identified for a completely manual development process. The most significant issue is that a manual development process is very labor-intensive and thus extremely expensive. Therefore, we propose in this paper an innovative ontology development methodology. Our contributions can be summarized as: (i) We have continued the development and critical improvement of OMIT, solidly based on our previous research outcomes. (ii) We have explored effective and efficient algorithms with which the ontology development can be seamlessly combined with machine intelligence and be accomplished in a semi-automated manner, thus significantly reducing large amounts of human efforts. A set of experiments have been conducted to thoroughly evaluate our proposed methodology.


A study on biofilm production and antifungal drug resistance among Candida species from vulvovaginal and bloodstream infections.
Candida species, one among the opportunistic fungi, has become a common pathogen causing vaginal thrush and nosocomial bloodstream infections (BSIs). This study aims to evaluate the prevalence and antifungal susceptibility of various Candida species and slime production by Candida species in BSIs and vulvovaginal candidiasis (VVC). A total of 176 samples were collected for a period of 1 year. Anti-fungal susceptibility testing and biofilm production testing were performed by the Kirby-Bauer method and crystal violet assay, respectively. Out of 176 samples, 74 (42%) were from BSIs and 102 (58%) were from VVC. The biofilm production was comparatively high in blood isolates, 55 (74%), than cervical isolates, 45 (44%). Increase in the trends of non-albicans Candida (NAC) species was seen in our setup. Good susceptibility rates were seen among Candida species, 82.38% to voriconazole and an increasing resistance pattern of 26.13% to fluconazole. Speciation of Candida becomes important as the prevalence of NAC is increasing. Antifungal susceptibility testing by the disk diffusion method is cost effective and should be adopted in routine testing as there is an increasing azole resistance, especially in invasive NAC infections. In this study, there was no correlation of antifungal drugs with the biofilm production.


Evaluating vegetation effects on animal demographics: the role of plant phenology and sampling bias.
Plant phenological processes produce temporal variation in the height and cover of vegetation. Key aspects of animal life cycles, such as reproduction, often coincide with the growing season and therefore may inherently covary with plant growth. When evaluating the influence of vegetation variables on demographic rates, the decision about when to measure vegetation relative to the timing of demographic events is important to avoid confounding between the demographic rate of interest and vegetation covariates. Such confounding could bias estimated effect sizes or produce results that are entirely spurious. We investigated how the timing of vegetation sampling affected the modeled relationship between vegetation structure and nest survival of greater sage-grouse (Centrocercus urophasianus), using both simulated and observational data. We used the height of live grasses surrounding nests as an explanatory covariate, and analyzed its effect on daily nest survival. We compared results between models that included grass height measured at the time of nest fate (hatch or failure) with models where grass height was measured on a standardized date - that of predicted hatch date. Parameters linking grass height to nest survival based on measurements at nest fate produced more competitive models, but slope coefficients of grass height effects were biased high relative to truth in simulated scenarios. In contrast, measurements taken at predicted hatch date accurately predicted the influence of grass height on nest survival. Observational data produced similar results. Our results demonstrate the importance of properly considering confounding between demographic traits and plant phenology. Not doing so can produce results that are plausible, but ultimately inaccurate.


Expression of DMRT genes in the gonads of Rana rugosa during sex determination.
Sex is determined by various transcription factors. Dmrt1, a gene that contains the DM domain (Doublesex/Mab-3 DNA-binding motif), is known to be one of the critical factors required for testicular development in vertebrates. Recently, other DM domain-containing genes (DMRT genes) were isolated in mice and fish. In mice, three of the seven known DMRT genes are expressed in the embryonic gonad. In amphibians, however, only Dmrt1 and Dmrt4 have been cloned. To clarify the role(s) of DMRT genes in sex determination in vertebrates, the molecular cloning of amphibian DMRT genes would be very helpful. In this study, we isolated Dmrt2, -3, and -5 from the frog Rana rugosa and analyzed by RT-PCR their expression during sex determination. The analysis revealed that all three genes are expressed in the developing gonad/mesonephros complex during sex determination with no dimorphism. The results suggest that Dmrt2, -3, and -5 may be involved in sexual development in R. rugosa and that they may function in both testicular and ovarian differentiation.


Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome.
Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Ca(v)1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.


Determining risk factors for developing systemic lupus erythematosus in patients with discoid lupus erythematosus.
Up to 28% of patients with discoid lupus erythematosus (DLE) are susceptible to developing systemic lupus erythematosus (SLE). To better characterize patients with DLE who have a higher potential of developing SLE, we reviewed studies contrasting, firstly, DLE-only patients (i.e. patients with DLE without SLE) and SLE patients with DLE (i.e. patients who are diagnosed with SLE and DLE simultaneously, and patients with SLE who later develop DLE), and secondly, DLE-only patients and patients with DLE who progress to SLE. These studies have commonly identified various clinical and laboratory indicators, such as widespread DLE lesions, arthralgias/arthritis, nail changes, anaemia, leucopenia, high erythrocyte sedimentation rates (ESRs) and high titres of antinuclear antibodies (ANAs), which are associated with progression to SLE in patients with DLE, and SLE patients with DLE. Limitations of these studies include inadequate follow-up time, small numbers of patients with DLE converting to SLE, outdated criteria for SLE diagnosis and retrospective study designs. However, because of the risk of SLE development in patients with DLE, complete skin examinations, joint assessments and laboratory tests including ANA, ESR and full blood counts should be performed regularly for patients with DLE. A prospective study following patients with DLE who do or do not develop SLE is currently underway through the Cutaneous Lupus Registry at the University of Texas Southwestern Medical Center. It will seek to identify clinical features and biomarkers that improve our assessment of risk of systemic spread in these patients.


Nonexercise activity thermogenesis in obesity management.
Obesity is linked to cardiovascular disease. The global increase in sedentary lifestyle is an important factor contributing to the rising prevalence of the obesity epidemic. Traditionally, counseling has focused on moderate- to vigorous-intensity exercise, with disappointing results. Nonexercise activity thermogenesis (NEAT) is an important component of daily energy expenditure. It represents the common daily activities, such as fidgeting, walking, and standing. These high-effect NEAT movements could result in up to an extra 2000 kcal of expenditure per day beyond the basal metabolic rate, depending on body weight and level of activity. Implementing NEAT during leisure-time and occupational activities could be essential to maintaining a negative energy balance. NEAT can be applied by being upright, ambulating, and redesigning workplace and leisure-time environments to promote NEAT. The benefits of NEAT include not only the extra calories expended but also the reduced occurrence of the metabolic syndrome, cardiovascular events, and all-cause mortality. We believe that to overcome the obesity epidemic and its adverse cardiovascular consequences, NEAT should be part of the current medical recommendations. The content of this review is based on a literature search of PubMed and the Google search engine between January 1, 1960, and October 1, 2014, using the search terms physical activity, obesity, energy expenditure, nonexercise activity thermogenesis, and NEAT.


Selective tuning of the right inferior frontal gyrus during target detection.
In the human brain, a network of frontal and parietal regions is commonly recruited during tasks that demand the deliberate, focused control of thought and action. Previously, using a simple target detection task, we reported striking differences in the selectivity of the BOLD response in anatomically distinct subregions of this network. In particular, it was observed that the right inferior frontal gyrus (IFG) followed a tightly tuned function, selectively responding only to the current target object. Here, we examine this functional specialization further, using adapted versions of our original task. Our results demonstrate that the response of the right IFG to targets is a strong and replicable phenomenon. It occurs under increased attentional load, when targets and distractors are equally frequent, and when controlling for inhibitory processes. These findings support the hypothesis that the right IFG responds selectively to those items that are of the most relevance to the currently intended task schema.


The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes.
Copper is an essential element and an integral component of various enzymes. However, excess copper is neurotoxic and has been implicated in the pathogenesis of Wilson's disease, Alzheimer's disease, prion conditions, and other disorders. Although mechanisms of copper neurotoxicity are not fully understood, copper is known to cause oxidative stress and mitochondrial dysfunction. As oxidative stress is an important factor in the induction of the mitochondrial permeability transition (mPT), we determined whether mPT plays a role in copper-induced neural cell injury. Cultured astrocytes and neurons were treated with 20 microM copper and mPT was measured by changes in the cyclosporin A (CsA)-sensitive inner mitochondrial membrane potential (Delta Psi m), employing the potentiometric dye TMRE. In astrocytes, copper caused a 36% decrease in the Delta Psi m at 12 h, which decreased further to 48% by 24 h and remained at that level for at least 72 h. Cobalt quenching of calcein fluorescence as a measure of mPT similarly displayed a 45% decrease at 24 h. Pretreatment with antioxidants significantly blocked the copper-induced mPT by 48-75%. Copper (24 h) also caused a 30% reduction in ATP in astrocytes, which was completely blocked by CsA. Copper caused death (42%) in astrocytes by 48 h, which was reduced by antioxidants (35-60%) and CsA (41%). In contrast to astrocytes, copper did not induce mPT in neurons. Instead, it caused early and extensive death with a concomitant reduction (63%) in ATP by 14 h. Neuronal death was prevented by antioxidants and nitric oxide synthase inhibitors but not by CsA. Copper increased protein tyrosine nitration in both astrocytes and neurons. These studies indicate that mPT, and oxidative and nitrosative stress represent major factors in copper-induced toxicity in astrocytes, whereas oxidative and nitrosative stress appears to play a major role in neuronal injury.


Dielectrophoretic sorting on a microfabricated flow cytometer: label free separation of Babesia bovis infected erythrocytes.
Dielectrophoresis is a method that has demonstrated great potential in cell discrimination and isolation. In this study, the dielectrophoretic sorting of normal and Babesia bovis infected erythrocytes was performed using a microfabricated flow cytometer. Separation was possible through exploitation of the dielectric differences between normal and infected erythrocytes, essentially due to the higher ionic membrane permeability of B. bovis infected cells. Sorting experiments were performed inside a microchip made from Pt microelectrodes and SU-8 channels patterned on a glass substrate. Optimum cell separation was achieved at 4 MHz using an in vitro culture of B. bovis suspended in 63 mS/m phosphate buffer and applying a sinusoidal voltage of 15 V peak-to-peak. Normal erythrocytes experienced stronger positive dielectrophoresis (pDEP) than B. bovis infected cells, moving them closer to the microelectrodes. Under these conditions it was possible to enrich the fraction of infected cells from 7 to 50% without the need of extensive sample preparation or labelling. Throughout the experiments very few microliters of sample were used, suggesting that this system may be considered suitable for integration in a low-cost automated device to be used in the in situ diagnostic of babesiosis.


Reliability of scoring EMG orofacial events: polysomnography compared with ambulatory recordings.
The study of sleep bruxism is usually based on clinical history, signs and symptoms. The recording of electromyographic signals with either ambulatory portable home recorders or with polysomnographic techniques in the laboratory environment allows collection of objective data. The present study showed a 100% agreement with clinical evaluation in the recognition of bruxism episodes from the masseter electromyogram recorded with portable recorders and using the polysomnographic technique. On the contrary, scorers had difficulties in discriminating between different types of episodes (phasic, tonic and mixed), the between-scorers agreement varied between 62% and 63% and the kappa-values between 0.43 and 0.33. The ideal time base at which electromyographic signals should be integrated to allow for a good discrimination of bruxism patterns is 0.06 s. The results indicate that portable electromyography recorders are a valuable complement to polysomnographic recordings of orofacial motor activities as they provide a very good recognition rate with adequate time base data collection.


The relevance of anatomy and morbid anatomy for medical practice and hence for postgraduate and continuing medical education of doctors.
A case is presented for the durability of anatomy including dissection of the cadaver and of morbid anatomy as elements in medical education and practice. It is these subjects, as consistently relevant over the centuries for medical practice as are communication skills, that are our hallmark as doctors. It is submitted that we should take stock very carefully of their relevance to us before it is too late easily to redress the balance, given the major trends of the last two decades.


Viral Infection and Stress Affect Protein Levels of Dicer 2 and Argonaute 2 in Drosophila melanogaster.
The small interfering RNA (siRNA) pathway of Drosophila melanogaster, mainly characterized by the activity of the enzymes Dicer 2 (Dcr-2) and Argonaute 2 (Ago-2), has been described as the major antiviral immune response. Several lines of evidence demonstrated its pivotal role in conferring resistance against viral infections at cellular and systemic level. However, only few studies have addressed the regulation and induction of this system upon infection and knowledge on stability and turnover of the siRNA pathway core components transcripts and proteins remains scarce. In the current work, we explore whether the siRNA pathway is regulated following viral infection in D. melanogaster. After infecting different fly strains with two different viruses and modes of infection, we observed changes in Dcr-2 and Ago-2 protein concentrations that were not related with changes in gene expression. This response was observed either upon viral infection or upon stress-related experimental procedure, indicating a bivalent function of the siRNA system operating as a general gene regulation rather than a specific antiviral system.


Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3'-UTR landscape across seven tumour types.
Alternative polyadenylation (APA) is a pervasive mechanism in the regulation of most human genes, and its implication in diseases including cancer is only beginning to be appreciated. Since conventional APA profiling has not been widely adopted, global cancer APA studies are very limited. Here we develop a novel bioinformatics algorithm (DaPars) for the de novo identification of dynamic APAs from standard RNA-seq. When applied to 358 TCGA Pan-Cancer tumour/normal pairs across seven tumour types, DaPars reveals 1,346 genes with recurrent and tumour-specific APAs. Most APA genes (91%) have shorter 3'-untranslated regions (3' UTRs) in tumours that can avoid microRNA-mediated repression, including glutaminase (GLS), a key metabolic enzyme for tumour proliferation. Interestingly, selected APA events add strong prognostic power beyond common clinical and molecular variables, suggesting their potential as novel prognostic biomarkers. Finally, our results implicate CstF64, an essential polyadenylation factor, as a master regulator of 3'-UTR shortening across multiple tumour types.


Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia.
We evaluate the prevalence and risk factors of the metabolic syndrome (MS) in young adults surviving childhood leukemia. During the years 2007 to 2008, assessment of MS was proposed to all adults included in the Leucémie de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of leukemia survivors. Among 220 eligible patients, 184 (83.6%) had complete evaluation. Median age at evaluation and follow-up duration were 21.2 and 15.4 years. Overall prevalence of MS was 9.2% (95% confidence interval, 5.5-14.4). There was no association of MS with sex, age at diagnosis, leukemia subtype, steroid therapy, and central nervous system irradiation. Patients were stratified according to 4 therapeutic modalities: chemotherapy alone (n = 97), chemotherapy and central nervous system irradiation (n = 27), hematopoietic stem cell transplantation (HSCT) without (n = 17) or with (n = 43) total body irradiation (TBI). MS occurred in 5.2%, 11.1%, 5.9%, and 18.6% of them, respectively. The higher risk observed in the HSCT-TBI group was significant in univariate and in multivariate analysis (odds ratio [OR] = 3.9, P = .03). HSCT with TBI was associated with a higher rate of hypertriglyceridemia (OR = 4.5, P = .004), low level of high-density lipoprotein cholesterol (OR = 2.5, P = .02), and elevated fasting glucose (OR = 6.1, P = .04) So, TBI is a major risk factor for MS. Further studies are warranted to explain this feature.


A dynamic magnetic tension force as the cause of failed solar eruptions.
Coronal mass ejections are solar eruptions driven by a sudden release of magnetic energy stored in the Sun's corona. In many cases, this magnetic energy is stored in long-lived, arched structures called magnetic flux ropes. When a flux rope destabilizes, it can either erupt and produce a coronal mass ejection or fail and collapse back towards the Sun. The prevailing belief is that the outcome of a given event is determined by a magnetohydrodynamic force imbalance called the torus instability. This belief is challenged, however, by observations indicating that torus-unstable flux ropes sometimes fail to erupt. This contradiction has not yet been resolved because of a lack of coronal magnetic field measurements and the limitations of idealized numerical modelling. Here we report the results of a laboratory experiment that reveal a previously unknown eruption criterion below which torus-unstable flux ropes fail to erupt. We find that such 'failed torus' events occur when the guide magnetic field (that is, the ambient field that runs toroidally along the flux rope) is strong enough to prevent the flux rope from kinking. Under these conditions, the guide field interacts with electric currents in the flux rope to produce a dynamic toroidal field tension force that halts the eruption. This magnetic tension force is missing from existing eruption models, which is why such models cannot explain or predict failed torus events.


HLA polymorphisms and detection of kaposi sarcoma-associated herpesvirus DNA in saliva and peripheral blood among children and their mothers in the uganda sickle cell anemia KSHV Study.
Kaposi sarcoma-associated herpesvirus (KSHV, also called Human herpesvirus 8 or HHV8) is a γ-2 herpesvirus that causes Kaposi sarcoma. KSHV seroprevalence rates vary geographically with variable rates recorded in different sub Sahara African countries, suggesting that effects of genetic and/or environmental factors may influence the risk of infection. One study conducted in South Africa, where KSHV seroprevalence is relatively low, found that carriage of human leukocyte antigen (HLA) alleles HLA-A*6801, HLA-A*30, HLA-A*4301, and HLA-DRB1*04 was associated with increased shedding of KSHV DNA in saliva. Confirmation of those results would strengthen the hypothesis that genetic factors may influence KSHV distribution by modulating KSHV shedding in saliva. To explore these associations in another setting, we used high resolution HLA-A, B, and DRB1 typing on residual samples from the Uganda Sickle Cell Anemia KSHV study, conducted in a high KSHV seroprevalence region, to investigate associations between HLA and KSHV shedding in saliva or peripheral blood among 233 children and their mothers. HLA-A and HLA-DRB1 alleles were not associated with KSHV shedding in our study, but our study was small and was not adequately powered to exclude small associations. In exploratory analyses, we found marginal association of KSHV DNA shedding in saliva but not in peripheral blood among children carrying HLA- B*4415 and marginal association of KSHV DNA shedding in peripheral blood but not in saliva among children carrying HLA- B*0801 alleles. The contribution of individual HLA polymorphisms to KSHV shedding is important but it may vary in different populations. Larger population-based studies are needed to estimate the magnitude and direction of association of HLA with KSHV shedding and viral control.


Cadmium-sensitive, cad1 mutants of Arabidopsis thaliana are phytochelatin deficient.
An allelic series of cad1, cadmium-sensitive mutants of Arabidopsis thaliana, was isolated. These mutants were sensitive to cadmium to different extents and were deficient in their ability to form cadmium-peptide complexes as detected by gel-filtration chromatography. Each mutant was deficient in its ability to accumulate phytochelatins (PCs) as detected by high-performance liquid chromatography and the amount of PCs accumulated by each mutant correlated with its degree of sensitivity to cadmium. The mutants had wild-type levels of glutathione, the substrate for PC biosynthesis, and in vitro assays demonstrated that each of the mutants was deficient in PC synthase activity. These results demonstrate conclusively the importance of PCs for cadmium tolerance in plants.


Improvement of a Three-Layered in vitro Skin Model for Topical Application of Irritating Substances.
In the field of skin tissue engineering, the development of physiologically relevant in vitro skin models comprising all skin layers, namely epidermis, dermis, and subcutis, is a great challenge. Increasing regulatory requirements and the ban on animal experiments for substance testing demand the development of reliable and in vivo-like test systems, which enable high-throughput screening of substances. However, the reproducibility and applicability of in vitro testing has so far been insufficient due to fibroblast-mediated contraction. To overcome this pitfall, an advanced 3-layered skin model was developed. While the epidermis of standard skin models showed an 80% contraction, the initial epidermal area of our advanced skin models was maintained. The improved barrier function of the advanced models was quantified by an indirect barrier function test and a permeability assay. Histochemical and immunofluorescence staining of the advanced model showed well-defined epidermal layers, a dermal part with distributed human dermal fibroblasts and a subcutis with round-shaped adipocytes. The successful response of these advanced 3-layered models for skin irritation testing demonstrated the suitability as an in vitro model for these clinical tests: only the advanced model classified irritative and non-irritative substances correctly. These results indicate that the advanced set up of the 3-layered in vitro skin model maintains skin barrier function and therefore makes them more suitable for irritation testing.


[Pain and functionality in primary health care].
Musculoskeletal pain and functionality are linked to the individual health and, thus, influence the mode of interaction between individuals and between them and the environment that surrounds them. However, there are not many studies that question such health issues concerning the population in general, especially when we look at these issues from the basic care point of view. The aim of this article is to present initial data on the subject of pain and functionality in individuals with musculoskeletal complaints enrolled in a primary care unit and prompt a discussion on how complete the services provided by these units are. This study was carried out in a primary care unit and various households, among subjects aging 20 years or older. A functionality assessment tool and a Visual Analogue Scale were applied, and social and demographic issues were also considered. By using these tools, it was made an attempt to evaluate the profile of individuals in association with their degree of musculoskeletal pain and the degree of functionality in the activities of their daily lives, ages and occupations. We found a predominance of women in both groups: 84.37% and 81.25%, respectively. Nearly half of all people with musculoskeletal pain were housewives, and the average age between groups was over 55.


Adverse events associated with apheresis procedures: Incidence and relative frequency.
Apheresis procedures [Plateletpheresis, Plasmapheresis/ Therapeutic Plasma Exchange (TPE), & Peripheral Blood Stem Cell Collection (PBSC)] are usually well tolerated. Occasionally, Adverse Events (AEs) of variable severity may occur during or after the procedure. AEs that occur in Donors/Patients are divided into local reactions and systemic reactions. A total of 3,367 apheresis procedures were performed, out of which 3,120 were plateletpheresis procedures, and out of which 1,401 were on Baxter CS 3000 & 1,719 were on Haemonetics MCS+ cell separators. Rest of 247 TPE & PBSC procedures were done on Haemonetics MCS+ cell separators. 90 AEs were reported in relation to the 3,367 procedures. Out of 90 AEs, 85 AEs (94%) were associated with plateletpheresis (n = 3,120) and 05 AEs (06%) with TPE & PBSC (n = 247). The rate of vascular injury (VI), Citrate reaction (CR), and Presyncopal/Syncopal (PS/S) in plateletpheresis was 1.6% (52/3,120), 0.96% (30/3,120), and 0.096% (03/3,120), respectively. The rate of CR in TPE and PBSC was 1.23% (02/162) and 2.3% (02/85), respectively. The rate of PS/S in PBSC was 1.17% (01/85). AEs for Plateletpheresis, TPE & PBSC were 2.7% (85/3,120), 1.23% (02/162), and 3.5% (03/85), respectively. VI, CR, and PS/S were mostly of mild intensity. Both cell separators were equally safe, when AEs associated with plateletpheresis were compared with each other; 2.8% on CS 3000 & 2.6% on MCS+. Apheresis procedures performed on cell separators are safe, with a low incidence of significant AEs. No significant difference was noted in AEs among the two cell separators studied.